COMPOUNDS, CONJUGATES, AND COMPOSITIONS OF EPIPOLYTHIODIKETOPIPERAZINES AND POLYTHIODIKETOPIPERAZINES AND USES THEREOF

Abstract

The present disclosure provides, e.g., compounds, compositions, kits, methods of synthesis, and methods of use, involving epipolythiodiketopiperazines and polythiodiketopiperazines.

Claims

1-107. (canceled)

108. A compound having the structure of Formula (X): ##STR00233## or salt thereof, wherein R.sup.X is unsubstituted alkyl, —Si(R.sup.S).sub.3, —Sn(R.sup.S).sub.3, substituted or unsubstituted benzyl, or M.sup.X; R.sup.Y is unsubstituted alkyl, —Si(R.sup.S).sub.3, —Sn(R.sup.S).sub.3, substituted or unsubstituted benzyl, hydrogen, or M.sup.Y; each R.sup.S is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; M.sup.X is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium; and M.sup.Y is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium.

109-134. (canceled)

135. The compound of claim 108, wherein the compound is not sodium benzhydryl trithiocarbonate.

136. The compound of claim 108, wherein the compound is not sodium benzhydryl trithiocarbonate or sodium p-methoxybenzhydryl trithiocarbonate.

137. The compound of claim 108, wherein the compound is of the formula: ##STR00234##

138. The compound of claim 108, wherein R.sup.X is M.sup.X.

139. The compound of claim 138, wherein M.sup.X is sodium.

140. The compound of claim 108, wherein R.sup.Y is substituted or unsubstituted benzyl.

141. The compound of claim 108, wherein the compound is of the formula: ##STR00235##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0137] FIG. 1 shows exemplary epithiodiketopiperazines.

[0138] FIG. 2 shows design of structurally diverse conjugatable ETP probes.

[0139] FIG. 3 shows the ratio of (+)-42 to (+)-45b.

[0140] FIG. 4 shows the ratio of (+)-42 to (+)-45b.

[0141] FIG. 5 shows the proposed mechanism of base-catalyzed decomposition of glycine-derived ETP.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0142] Recent studies describe the potent cytotoxic activities of a structurally diverse collection of ETPs and demonstrated the potential of this class of compounds as anti-cancer therapeutics..sup.3p Synthetic access to ETPs containing a conjugatable chemical handle would provide a powerful tool to further evaluate the biological activity of these compounds. In recent studies, bioactive small molecules were structurally modified and used as photoaffinity labels for target identification.sup.7, in situ small molecule clickable imaging probes.sup.8, polymer-drug conjugates for improved pharmacokinetics.sup.9, and antibody-drug conjugates for targeted drug delivery.sup.10. Based on these precedents, efforts to attach an alkyl azide handle to ETPs were undertaken to provide a robust and general method for coupling various chemical groups using CuAAC for utilization in biological applications such as those described above (e.g., drug delivery).

Compounds

[0143] In some embodiments, the present disclosure provides a compound having the structure of Formula (I):

##STR00008##

or a salt thereof, wherein [0144] each is independently a single bond or a double bond, as valency permits; [0145] each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —C(R).sub.2OR, or —S(O).sub.2N(R).sub.2; [0146] each R is independently hydrogen, -L.sup.2-R.sup.H-L.sup.3-D, or an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: [0147] two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0148] each R.sup.2 is independently R, —[C(R).sub.2].sub.q—OR, —[C(R).sub.2].sub.q—N(R).sub.2, —[C(R).sub.2].sub.q—SR, —[C(R).sub.2].sub.q—OSi(R).sub.3, —[C(R).sub.2].sub.q—OC(O)R, —[C(R).sub.2].sub.q—OC(O)OR, —[C(R).sub.2].sub.q—OC(O)N(R).sub.2, —[C(R).sub.2].sub.q—OC(O)N(R)—S(═O).sub.2R, or —[C(R).sub.2].sub.q—OP(OR).sub.2; or [0149] R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; [0150] each q is independently 0, 1, 2, 3, or 4; [0151] each R.sup.3 is independently —S(O).sub.2R, —S(O).sub.2—[C(R).sub.2].sub.q—R, —S(O).sub.2—[C(R).sub.2].sub.q—B(OR).sub.2, —S(O).sub.2—[C(R).sub.2].sub.q—Si(R).sub.3, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —P(O)(R).sub.2, —P(O)(OR).sub.2, or —P(O)[N(R).sub.2].sub.2; [0152] R.sup.4 is absent when is a double bond or is selected from R, halogen, and

##STR00009##

wherein [0153] at least one instance of R.sup.1, R.sup.3, and R.sup.4 comprises R wherein R is -L.sup.2-R.sup.H-L.sup.3-D; [0154] each L.sup.2 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein: [0155] optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and [0156] optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0157] each R.sup.H is independently substituted or unsubstituted triazolylene, —O—, —S—, —NR.sup.A—, —C(═O)O—, —C(═NR.sup.A)O—, —S(═O)O—, —S(═O).sub.2O—, —C(═O)NR.sup.A—, —C(═NR.sup.A)NR.sup.A—, —S(═O)NR.sup.A—, —S(═O).sub.2NR.sup.A—, —OC(═O)—, —OC(═NR.sup.A)—, —OS(═O)—, —OS(═O).sub.2—, —NR.sup.AC(═O)—, —NR.sup.AC(═NR.sup.A)—, —NR.sup.AS(═O)—, —NR.sup.AS(═O).sub.2—, —OC(═O)O—, —OC(═NR.sup.A)O—, —OS(═O)O—, —OS(═O).sub.2O—, —NR.sup.AC(═O)O—, —NR.sup.AC(═NR.sup.A)O—, —NR.sup.AS(═O)O—, —NR.sup.AS(═O).sub.2O—, —OC(═O)NR.sup.A—, —OC(═NR.sup.A)NR.sup.A—, —OS(═O)NR.sup.A—, —OS(═O).sub.2NR.sup.A—, —NR.sup.AC(═O)NR.sup.A—, —NR.sup.AC(═NR.sup.A)NR.sup.A—, —NR.sup.AS(═O)NR.sup.A—, —NR.sup.AS(═O).sub.2NR.sup.A—, —C(═O)—, —C(═NR.sup.A)—, —S(═O)—, —S(═O).sub.2—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0158] each R.sup.A is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; [0159] each L.sup.3 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein: [0160] optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and [0161] optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0162] each D is independently absent, polymeric moiety, dendrimeric moiety, antibody, particle, bead, nanostructure, liposome, micelle, or vesicle; [0163] each R.sup.5 is absent when is a double bond or is independently hydrogen or an optionally substituted C.sub.1-6 aliphatic group; [0164] each of R.sup.6 and R.sup.6′ is independently R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3; or [0165] R.sup.6 and R.sup.6′ are taken together to form ═O, ═C(R).sub.2 or ═NR; [0166] each n is independently 0, 1, 2, 3, or 4; [0167] each R.sup.7 is independently R, halogen, —CN, —NO.sub.2, —OR, —OSi(R).sub.3, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —P(R).sub.2, —P(OR).sub.2, —P(O)(R).sub.2, —P(O)(OR).sub.2, —P(O)[N(R).sub.2]2, —B(R).sub.2, —B(OR).sub.2, or —Si(R).sub.3; or: [0168] two R.sup.7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0169] each L.sup.1 independently is —S—, —(S).sub.m—[C(R).sub.2].sub.q—(S).sub.p—, —(S).sub.m(S).sub.p—, —(S).sub.m—C(O)—(S).sub.p—, —(S).sub.m—C(S)—(S).sub.p—, —(S).sub.m—S(O)—(S).sub.p—, or —(S).sub.m—S(O).sub.2—(S).sub.p—; [0170] each m is independently 1, 2, or 3; and [0171] each p is independently 1, 2, or 3.

[0172] In the compounds and formulae disclosed herein, wherein more than one instance of a particular variable (e.g., R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, R, R.sup.H, R.sup.H1, R.sup.H2, R.sup.A, R.sup.P, R.sup.S, R.sup.X, R.sup.Y, R.sup.Z, L.sup.1, L.sup.2, L.sup.2′, L.sup.3, M.sup.X, M.sup.Y, D, Ring A, , h, g, m, n, p, and q) is present, each instance of the variable is independent from one another (i.e., each instance of the variable is independently selected from the definition of the variable as described herein). In certain embodiments, at least two instances of a variable are different from each other. In certain embodiments, all instances of a variable are different from each other. In certain embodiments, all instances of a variable are the same.

[0173] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00010##

or stereoisomer thereof.

[0174] As generally defined, is a single bond or a double bond, as valency permits. In some embodiments, is a single bond. In some embodiments, is a double bond. In some embodiments, there are two or more in a provided compound, and at least one is a single bond, and at least one is a double bond. In some other embodiments, there are two or more in a provided compound, and each is a single bond. In some other embodiments, there are two or more in a provided compound, and each is a double bond. In some embodiments, is a single bond, R.sup.4 is R or halogen, and R.sup.5 is hydrogen or an optionally substituted C.sub.1-6 aliphatic. In some embodiments, is a double bond, R.sup.4 is absent and R.sup.5 is absent.

[0175] As generally defined above, each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —C(R).sub.2OR, or —S(O).sub.2N(R).sub.2, or R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —CH.sub.2OR, or —S(O).sub.2N(R).sub.2, or R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —C(R).sub.2OR, or —S(O).sub.2N(R).sub.2, or R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 is R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, or —S(O).sub.2N(R).sub.2. In some embodiments, R.sup.1 is R. In some embodiments, R.sup.1 is —C(O)R. In some embodiments, R.sup.1 is —C(O)N(R).sub.2. In some embodiments, R.sup.1 is —S(O)R. In some embodiments, R.sup.1 is —S(O).sub.2R. In some embodiments, R.sup.1 is —S(O).sub.2OR. In some embodiments, R.sup.1 is —C(R).sub.2OR. In some embodiments, R.sup.1 is —CH.sub.2OR. In some embodiments, R.sup.1 is —S(O).sub.2N(R).sub.2. In some embodiments, a provided compound has more than one R.sup.1 groups. In some embodiments, each R.sup.1 of a provided compound is the same. In some embodiments, at least one R.sup.1 is different from the other R.sup.1.

[0176] In some embodiments, R.sup.1 is R. In some embodiments, R.sup.1 is hydrogen. In some embodiments, R.sup.1 is optionally substituted C.sub.1-20 alkyl. In some embodiments, R.sup.1 is optionally substituted C.sub.1-10 alkyl. In some embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.1 is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R.sup.1 is optionally substituted hexyl. In some embodiments, R.sup.1 is optionally substituted pentyl. In some embodiments, R.sup.1 is optionally substituted butyl. In some embodiments, R.sup.1 is optionally substituted propyl. In some embodiments, R.sup.1 is optionally substituted ethyl. In some embodiments, R.sup.1 is optionally substituted methyl. In some embodiments, R.sup.1 is hexyl. In some embodiments, R.sup.1 is pentyl. In some embodiments, R.sup.1 is butyl. In some embodiments, R.sup.1 is propyl. In some embodiments, R.sup.1 is ethyl. In some embodiments, R.sup.1 is methyl. In some embodiments, R.sup.1 is isopropyl. In some embodiments, R.sup.1 is n-propyl. In some embodiments, R.sup.1 is tert-butyl. In some embodiments, R.sup.1 is sec-butyl. In some embodiments, R.sup.1 is n-butyl. In some embodiments, R.sup.1 is benzyloxymethyl. In some embodiments, R.sup.1 is benzyl. In some embodiments, R.sup.1 is allyl. In some embodiments, R.sup.1 comprises an —OH, —NHR or —SH.

[0177] In some embodiments, R.sup.1 is methyl, R.sup.3 is not Boc (tert-butyloxycarbonyl) and CF.sub.3C(O)—. In some embodiments, R.sup.1 is methyl, R.sup.3 is not CF.sub.3C(O)—. In some embodiments, R.sup.1 is methyl, R.sup.3 is not Boc (tert-butyloxycarbonyl) and CF.sub.3C(O)—. In some embodiments, R.sup.1 is other than methyl. In some embodiments, R.sup.1 is methyl, R.sup.3 is Boc (tert-butyloxycarbonyl) or CF.sub.3C(O)—In some embodiments, R.sup.1 is methyl, R.sup.3 is CF.sub.3C(O)—. In some embodiments, R.sup.1 is methyl, R.sup.3 is Boc (tert-butyloxycarbonyl) or CF.sub.3C(O)—. In some embodiments, R.sup.1 is methyl.

[0178] Exemplary R.sup.1 groups are depicted below.

##STR00011##

[0179] In certain embodiments, R.sup.1 is

##STR00012##

In certain embodiments, R.sup.1 is

##STR00013##

In certain embodiments, R.sup.1 is

##STR00014##

In some embodiments, each R is independently optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0180] In some embodiments, R is optionally substituted C.sub.1-20 alkyl. In some embodiments, R is optionally substituted C.sub.1-15 alkyl. In some embodiments, R is optionally substituted C.sub.1-10 alkyl. In some embodiments, R is optionally substituted C.sub.1-6 alkyl. In some embodiments, R is optionally substituted C.sub.1-6 alkyl. In some embodiments, R is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R is optionally substituted hexyl. In some embodiments, R is optionally substituted pentyl. In some embodiments, R is optionally substituted butyl. In some embodiments, R is optionally substituted propyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted methyl. In some embodiments, R is halogen substituted methyl. In some embodiments, R is —CF.sub.3. In some embodiments, R is hexyl. In some embodiments, R is pentyl. In some embodiments, R is butyl. In some embodiments, R is propyl. In some embodiments, R is ethyl. In some embodiments, R is methyl. In some embodiments, R is isopropyl. In some embodiments, R is n-propyl. In some embodiments, R is tert-butyl. In some embodiments, R is sec-butyl. In some embodiments, R is n-butyl. In some embodiments, R is benzyloxymethyl. In some embodiments, R is benzyl. In some embodiments, R is allyl. In some embodiments, R is not hydrogen. In some embodiments, R is not alkyl.

[0181] In some embodiments, R is optionally substituted C.sub.1-20 heteroalkyl. In some embodiments, R is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus selenium, silicon and boron within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus, selenium, silicon and boron within the C.sub.1-20 heteroalkyl backbone, optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, selenium, silicon or boron within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 groups independently selected from

##STR00015##

—N═, ≡N, —S—, —S(O)—, —S(O).SUB.2.—, —O—, ═O,

[0182] ##STR00016##

—Se—, —Se(O)—, and

[0183] ##STR00017##

within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R is not heteroalkyl. In some embodiments, R is methoxymethyl. In some embodiments, R is benzyloxymethyl.

[0184] In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted phenyl wherein one or more substituents are halogen. In some embodiments, R is optionally substituted phenyl wherein one or more substituents are —F. In some embodiments, R is optionally substituted phenyl wherein one or more substituents are —Cl. In some embodiments, R is optionally substituted phenyl wherein one or more substituents are —Br. In some embodiments, R is optionally substituted phenyl wherein one or more substituents are —I. In some embodiments, R is phenyl.

[0185] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is optionally substituted cycloheptyl. In some embodiments, R is cycloheptyl. In some embodiments, R is optionally substituted cyclohexyl. In some embodiments, R is cyclohexyl. In some embodiments, R is optionally substituted cyclopentyl. In some embodiments, R is cyclopentyl. In some embodiments, R is optionally substituted cyclobutyl. In some embodiments, R is cyclobutyl. In some embodiments, R is optionally substituted cyclopropyl. In some embodiments, R is cyclopropyl.

[0186] In some embodiments, R is an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring. In some embodiments, R is an optionally substituted 8-14 membered bicyclic or polycyclic saturated ring. In some embodiments, R is an optionally substituted 8-14 membered bicyclic or polycyclic partially saturated ring. In some embodiments, R is an optionally substituted 8-14 membered bicyclic or polycyclic aryl ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated or aryl ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic saturated ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic partially unsaturated ring. In some embodiments, R is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is optionally substituted naphthyl. In some embodiments, R is optionally substituted anthracenyl. In some embodiments, R is optionally substituted 9-anthracenyl.

[0187] In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is optionally substituted phenyl. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is optionally substituted naphthyl. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently optionally substituted phenyl. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently optionally substituted phenyl, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, R is optionally substituted biaryl wherein each aryl group is independently an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is optionally substituted biaryl wherein one aryl group is optionally substituted naphthyl, and the other aryl group is independently an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is optionally substituted biaryl wherein each aryl group is optionally substituted naphthyl. In some embodiments, R is optionally substituted biaryl wherein one aryl group is optionally substituted naphthyl, and the other aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0188] In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0189] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0190] In some embodiments, R is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is selected from optionally substituted pyrrolyl, furanyl, or thienyl.

[0191] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom, and an additional heteroatom selected from sulfur or oxygen. Exemplary R groups include but are not limited to optionally substituted pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl.

[0192] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted triazolyl, oxadiazolyl or thiadiazolyl.

[0193] In some embodiments, R is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted tetrazolyl, oxatriazolyl and thiatriazolyl.

[0194] In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In other embodiments, R is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having four nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having three nitrogen atoms. In some embodiments, R is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. In certain embodiments, R is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom. Exemplary R groups include but are not limited to optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or tetrazinyl.

[0195] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an unsubstituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0196] In some embodiments, R is optionally substituted 3-membered heterocyclic ring having one heteroatom selected from nitrogen, oxygen or sulfur. Exemplary R groups include but are not limited to optionally substituted aziridinyl, thiiranyl or oxiranyl. In some embodiments, R is optionally substituted 4-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted azetidinyl, oxetanyl, thietanyl, oxazetidinyl, thiazetidinyl, or diazetidinyl. In some embodiments, R is optionally substituted 5-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, dithiolanyl, imidazolidinyl, isothiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, triazolidinyl, oxadiazolidinyl, thiadiazolidinyl, oxadiazolidinyl, dioxazolidinyl, oxathiazolidinyl, thiadiazolidinyl or dithiazolidinyl. In some embodiments, R is optionally substituted 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, oxathianyl, triazinanyl, oxadiazinanyl, thiadiazinanyl, dithiazinanyl, dioxazinanyl, oxathiazinanyl, oxadithianyl, trioxanyl, dioxathianyl or trithianyl. In some embodiments, R is optionally substituted 7-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted azepanyl, oxepanyl, thiepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxepanyl, oxathiepanyl, dithiepanyl, triazepanyl, oxadiazepanyl, thiadiazepanyl, dioxazepanyl, oxathiazepanyl, dithiazepanyl, trioxepanyl, dioxathiepanyl, oxadithiepanyl or trithiepanyl.

[0197] In certain embodiments, R is an optionally substituted 5-7 membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted dihydroimidazolyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl. In certain embodiments, R is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrohydropyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, dihydrodioxinyl, dihydrooxathiinyl, dihydrooxazinyl, dihydrodithiine, dihydrothiazine, dioxinyl, oxathiinyl, oxazinyl, dithiinyl, or thiazinyl. In certain embodiments, R is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R groups include but are not limited to optionally substituted azepiyl, oxepinyl, thiepinyl, diazepinyl, oxazepinyl, thiazepinyl, triazepinyl, oxadiazepinyl, thiadiazepinyl, dihydroazepiyl, dihydrooxepinyl, dihydrothiepinyl, dihydrodiazepinyl, dihydrooxazepinyl, dihydrothiazepinyl, dihydrotriazepinyl, dihydrooxadiazepinyl, dihydrothiadiazepinyl, tetrahydroazepiyl, tetrahydrooxepinyl, tetrahydrothiepinyl, tetrahydrodiazepinyl, tetrahydrooxazepinyl, tetrahydrothiazepinyl, tetrahydrotriazepinyl, tetrahydrooxadiazepinyl, or tetrahydrothiadiazepinyl.

[0198] In certain embodiments, R is optionally substituted oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepaneyl, aziridineyl, azetidineyl, pyrrolidinyl, piperidinyl, azepanyl, thiiranyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiepanyl, dioxolanyl, oxathiolanyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, dithiolanyl, dioxanyl, morpholinyl, oxathianyl, piperazinyl, thiomorpholinyl, dithianyl, dioxepanyl, oxazepanyl, oxathiepanyl, dithiepanyl, diazepanyl, dihydrofuranonyl, tetrahydropyranonyl, oxepanonyl, pyrolidinonyl, piperidinonyl, azepanonyl, dihydrothiophenonyl, tetrahydrothiopyranonyl, thiepanonyl, oxazolidinonyl, oxazinanonyl, oxazepanonyl, dioxolanonyl, dioxanonyl, dioxepanonyl, oxathiolinonyl, oxathianonyl, oxathiepanonyl, thiazolidinonyl, thiazinanonyl, thiazepanonyl, imidazolidinonyl, tetrahydropyrimidinonyl, diazepanonyl, imidazolidinedionyl, oxazolidinedionyl, thiazolidinedionyl, dioxolanedionyl, oxathiolanedionyl, piperazinedionyl, morpholinedionyl, thiomorpholinedionyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothienyl, or tetrahydrothiopyranyl.

[0199] In some embodiments, R is an optionally substituted 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted indolinyl. In some embodiments, R is optionally substituted isoindolinyl. In some embodiments, R is optionally substituted 1, 2, 3, 4-tetrahydroquinolinyl. In some embodiments, R is optionally substituted 1, 2, 3, 4-tetrahydroisoquinolinyl. In some embodiments, R is an optionally substituted azabicyclo[3.2.1]octanyl.

[0200] In some embodiments, R is an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0201] In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, furo[3,2-b]furanyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, 1H-pyrrolo[1,2-a]imidazolyl, pyrrolo[2,1-b]oxazolyl or pyrrolo[2,1-b]thiazolyl. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted dihydropyrroloimidazolyl, 1H-furoimidazolyl, 1H-thienoimidazolyl, furooxazolyl, furoisoxazolyl, 4H-pyrrolooxazolyl, 4H-pyrroloisoxazolyl, thienooxazolyl, thienoisoxazolyl, 4H-pyrrolothiazolyl, furothiazolyl, thienothiazolyl, 1H-imidazoimidazolyl, imidazooxazolyl or imidazo[5,1-b]thiazolyl. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0202] In some embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted indolyl. In some embodiments, R is optionally substituted benzofuranyl. In some embodiments, R is optionally substituted benzo[b]thienyl. In certain embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted azaindolyl. In some embodiments, R is optionally substituted benzimidazolyl. In some embodiments, R is optionally substituted benzothiazolyl. In some embodiments, R is optionally substituted benzoxazolyl. In some embodiments, R is an optionally substituted indazolyl. In certain embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted oxazolopyridiyl, thiazolopyridinyl or imidazopyridinyl. In certain embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted purinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrazinyl, thiazolopyrazinyl, imidazopyrazinyl, oxazolopyridazinyl, thiazolopyridazinyl or imidazopyridazinyl. In certain embodiments, R is an optionally substituted 5,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0203] In certain embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted quinolinyl. In some embodiments, R is optionally substituted isoquinolinyl. In some embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted quinazolinyl, phthalazinyl, quinoxalinyl or naphthyridinyl. In some embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyridopyrimidinyl, pyridopyridazinyl, pyridopyrazinyl, or benzotriazinyl. In some embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted pyridotriazinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyridazinopyridazinyl, pyrimidopyridazinyl or pyrimidopyrimidinyl. In some embodiments, R is an optionally substituted 6,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, R is optionally substituted heterobiaryl wherein each heteroaryl group is independently an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted heterobiaryl wherein each aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0205] In some embodiments, two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are optionally taken together with the atom to which they are attached to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon atom are optionally taken together with the carbon atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen atom are optionally taken together with the nitrogen atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same sulfur atom are optionally taken together with the sulfur atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same oxygen atom are optionally taken together with the oxygen atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same phosphorus atom are optionally taken together with the phosphorus atom to form an optionally substituted 3-14 membered, monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having, in addition to the phosphorus atom, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the two R groups are attached to two different atoms.

[0206] In some embodiments, two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups are taken together to form an optionally substituted saturated ring. In some embodiments, two R groups are taken together to form an optionally substituted partially unsaturated ring. In some embodiments, two R groups are taken together to form an optionally substituted carbocyclic ring. In some embodiments, two R groups are taken together to form an optionally substituted aryl ring. In some embodiments, two R groups are taken together to form an optionally substituted phenyl ring. In some embodiments, two R groups are taken together to form an optionally substituted heterocyclic ring. In some embodiments, two R groups are taken together to form an optionally substituted heteroaryl ring.

[0207] In some embodiments, a ring formed by taking two R groups together is monocyclic, bicyclic or tricyclic. In some embodiments, a ring formed by taking two R groups together is monocyclic. In some embodiments, a ring formed by taking two R groups together is bicyclic. In some embodiments, a ring formed by taking two R groups together is monocyclic or bicyclic. In some embodiments, a ring formed by taking two R groups together is tricyclic. In some embodiments, a ring formed by taking two R groups together is monocyclic, bicyclic or tricyclic.

[0208] In some embodiments, R is -L.sup.2-R.sup.H-L.sup.3-D. In some embodiments, each instance of R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.6′, R.sup.7 comprise -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, only one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.6′, R.sup.7 comprise -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, at least one instance of R.sup.1, R.sup.3, and R.sup.4 comprise R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, at least one instance of R.sup.1 comprises R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In some embodiments, at least one instance of R.sup.1 is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, at least one instance of R.sup.3 comprises R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, at least one instance of R.sup.3 is —C(O)R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, R.sup.4 comprises R wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In some embodiments, R.sup.4 is -L.sup.2-R.sup.H-L.sup.3-D.

[0209] In some embodiments, each L.sup.2 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, each L.sup.2 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0210] In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 alkylene. In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 alkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 alkylene wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene.

[0211] In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 heteroalkylene. In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 heteroalkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 heteroalkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.2 is substituted or unsubstituted, C.sub.1-20 heteroarylene wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene.

[0212] In certain embodiments, L.sup.2 comprises

##STR00018##

[0213] In certain embodiments, each instance of L.sup.2′ is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene. In some embodiments, L.sup.2′ is substituted or unsubstituted, C.sub.1-20 alkylene. In certain embodiments, L.sup.2′ is substituted or unsubstituted, C.sub.1-20 heteroalkylene. In some embodiments, L.sup.2′ is substituted or unsubstituted, C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments, L.sup.2′ is

##STR00019##

In certain embodiments, L.sup.2′ is

##STR00020##

In some embodiments, L.sup.2′ is

##STR00021##

In some embodiments, L.sup.2′ is

##STR00022##

[0214] In some embodiments, each instance of Ring A is independently selected from the group consisting of substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, substituted or unsubstituted pyrrolylene, substituted or unsubstituted imidazolylene, substituted or unsubstituted pyridinylene, substituted or unsubstituted quinolinylene, substituted or unsubstituted oxazolylene, substituted or unsubstituted isooxazolylene, substituted or unsubstituted thiazolylene, substituted or unsubstituted isothiazolylene, substituted or unsubstituted benzimidazolylene, substituted or unsubstituted thiadiazolylene, and substituted or unsubstituted quinazolylene. In certain embodiments, Ring A is substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, or substituted or unsubstituted pyrrolylene. In some embodiments, Ring A is substituted or unsubstituted indolylene. In some embodiments, Ring A is indolylene substituted with 1-4 substituents each independently selected from —F, —Br, —OH, —OCH.sub.3, —NO.sub.2, —SCH.sub.3, and —Boc. In certain embodiments, Ring A is substituted or unsubstituted pyrrolylene. In certain embodiments, Ring A is pyrrolylene substituted with 1-3 substituents each independently selected from —F, —Br, —OH, —OCH.sub.3, —NO.sub.2, —SCH.sub.3, and —Boc. In certain embodiments, Ring A is substituted or unsubstituted phenylene. In certain embodiments, Ring A is phenylene substituted with 1-4 substituents each independently selected from —F, —Br, —OH, —OCH.sub.3, —NO.sub.2, and —SCH.sub.3.

[0215] In some embodiments, each instance of R.sup.H is independently selected from substituted or unsubstituted triazolylene, —O—, —S—, —NR.sup.A—, —C(═O)O—, —C(═NR.sup.A)O—, —S(═O)O—, —S(═O).sub.20—, —C(═O)NR.sup.A—, —C(═NR.sup.A)NR.sup.A—, —S(═O)NR.sup.A—, —S(═O).sub.2NR.sup.A—, —OC(═O)—, —OC(═NR.sup.A)—, —OS(═O)—, —OS(═O).sub.2—, —NR.sup.AC(═O)—, —NR.sup.AC(═NR.sup.A)—, —NR.sup.AS(═O)—, —NR.sup.AS(═O).sub.2—, —OC(═O)O—, —OC(═NR.sup.A)O—, —OS(═O)O—, —OS(═O).sub.2O—, —NR.sup.AC(═O)O—, —NR.sup.AC(═NR.sup.A)O—, —NR.sup.AS(═O)O—, —NR.sup.AS(═O).sub.2O—, —OC(═O)NR.sup.A—, —OC(═NR.sup.A)NR.sup.A—, —OS(═O)NR.sup.A—, —OS(═O).sub.2NR.sup.A—, —NR.sup.AC(═O)NR.sup.A—, —NR.sup.AC(═NR.sup.A)NR.sup.A—, —NR.sup.AS(═O)NR.sup.A—, —NR.sup.AS(═O).sub.2NR.sup.A—, —C(═O)—, —C(═NR.sup.A)—, —S(═O)—, —S(═O).sub.2—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene. In certain embodiments, R.sup.H is substituted or unsubstituted triazolylene. In certain embodiments, R.sup.H is substituted or unsubstituted 1,5-triazolylene. In certain embodiments, R.sup.H is substituted or unsubstituted 1,4-triazolylene. In some embodiments, R.sup.H is unsubstituted triazolylene. In some embodiments, R.sup.H is unsubstituted 1,4-triazolylene. In some embodiments, R.sup.H is —C(═O)NR.sup.A—. In certain embodiments, R.sup.H is-NR.sup.AC(═O)—. In certain embodiments, R.sup.H is —NR.sup.A—.

[0216] In some embodiments, each instance of R.sup.A is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, R.sup.A is methyl, ethyl, or propyl.

[0217] In certain embodiments, each instance of L.sup.3 is independently selected from substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, each instance of L.sup.3 is independently selected from substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

[0218] In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkylene wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkylene. In certain embodiments, L.sup.3 is substituted C.sub.1-20 alkylene. In certain embodiments, L.sup.3 is substituted C.sub.1-20 alkylene wherein at least one substituent on the C.sub.1-20 alkylene is —NHBoc. In certain embodiments, L.sup.3 is substituted C.sub.1-20 alkylene wherein at least one substituent on the C.sub.1-20 alkylene is —NH.sub.2.

[0219] In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkylene, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroarylene wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen. In some embodiments, L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkylene comprising at least one backbone carbon atom and at least one backbone nitrogen atom. In certain embodiments, L.sup.3 is

##STR00023##

wherein g is an integer from 1 to 10, inclusive. In certain embodiments, L.sup.3 is

##STR00024##

wherein g is 1, 2, or 3. In certain embodiments, L.sup.3 is

##STR00025##

wherein g is 1. In certain embodiments, L.sup.3 is

##STR00026##

wherein g is 3.

[0220] In some embodiments, L.sup.3 comprises phenylene. In certain embodiments, L.sup.3 comprises substituted or unsubstituted,

##STR00027##

In some embodiments, L.sup.3 comprises substituted or unsubstituted,

##STR00028##

In certain embodiments, L.sup.3 is a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene. In some embodiments, L.sup.3 is a substituted C.sub.1-20 heteroalkylene wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NHBoc. In certain embodiments, L.sup.3 is a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NHBoc. In some embodiments, L.sup.3 is a substituted C.sub.1-20 heteroalkylene wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NH.sub.2. In certain embodiments, L.sup.3 is a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NH.sub.2.

[0221] In certain embodiments, g is 1. In some embodiments, g is 2. In certain embodiments, g is 3. In some embodiments, g is 4, 5, or 6. In certain embodiments, g is 7, 8, or 9.

[0222] In some embodiments, D is a polymeric moiety, dendrimeric moiety, antibody, nanostructure, liposome, micelle, or vesicle. In certain embodiments, D is a polymeric moiety. In some embodiments, D is a brush polymeric moiety. In certain embodiments D is a brush-arm star polymeric moiety. In some embodiments, D is a dendrimeric moiety In some embodiments, D is a particle or bead. In certain embodiments, D is nanostructure (e.g., nanoparticle, nanoflake). In some embodiments, D is a microparticle. In certain embodiments, D is a supraparticle. In some embodiments, D is liposome, micelle, or vesicle. In some embodiments, D is an antibody. In certain embodiments, D is not an antibody. In some embodiments, D facilitates endocytosis delivery of an derivatized ETP, improves bioavailability, or/and reduces cell toxicity by lowering the concentration of ETP needed for treatment.

[0223] In certain embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkyl, substituted or unsubstituted, C.sub.2-20 alkenyl, substituted or unsubstituted, C.sub.2-20 alkynyl, substituted or unsubstituted, C.sub.1-20 heteroalkyl, substituted or unsubstituted, C.sub.2-20 heteroalkenyl, or C.sub.2-20 heteroalkynyl, wherein: optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkyl, substituted or unsubstituted, C.sub.2-20 alkenyl, substituted or unsubstituted, C.sub.2-20 alkynyl, substituted or unsubstituted, C.sub.1-20 heteroalkyl, substituted or unsubstituted, C.sub.2-20 heteroalkenyl, and C.sub.2-20 heteroalkynyl are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkyl, substituted or unsubstituted, C.sub.2-20 heteroalkenyl, and substituted or unsubstituted, C.sub.2-20 heteroalkynyl are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In certain embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkyl, substituted or unsubstituted, C.sub.2-20 alkenyl, substituted or unsubstituted, C.sub.2-20 alkynyl, substituted or unsubstituted, C.sub.1-20 heteroalkyl, substituted or unsubstituted, C.sub.2-20 heteroalkenyl, or C.sub.2-20 heteroalkynyl.

[0224] In certain embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkyl. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkyl, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkyl are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 alkyl wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In certain embodiments, D is absent, and L.sup.3 is substituted C.sub.1-20 alkyl. In certain embodiments, D is absent, and L.sup.3 is substituted C.sub.1-20 alkyl wherein at least one substituent on the C.sub.1-20 alkylene is —NHBoc. In certain embodiments, D is absent, and L.sup.3 is substituted C.sub.1-20 alkyl wherein at least one substituent on the C.sub.1-20 alkylene is —NH.sub.2.

[0225] In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkyl are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl, wherein optionally 1, 2, or 3 backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkyl are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroaryl wherein one or more backbone carbon atoms are replaced with substituted or unsubstituted arylene. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen. In some embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl comprising at least one backbone carbon atom and at least one backbone nitrogen atom.

[0226] In certain embodiments, D is absent, and L.sup.3 is substituted or unsubstituted, C.sub.1-20 heteroalkyl comprising substituted or unsubstituted phenylene. In some embodiments, D is absent, and L.sup.3 comprises a phenylene. In certain embodiments, D is absent, and L.sup.3 comprises substituted or unsubstituted,

##STR00029##

In some embodiments, D is absent, and L.sup.3 comprises substituted or unsubstituted,

##STR00030##

[0227] As generally defined above, each R.sup.2 is independently R, —[C(R).sub.2].sub.q—OR, —[C(R).sub.2].sub.q—N(R).sub.2, —[C(R).sub.2].sub.q—SR, —[C(R).sub.2].sub.q—OSi(R).sub.3, —[C(R).sub.2].sub.q—OC(O)R, —[C(R).sub.2].sub.q—OC(O)OR, —[C(R).sub.2].sub.q—OC(O)N(R).sub.2, —[C(R).sub.2].sub.q—OC(O)N(R)—SO.sub.2R or —[C(R).sub.2].sub.q—OP(OR).sub.2, or R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.2 is R, —[C(R).sub.2].sub.q—OR, —[C(R).sub.2].sub.q—N(R).sub.2, —[C(R).sub.2].sub.q—SR, —[C(R).sub.2].sub.q—OSi(R).sub.3, —[C(R).sub.2].sub.q—OC(O)R, —[C(R).sub.2].sub.q—OC(O)OR, —[C(R).sub.2].sub.q—OC(O)N(R).sub.2, —[C(R).sub.2].sub.q—OC(O)N(R)—SO.sub.2R or —[C(R).sub.2].sub.q—OP(OR).sub.2. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0228] In some embodiments, R.sup.2 is R. In some embodiments, R.sup.2 is hydrogen. In some embodiments, R.sup.2 is optionally substituted C.sub.1-20 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-15 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-10 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.2 is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R.sup.2 is optionally substituted hexyl. In some embodiments, R.sup.2 is optionally substituted pentyl. In some embodiments, R.sup.2 is optionally substituted butyl. In some embodiments, R.sup.2 is optionally substituted propyl. In some embodiments, R.sup.2 is optionally substituted ethyl. In some embodiments, R.sup.2 is optionally substituted methyl. In some embodiments, R.sup.2 is hexyl. In some embodiments, R.sup.2 is pentyl. In some embodiments, R.sup.2 is butyl. In some embodiments, R.sup.2 is propyl. In some embodiments, R.sup.2 is ethyl. In some embodiments, R.sup.2 is methyl. In some embodiments, R.sup.2 is isopropyl. In some embodiments, R.sup.2 is n-propyl. In some embodiments, R.sup.2 is tert-butyl. In some embodiments, R.sup.2 is sec-butyl. In some embodiments, R.sup.2 is n-butyl. In some embodiments, R.sup.2 is benzyloxymethyl. In some embodiments, R.sup.2 is benzyl.

[0229] In some embodiments, R.sup.2 is optionally substituted C.sub.1-20 heteroalkyl. In some embodiments, R.sup.2 is optionally substituted C.sub.1-20 heteroalkyl having 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus selenium, silicon or boron. In some embodiments, R.sup.2 is optionally substituted C.sub.1-20 heteroalkyl having 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus, selenium, silicon or boron, optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, selenium, silicon or boron.

[0230] In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OR. In some embodiments, R.sup.2 is —OR. In some embodiments, R.sup.2 is —OH. In some embodiments, R.sup.2 is —CH.sub.2OR. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—N(R).sub.2. In some embodiments, R.sup.2 is —CH.sub.2N(R).sub.2. In some embodiments, R.sup.2 is —CH.sub.2NHR. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—SR. In some embodiments, R.sup.2 is —CH.sub.2SR. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OSi(R).sub.3. In some embodiments, R.sup.2 is —CH.sub.2OSi(R).sub.3. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OC(O)R. In some embodiments, R.sup.2 is —CH.sub.2OC(O)R. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OC(O)OR. In some embodiments, R.sup.2 is —CH.sub.2OC(O)OR. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OC(O)N(R).sub.2. In some embodiments, R.sup.2 is —CH.sub.2OC(O)N(R).sub.2. In some embodiments, R.sup.2 is —CH.sub.2OC(O)NHR. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OC(O)N(R)—SO.sub.2R. In some embodiments, R.sup.2 is —CH.sub.2OC(O)N(R)—SO.sub.2R. In some embodiments, R.sup.2 is —CH.sub.2OC(O)NHSO.sub.2R. In some embodiments, R.sup.2 is —[C(R).sub.2].sub.q—OP(OR).sub.2. In some embodiments, R.sup.2 is —CH.sub.2OP(OR).sub.2. In some embodiments, R.sup.2 comprises an —OH, —NHR or —SH group.

[0231] Exemplary R.sup.2 groups are depicted below:

##STR00031## ##STR00032##

[0232] In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 5-membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 6-membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 7-membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form

##STR00033##

In some embodiments, R.sup.1 and R.sup.2 are taken together with their intervening atoms to form substituted or unsubstituted

##STR00034##

[0233] As generally defined above, each q is independently 0, 1, 2, 3 or 4. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0234] In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2R, —S(O).sub.2—[C(R).sub.2].sub.q—R, —S(O).sub.2—[C(R).sub.2].sub.q—B(OR).sub.2, —S(O).sub.2—[C(R).sub.2].sub.q—Si(R).sub.3, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —P(O)(R).sub.2, —P(O)(OR).sub.2, or —P(O)[N(R).sub.2]2. In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2—[C(R).sub.2].sub.q—R, —S(O).sub.2—[C(R).sub.2].sub.q—B(OR).sub.2, —S(O).sub.2—[C(R).sub.2].sub.q—Si(R).sub.3, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, or —S(O)R. In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2R. In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2 (substituted phenyl). In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2 (unsubstituted phenyl). In certain embodiments, at least one instance of R.sup.3 is —C(O)OR, —C(O)N(R).sub.2, or —C(O)N(R)—OR. In certain embodiments, at least one instance of R.sup.3 is —C(O)R. In certain embodiments, at least one instance of R.sup.3 is —C(O)(substituted phenyl). In certain embodiments, at least one instance of R.sup.3 is —C(O)(unsubstituted phenyl). In certain embodiments, at least one instance of R.sup.3 is —P(O)(R).sub.2, —P(O)(OR).sub.2, or —P(O)[N(R).sub.2]2. Exemplary R.sup.3 groups include:

##STR00035## ##STR00036##

[0235] In some embodiments, R.sup.4 is absent when is a double bond. In some other embodiments, is a single bond and R.sup.4 is R or halogen.

[0236] In some embodiments, R.sup.4 is R. In some embodiments, R.sup.4 is hydrogen. In some embodiments, R.sup.4 is an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0237] In some embodiments, R.sup.4 is an optionally substituted C.sub.1-20 alkyl. In some embodiments, R.sup.4 is an optionally substituted C.sub.1-10 alkyl. In some embodiments, R.sup.4 is an optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.4 is optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.4 is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R.sup.4 is optionally substituted hexyl. In some embodiments, R.sup.4 is optionally substituted pentyl. In some embodiments, R.sup.4 is optionally substituted butyl. In some embodiments, R.sup.4 is optionally substituted propyl. In some embodiments, R.sup.4 is optionally substituted ethyl. In some embodiments, R.sup.4 is optionally substituted methyl. In some embodiments, R.sup.4 is hexyl. In some embodiments, R.sup.4 is pentyl. In some embodiments, R.sup.4 is butyl. In some embodiments, R.sup.4 is propyl. In some embodiments, R.sup.4 is ethyl. In some embodiments, R.sup.4 is methyl. In some embodiments, R.sup.4 is isopropyl. In some embodiments, R.sup.4 is n-propyl. In some embodiments, R.sup.4 is tert-butyl. In some embodiments, R.sup.4 is sec-butyl. In some embodiments, R.sup.4 is n-butyl. In some embodiments, R.sup.4 is benzyloxymethyl. In some embodiments, R.sup.4 is benzyl. In some embodiments, R.sup.4 is an optionally substituted C.sub.1-6 alkyl. In some embodiments, R.sup.4 is optionally substituted allyl. In some embodiments, R.sup.4 is ally. In some embodiments, R.sup.4 is styrenyl. In some embodiments, R.sup.4 is other than hydrogen.

[0238] In some embodiments, R.sup.4 is optionally substituted C.sub.1-20 heteroalkyl. In some embodiments, R.sup.4 is optionally substituted C.sub.1-10 heteroalkyl. In some embodiments, R.sup.4 is optionally substituted C.sub.1-6 heteroalkyl.

[0239] In some embodiments, R.sup.4 is optionally substituted phenyl. In some embodiments, R.sup.4 is substituted phenyl. In some embodiments, R.sup.4 is unsubstituted phenyl. In some embodiments, R.sup.4 is p-MeOPh.

[0240] In some embodiments, R.sup.4 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.4 is an optionally substituted 3-membered saturated ring. In some embodiments, R.sup.4 is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.4 is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.4 is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.4 is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring.

[0241] In some embodiments, R.sup.4 is an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring. In some embodiments, R.sup.4 is an optionally substituted an 8-14 membered bicyclic or polycyclic saturated ring. In some embodiments, R.sup.4 is an optionally substituted 8-14 membered bicyclic or polycyclic partially unsaturated ring. In some embodiments, R.sup.4 is an optionally substituted 8-14 membered bicyclic or polycyclic aryl ring. In some embodiments, R.sup.4 is an optionally substituted 10-membered bicyclic aryl ring. In some embodiments, R.sup.4 is an optionally substituted 14-membered tricyclic aryl ring.

[0242] In some embodiments, R.sup.4 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is optionally substituted pyrrolyl. In some embodiments, R.sup.4 is optionally substituted pyrrol-3-yl. In some embodiments, R.sup.4 is N-TIPS-pyrrol-3-yl. In some embodiments, R.sup.4 is pyrrol-3-yl.

[0243] In some embodiments, R.sup.4 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 3-7 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 3-7 membered partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0244] In some embodiments, R.sup.4 is an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 8-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 8-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 9-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 10-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 11-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 11-membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 12-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 12-membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 13-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 13-membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 14-membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is an optionally substituted 14-membered tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.4 is optionally substituted indolyl. In some embodiments, R.sup.4 is optionally substituted indol-3-yl. In some embodiments, R.sup.4 is indol-3-yl. In some embodiments, R.sup.4 is

##STR00037##

In some embodiments, R.sup.4 is

##STR00038##

[0245] In some embodiments, R.sup.4 is an optionally substituted group selected from phenyl, a 8-14 membered bicyclic or tricyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.4 substituents include

##STR00039##

[0246] In some embodiments, R.sup.4 is halogen. In some embodiments, R.sup.4 is —F. In some embodiments, R.sup.4 is —Cl. In some embodiments, R.sup.4 is —Br. In some embodiments, R.sup.4 is —I. In some embodiments, R.sup.4 comprises an —OH, —NHR or —SH group.

[0247] In certain embodiments, R.sup.4 is

##STR00040##

In certain embodiments, R.sup.4 is

##STR00041##

[0248] In some embodiments, a compound of Formula (I) is of the formula:

##STR00042##

In some embodiments, a compound of Formula (I) is of the formula:

##STR00043##

or stereoisomer thereof.

[0249] In some embodiments, R.sup.5 is absent when is a double bond. In some embodiments, each R.sup.5 is independently hydrogen or an optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.5 is hydrogen. In some embodiments, R.sup.5 optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.5 is a substituted C.sub.16 aliphatic comprising an —OH, —NHR or —SH group.

[0250] As generally defined above, each of R.sup.6 and R.sup.6′ is independently R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3; or R.sup.6 and R.sup.6′ are taken together to form ═O, ═C(R).sub.2 or ═NR.

[0251] In some embodiments, each of R.sup.6 and R.sup.6′ is hydrogen. In some embodiments, each of R.sup.6 and R.sup.6′ is independently R.

[0252] In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is R. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is halogen. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —CN. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —NO.sub.2. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —OR. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —SR. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —N(R).sub.2. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —S(O).sub.2R. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —S(O).sub.2N(R).sub.2. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —S(O)R. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —C(O)R. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —C(O)OR. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —C(O)N(R).sub.2. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —C(O)N(R)—OR. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —N(R)C(O)OR. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —N(R)C(O)N(R).sub.2. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —N(R)S(O).sub.2R. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —OSi(R).sub.3. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —OSi(R).sub.3, wherein one R is optionally substituted indolyl. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —OSi(R).sub.3, wherein one R is optionally substituted indol-2-yl. In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is —OSi(R).sub.3, wherein one R is optionally substituted

##STR00044##

In some embodiments, one of R.sup.6 and R.sup.6′ is hydrogen, and the other is

##STR00045##

[0253] In some embodiments, R.sup.6 and R.sup.6′ are taken together to form ═O, ═C(R).sub.2 or ═NR. In some embodiments, R.sup.6 and R.sup.6′ are taken together to form ═O. In some embodiments, R.sup.6 and R.sup.6′ are taken together to form ═C(R).sub.2. In some embodiments, R.sup.6 and R.sup.6′ are taken together to form ═NR.

[0254] In some embodiments, R.sup.6 is R. In some embodiments, R.sup.6 is hydrogen. In some embodiments, R.sup.6 is an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0255] In some embodiments, R.sup.6 is halogen. In some embodiments, R.sup.6 is —F. In some embodiments, R.sup.6 is —Cl. In some embodiments, R.sup.6 is —Br. In some embodiments, R.sup.6 is —I.

[0256] In some embodiments, R.sup.6 is —CN. In some embodiments, R.sup.6 comprises an —OH, —NHR or —SH group. In some embodiments, R.sup.6 is —N.sub.02. In some embodiments, R.sup.6 is —OR. In some embodiments, R.sup.6 is —SR. In some embodiments, R.sup.6 is —N(R).sub.2. In some embodiments, R.sup.6 is —S(O).sub.2R. In some embodiments, R.sup.6 is —S(O).sub.2N(R).sub.2. In some embodiments, R.sup.6 is —S(O)R. In some embodiments, R.sup.6 is —C(O)R. In some embodiments, R.sup.6 is —C(O)OR. In some embodiments, R.sup.6 is —C(O)N(R).sub.2. In some embodiments, R.sup.6 is —C(O)N(R)—OR. In some embodiments, R.sup.6 is —N(R)C(O)OR. In some embodiments, R.sup.6 is —N(R)C(O)N(R).sub.2. In some embodiments, R.sup.6 is —N(R)S(O).sub.2R. In some embodiments, R.sup.6 is —OSi(R).sub.3. In some embodiments, R.sup.6 is —OSi(R).sub.3, wherein one R is optionally substituted indolyl. In some embodiments, R.sup.6 is —OSi(R).sub.3, wherein one R is optionally substituted indol-2-yl. In some embodiments, R.sup.6 is —OSi(R).sub.3, wherein one R is

##STR00046##

In some embodiments, R.sup.6 is

##STR00047##

[0257] In some embodiments, R.sup.6 is hydrogen, and R.sup.6′ is R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3.

[0258] In some embodiments, R.sup.6′ is R. In some embodiments, R.sup.6′ is hydrogen. In some embodiments, R.sup.6′ is an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0259] In some embodiments, R.sup.6′ is halogen. In some embodiments, R.sup.6′ is —F. In some embodiments, R.sup.6′ is —C.sub.1. In some embodiments, R.sup.6′ is —Br. In some embodiments, R.sup.6′ is —I.

[0260] In some embodiments, R.sup.6′ is —CN. In some embodiments, R.sup.6′ comprises an —OH, —NHR or —SH group. In some embodiments, R.sup.6′ is —N.sub.02. In some embodiments, R.sup.6′ is —OR. In some embodiments, R.sup.6′ is —SR. In some embodiments, R.sup.6′ is —N(R).sub.2. In some embodiments, R.sup.6′ is —S(O).sub.2R. In some embodiments, R.sup.6′ is —S(O).sub.2N(R).sub.2. In some embodiments, R.sup.6′ is —S(O)R. In some embodiments, R.sup.6′ is —C(O)R. In some embodiments, R.sup.6′ is —C(O)OR. In some embodiments, R.sup.6′ is —C(O)N(R).sub.2. In some embodiments, R.sup.6′ is —C(O)N(R)—OR. In some embodiments, R.sup.6′ is —N(R)C(O)OR. In some embodiments, R.sup.6′ is —N(R)C(O)N(R).sub.2. In some embodiments, R.sup.6′ is —N(R)S(O).sub.2R. In some embodiments, R.sup.6′ is —OSi(R).sub.3. In some embodiments, R.sup.6′ is —OSi(R).sub.3, wherein one R is optionally substituted indolyl. In some embodiments, R.sup.6′ is —OSi(R).sub.3, wherein one R is optionally substituted indol-2-yl. In some embodiments, R.sup.6′ is —OSi(R).sub.3, wherein one R is

##STR00048##

In some embodiments, R.sup.6′ is

##STR00049##

[0261] In some embodiments, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1-4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0262] As generally defined above, each R.sup.7 is independently R, halogen, —CN, —NO.sub.2, —OR, —OSi(R).sub.3, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —P(R).sub.2, —P(OR).sub.2, —P(O)(R).sub.2, —P(O)(OR).sub.2, —P(O)[N(R).sub.2]2, —B(R).sub.2, —B(OR).sub.2, or —Si(R).sub.3; or two R.sup.7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R.sup.7 is independently R, halogen, —CN, —NO.sub.2, —OR, —OSi(R).sub.3, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —P(R).sub.2, —P(OR).sub.2, —P(O)(R).sub.2, —P(O)(OR).sub.2, —P(O)[N(R).sub.2].sub.2, —B(R).sub.2, —B(OR).sub.2, or —Si(R).sub.3. In some embodiments, two R.sup.7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0263] In some embodiments, R.sup.7 is R. In some embodiments, R.sup.7 is hydrogen. In some embodiments, R.sup.7 is independently hydrogen or an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0264] In some embodiments, R.sup.7 is halogen. In some embodiments, R.sup.7 is —F. In some embodiments, R.sup.7 is —Cl. In some embodiments, R.sup.7 is —Br. In some embodiments, R.sup.7 is —I.

[0265] In some embodiments, R.sup.7 is —CN. In some embodiments, R.sup.7 comprises an —OH, —NHR, or —SH group. In some embodiments, R.sup.7 is —NO.sub.2. In some embodiments, R.sup.7 is —OR. In some embodiments, R.sup.7 is —OSi(R).sub.3. In some embodiments, R.sup.7 is —SR. In some embodiments, R.sup.7 is —N(R).sub.2. In some embodiments, R.sup.7 is —S(O).sub.2R. In some embodiments, R.sup.7 is —S(O).sub.2OR. In some embodiments, R.sup.7 is —S(O).sub.2N(R).sub.2. In some embodiments, R.sup.7 is —S(O)R. In some embodiments, R.sup.7 is —C(O)R. In some embodiments, R.sup.7 is —C(O)OR. In some embodiments, R.sup.7 is —C(O)N(R).sub.2. In some embodiments, R.sup.7 is —C(O)N(R)—OR. In some embodiments, R.sup.7 is —N(R)C(O)OR. In some embodiments, R.sup.7 is —N(R)C(O)N(R).sub.2. In some embodiments, R.sup.7 is —N(R)S(O).sub.2R. In some embodiments, R.sup.7 is —P(R).sub.2. In some embodiments, R.sup.7 is —P(OR).sub.2. In some embodiments, R.sup.7 is —P(O)(R).sub.2. In some embodiments, R.sup.7 is —P(O)(OR).sub.2. In some embodiments, R.sup.7 is —P(O)[N(R).sub.2].sub.2. In some embodiments, R.sup.7 is —B(R).sub.2. In some embodiments, R.sup.7 is —B(OR).sub.2. In some embodiments, R.sup.7 is —Si(R).sub.3.

[0266] In some embodiments, R.sup.7 is an electron-withdrawing group. In some embodiments, R.sup.7 is an electron-donating group.

[0267] In some embodiments, n is 1, 2, 3 or 4, and at least one R.sup.7 is not hydrogen.

[0268] As generally defined above, each L.sup.1 is independently —S—, —(S).sub.m—[C(R).sub.2].sub.q—(S).sub.p—, —(S).sub.m(S).sub.p—, —(S).sub.mC(O)—(S).sub.p—, —(S).sub.mC(S)—(S).sub.p—, —(S).sub.mS(O)—(S).sub.p—, or —(S).sub.mS(O).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—, —(S).sub.m—[C(R).sub.2].sub.q—(S).sub.p—, —(S).sub.m(S).sub.p—, —(S).sub.m—C(O)—(S).sub.p—, —(S).sub.mC(S)—(S).sub.p—, —(S).sub.mS(O)—(S).sub.p—, or —(S).sub.mS(O).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—, —(S).sub.mC(R).sub.2—(S).sub.p—, —(S).sub.m(S).sub.p—, —(S).sub.mC(O)—(S).sub.p—, —(S).sub.m—C(S)—(S).sub.p—, —(S).sub.mS(O)—(S).sub.p—, or —(S).sub.mS(O).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —(S).sub.m(S).sub.p—, —(S).sub.mC(O)—(S).sub.p—, —(S).sub.m—C(S)—(S).sub.p—, —(S).sub.m—S(O)—(S).sub.p—, or —(S).sub.m—S(O).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—. In some embodiments, each L.sup.1 is independently —S—S—. In some embodiments, each L.sup.1 is independently —(S).sub.m—[C(R).sub.2].sub.q—(S).sub.p—. In some embodiments, each L.sup.1 is independently —(S).sub.mC(R).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —(S).sub.m—CH.sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—CH.sub.2—S—. In some embodiments, each L.sup.1 is independently —(S).sub.m—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—S—. In some embodiments, each L.sup.1 is independently —S—S—S—. In some embodiments, each L.sup.1 is independently —S—S—S—S—. In some embodiments, each L.sup.1 is independently —(S).sub.mC(O)—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—C(O)—S—. In some embodiments, each L.sup.1 is independently —(S).sub.mC(S)—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—C(S)—S—. In some embodiments, each L.sup.1 is independently —(S).sub.m—S(O)—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—S(O)—S—. In some embodiments, each L.sup.1 is independently —(S).sub.mS(O).sub.2—(S).sub.p—. In some embodiments, each L.sup.1 is independently —S—S(O).sub.2—S—. In certain embodiments, each L.sup.1 can be cleaved. In some embodiments, each L.sup.1 can be cleaved when administered to a subject.

[0269] In some embodiments, m is 1. In some embodiments, m is 2-3. In some embodiments, m is 2. In some embodiments, m is 3.

[0270] In some embodiments, p is 1. In some embodiments, p is 2-3. In some embodiments, p is 2. In some embodiments, p is 3.

[0271] In some embodiments, R.sup.1 is R, wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00050##

In certain embodiments, a compound of Formula (I) is of the formula:

##STR00051##

In certain embodiments of a compound of formula (I-c), L.sup.2 is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (I-c), L.sup.2 is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (I-c), L.sup.2 is

##STR00052##

In certain embodiments of a compound of formula (I-c), L.sup.2 is

##STR00053##

[0272] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00054##

wherein h is an integer 0 to 10, inclusive. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00055##

wherein h is 3. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00056##

wherein h is an integer 0 to 10, inclusive. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00057##

wherein h is 3.

[0273] In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises substituted or unsubstituted,

##STR00058##

In some embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises substituted or unsubstituted,

##STR00059##

In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises a C.sub.1-20 heteroalkylene. In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises

##STR00060##

wherein g is 1, 2, or 3. In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-c) or (I-c′), L.sup.3 comprises a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene.

[0274] In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 comprises a C.sub.1-20 heteroalkyl. In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 comprises

##STR00061##

wherein g is 1, 2, or 3. In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 comprises a substituted C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-c) or (I-c′), D is absent, and L.sup.3 is para-methoxyphenyl.

[0275] In certain embodiments, h is 1. In some embodiments, h is 2. In certain embodiments, h is 3. In some embodiments, h is 4, 5, or 6. In certain embodiments, h is 7, 8, or 9.

[0276] In some embodiments, R.sup.3 comprises R, wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, R.sup.3 is —S(O).sub.2R, wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In some embodiments, R.sup.3 is —C(═O)R, wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00062##

In some embodiments, a compound of Formula (I) is of the formula:

##STR00063##

In certain embodiments, a compound of Formula (I) is of the formula:

##STR00064##

In some embodiments, a compound of Formula (I) is of the formula:

##STR00065##

In certain embodiments of a compound of formula (I-b) or (I-b-i), Ring A is substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, or substituted or unsubstituted pyrrolylene. In certain embodiments of a compound of formula (I-b) or (I-b-i), Ring A is substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-b) or (I-b-i), L.sup.2′ is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (I-b) or (I-b-i), L.sup.2′ is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (I-b) or (I-b-i), L.sup.2′ is

##STR00066##

In certain embodiments of a compound of formula (I-b) or (I-b-i), L.sup.2′ is

##STR00067##

[0277] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00068##

In some embodiments, a compound of Formula (I) is of the formula:

##STR00069##

In certain embodiments, a compound of Formula (I) is of the formula:

##STR00070##

In some embodiments, a compound of Formula (I) is of the formula:

##STR00071##

[0278] In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises substituted or unsubstituted,

##STR00072##

In some embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises substituted or unsubstituted,

##STR00073##

[0279] In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises a C.sub.1-20 heteroalkylene. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises

##STR00074##

wherein g is 1, 2, or 3. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), L.sup.3 comprises a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene.

[0280] In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), D is absent, and L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), D is absent, and L.sup.3 comprises a C.sub.1-20 heteroalkyl. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), D is absent, and L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), D is absent, and L.sup.3 comprises a substituted C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-b), (I-b-i), (I-b′) or (I-b-i′), D is absent, and L.sup.3 is para-methoxyphenyl.

[0281] In some embodiments, R.sup.4 is R, wherein R is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, a compound of Formula (I) is of the formula:

##STR00075##

In certain embodiments, a compound of Formula (I) is of the formula:

##STR00076##

In certain embodiments of a compound of formula (I-a), Ring A is substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, or substituted or unsubstituted pyrrolylene. In certain embodiments of a compound of formula (I-a), Ring A is substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-a), L.sup.2′ is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (I-a), L.sup.2′ is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (I-a), L.sup.2′ is

##STR00077##

In certain embodiments of a compound of formula (I-a), L.sup.2′ is

##STR00078##

[0282] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00079##

In certain embodiments, a compound of Formula (I) is of the formula:

##STR00080##

[0283] In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises a C.sub.1-20 heteroalkylene. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises

##STR00081##

wherein g is 1, 2, or 3. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises substituted or unsubstituted,

##STR00082##

In some embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 comprises substituted or unsubstituted,

##STR00083##

[0284] In some embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 alkylene, wherein at least one substituent on the C.sub.1-20 alkylene is —NHBoc. In some embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 heteroalkyl wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NHBoc. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NHBoc. In some embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 alkylene, wherein at least one substituent on the C.sub.1-20 alkylene is —NH.sub.2. In some embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 heteroalkyl wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NH.sub.2. In certain embodiments of a compound of formula (I-a) or (I-a′), L.sup.3 is a substituted C.sub.1-20 heteroalkylene with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkylene is —NH.sub.2.

[0285] In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises phenylene. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises a C.sub.1-20 heteroalkyl. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises substituted or unsubstituted, C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises

##STR00084##

wherein g is 1, 2, or 3. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises a substituted C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (I-aa) or (I-a′), D is absent, and L.sup.3 comprises substituted or unsubstituted,

##STR00085##

In some embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 comprises substituted or unsubstituted,

##STR00086##

In some embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 alkyl wherein at least one substituent on the C.sub.1-20 alkyl is —NHBoc. In some embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 heteroalkyl wherein at least one substituent on the C.sub.1-20 heteroalkyl is —NHBoc. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkyl is —NHBoc. In some embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 alkyl wherein at least one substituent on the C.sub.1-20 alkyl is —NH.sub.2. In some embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 heteroalkyl wherein at least one substituent on the C.sub.1-20 heteroalkyl is —NH.sub.2. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is a substituted C.sub.1-20 heteroalkyl with one or more backbone atoms selected from oxygen and nitrogen and a backbone substituted or unsubstituted phenylene, wherein at least one substituent on the C.sub.1-20 heteroalkyl is —NH.sub.2. In certain embodiments of a compound of formula (I-a) or (I-a′), D is absent, and L.sup.3 is para-methoxyphenyl.

[0286] In certain embodiments, a compound of Formula (I) is of the formula:

##STR00087## ##STR00088##

[0287] In some embodiments, a compound of Formula (I) is of the formula:

##STR00089##

[0288] In some embodiments, the present disclosure provides a compound having the structure of Formula (II):

##STR00090##

or a salt thereof, wherein: [0289] each is independently a single bond or a double bond, as valency permits; [0290] each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —C(R).sub.2OR, or —S(O).sub.2N(R).sub.2; [0291] each R is independently hydrogen, -L.sup.2-R.sup.H1, or an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: [0292] two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0293] each R.sup.2 is independently R, —[C(R).sub.2].sub.q—OR, —[C(R).sub.2].sub.q—N(R).sub.2, —[C(R).sub.2].sub.q—SR, —[C(R).sub.2].sub.q—OSi(R).sub.3, —[C(R).sub.2].sub.q—OC(O)R, —[C(R).sub.2].sub.q—OC(O)OR, —[C(R).sub.2].sub.q—OC(O)N(R).sub.2, —[C(R).sub.2].sub.q—OC(O)N(R)—S(═O).sub.2R or —[C(R).sub.2].sub.q—OP(OR).sub.2; or [0294] R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; [0295] each q is independently 0, 1, 2, 3, or 4; [0296] each R.sup.3 is independently —S(O).sub.2R, —S(O).sub.2—[C(R).sub.2].sub.q—R, —S(O).sub.2—[C(R).sub.2].sub.q—B(OR).sub.2, —S(O).sub.2—[C(R).sub.2].sub.q—Si(R).sub.3, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —P(O)(R).sub.2, —P(O)(OR).sub.2, or —P(O)[N(R).sub.2].sub.2; [0297] each R.sup.4 is absent when is a double bond or is independently R, halogen, or

##STR00091## [0298] at least one instance of R.sup.1, R.sup.3, and R.sup.4 comprises R wherein R is -L.sup.2-R.sup.H1. [0299] each L.sup.2 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein: [0300] optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and [0301] optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0302] each R.sup.H1 is independently a first click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHR.sup.A, —N.sub.3, —C(═O)OH, —C(═NR.sup.A)OH, —S(═O)OH, —S(═O).sub.2OH, —C(═O)— (a leaving group), —C(═NR.sup.A)— (a leaving group), —S(═O)— (a leaving group), or —S(═O).sub.2— (a leaving group), provided that each R.sup.H1 is not —OCH.sub.3 or —NR.sup.AC(═O)R.sup.A; [0303] each R.sup.A is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; [0304] each R.sup.5 is absent when is a double bond or is independently hydrogen or an optionally substituted C.sub.1-6 aliphatic group; [0305] each of R.sup.6 and R.sup.6′ is independently R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3; or [0306] R.sup.6 and R.sup.6′ are taken together to form ═O, ═C(R).sub.2 or ═NR; [0307] each n is independently 0, 1, 2, 3, or 4; [0308] each R.sup.7 is independently R, halogen, —CN, —NO.sub.2, —OR, —OSi(R).sub.3, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —P(R).sub.2, —P(OR).sub.2, —P(O)(R).sub.2, —P(O)(OR).sub.2, —P(O)[N(R).sub.2].sub.2, —B(R).sub.2, —B(OR).sub.2, or —Si(R).sub.3; or: [0309] two R.sup.7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0310] each L.sup.1 is independently —S—, —(S).sub.m—[C(R).sub.2].sub.q—(S).sub.p—, —(S).sub.m(S).sub.p—, —(S).sub.mC(O)—(S).sub.p—, —(S).sub.m C(S)—(S).sub.p—, —(S).sub.mS(O)—(S).sub.p—, or —(S).sub.m—S(O).sub.2—(S).sub.p—; [0311] each m is independently 1, 2, or 3; and [0312] each p is independently 1, 2, or 3.

[0313] In certain embodiments, a compound of Formula (II) is of the formula:

##STR00092##

or stereoisomer thereof.

[0314] In certain embodiments, a compound of Formula (II) is of the formula:

##STR00093##

In certain embodiments, a compound of Formula (II) is of the formula:

##STR00094##

or stereoisomer thereof.

[0315] In some embodiments, R is -L.sup.2-R.sup.H1. In some embodiments, each instance of R is -L.sup.2-R.sup.H1. In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.6′, and R.sup.7 comprise -L.sup.2-R.sup.H1. In certain embodiments, only one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.6′, and R.sup.7 comprise -L.sup.2-R.sup.H1. In certain embodiments, at least one instance of R.sup.1, R.sup.3, and R.sup.4 comprise R wherein R is -L.sup.2-R.sup.H1. In certain embodiments, at least one instance of R.sup.1 comprises R wherein R is -L.sup.2-R.sup.H1. In some embodiments, at least one instance of R.sup.1 is -L.sup.2-R.sup.H1. In certain embodiments, at least one instance of R.sup.3 comprises R wherein R is -L.sup.2-R.sup.H1. In certain embodiments, at least one instance of R.sup.3 is —S(O).sub.2R wherein R is -L.sup.2-R.sup.H1. In certain embodiments, at least one instance of R.sup.3 is —C(O)R wherein R is -L.sup.2-R.sup.H1. In certain embodiments, R.sup.4 comprises R wherein R is -L.sup.2-R.sup.H1. In some embodiments, R.sup.4 is -L.sup.2-R.sup.H1.

[0316] In certain embodiments, each R.sup.H1 is independently selected from a first click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHR.sup.A, —N.sub.3, —C(═O)OH, —C(═NR.sup.A)OH, —S(═O)OH, —S(═O).sub.2OH, —C(═O)—(a leaving group), —C(═NR.sup.A)—(a leaving group), —S(═O)—(a leaving group), and —S(═O).sub.2—(a leaving group). In certain embodiments, R.sup.H1 is not —OCH.sub.3. In some embodiments, R.sup.H1 is not —NR.sup.AC(═O)R.sup.A. In certain embodiments, R.sup.H1 is a first click-chemistry handle. In certain embodiments, R.sup.H1 is —N.sub.3. In certain embodiments, R.sup.H1 is —C≡CH. In certain embodiments, at least one instance of R.sup.H1 is a first click-chemistry handle. In certain embodiments, at least one instance of R.sup.H1 is —N.sub.3. In certain embodiments, at least one instance of R.sup.H1 is —C≡CH. In certain embodiments, R.sup.H1 is a leaving group. In certain embodiments, R.sup.H1 is a metathesis handle.

[0317] In some embodiments, a compound of Formula (II) is of the formula:

##STR00095##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00096##

In certain embodiments of a compound of formula (II-a), Ring A is substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, or substituted or unsubstituted pyrrolylene. In certain embodiments of a compound of formula (II-a), Ring A is substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (II-a), L.sup.2′ is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (II-a), L.sup.2′ is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (II-a), L.sup.2′ is

##STR00097##

In certain embodiments of a compound of formula (II-a), L.sup.2′ is

##STR00098##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00099##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00100##

[0318] In some embodiments, a compound of Formula (II) is of the formula:

##STR00101##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00102##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00103##

In some embodiments, a compound of Formula (II) is of the formula:

##STR00104##

In certain embodiments of a compound of formula (II-b) or (II-b-i), Ring A is substituted or unsubstituted phenylene, substituted or unsubstituted indolylene, or substituted or unsubstituted pyrrolylene. In certain embodiments of a compound of formula (II-b) or (II-b-i), Ring A is substituted or unsubstituted phenylene. In certain embodiments of a compound of formula (II-b) or (II-b-i), L.sup.2′ is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (II-b) or (II-b-i), L.sup.2′ is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (II-b) or (II-b-i), L.sup.2′ is

##STR00105##

In certain embodiments of a compound of formula (II-b) or (II-b-i), L.sup.2′ is

##STR00106##

In certain embodiments, a compound of Formula (II) is of the formula:

##STR00107##

In certain embodiments, a compound of Formula (II) is of the formula:

##STR00108##

[0319] In certain embodiments, a compound of Formula (II) is of the formula:

##STR00109##

In certain embodiments, a compound of Formula (II) is of the formula:

##STR00110##

In certain embodiments of a compound of formula (II-c), L.sup.2′ is substituted or unsubstituted C.sub.1-20 heteroalkylene comprising one or more backbone oxygen atoms. In certain embodiments of a compound of formula (II-c), L.sup.2′ is substituted or unsubstituted C.sub.1-20 alkylene. In certain embodiments of a compound of formula (II-c), L.sup.2′ is

##STR00111##

In certain embodiments of a compound of formula (II-c), L.sup.2′ is

##STR00112##

In certain embodiments, a compound of Formula (II) is of the formula:

##STR00113##

wherein h is an integer from 0 to 10, inclusive. In certain embodiments, a compound of Formula (II) is of the formula:

##STR00114##

[0320] wherein h is an integer from 0 to 10, inclusive. In certain embodiments of a compound of formula (II-c′), h is 1. in certain embodiments of a compound of formula (II-c′), h is 2. in certain embodiments of a compound of formula (II-c′), h is 3.

[0321] In certain embodiments, a compound of Formula (II) is of the formula:

##STR00115##

[0322] Also provided herein are compounds of Formula (III):

R.sup.H2-L.sup.3-D  (III)

or a salt thereof, wherein R.sup.H2 is a reaction handle, wherein the reaction handle is able to react with R.sup.H1 to form R.sup.H.

[0323] In certain embodiments, R.sup.H2 is a second click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHR.sup.A, —N.sub.3, —C(═O)OH, —C(═NR.sup.A)OH, —S(═O)OH, —S(═O).sub.2OH, —C(═O)—(a leaving group), —C(═NR.sup.A)—(a leaving group), —S(═O)—(a leaving group), or —S(═O).sub.2-(a leaving group). In certain embodiments, R.sup.H2 is —C≡CH. In some embodiments, R.sup.H2 is —N.sub.3. In certain embodiments, R.sup.H2 is a nucleophile. In certain embodiments, R.sup.H2 is a leaving group. In some embodiments, R.sup.H2 is —C(═O)—(a leaving group).

[0324] In certain embodiments, R.sup.H1 is —N.sub.3, and R.sup.H2 is —C≡CH. In some embodiments, R.sup.H1 is —C≡CH, and R.sup.H2 is —N.sub.3. In certain embodiments, R.sup.H1 is a leaving group, and R.sup.H2 is —N.sub.3. In some embodiments, R.sup.H1 is a leaving group, and R.sup.H2 is a nucleophile. In certain embodiments, R.sup.H1 is a nucleophile, and R.sup.H2 is a leaving group. In some embodiments, R.sup.H1 is —NH.sub.2, and R.sup.H2 is —C(═O)—(a leaving group).

[0325] In aspects of the disclosure, provided herein are compounds of Formula (V):

##STR00116##

or salt thereof, wherein: [0326] each is independently a single bond or a double bond, as valency permits; [0327] each R.sup.1 is independently R, —C(O)R, —C(O)N(R).sub.2, —S(O)R, —S(O).sub.2R, —S(O).sub.2OR, —C(R).sub.2OR, or —S(O).sub.2N(R).sub.2; [0328] each R is independently hydrogen or an optionally substituted group selected from C.sub.1-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or: [0329] two R groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0330] each R.sup.2 is independently R, —[C(R).sub.2].sub.q—OR, —[C(R).sub.2].sub.q—N(R).sub.2, —[C(R).sub.2].sub.q—SR, —[C(R).sub.2].sub.q—OSi(R).sub.3, —[C(R).sub.2].sub.q—OC(O)R, —[C(R).sub.2].sub.q—OC(O)OR, —[C(R).sub.2].sub.q—OC(O)N(R).sub.2, —[C(R).sub.2].sub.q—OC(O)N(R)—S(═O).sub.2R, or —[C(R).sub.2].sub.q—OP(OR).sub.2; or [0331] R.sup.1 and R.sup.2 are taken together with their intervening atoms to form an optionally substituted 4-7 membered heterocyclic ring having, in addition to the nitrogen atom to which R.sup.1 is attached, 0-2 heteroatoms independently selected from oxygen, nitrogen, and sulfur; [0332] each q is independently 0, 1, 2, 3, or 4; [0333] each R.sup.3 is independently —S(O).sub.2R, —S(O).sub.2—[C(R).sub.2].sub.q—R, —S(O).sub.2—[C(R).sub.2].sub.q—B(OR).sub.2, —S(O).sub.2—[C(R).sub.2].sub.q—Si(R).sub.3, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —P(O)(R).sub.2, —P(O)(OR).sub.2, or —P(O)[N(R).sub.2].sub.2; [0334] R.sup.4 is absent when is a double bond or is selected from R, halogen, and

##STR00117## [0335] each R.sup.5 is absent when is a double bond or is independently hydrogen or an optionally substituted C.sub.1-6 aliphatic group; [0336] each of R.sup.6 and R.sup.6′ is independently R, halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, or —OSi(R).sub.3; or [0337] R.sup.6 and R.sup.6′ are taken together to form ═O, ═C(R).sub.2, or ═NR; [0338] each n is independently 0, 1, 2, 3, or 4; [0339] each R.sup.7 is independently R, halogen, —CN, —NO.sub.2, —OR, —OSi(R).sub.3, —SR, —N(R).sub.2, —S(O).sub.2R, —S(O).sub.2OR, —S(O).sub.2N(R).sub.2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R).sub.2, —C(O)N(R)—OR, —N(R)C(O)OR, —N(R)C(O)N(R).sub.2, —N(R)S(O).sub.2R, —P(R).sub.2, —P(OR).sub.2, —P(O)(R).sub.2, —P(O)(OR).sub.2, —P(O)[N(R).sub.2]2, —B(R).sub.2, —B(OR).sub.2, or —Si(R).sub.3; or: [0340] two R.sup.7 are taken together with their intervening atoms to form an optionally substituted 4-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0341] each R.sup.Z is independently hydrogen, -L.sup.2-R.sup.H1, -L.sup.2-R.sup.H-L.sup.3-D, -(L.sup.2).sub.0-1-R.sup.P, substituted methyl, or an optionally substituted group selected from C.sub.2-20 alkyl, C.sub.1-20 heteroalkyl, phenyl, a 3-7 membered saturated or partially unsaturated, carbocyclic ring, an 8-14 membered bicyclic or polycyclic, saturated carbocyclic ring, partially unsaturated carbocyclic ring, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated or partially unsaturated, heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-14 membered bicyclic or polycyclic, saturated or partially unsaturated, heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; [0342] wherein at least one instance of R.sup.Z is not hydrogen; [0343] each L.sup.2 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein: [0344] optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with —C(═O)—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and [0345] optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0346] each R.sup.H1 is independently a first click-chemistry handle, a nucleophile, an electrophile, a leaving group, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, halogen, —OH, —SH, —NHR.sup.A, —N.sub.3, —C(═O)OH, —C(═NR.sup.A)OH, —S(═O)OH, —S(═O).sub.2OH, —C(═O)—(a leaving group), —C(═NR.sup.A)—(a leaving group), —S(═O)—(a leaving group), or —S(═O).sub.2—(a leaving group); [0347] each R.sup.H is independently substituted or unsubstituted triazolylene, —O—, —S—, —NR.sup.A—, —C(═O)O—, —C(═NR.sup.A)O—, —S(═O)O—, —S(═O).sub.2O—, —C(═O)NR.sup.A—, —C(═NR.sup.A)NR.sup.A—, —S(═O)NR.sup.A—, —S(═O).sub.2NR.sup.A—, —OC(═O)—, —OC(═NR.sup.A)—, —OS(═O)—, —OS(═O).sub.2—, —NR.sup.AC(═O)—, —NR.sup.AC(═NR.sup.A)—, —NR.sup.AS(═O)—, —NR.sup.AS(═O).sub.2—, —OC(═O)O—, —OC(═NR.sup.A)O—, —OS(═O)O—, —OS(═O).sub.2O—, —NR.sup.AC(═O)O—, —NR.sup.AC(═NR.sup.A)O—, —NR.sup.AS(═O)O—, —NR.sup.AS(═O).sub.2O—, —OC(═O)NR.sup.A—, —OC(═NR.sup.A)NR.sup.A—, —OS(═O)NR.sup.A—, —OS(═O).sub.2NR.sup.A—, —NR.sup.AC(═O)NR.sup.A—, —NR.sup.AC(═NR.sup.A)NR.sup.A—, —NR.sup.AS(═O)NR.sup.A—, —NR.sup.AS(═O).sub.2NR.sup.A—, —C(═O)—, —C(═NR.sup.A)—, —S(═O)—, —S(═O).sub.2—, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0348] each R.sup.A is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; [0349] each L.sup.3 is independently substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, or C.sub.2-20 heteroalkynylene, wherein: [0350] optionally one or more backbone carbons in each instance of the substituted or unsubstituted, C.sub.1-20 alkylene, substituted or unsubstituted, C.sub.2-20 alkenylene, substituted or unsubstituted, C.sub.2-20 alkynylene, substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and [0351] optionally one or more backbone heteroatoms in each instance of the substituted or unsubstituted, C.sub.1-20 heteroalkylene, substituted or unsubstituted, C.sub.2-20 heteroalkenylene, and substituted or unsubstituted, C.sub.2-20 heteroalkynylene are independently replaced with substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; [0352] each D is independently absent, polymeric moiety, dendrimeric moiety, antibody, particle, bead, nanostructure, liposome, micelle, or vesicle; and [0353] R.sup.P is an amino acid, a peptide, or a polypeptide.

[0354] In certain embodiments, a compound of Formula (V) is of the formula:

##STR00118##

or stereoisomer thereof. In certain embodiments, a compound of Formula (V) is of the formula:

##STR00119##

In certain embodiments, a compound of Formula (V) is of the formula:

##STR00120##

or stereoisomer thereof.

[0355] In certain embodiments, each instance of R.sup.Z is the same. In certain embodiments, each instance of R.sup.Z is different.

[0356] In certain embodiments, at least one R.sup.Z is not hydrogen. In certain embodiments, R.sup.Z is hydrogen. In some embodiments, R.sup.Z is a substituted methyl. In certain embodiments, R.sup.Z is —CH.sub.2F, —CHF.sub.2, —CF.sub.3, or benzyl. In some embodiments, R.sup.Z is -L.sup.2-R.sup.H1. In some embodiments, R.sup.Z is -L.sup.2-R.sup.H, and L.sup.2 comprises a substituted or unsubstituted,

##STR00121##

In some embodiments, R.sup.Z is -L.sup.2-R.sup.H, and L.sup.2 comprises

##STR00122##

substituted with halogen. In some embodiments, -L.sup.2-R.sup.H1 comprises

##STR00123##

In certain embodiments, R.sup.Z is -L.sup.2-R.sup.H-L.sup.3-D. In certain embodiments, R.sup.Z is -(L.sup.2).sub.1-R.sup.P. In certain embodiments, R.sup.Z is —R.sup.P.

[0357] In some embodiments, R.sup.Z is optionally substituted C.sub.2-20 alkyl. In some embodiments, R.sup.Z is optionally substituted C.sub.2-15 alkyl. In some embodiments, R.sup.Z is optionally substituted C.sub.2-10 alkyl. In some embodiments, R.sup.Z is optionally substituted C.sub.2-6 alkyl. In some embodiments, R.sup.Z is optionally substituted C.sub.2-6 alkyl. In some embodiments, R.sup.Z is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments, R.sup.Z is optionally substituted hexyl. In some embodiments, R.sup.Z is optionally substituted pentyl. In some embodiments, R.sup.Z is optionally substituted butyl. In some embodiments, R.sup.Z is optionally substituted propyl. In some embodiments, R.sup.Z is optionally substituted ethyl. In some embodiments, R.sup.Z is hexyl. In some embodiments, R.sup.Z is pentyl. In some embodiments, R.sup.Z is butyl. In some embodiments, R.sup.Z is propyl. In some embodiments, R.sup.Z is ethyl. In some embodiments, R.sup.Z is methyl. In some embodiments, R.sup.Z is isopropyl. In some embodiments, R.sup.Z is n-propyl. In some embodiments, R.sup.Z is tert-butyl. In some embodiments, R.sup.Z is sec-butyl. In some embodiments, R.sup.Z is n-butyl. In some embodiments, R.sup.Z is benzyloxymethyl. In some embodiments, R.sup.Z is benzyl. In some embodiments, R.sup.Z is allyl. In some embodiments, R.sup.Z is not hydrogen. In some embodiments, R.sup.Z is not alkyl.

[0358] In some embodiments, R.sup.Z is optionally substituted C.sub.1-20 heteroalkyl. In some embodiments, R.sup.Z is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus selenium, silicon and boron within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R.sup.Z is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 heteroatoms independently selected from nitrogen, sulfur, phosphorus, selenium, silicon and boron within the C.sub.1-20 heteroalkyl backbone, optionally including one or more oxidized forms of nitrogen, sulfur, phosphorus, selenium, silicon or boron within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R.sup.Z is optionally substituted C.sub.1-20 heteroalkyl comprising 1-6 groups independently selected from

##STR00124##

—N═, ≡N, —S—, —S(O)—, —S(O).SUB.2.—, —O—, ═O,

[0359] ##STR00125##

—Se—, —Se(O)—, and

[0360] ##STR00126##

within the C.sub.1-20 heteroalkyl backbone. In some embodiments, R.sup.Z is not heteroalkyl. In some embodiments, R.sup.Z is methoxymethyl. In some embodiments, R.sup.Z is benzyloxymethyl.

[0361] In some embodiments, R.sup.Z is optionally substituted phenyl. In some embodiments, R.sup.Z is optionally substituted phenyl wherein one or more substituents are halogen. In some embodiments, R.sup.Z is optionally substituted phenyl wherein one or more substituents are —F. In some embodiments, R.sup.Z is optionally substituted phenyl wherein one or more substituents are —C.sub.1. In some embodiments, R.sup.Z is optionally substituted phenyl wherein one or more substituents are —Br. In some embodiments, R.sup.Z is optionally substituted phenyl wherein one or more substituents are —I. In some embodiments, R.sup.Z is phenyl.

[0362] In some embodiments, R.sup.Z is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is an optionally substituted 3-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is an optionally substituted 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R.sup.Z is optionally substituted cycloheptyl. In some embodiments, R.sup.Z is cycloheptyl. In some embodiments, R.sup.Z is optionally substituted cyclohexyl. In some embodiments, R.sup.Z is cyclohexyl. In some embodiments, R.sup.Z is optionally substituted cyclopentyl. In some embodiments, R.sup.Z is cyclopentyl. In some embodiments, R.sup.Z is optionally substituted cyclobutyl. In some embodiments, R.sup.Z is cyclobutyl. In some embodiments, R.sup.Z is optionally substituted cyclopropyl. In some embodiments, R.sup.Z is cyclopropyl.

[0363] In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or polycyclic saturated, partially unsaturated or aryl ring. In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or polycyclic saturated ring. In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or polycyclic partially saturated ring. In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or polycyclic aryl ring. In some embodiments, R.sup.Z is an optionally substituted 8-10 membered bicyclic saturated, partially unsaturated or aryl ring. In some embodiments, R.sup.Z is an optionally substituted 8-10 membered bicyclic saturated ring. In some embodiments, R.sup.Z is an optionally substituted 8-10 membered bicyclic partially unsaturated ring. In some embodiments, R.sup.Z is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R.sup.Z is optionally substituted naphthyl. In some embodiments, R.sup.Z is optionally substituted anthracenyl. In some embodiments, R.sup.Z is optionally substituted 9-anthracenyl.

[0364] In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is optionally substituted phenyl. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is optionally substituted naphthyl. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted group selected from phenyl, 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and wherein at least one aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently optionally substituted phenyl. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently optionally substituted phenyl, or an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is independently an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R.sup.Z is optionally substituted biaryl wherein one aryl group is optionally substituted naphthyl, and the other aryl group is independently an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R.sup.Z is optionally substituted biaryl wherein each aryl group is optionally substituted naphthyl. In some embodiments, R.sup.Z is optionally substituted biaryl wherein one aryl group is optionally substituted naphthyl, and the other aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0365] In some embodiments, R.sup.Z is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is a substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an unsubstituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0366] In some embodiments, R.sup.Z is an optionally substituted 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R.sup.Z is an optionally substituted 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0367] In some embodiments, R.sup.Z is an optionally substituted 5-membered monocyclic heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is selected from optionally substituted pyrrolyl, furanyl, or thienyl.

[0368] In some embodiments, R.sup.Z is an optionally substituted 5-membered heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.Z is an optionally substituted 5-membered heteroaryl ring having one nitrogen atom, and an additional heteroatom selected from sulfur or oxygen. Exemplary R.sup.Z groups include but are not limited to optionally substituted pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl.

[0369] In some embodiments, R.sup.Z is an optionally substituted 5-membered heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted triazolyl, oxadiazolyl or thiadiazolyl.

[0370] In some embodiments, R.sup.Z is an optionally substituted 5-membered heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted tetrazolyl, oxatriazolyl and thiatriazolyl.

[0371] In some embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having 1-4 nitrogen atoms. In some embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogen atoms. In other embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having four nitrogen atoms. In some embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having three nitrogen atoms. In some embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having two nitrogen atoms. In certain embodiments, R.sup.Z is an optionally substituted 6-membered heteroaryl ring having one nitrogen atom. Exemplary R.sup.Z groups include but are not limited to optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, or tetrazinyl.

[0372] In some embodiments, R.sup.Z is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is a substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an unsubstituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0373] In some embodiments, R.sup.Z is optionally substituted 3-membered heterocyclic ring having one heteroatom selected from nitrogen, oxygen or sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted aziridinyl, thiiranyl or oxiranyl. In some embodiments, R.sup.Z is optionally substituted 4-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted azetidinyl, oxetanyl, thietanyl, oxazetidinyl, thiazetidinyl, or diazetidinyl. In some embodiments, R.sup.Z is optionally substituted 5-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, oxazolidinyl, dioxolanyl, oxathiolanyl, thiazolidinyl, dithiolanyl, imidazolidinyl, isothiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, triazolidinyl, oxadiazolidinyl, thiadiazolidinyl, oxadiazolidinyl, dioxazolidinyl, oxathiazolidinyl, thiadiazolidinyl or dithiazolidinyl. In some embodiments, R.sup.Z is optionally substituted 6-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, oxathianyl, triazinanyl, oxadiazinanyl, thiadiazinanyl, dithiazinanyl, dioxazinanyl, oxathiazinanyl, oxadithianyl, trioxanyl, dioxathianyl or trithianyl. In some embodiments, R.sup.Z is optionally substituted 7-membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted azepanyl, oxepanyl, thiepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxepanyl, oxathiepanyl, dithiepanyl, triazepanyl, oxadiazepanyl, thiadiazepanyl, dioxazepanyl, oxathiazepanyl, dithiazepanyl, trioxepanyl, dioxathiepanyl, oxadithiepanyl or trithiepanyl.

[0374] In certain embodiments, R.sup.Z is an optionally substituted 5-7 membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.Z is an optionally substituted 5-6 membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.Z is an optionally substituted 5-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted dihydroimidazolyl, dihydrothiazolyl, dihydrooxazolyl, or oxazolinyl. In certain embodiments, R.sup.Z is an optionally substituted 6-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydropyrazinyl, tetrohydropyrazinyl, dihydrotriazinyl, tetrahydrotriazinyl, dihydrodioxinyl, dihydrooxathiinyl, dihydrooxazinyl, dihydrodithiine, dihydrothiazine, dioxinyl, oxathiinyl, oxazinyl, dithiinyl, or thiazinyl. In certain embodiments, R.sup.Z is an optionally substituted 7-membered partially unsaturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary R.sup.Z groups include but are not limited to optionally substituted azepiyl, oxepinyl, thiepinyl, diazepinyl, oxazepinyl, thiazepinyl, triazepinyl, oxadiazepinyl, thiadiazepinyl, dihydroazepiyl, dihydrooxepinyl, dihydrothiepinyl, dihydrodiazepinyl, dihydrooxazepinyl, dihydrothiazepinyl, dihydrotriazepinyl, dihydrooxadiazepinyl, dihydrothiadiazepinyl, tetrahydroazepiyl, tetrahydrooxepinyl, tetrahydrothiepinyl, tetrahydrodiazepinyl, tetrahydrooxazepinyl, tetrahydrothiazepinyl, tetrahydrotriazepinyl, tetrahydrooxadiazepinyl, or tetrahydrothiadiazepinyl.

[0375] In certain embodiments, R.sup.Z is optionally substituted oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepaneyl, aziridineyl, azetidineyl, pyrrolidinyl, piperidinyl, azepanyl, thiiranyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiepanyl, dioxolanyl, oxathiolanyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, dithiolanyl, dioxanyl, morpholinyl, oxathianyl, piperazinyl, thiomorpholinyl, dithianyl, dioxepanyl, oxazepanyl, oxathiepanyl, dithiepanyl, diazepanyl, dihydrofuranonyl, tetrahydropyranonyl, oxepanonyl, pyrolidinonyl, piperidinonyl, azepanonyl, dihydrothiophenonyl, tetrahydrothiopyranonyl, thiepanonyl, oxazolidinonyl, oxazinanonyl, oxazepanonyl, dioxolanonyl, dioxanonyl, dioxepanonyl, oxathiolinonyl, oxathianonyl, oxathiepanonyl, thiazolidinonyl, thiazinanonyl, thiazepanonyl, imidazolidinonyl, tetrahydropyrimidinonyl, diazepanonyl, imidazolidinedionyl, oxazolidinedionyl, thiazolidinedionyl, dioxolanedionyl, oxathiolanedionyl, piperazinedionyl, morpholinedionyl, thiomorpholinedionyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothienyl, or tetrahydrothiopyranyl.

[0376] In some embodiments, R.sup.Z is an optionally substituted 7-14 membered bicyclic or polycyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted indolinyl. In some embodiments, R.sup.Z is optionally substituted isoindolinyl. In some embodiments, R.sup.Z is optionally substituted 1, 2, 3, 4-tetrahydroquinolinyl. In some embodiments, R.sup.Z is optionally substituted 1, 2, 3, 4-tetrahydroisoquinolinyl. In some embodiments, R.sup.Z is an optionally substituted azabicyclo[3.2.1]octanyl.

[0377] In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or polycyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0378] In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted 1,4-dihydropyrrolo[3,2-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, furo[3,2-b]furanyl, thieno[3,2-b]furanyl, thieno[3,2-b]thienyl, 1H-pyrrolo[1,2-a]imidazolyl, pyrrolo[2,1-b]oxazolyl or pyrrolo[2,1-b]thiazolyl. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted dihydropyrroloimidazolyl, 1H-furoimidazolyl, 1H-thienoimidazolyl, furooxazolyl, furoisoxazolyl, 4H-pyrrolooxazolyl, 4H-pyrroloisoxazolyl, thienooxazolyl, thienoisoxazolyl, 4H-pyrrolothiazolyl, furothiazolyl, thienothiazolyl, 1H-imidazoimidazolyl, imidazooxazolyl or imidazo[5,1-b]thiazolyl. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0379] In some embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having one heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted indolyl. In some embodiments, R.sup.Z is optionally substituted benzofuranyl. In some embodiments, R.sup.Z is optionally substituted benzo[b]thienyl. In certain embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted azaindolyl. In some embodiments, R.sup.Z is optionally substituted benzimidazolyl. In some embodiments, R.sup.Z is optionally substituted benzothiazolyl. In some embodiments, R.sup.Z is optionally substituted benzoxazolyl. In some embodiments, R.sup.Z is an optionally substituted indazolyl. In certain embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted oxazolopyridiyl, thiazolopyridinyl or imidazopyridinyl. In certain embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted purinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, oxazolopyrazinyl, thiazolopyrazinyl, imidazopyrazinyl, oxazolopyridazinyl, thiazolopyridazinyl or imidazopyridazinyl. In certain embodiments, R.sup.Z is an optionally substituted 5,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0380] In certain embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In other embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted quinolinyl. In some embodiments, R.sup.Z is optionally substituted isoquinolinyl. In some embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted quinazolinyl, phthalazinyl, quinoxalinyl or naphthyridinyl. In some embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having three heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted pyridopyrimidinyl, pyridopyridazinyl, pyridopyrazinyl, or benzotriazinyl. In some embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having four heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted pyridotriazinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyridazinopyridazinyl, pyrimidopyridazinyl or pyrimidopyrimidinyl. In some embodiments, R.sup.Z is an optionally substituted 6,6-fused heteroaryl ring having five heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0381] In some embodiments, R.sup.Z is optionally substituted heterobiaryl wherein each heteroaryl group is independently an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R.sup.Z is optionally substituted heterobiaryl wherein each aryl group is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0382] In some embodiments, two R.sup.Z groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same atom are optionally taken together with the atom to which they are attached to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same carbon atom are optionally taken together with the carbon atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same nitrogen atom are optionally taken together with the nitrogen atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same sulfur atom are optionally taken together with the sulfur atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same oxygen atom are optionally taken together with the oxygen atom to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups on the same phosphorus atom are optionally taken together with the phosphorus atom to form an optionally substituted 3-14 membered, monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having, in addition to the phosphorus atom, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the two R.sup.Z groups are attached to two different atoms.

[0383] In some embodiments, two R.sup.Z groups are optionally taken together with their intervening atoms to form an optionally substituted 3-14 membered, saturated, partially unsaturated, or aryl ring having, in addition to the intervening atoms, 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted saturated ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted partially unsaturated ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted carbocyclic ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted aryl ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted phenyl ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted heterocyclic ring. In some embodiments, two R.sup.Z groups are taken together to form an optionally substituted heteroaryl ring.

[0384] In some embodiments, a ring formed by taking two R.sup.Z groups together is monocyclic, bicyclic or tricyclic. In some embodiments, a ring formed by taking two R.sup.Z groups together is monocyclic. In some embodiments, a ring formed by taking two R.sup.Z groups together is bicyclic. In some embodiments, a ring formed by taking two R.sup.Z groups together is monocyclic or bicyclic. In some embodiments, a ring formed by taking two R.sup.Z groups together is tricyclic. In some embodiments, a ring formed by taking two R.sup.Z groups together is monocyclic, bicyclic or tricyclic.

[0385] In certain embodiments, R.sup.P is an amino acid. In certain embodiments, R.sup.P is a peptide. In some embodiments, R.sup.P is a peptide comprising 2 to 10 amino acids. In some embodiments, R.sup.P is a peptide comprising 2 to 5 amino acids. In some embodiments, R.sup.P is a peptide comprising glutamic acid, cysteine, and glycine. In certain embodiments, an amino acid is selected from the group consisting alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In certain embodiments, R.sup.P is a peptide bound through the N-terminus. In certain embodiments, R.sup.P is a peptide bound through the C-terminus. In certain embodiments, R.sup.P is a peptide bound through a side chain.

[0386] In certain embodiments, a compound of Formula (V) is of the formula:

##STR00127##

[0387] In some embodiments, a compound of Formula I, II, or V is deprotected. In certain embodiments, a compound of Formula I, II, or V is a free base. In certain embodiments, a compound of Formula I, II, or V is a salt. In some embodiments, a compound of Formula I is of the formula:

##STR00128##

In some embodiments, a compound of Formula I is a salt of

##STR00129## ##STR00130## ##STR00131##

[0388] In certain aspects, the scope of this disclosure also includes the in vivo metabolic products of compounds described herein, e.g., compounds of Formula I, II, or V. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the disclosure includes compounds produced by a process comprising contacting a provided compound, e.g., a compound of Formula I, II, or V, with a subject for a period of time sufficient to yield a metabolic product thereof.

[0389] In some embodiments, a provided compound generates reactive oxygen species (ROS). Exemplary ROS includes superoxide radical anion, hydroxyl radical and hydrogen peroxide. In some embodiments, the present disclosure provides compounds capable of generating reactive oxygen species in a subject. In some embodiments, a provided compound conjugates with and/or inhibits cellular proteins by forming mixed disulfides between cysteine residues. In some embodiments, a provided compound conjugates with and/or inhibits cellular proteins by catalytic formation of intramolecular disulfide bonds between cysteine residues. In some embodiments, the present disclosure provides compounds capable of conjugating with and/or inhibiting cellular proteins. In some embodiments, a provided compound disrupts tertiary structure of proteins containing a thiol or disulfide in the active site. In certain embodiments, a provided compound disrupts the tertiary structure of proteins containing a metal (e.g., metal ion). In certain embodiments, the metal is Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, or Mo. In certain embodiments, the metal is Fe. In certain embodiments, the metal is Cu. In certain embodiments, the metal is Zn (e.g., Zn(II)). In some embodiments, a provided compound disrupts tertiary structure of proteins containing a Zn.sup.2+-binding cysteine-histidine rich protein domain. In some embodiments, the present disclosure provides compounds capable of disrupting tertiary structures of proteins containing a Zn.sup.2+-binding cysteine-histidine rich protein domain In some embodiments, a provided compound ejects Zn.sup.2+ ions from a protein. In some embodiments, the present disclosure provides compounds capable of ejecting a Zn.sup.2+ ion from a protein. In some embodiments, a provided compound induces caspase-dependent apoptosis. In some embodiments, the present disclosure provides compounds capable of inducing apoptosis. In some embodiments, the present disclosure provides compounds capable of inducing caspase-dependent apoptosis.

[0390] In certain aspects, the disclosure provides compounds of Formula (X):

##STR00132##

or salt thereof, wherein

[0391] R.sup.X is unsubstituted alkyl, —Si(R.sup.S).sub.3, —Sn(R.sup.S).sub.3, substituted or unsubstituted benzyl, or M.sup.X;

[0392] R.sup.Y is unsubstituted alkyl, —Si(R.sup.S).sub.3, —Sn(R.sup.S).sub.3, substituted or unsubstituted benzyl, hydrogen, or M.sup.Y;

[0393] each R.sup.S is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0394] M.sup.X is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium; and

[0395] M.sup.Y is a metal selected from the group consisting of sodium, potassium, lithium, rubidium, and cesium.

[0396] In some embodiments, a compound of formula (X) is not sodium benzhydryl trithiocarbonate. In some embodiments, a compound of formula (X) is not sodium p-methoxybenzhydryl trithiocarbonate.

[0397] In certain embodiments, R.sup.X is unsubstituted alkyl. In some embodiments, R.sup.X is unsubstituted methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, or pentyl. In certain embodiments, R.sup.X is —Si(R.sup.S).sub.3, and R.sup.S is methyl. In some embodiments, R.sup.X is —Sn(R.sup.S).sub.3, and R.sup.S is methyl. In some embodiments, R.sup.X is substituted benzyl. In certain embodiments, R.sup.X is unsubstituted benzyl. In some embodiments, R.sup.X is M.sup.X.

[0398] In certain embodiments, R.sup.Y is unsubstituted alkyl. In some embodiments, R.sup.Y is unsubstituted methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, or pentyl. In certain embodiments, R.sup.Y is —Si(R.sup.S).sub.3, and R.sup.S is methyl. In some embodiments, R.sup.Y is —Sn(R.sup.S).sub.3, and R.sup.S is methyl. In some embodiments, R.sup.Y is substituted benzyl. In certain embodiments, R.sup.Y is unsubstituted benzyl. In some embodiments, R.sup.Y is M.sup.Y.

[0399] In some embodiments, R.sup.S is hydrogen. In certain embodiments, R.sup.S is halogen. In certain embodiments, R.sup.S is hydroxyl. In certain embodiments, R.sup.S is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.S is methyl. In certain embodiments, R.sup.S is C.sub.1-6 heteroalkyl. In certain embodiments, R.sup.S is —OCH.sub.3.

[0400] In certain embodiments, M.sup.X is sodium. In some embodiments, M.sup.X is potassium. In certain embodiments, M.sup.X is lithium. In some embodiments, M.sup.X is rubidium. In certain embodiments, M.sup.X is cesium.

[0401] In certain embodiments, M.sup.Y is sodium. In certain embodiments, M.sup.Y is potassium. In certain embodiments, M.sup.Y is lithium. In certain embodiments, M.sup.Y is rubidium. In certain embodiments, M.sup.Y is cesium. In certain embodiments, M.sup.X and M.sup.Y are not both sodium and are not both potassium.

[0402] In certain embodiments, a compound of Formula (X) is of the formula:

##STR00133##

In certain embodiments, a compound of Formula (X) is of the formula:

##STR00134##

[0403] Also provided herein are compounds of Formula (XII):

##STR00135##

or a salt thereof, wherein:

[0404] one of R.sup.U and R.sup.V is hydrogen, and the other one of R.sup.U and R.sup.V is an oxygen protecting group or —Si(R.sup.S).sub.3;

[0405] or R.sup.U and R.sup.V are each attached to the same to form a ring; and

[0406] each R.sup.S is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0407] In certain embodiments, a compound of Formula (XII) comprises only one —OH.

[0408] In some embodiments, a compound of Formula (XII) is of the formula:

##STR00136##

In certain embodiments, a compound of Formula (XII) is of the formula:

##STR00137##

In certain embodiments, a compound of Formula (XII) is of the formula:

##STR00138##

[0409] In some embodiments, R.sup.U is hydrogen. In certain embodiments, R.sup.U is an oxygen protecting group. In some embodiments, R.sup.U is an oxygen protecting group selected from the group consisting of acetyl, benzoyl, methoxymethyl ether, or pivaloyl. In some embodiments, R.sup.U is —Si(R.sup.S).sub.3. In some embodiments, R.sup.U is —Si(Me).sub.3, —Si(iPr).sub.3, or —Si(tBu)(Me).sub.2.

[0410] In some embodiments, R.sup.V is hydrogen. In certain embodiments, R.sup.V is an oxygen protecting group. In some embodiments, R.sup.V is an oxygen protecting group selected from the group consisting of acetyl, benzoyl, methoxymethyl ether, or pivaloyl. In some embodiments, R.sup.V is —Si(R.sup.S).sub.3. In some embodiments, R.sup.V is —Si(Me).sub.3, —Si(iPr).sub.3, or —Si(tBu)(Me).sub.2.

[0411] In certain embodiments, R.sup.U is hydrogen, and R.sup.V is —Si(Me).sub.3. In certain embodiments, R.sup.V is hydrogen, and R.sup.U is —Si(Me).sub.3. In certain embodiments, R.sup.U is hydrogen, and R.sup.V is —Si(tBu)(Me).sub.2. In certain embodiments, R.sup.V is hydrogen, and R.sup.U is —Si(tBu)(Me).sub.2.

[0412] In certain embodiments, R.sup.U and R.sup.V are each attached to the same

##STR00139##

to form a ring (e.g., R.sup.U and R.sup.V are joined to form a ring that comprises

##STR00140##

in the ring system, wherein the two attachment points of

##STR00141##

are attached to the two oxygen atoms to which R.sup.U and R.sup.V are attached, respectively).

Methods of Preparation

[0413] In certain aspects, the present disclosure provides methods of making a compound of Formula (I), or a salt thereof, comprising reacting a compound of Formula (II), or a salt thereof, with a compound of Formula (III):

R.sup.H2-L.sup.3-D  (III),

or a salt thereof, wherein R.sup.H2 is a reaction handle, wherein the reaction handle is able to react with R.sup.H1 of Formula (II) to form R.sup.H of Formula (I). In some embodiments, the step of reacting comprises a click-chemistry reaction. In certain embodiments, the step of reacting comprises a metathesis reaction. In certain embodiments, the step of reacting comprises a condensation reaction. In certain embodiments, the step of reacting comprises a nucleophilic substitution reaction. In certain embodiments, the step of reacting comprises an addition reaction. In some embodiments, the step of reacting comprises an elimination reaction. In certain embodiments, the step of reacting comprises a substitution reaction. In certain embodiments, the step of reacting comprises a rearrangement reaction. In some embodiments, the step of reacting comprises photochemical reaction. In certain embodiments, the step of reacting comprises redox reaction.

[0414] Also provided herein are methods of synthesizing a compound of the formula:

##STR00142##

or salt thereof, comprising reacting a compound of the formula:

##STR00143##

or a salt thereof, with a compound of Formula (X), or a salt thereof, wherein: one of R.sup.U and R.sup.V is hydrogen, and the other one of R.sup.U and R.sup.V is an oxygen protecting group or —Si(R.sup.S).sub.3; and each R.sup.S is independently hydrogen, halogen, hydroxyl, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 heteroalkyl, substituted or unsubstituted C.sub.2-6 alkenyl, substituted or unsubstituted C.sub.2-6 alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, R.sup.U, R.sup.V, , and n are as defined herein. In some embodiments, R.sup.4 is absent when is a double bond or is R or halogen; and R, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, R.sup.U, R.sup.V, , and n are as defined herein. In certain embodiments, the compound of Formula (X) is of the formula:

##STR00144##

In certain embodiments, R.sup.U is hydrogen, and R.sup.V is —Si(Me).sub.3. In certain embodiments, R.sup.U is hydrogen, and R.sup.U is —Si(Me).sub.3. In certain embodiments, R.sup.U is hydrogen, and R.sup.V is —Si(tBu)(Me).sub.2. In certain embodiments, R.sup.V is hydrogen, and R.sup.U is —Si(tBu)(Me).sub.2. In certain embodiments, a compound of Formula (XII) comprises only one —OH. In some embodiments, a compound of formula (XI) is of the formula:

##STR00145##

[0415] Also provided herein are methods of synthesizing a compound of the formula:

##STR00146##

or salt thereof, comprising reacting a compound of the formula:

##STR00147##

or salt thereof, with tritylhydrodisulfane. In some embodiments, a compound of the formula:

##STR00148##

or stereoisomer or salt thereof, is formed by reacting a compound of the formula:

##STR00149##

with tritylhydrodisulfane. In certain embodiments, each instance of R.sup.S is unsubstituted alkyl (e.g., isopropyl).

[0416] Also provided herein are methods of synthesizing a substituted or unsubstituted dihydroxypiperazinedione, or salt thereof, comprising reacting a substituted or unsubstituted piperazinedione, or salt thereof, with bis(2,2′-bipyridyl)copper(II) permanganate. In certain embodiments, the dihydroxypiperazinedione is a substituted or unsubstituted 3,6-dihydroxypiperazine-2,5-dione. In some embodiments, the piperazinedione is a substituted or unsubstituted piperazine-2,5-dione. In certain embodiments, the dihydroxypiperazinedione is a substituted or unsubstituted 3,6-dihydroxypiperazine-2,5-dione and the piperazinedione is a substituted or unsubstituted piperazine-2,5-dione. In certain embodiments, the piperazinedione is

of the formula:

##STR00150##

or salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, , and n are as defined herein. In some embodiments, the dihydroxypiperazinedione is of the formula

##STR00151##

or salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, , and n are as defined herein. In some embodiments, the piperazinedione is of the formula:

##STR00152##

or salt thereof, and the dihydroxypiperazinedione is of the formula:

##STR00153##

or salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, , and n are as defined herein. In certain embodiments, provided herein are methods of synthesizing a piperazinedione of the formula:

##STR00154##

or salt thereof, by reacting a dihydroxypiperazinedione of the formula:

##STR00155##

or salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.6′, R.sup.7, , and n are as defined herein, with bis(2,2′-bipyridyl)copper(II) permanganate. In some embodiments, the method is useful in the synthesis of ETPs and derivatives thereof. In certain embodiments, a piperazinedione is of the formula:

##STR00156##

In some embodiments, a dihydroxypiperazinedione is of the formula:

##STR00157##

[0417] In some embodiments, the present disclosure recognizes the challenges for preparing ETP or thiodiketopiperazine alkaloids or derivatives or analogs thereof. In some embodiments, the present disclosure provides a method for preparing ETP or thiodiketopiperazine alkaloids or derivatives or analogs thereof. In some embodiments, the present disclosure provides a method for preparing a provided compound. In some embodiments, the present disclosure provides new reagents for preparing ETP or thiodiketopiperazine alkaloids or derivatives or analogs thereof. In some embodiments, the present disclosure provides new reagents for preparing a provided compound. In some embodiments, a provided method and/or reagent provides unexpectedly high synthetic efficiency, for example, in terms of product yield and/or purity.

[0418] In some embodiments, the present disclosure provides methods for flexible and scalable synthesis of ETP or thiodiketopiperazine alkaloids or derivatives or analogs thereof, for example, a provided compound of formula I, II, or V. In some embodiments, the present disclosure provides a method for scalable synthesis, e.g., >5 g, >6 g, >7 g, >8 g, >9 g, >10 g, >11 g, >12 g, >13 g, >14 g, >15 g, >16 g, >17 g, >18 g, >19 g, or >20 g, >15 g or >20 g scale, of an erythro-o-hydroxytryptophan compound, an intermediate useful for the preparation of ETP or thiodiketopiperazine compounds, or derivatives or analogs thereof.

Compositions and Kits

[0419] The present disclosure provides compositions (e.g., pharmaceutical compositions) comprising a compound or conjugate as described herein, and optionally an excipient (e.g., pharmaceutically acceptable excipient). In certain embodiments, the composition is a pharmaceutical composition. In certain embodiments, the excipient is a pharmaceutically acceptable excipient.

[0420] In certain embodiments, the pharmaceutical compositions are useful for delivering an agent (e.g., to a subject or cell). In certain embodiments, the pharmaceutical compositions are useful for treating a disease in a subject in need thereof. In certain embodiments, the pharmaceutical compositions are useful for preventing a disease in a subject. In certain embodiments, the pharmaceutical compositions are useful for diagnosing a disease in a subject.

[0421] In certain embodiments, the compound or conjugate described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing cancer in a subject in need thereof. In some embodiments, the cancer is cervical cancer, lung cancer, breast cancer, colorectal cancer, or prostate cancer. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is characterized by higher extracellular thiol concentrations. In certain embodiments, the effective amount is an amount effective for treating an autoimmune disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an autoimmune disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for generating reactive oxygen species in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for generating reactive oxygen species in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting a protein in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for inhibiting a protein in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a thiol or disulfide in the active site in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a thiol or disulfide in the active site in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a metal (e.g., a metal ion) (e.g., Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, or Mo (e.g., Zn, Fe, or Cu) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a metal (e.g., Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, or Mo (e.g., Zn, Fe, or Cu) in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a Zn.sup.2+ in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for disrupting structures of proteins containing a Zn.sup.2+ in a cell, tissue, or biological sample. In certain embodiments, the effective amount is an amount effective for inducing apoptosis of a cell. In certain embodiments, the effective amount is an amount effective for inducing apoptosis of a cell in a subject. In certain embodiments, the effective amount is an amount effective for inducing apoptosis of a cell in a tissue or biological sample. In certain embodiments, the effective amount is an amount effective for inhibiting proliferation of a cell. In certain embodiments, the effective amount is an amount effective for inhibiting proliferation of a cell in a subject. In certain embodiments, the effective amount is an amount effective for inhibiting proliferation of a cell in a tissue or biological sample. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., proliferative disease, autoimmune disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for diagnosing a disease in a subject in need thereof.

[0422] In certain embodiments, the effective amount is an amount effective for delivering a pharmaceutical agent to a biological sample or cell. In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in vivo. In certain embodiments, the cell is a malignant cell. In some embodiments, the cell is a premalignant cell.

[0423] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound or conjugate described herein (which may include a therapeutic agent (the “active ingredient”)) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0424] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0425] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0426] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the composition.

[0427] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0428] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0429] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan monostearate (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0430] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0431] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0432] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0433] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0434] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0435] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0436] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0437] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip©, methylparaben, Germall© 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0438] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0439] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0440] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0441] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0442] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0443] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0444] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0445] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0446] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0447] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0448] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0449] Dosage forms for topical and/or transdermal administration of a compound or conjugate described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0450] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the polymer in powder form through the outer layers of the skin to the dermis are suitable.

[0451] Formulations suitable for topical administration include liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0452] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0453] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0454] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.

[0455] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0456] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0457] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0458] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0459] Compounds and conjugates provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0460] The compounds, conjugates, and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound, conjugate, or pharmaceutical compositions described herein is suitable for topical administration to the eye of a subject. In some embodiments, provided pharmaceutical formulations of provided compounds or conjugates are typically prepared for parenteral administration, i.e. bolus, intravenous, intratumor injection with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form. In some embodiments, the compounds or conjugates having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the form of a lyophilized formulation or an aqueous solution.

[0461] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0462] A provided pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0463] The exact amount of a compound or conjugate required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound or conjugate, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound or conjugate described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound or conjugate described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound or conjugate described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound or conjugate described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound or conjugate described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound or conjugate described herein.

[0464] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg.

[0465] A compound, conjugate, or composition as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compound, conjugate, or composition can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and/or in diagnosing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound or conjugate described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound or conjugate and the additional pharmaceutical agent, but not both.

[0466] The compound, conjugate, or compositions can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound, conjugate, or composition and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound, conjugate, or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound or conjugate described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0467] The additional pharmaceutical agents include anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, and pain-relieving agents. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation.

[0468] In certain embodiments, the compounds or conjugates described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In certain embodiments, the compounds or conjugates described herein or pharmaceutical compositions can be administered in combination with an additional therapy. In some embodiments, the compounds or conjugates described herein or pharmaceutical compositions can be administered in combination with radiation therapy.

[0469] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition, compound, or conjugate described herein and instructions for use. The kits may further comprise a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition, compound, or conjugate described herein. In some embodiments, the pharmaceutical composition, compound, or conjugate described herein provided in the first container and the second container are combined to form one unit dosage form.

[0470] In some embodiments, the percentage of the conjugate that comprise an agent is between about 1 and about 100% (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%). In some embodiments, the percentage of the conjugate that comprise an agent is less than about 50%, e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, or less than about 10%. In some embodiments, the percentage of the conjugate that comprise an agent is between about 5% and about 50%, about 5% and about 40%, about 5% and about 30%, about 5% and about 25%, or about 5% and about 20%. In some embodiments, the percentage of the conjugate that comprise an agent is between about 5% and 90%. In some embodiments, the percentage of the conjugate that comprise an agent is between about 5% and about 75%. In the some embodiments, the conjugate that comprise an agent is between about 5% and about 50%. In the some embodiments, the percentage of the conjugate that comprise an agent is between about 10% and about 25%.

[0471] In some embodiments, the total amount of the agent present in the conjugate is greater than about 5% (e.g., about 6%, about 7%, about 8%, about 9%, about 10%, about 12%, about 15%, about 20%, about 25%, about 30%, or more) of the total size or weight of the conjugate. In some embodiments, the total amount of the agent present in the conjugate is greater than about 10% (e.g., about 12%, about 15%, about 20%, about 25%, about 30%, or more) of the total size or weight of the conjugate.

[0472] Without being bound by theory, the conjugate disclosed herein may improve the efficiency of an agent by one or more of increasing the localization and/or release (e.g., preferential release) of the agent to a target cell (e.g., a cancer cell), or increasing the half-life of the agent, thus resulting in a significantly higher amount of a released agent at a target site (e.g., a tumor or liver (e.g., cirrhotic cell). According, the conjugates disclosed herein can be more effective therapeutically than the free agent (e.g., due to enhanced drug uptake in the target tissue) and/or allow for a lower therapeutic dose of the agent, e.g., without substantially compromising the resulting drug concentration at a target tissue. In some embodiments, the conjugates disclosed herein can reduce the adverse effect associated with systemic administration of an agent in free form (e.g., not coupled to polymer, conjugate or particle described herein).

[0473] Without being bound by theory, due to the localized delivery of the conjugate or compositions described herein, a lower dose or amount of the agent can be administered (e.g., through local sustained delivery) compared to the agent in free form. In other embodiments, the agent-containing conjugates are administered at a dose or amount of the agent that is less than the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect).

[0474] In some embodiments, the agent is incorporated into a conjugate at a dose that is less than the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., the standard of care dose for the intended use of the free agent. In one embodiment, the agent is incorporated into the conjugate at a dose or amount of the agent that is less than the standard of care dose of the agent for a desired therapy (e.g., a dose that is less than about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, or about 0.95 that of the standard of care dose of the agent).

[0475] In some embodiments, the agent is incorporated into a conjugate at a dose equivalent to the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., the standard of care dose for the intended use of the free agent. In these embodiments, the conjugate produces a greater therapeutic effect and/or a less adverse effect than the free agent. In certain embodiments, the conjugate increases the amount of the agent delivered to a tissue or cell in need thereof and reduces the amount of the agent exposed to a non-target tissue or cell, as compared to the free agent.

[0476] In some embodiments, the agent is incorporated into a conjugate at a dose higher than the dose or amount of said agent in free form to have a desired effect (e.g., a desired therapeutic effect), e.g., the standard of care dose for the intended use of the free agent. In some embodiments, the agent is incorporated into a conjugate at a dose higher than the dose or amount of said agent in free form that would produce an adverse effect by systemic administration (e.g., a reduction in blood pressure). In some embodiments, since the conjugate described herein releases the agent at a target site based on pH microenvironment, other non-target sites (e.g., blood vessels) with different pH would be less likely to be exposed to the agent.

[0477] In another aspect, provided are kits including a first container comprising a compound, conjugate, or pharmaceutical composition described herein. In certain embodiments, the kits are useful for delivering an agent (e.g., to a subject, cell, biological sample,). In certain embodiments, the kits are useful for treating a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein in a subject or cell, tissue, or biological sample. In certain embodiments, the kits are useful for generating a reactive oxygen species in a subject, cell, tissue or biological sample. In certain embodiments, the kits are useful for disrupting structures of proteins in a subject, cell, tissue or biological sample. In certain embodiments, the kits are useful for disrupting structures of proteins containing a Zn.sup.2+ in a subject, cell, tissue or biological sample. In certain embodiments, the kits are useful for inducing apoptosis of a cell, a cell in a subject, or a cell in a tissue or biological sample. In certain embodiments, the kits are useful for inhibiting proliferation of a cell, a cell in a subject, or a cell in a tissue or biological sample.

[0478] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In some embodiments, a kit comprises a compound, conjugate, or composition as described herein and instructions for using the polymer or composition. In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for delivering an agent. In certain embodiments, the kits and instructions provide for treating a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease (e.g., proliferative disease, autoimmune disease, infectious disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein in a subject, cell, tissue, or biological sample. In certain embodiments, the kits are useful for generating a reactive oxygen species in a subject, cell, tissue or biological sample. In certain embodiments, the kits are useful for disrupting structures of proteins containing a Zn.sup.2+ in a subject, cell, tissue or biological sample. In certain embodiments, the kits are useful for inducing apoptosis of a cell, a cell in a subject, or a cell in a tissue or biological sample. In certain embodiments, the kits are useful for inhibiting proliferation of a cell, a cell in a subject, or a cell in a tissue or biological sample. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0479] In some embodiments, the present disclosure provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Methods and Uses

[0480] The compounds and compositions of the present disclosure may be used to treat various diseases or disorders. In certain embodiments, the present disclosure provides methods for treating or preventing a cancer, an autoimmune disease, or infectious disease in a subject in need thereof. In certain embodiments, the present disclosure provides methods for generating reactive oxygen species in a subject in need thereof. In certain embodiments, the present disclosure provides methods for generating reactive oxygen species in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides methods for inhibiting a protein in a subject in need thereof. In certain embodiments, the present disclosure provides methods for inhibiting a protein in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing a thiol or disulfide in the active site in a subject in need thereof. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing a thiol or disulfide in the active site in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing an iron or copper in a subject in need thereof. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing an iron or copper in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing a Zn.sup.2+ in a subject in need thereof. In certain embodiments, the present disclosure provides methods for disrupting structures of proteins containing a Zn.sup.2+ in a cell, tissue, or biological sample. In certain embodiments, the present disclosure provides methods for inducing apoptosis of a cell. In certain embodiments, the present disclosure provides methods for inducing apoptosis of a cell in a subject. In certain embodiments, the present disclosure provides methods for inducing apoptosis of a cell in a tissue or biological sample. In certain embodiments, the present disclosure provides methods for inhibiting proliferation of a cell. In certain embodiments, the present disclosure provides methods for inhibiting proliferation of a cell in a subject. In certain embodiments, the present disclosure provides methods for inhibiting proliferation of a cell in a tissue or biological sample. In certain embodiments, the present disclosure provides methods for reducing the risk of developing a disease (e.g., proliferative disease, autoimmune disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. In certain embodiments, the present disclosure provides methods for preventing a disease in a subject in need thereof. In certain embodiments, the present disclosure provides methods for diagnosing a disease in a subject in need thereof.

[0481] A provided compound or composition of the present disclosure may be used to treat various diseases or disorders, e.g. characterized by the overexpression of an antigen such as a cancer antigen. In some embodiments, the disease is cervical cancer, lung cancer, breast cancer, colorectal cancer, or prostate cancer. Exemplary conditions or hyperproliferative disorders include benign or malignant tumors; leukemia and lymphoid malignancies. Others include neuronal, glial, astrocytal, hypothalamic, glandular, macrophagal, epithelial, stromal, blastocoelic, inflammatory, angiogenic and immunologic, including autoimmune, disorders.

[0482] In some embodiments, the present disclosure provides a method for killing or inhibiting proliferation of cells comprising treating the cells with an amount of a provided compound, or a pharmaceutically acceptable salt thereof, being effective to kill or inhibit proliferation of the cells. In some embodiments, the cells are tumor cells or cancer cells. In some embodiments, the present disclosure provides a method of treating a disease, comprising administering to a subject in need an effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a method of treating a disease, comprising administering to a subject suffering therefrom or susceptible thereto an effective amount of a provided compound or pharmaceutically salt thereof. In some embodiments, a disease is a cancer, autoimmune disease or infectious disease. In some embodiments, a disease is cancer. In some embodiments, a disease is an autoimmune disease. In some embodiments, a disease is an infectious disease. In some embodiments, a provided is a compound of formula I. In some embodiments, a provided is a compound of formula II. In some embodiments, a provided is a compound of formula V.

[0483] A provided compound of the disclosure may be combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second compound having therapeutic properties. A second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to a provided compound of the combination such that they do not adversely affect each other.

[0484] In some embodiments, a second compound is a chemotherapeutic agent, cytotoxic agent, cytokine, growth inhibitory agent, anti-hormonal, a drug for an autoimmune disease, a drug for an infectious disease, and/or cardioprotectant. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0485] A combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

[0486] Suitable dosages for co-administered agents are those presently used and may be lowered due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or treatments.

[0487] A provided combination therapy may provide “synergy” and prove “synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

[0488] In some embodiments, the present disclosure provides methods of treating cancer. In some embodiments, the present disclosure provides a method of treating cancer in a subject suffering therefrom, comprising administering to the subject a therapeutically effective amount of a provided compound. In some embodiments, a provided compound has the structure of formula I. In some embodiments, a provided compound has the structure of formula II. In some embodiments, a provided compound has the structure of formula V.

[0489] Provided compounds and/or compositions are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating cancer in a subject. Provided compounds and compositions can be used in a variety of settings for the treatment of cancers. A provided conjugate compound, e.g., a compound of formula I, can be used to deliver a drug to a tumor cell or cancer cell. Without being bound by theory, in one embodiment, a portion of a conjugate o binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and a provided compound can be taken up inside a tumor cell or cancer cell through receptor-mediated endocytosis. An antigen can be attached to a tumor cell or cancer cell or can be an extracellular matrix protein associated with the tumor cell or cancer cell. In some embodiments, once inside the cell, a conjugate compound is cleaved, for example, one or more specific peptide sequences within a linker unit are hydrolytically cleaved by one or more tumor-cell or cancer-cell-associated proteases, resulting in release of a drug comprising part or all of the drug unit and optionally part or all of the linker unit. A released drug is then free to migrate within the cell and induce cytotoxic or cytostatic activities. In some other embodiments, a provided conjugate compound is cleaved outside a tumor cell or cancer cell, and a drug or drug-linker compound subsequently penetrates the cell.

[0490] In some embodiments, a portion of a conjugate binds to a tumor cell or cancer cell. In some embodiments, a portion of a conjugate binds to a tumor cell or cancer cell antigen which is on the surface of the tumor cell or cancer cell. In some embodiments, a portion of a conjugate binds to a tumor cell or cancer cell antigen which is an extracellular matrix protein associated with a tumor cell or cancer cell. In some embodiments, the specificity of a portion of a conjugate for a particular tumor cell or cancer cell can be important for determining those tumors or cancers that are most effectively treated. For example, a provided conjugate compound having a BR96 Ligand unit can be useful for treating antigen positive carcinomas including those of the lung, breast, colon, ovaries, and pancreas. In some embodiments, a provided conjugate compound having an Anti-CD30 or an anti-CD40 Ligand unit can be useful for treating hematologic malignancies.

[0491] In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In certain embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated as being within the scope of the disclosure.

[0492] In some embodiments, the compounds and conjugates described herein, or a pharmaceutical composition thereof are useful for treating a cancer including, but not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewing sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenström's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM), a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva).

[0493] Other particular types of cancers that can be treated with provided compounds and/or compositions include, but are not limited to, those listed below: Solid tumors, including but not limited to: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophogeal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma ultiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, emangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma. Blood-borne cancers, including but not limited to: acute lymphoblastic leukemia “ALL”, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia AML”, acute promyelocytic leukemia “APL”, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia “CML”, chronic lymphocytic leukemia “CLL”, hairy cell leukemia, multiple myeloma, acute and chronic leukemias, lymphoblastic, myelogenous, lymphocytic and myelocytic leukemias. Lymphomas, Hodgkin's disease, non-Hodgkin's Lymphoma, Multiple myeloma, Waldenström's macroglobulinemia, Heavy chain disease, and Polycythemia vera.

[0494] In some embodiments, the cancer is cervical cancer, lung cancer, breast cancer, colorectal cancer, or prostate cancer. In some embodiments, the cancer is leukemia or lymphoma. In some embodiments, the cancer is cervical cancer, lung cancer, breast cancer, colorectal cancer, prostate cancer, leukemia, or lymphoma.

[0495] In some embodiments, the cancer is leukemia. In certain embodiments, the cancer is chronic myelogenous leukemia (CML) (also known as chronic myeloid leukemia). In certain embodiments, the cancer is acute T cell leukemia.

[0496] In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is non-Hodgkin's lymphoma. In certain embodiments, the cancer is non-Hodgkin's B cell lymphoma. In some embodiments, the cancer is diffuse large cell lymphoma.

[0497] In some embodiments, a cancer being treated is carcinoma, lymphoma, blastoma, sarcoma, leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.

[0498] In some embodiments, a provided conjugate compound provides conjugation-specific tumor or cancer targeting, thus reducing general toxicity of these compounds. In some embodiments, a linker unit stabilizes a provided compound in blood, yet are cleavable by tumor-specific proteases within the cell, liberating a drug unit optionally comprising part of the linker unit.

[0499] Cancers, including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by uncontrolled cell growth, can be treated or prevented by administration of a provided compound or composition. In some embodiments, a provided compound or composition is administered with another cancer treatment. In some embodiments, the other cancer treatment (e.g., an anti-cancer agent) is an agent including, but not limited to, abiraterone acetate, ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine, afatinib dimaleate, aldesleukin, alemtuzumab, anastrozole, arsenic trioxide, asparaginase Erwinia chrysanthemi, axitinib, azacitidine, BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab, bicalutamide, bleomycin, blinatumomab, bortezomib, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-s-malate, CAF, capecitabine, CAPOX, carboplatin, carboplatin-taxol, carfilzomibcarmustine, carmustine implant, ceritinib, cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, clofarabine, CMF, COPP, COPP-ABV, crizotinib, CVP, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dactinomycin, dasatinib, daunorubicin hydrochloride, decitabine, degarelix, denileukin diftitox, denosumab, Dinutuximab, docetaxel, doxorubicin hydrochloride, doxorubicin hydrochloride liposome, enzalutamide, epirubicin hydrochloride, EPOCH, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane, FEC, fludarabine phosphate, fluorouracil, FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV, fulvestrant, gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, goserelin acetate, Hyper-CVAD, ibritumomab tiuxetan, ibrutinib, ICE, idelalisib, ifosfamide, imatinib mesylate, imiquimod, ipilimumab, irinotecan hydrochloride, ixabepilone, lanreotide acetate, lapatinib ditosylate, lenalidomide, lenvatinib, letrozole, leucovorin calcium, leuprolide acetate, liposomal cytarabine, lomustine, mechlorethamine hydrochloride, megestrol acetate, mercaptopurine, methotrexate, mitomycin c, mitoxantrone hydrochloride, MOPP, nelarabine, nilotinib, nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, OPPA, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, PAD, palbociclib, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegaspargase, peginterferon alfa-2b, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pertuzumab, plerixafor, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride, radium 223 dichloride, raloxifene hydrochloride, ramucirumab, R-CHOP, recombinant HPV bivalent vaccine, recombinant human papillomavirus, nonavalent vaccine, recombinant human papillomavirus, quadrivalent vaccine, recombinant interferon alfa-2b, regorafenib, rituximab, romidepsin, ruxolitinib phosphate, siltuximab, sipuleucel-t, sorafenib tosylate, STANFORD V, sunitinib malate, TAC, tamoxifen citrate, temozolomide, temsirolimus, thalidomide, thiotepa, topotecan hydrochloride, toremifene, tositumomab and iodine I 131, tositumomab, TPF, trametinib, trastuzumab, VAMP, vandetanib, VEIP, vemurafenib, vinblastine sulfate, vincristine sulfate, vincristine sulfate liposome, vinorelbine tartrate, vismodegib, vorinostat, XELIRI, XELOX, ziv-aflibercept, and zoledronic acid. Anti-cancer agents encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca.sup.2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS—354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TK1258, CHIR-258), BIBW 2992 (TOVOK™) SGX523, PF-04217903, PF-02341066, PF-299804, BMS—777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS—690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.

[0500] In some embodiments, methods for treating or preventing cancer are provided, comprising administering to a subject in need thereof an effective amount of a provided compound or composition. In some embodiments, a provided compound is administered prior to, concurrently with, or subsequent to, a chemotherapeutic agent. In some embodiments, a chemotherapeutic agent is that with which treatment of the cancer has not been found to be refractory. In some embodiments, a chemotherapeutic agent is that with which the treatment of cancer has been found to be refractory. In some embodiments, a provided compound is administered to a patient that has also undergone surgery as treatment for the cancer.

[0501] In some embodiments, an additional method of treatment is radiation therapy. In some embodiments, a provided compound or composition is administered prior to, concurrently with or subsequent to radiation.

[0502] In some embodiments, a provided compound or composition is administered concurrently with a chemotherapeutic agent or with radiation therapy. In some embodiments, a chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a provided compound or composition. In some embodiments, a chemotherapeutic agent or radiation therapy is administered concurrently with administration of a provided compound or composition. In some embodiments, a provided compound or composition is administered at least one hour, five hours, 12 hours, a day, a week, a month, or several months (e.g., up to three months), prior or subsequent to administration of a provided compound or composition.

[0503] A chemotherapeutic agent can be administered over a series of sessions. Any one or a combination of the chemotherapeutic agents can be administered.

[0504] Exemplary chemotherapy drugs are widely known in the art, including but not limited to tubulin-binding drugs, kinase inhibitors, alkylating agents, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, hormonal therapies, retinoids/deltoids, photodynamic therapies, cytokines, angiogenesis inhibitors, histone modifying enzyme inhibitors, and antimitotic agents. Examples are extensively described in the art, including but not limited to those in PCT Application Publication No. WO2010/025272. In some embodiments, a “tubulin-binding drug” refers to a ligand of tubulin or to a compound capable of binding α or β-tubulin monomers or oligomers thereof, αβ-tubulin heterodimers or oligomers thereof, or polymerized microtubules. Exemplary tubulin-binding drugs include, but are not limited to: (a) Combretastatins or other stilbene analogs (e.g., described in Pettit et al, Can. J. Chern., 1982; Pettit et al, J. Org. Chern., 1985; Pettit et al, J. Nat. Prod., 1987; Lin et al, Biochemistry, 1989; Singh et al, J. Org. Chern., 1989; Cushman et al, J. Med. Chern., 1991; Getahun et al, J. Med. Chern., 1992; Andres et al, Bioorg. Med. Chern. Lett., 1993; Mannila, Liebigs. Ann. Chern., 1993; Shirai et al, Bioorg. Med. Chern. Lett., 1994; Medarde et al., Bioorg. Med. Chern. Lett., 1995; Pettit et al, J. Med. Chern., 1995; Wood et al, Br. J. Cancer., 1995; Bedford et al, Bioorg. Med. Chern. Lett., 1996; Dorr et al, Invest. New Drugs, 1996; Jonnalagadda et al., Bioorg. Med. Chern. Lett., 1996; Shirai et al, Heterocycles, 1997; Aleksandrzak K, Anticancer Drugs, 1998; Chen et al, Biochem. Pharmacal., 1998; Ducki et al, Bioorg. Med. Chern. Lett., 1998; Hatanaka et al, Bioorg. Med. Chern. Lett., 1998; Medarde, Eur. J. Med. Chern., 1998; Medina et al, Bioorg. Med. Chern. Lett., 1998; Ohsumi et al, Bioorg. Med. Chern. Lett., 1998; Ohsumi et al., J. Med. Chern., 1998; Pettit G R et al., J. Med. Chern., 1998; Shirai et al, Bioorg. Med. Chern. Lett., 1998; Banwell et al, Aust. J. Chern., 1999; Medarde et al, Bioorg. Med. Chern. Lett., 1999; Shan et al, PNAS, 1999; Combeau et al, Mol. Pharmacal, 2000; Pettit et al, J. Med Chern, 2000; Pettit et al, Anticancer Drug Design, 2000; Pinney et al, Bioorg. Med. Chern. Lett., 2000; Flynn et al., Bioorg. Med. Chern. Lett., 2001; Gwaltney et al, Bioorg. Med. Chern. Lett., 2001; Lawrence et al, 2001; Nguyen-Hai et al, Bioorg. Med. Chern. Lett., 2001; Xia et al, J. Med. Chern., 2001; Tahir et al., Cancer Res., 2001; Wu-Wong et al., Cancer Res., 2001; Janik et al, Biooorg. Med. Chern. Lett., 2002; Kim et al., Bioorg Med Chern Lett., 2002; Li et al, Biooorg. Med. Chern. Lett., 2002; Nam et al, Bioorg. Med. Chern. Lett., 2002; Wang et al, J. Med. Chern. 2002; Hsieh et al, Biooorg. Med. Chern. Lett., 2003; Hadimani et al., Bioorg. Med. Chern. Lett., 2003; Mu et al, J. Med. Chern, 2003; Nam, Curr. Med. Chern., 2003; Pettit et al, J. Med. Chern., 2003; WO 02/50007, WO 02/22626, WO 02/14329, WO 01/81355, WO 01/12579, WO 01/09103, WO 01/81288, WO 01/84929, WO 00/48591, WO 00/48590, WO 00/73264, WO 00/06556, WO 00/35865, WO 00/48590, WO 99/51246, WO 99/34788, WO 99/35150, WO 99/48495, WO 92/16486, U.S. Pat. Nos. 6,433,012, 6,201,001, 6,150,407, 6,169,104, 5,731,353, 5,674,906, 5,569,786, 5,561,122, 5,430,062, 5,409,953, 5,525,632, 4,996,237 and 4,940,726 and U.S. patent application Ser. No. 10/281,528); (b) 2,3-substituted Benzo[b]thiophenes (e.g., described in Pinney et al, Bioorg. Med. Chern. Lett., 1999; Chen et al, J. Org. Chern., 2000; U.S. Pat. Nos. 5,886,025; 6,162,930, and 6,350,777; WO 98/39323); (c) 2,3-disubstituted Benzo[b]furans (e.g., described in WO 98/39323, WO 02/060872); (d) Disubstituted Indoles (e.g., described in Gastpar R, J. Med. Chern., 1998; Bacher et al, Cancer Res., 2001; Flynn et al, Bioorg. Med. Chern. Lett, 2001; WO 99/51224, WO 01/19794, WO 01/92224, WO 01/22954; WO 02/060872, WO 02/12228, WO 02/22576, and U.S. Pat. No. 6,232,327); (e) 2-Aroylindoles (e.g., described in Mahboobi et al, J. Med. Chern., 2001; Gastpar et al., J. Med. Chern., 1998; WO 01/82909); (f) 2,3-disubstituted Dihydronaphthalenes (e.g., described in WO 01/68654, WO 02/060872); (g) Benzamidazoles (e.g., described in WO 00/41669); (h) Chalcones (e.g., described in Lawrence et al, Anti-Cancer Drug Des, 2000; WO 02/47604); (i) Colchicine, Allocolchicine, Thiocolcichine, Halichondrin B, and Colchicine derivatives (e.g., described in WO 99/02166, WO 00/40529, WO 02/04434, WO 02/08213, U.S. Pat. Nos. 5,423,753, 6,423,753) in particular the N-acetyl colchinol prodrug, ZD-6126; (j) Curacin A and its derivatives (e.g., described in Gerwick et al, J. Org. Chern., 1994, Blokhin et al, Mol. Phamacol., 1995; Verdier-Pinard, Arch. Biochem. Biophys., 1999; WO 02/06267); (k) Dolastatins such as Dolastatin-10, Dolastatin-15, and their analogs (e.g., described in Pettit et al, J. Am. Chern. Soc., 1987; Bai et al, Mol. Pharmacal, 1995; Pettit et al, Anti-Cancer Drug Des., 1998; Poncet, Curr. Pharm. Design, 1999; WO 99/35164; WO 01/40268; U.S. Pat. No. 5,985,837); (1) Epothilones such as Epothilones A, B, C, D, and Desoxyepothilones A and B, Fludelone (e.g., described in Chou et al. Cancer Res. 65:9445-9454, 2005, the entirety of which is hereby incorporated by reference), 9,10-dehydro-desoxyepothilone B (dehydelone), iso-oxazole-dehydelone (17-isooxazole-dehydelone), fludelone, iso-oxazolefludelone (17-isooxazole-fludelone), (Danishefsky, et al., PNAS, v. 105, 35:13157-62, 2008; WO 99/02514, U.S. Pat. No. 6,262,094, Nicolau et al., Nature, 1997, Pub. No. US2005/0143429); (m) Inadones (e.g., described in Leoni et al., J. Natl. Cancer Inst., 2000; U.S. Pat. No. 6,162,810); (n) Lavendustin A and its derivatives (Mu F et al, J. Med. Chern., 2003, the entirety of which is hereby incorporated by reference); (o) 2-Methoxyestradiol and its derivatives (e.g., described in Fotsis et al, Nature, 1994; Schumacher et al, Clin. Cancer Res., 1999; Cushman et al, J. Med. Chern., 1997; Verdier-Pinard et al, Mol. Pharmacal, 2000; Wang et al, J. Med. Chern., 2000; WO 95/04535, WO 01/30803, WO 00/26229, WO 02/42319 and U.S. Pat. Nos. 6,528,676, 6,271,220, 5,892,069, 5,661,143, and 5,504,074); (p) Monotetrahydrofurans (e.g., “COBRAs”; Uckun, Bioorg. Med. Chern. Lett., 2000; U.S. Pat. No. 6,329,420); (q) Phenylhistin and its derivatives (e.g., described in Kanoh et al, J. Antibiot., 1999; Kano et al, Bioorg. Med. Chern., 1999 and U.S. Pat. No. 6,358,957); (r) Podophyllotoxins such as Epidophyllotoxin (e.g., described in Hammonds et al, J. Med. Microbial, 1996; Coretese et al, J. Biol. Chem., 1977); (s) Rhizoxins (e.g., described in Nakada et al, Tetrahedron Lett., 1993; Boger et al, J. Org. Chern., 1992; Rao, et al, Tetrahedron Lett., 1992; Kobayashi et al, Pure Appl. Chern., 1992; Kobayashi et al, Indian J. Chern., 1993; Rao et al, Tetrahedron Lett., 1993); (t) 2-strylquinazolin-4(3H)-ones (e.g., “SQOs”, Jiang et al, J. Med. Chern., 1990, the entirety of which is hereby incorporated by reference); (u) Spongistatin and Synthetic spiroketal pyrans (e.g., “SPIKETs”; Pettit et al, J. Org. Chern., 1993; Uckun et al, Bioorgn. Med. Chern. Lett., 2000; U.S. Pat. No. 6,335,364, WO00/00514); (v) Taxanes such as Paclitaxel (TAXOL®), Docetaxel (TAXOTERE®), and Paclitaxel derivatives (e.g., described in U.S. Pat. No. 5,646,176, WIPO Publication No. WO 94/14787, Kingston, J. Nat. Prod., 1990; Schiff et al, Nature, 1979; Swindell et al, J. Cell Biol., 1981); (x) Vinca Alkaloids such as Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine (NAVELBINE®) (e.g., described in Owellen et al, Cancer Res., 1976; Lavielle et al, J. Med. Chern., 1991; Holwell et al, Br. J. Cancer., 2001); and (y) Welwistatin (e.g., described in Zhang et al, Molecular Pharmacology, 1996, the entirety of which is hereby incorporated by reference).

[0505] Exemplary specific examples of tubulin-binding drugs include, but are not limited to, allocolchicine, amphethinile, chelidonine, colchicide, colchicine, combrestatin A1, combretastin A4, combretastain A4 phosphate, combrestatin 3, combrestatin 4, cryptophycin, curacin A, deo-dolastatin 10, desoxyepothilone A, desoxyepothilone B, dihydroxypentamethoxyflananone, docetaxel, dolastatin 10, dolastatin 15, epidophyllotoxin, epothilone A, epothilone B, epothilone C, epothilone D, etoposide, 9,10-dehydro-desoxyepothilone B (dehydelone), iso-oxazole-dehydelone (17-isooxazole-dehydelone), fludelone, iso-oxazolefludelone (17-isooxazole-fludelone), griseofulvin, halichondrin B, isocolchicine, lavendustin A, methyl-3,5-diiodo-4-(4′-methoxyphenoxy)benzoate, N-acetylcolchinol, N-acetylcolchinol-O-phosphate, N—[2-[(4-hydroxyphenyl)amino]-3-pyridyl]-4-methoxybenzenesulfonamide, nocodazole, paclitaxel, phenstatin, phenylhistin, piceid, podophyllotoxin, resveratrol, rhizoxin, sanguinarine, spongistatin 1, steganacin, TAXOL, teniposide, thiocolchicine, vincristine, vinblastine, welwistatin, (Z)-2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl] phenylamine, (Z)-3,5,4′-trimethoxystilbene (R.sup.3), 2-aryl-1,8-naphthyridin-4(1H)-one, 2-(41-methoxyphenyl)-3-(3 1,4 1,5 1-rimethoxybenzoyl)-6-methoxybenzo[b]thiophene, 2-methoxy estradiol, 2-strylquinazolin-4(3H)-one, 5,6-dihydroindolo(2, 1-a)isoquinoline, and 10-deacetylbaccatin III.

[0506] In some other embodiments, exemplary chemotherapy drugs include but are not limited to nitrogen mustards, nitrosoureas, alkylsulphonates, triazenes, platinum complexes, epipodophyllins, mitomycins, DHFR inhibitors, IMP dehydrogenase inhibitors, ribonucleotide reductase inhibitors, uracil analogs, cytosine analogs, purine analogs, receptor antagonists (for example, anti-estrogen, LHRH agonists, anti-androgens), vitamin derivative or analogs, isoprenylation inhibitors, dopaminergic neurotoxins, cell cycle inhibitors, actinomycins, bleomycins, anthracyclines, MDR inhibitors, Ca.sup.2+ ATPase inhibitors, and anti-metastatis agents. In some embodiments, exemplary specific examples of tubulin-binding drugs include, but are not limited to, Cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Carmustine, Lomustine, Busulfan, Treosulfan, Dacarbazine, Procarbazine, Temozolomide, Cisplatin, Carboplatin, Aroplatin, Oxaliplatin, Topotecan, Irinotecan, 9-aminocamptothecin, Camptothecin, Crisnatol, Mitomycin C, Methotrexate, Trimetrexate, Mycophenolic acid, Tiazofurin, Ribavirin, 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), Hydroxyurea, Deferoxamine, 5-Fluorouracil, Fluoxuridine, Doxifluridine, Ralitrexed, Cytarabine, Cytosine arabinoside, Fludarabine, Gemcitabine, Capecitabine, Mercaptopurine, Thioguanine, O—6-benzylguanine, 3-HP, 2′-deoxy-5-fluorouridine, 5-HP, alpha-TGDR, aphidicolin glycinate, ara-C, 5-aza-2′-deoxycytidine, beta-TGDR, cyclocytidine, guanazole, inosine glycodialdehyde, macebecin II, Pyrazoloimidazole, Tamoxifen, Raloxifene, Megestrol, Goserelin, Leuprolide acetate, Flutamide, Bicalutamide, Cis-retinoic acid, All-trans retinoic acid (ATRA-IV), EB 1089, CB 1093, KH 1060, Vertoporfin, Phthalocyanine, Photosensitizer Pc4, Demethoxy-hypocrellin A, ABT-627, Bay 12-9566, Benefin, BMS—275291, cartilage-derived inhibitor, CAI, CEP-7055, Col 3, Halofuginone, Heparin hexasaccharide fragment, IM-862, Marimastat, Metalloproteinase inhibitors, 2-Methoxyestra diol, MMI 270, Neovastat, NM-3, Panzem, PI-88, Placental ribonuclease inhibitor, Plasminogen activator inhibitor, Prinomastat, Retinoids, Solimastat, Squalamine, SS 3304, SU 5416, SU 6668, SU 11248, Tetrahydrocortisol-S, Tetrathiomolybdate, Thalidomide, TNP-470, ZD 6126, ZD 6474, farnesyl transferase inhibitors, Bisphosphonates, trityl cysteine, 1-methyl-4-phenylpyridinium ion, Staurosporine, Actinomycin D, Dactinomycin, Bleomycin A2, Bleomycin B2, Peplomycin, Daunorubicin, Doxorubicin, Idarubicin, Epirubicin, Pirarubicin, Zorubicin, Mitoxantrone, Verapamil, Ardeemin, Ningalin, Thapsigargin, Metastatin, GLiY-SD-ME-1, Sorafenib, Imatinib, Gefinitib, Lapatinib, Dasatinib, Nilotinib, Temsirolimus, Erlotinib, Pomalidomide, Regorafenib, Paclitaxel Protein-Bound Particles For Injectable Suspension, Everolimus, Bosutinib, Cabozantinib, Cabozantinib, Ponatinib, Axitinib, Carfilzomib, Ingenol Mebutate, Regorafenib, Fentanyl, Omacetaxine Mepesuccinate, Cephalotaxine, Pazopanib, Enzalutamide, Fentanyl Citrate, Sunitinib, Vandetanib, Crizotinib, Vemurafenib, Abiraterone Acetate, Eribulin Mesylate, Cabazitaxel, Ondansetron, Pralatrexate, Romidepsin, Plerixafor, Granisetron, Bendamustine Hydrochloride, Raloxifene Hydrochloride, Topotecan, Ixabepilone, Nilotinib, Temsirolimus, Lapatinib, Nelarabine, Sorafenib, Clofarabine, Cinacalcet, Erlotinib, Palonosetron, Tositumomab, Aprepitant, Gefitinib, Abarelix, Conjugated Estrogens, Alfuzosin, Bortezomib, Leucovorin, Fulvestrant, Ibritumomab Tiuxetan, Zoledronic Acid, Triptorelin Pamoate, Arsenic Trioxide, Aromasin, Busulfan, Amifostine, Temozolomide, Odansetron, Dolasetron, Irinotecan, Gemcitabine, Porfimer Sodium, Valrubicin, Capecitabine, Zofran, Bromfenac, Letrozole, Leuprolide, Samarium (.sup.153 sm) Lexidronam, Pamidronate, Anastrozole, Levoleucovorin, Flutamide And Goserelin.

[0507] In some embodiments, a provided compound or composition is administered prior to, concurrently with or subsequent to a polypeptide or protein. In some embodiments, a polypeptide or protein is a recombinant polypeptide or protein. Exemplary polypeptides or proteins include but are not limited to cytokines, interferon alfa-2b, interleukin 2, filgrastim, rasburicase, secretin, asparaginase Erwinia chrysanthemi, and ziv-aflibercept. In some embodiments, a polypeptide or protein comprises an antibody or a fragment of an antibody. In some embodiments, a polypeptide or protein is an antibody or a fragment of an antibody. Examples include but are not limited to rituximab, trastuzumab, tositumomab, alemtuzumab, bevacizumab, cetuximab, panitumumab, ofatumumab, denosumab, ipilimumab, pertuzumab. In some embodiments, a polypeptide or protein is chemically modified. In some embodiments, a polypeptide or protein is conjugated to a drug. In some embodiments, an antibody or an antibody fragment is conjugated to a payload drug, forming an antibody-drug conjugate. In some embodiments, a payload drug is cytotoxic. Exemplary antibody-drug conjugates include but are not limited to gemtuzumab ozogamicin, brentuximab vedotin, and ado-trastuzumab emtansine. In some embodiments, a cancer treatment comprises the use of a vaccine. Exemplary vaccines for cancer treatment are well known in the art, for example but not limited to sipuleucel-T.

[0508] A provided compound may be combined with an anti-hormonal compound; e.g., an anti-estrogen compound such as tamoxifen; an anti-progesterone such as onapristone (EP 616812); or an anti-androgen such as flutamide, in dosages known for such molecules. Where the cancer to be treated is hormone independent cancer, the patient may previously have been subjected to anti-hormonal therapy and, after the cancer becomes hormone independent, a provided compound (and optionally other agents as described herein) may be administered to the patient. In some embodiments, it may be beneficial to also co-administer a cardioprotectant (to prevent or reduce myocardial dysfunction associated with the therapy) or one or more cytokines to the patient. In addition to the above therapeutic regimes, the patient may be subjected to surgical removal of cancer cells and/or radiation therapy.

[0509] With respect to radiation, any radiation therapy protocol can be used depending upon the type of cancer to be treated. For example, but not by way of limitation, X-ray radiation can be administered; in some embodiments, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers. Gamma-ray emitting radioisotopes, such as radioactive isotopes of radium, cobalt and other elements, can also be administered.

[0510] In some embodiments, methods of treatment of cancer with a provided compound or composition are provided as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for a subject being treated. A subject being treated can, optionally, be treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable.

[0511] In some embodiments, a provided compound or composition can be used in an in vitro or ex vivo fashion, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas. In some embodiments, such a treatment involves autologous stem cell transplants. In some embodiments, this can involve a multi-step process in which a subject's autologous hematopoietic stem cells are harvested and purged of all cancer cells, a subject's remaining bone-marrow cell population is then eradicated via the administration of a high dose of a provided compound or composition with or without accompanying high dose radiation therapy, and the stem cell graft is infused back into the animal. Supportive care is then provided while bone marrow function is restored and a subject recovers.

[0512] In some embodiments, the present disclosure provides methods for treating an autoimmune disease, comprising administering to a subject suffering therefrom or susceptible thereto an effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, a subject is suffering from an autoimmune disease. In some embodiments, a provided compound is useful for killing or inhibiting replication of a cell that produces an autoimmune disease or for treating an autoimmune disease. A provided compound or composition can be used in a variety of settings for the treatment of an autoimmune disease in a patient. A provided compound can be used to deliver a drug to a target cell. Without being bound by theory, in some embodiments, a provided conjugate compound associates with an antigen on the surface of a target cell, and a provided conjugate compound is then taken up inside a target-cell through receptor-mediated endocytosis. Once inside the cell, a provided conjugate compound can be cleaved. In some embodiments, one or more specific peptide sequences within the linker unit are enzymatically or hydrolytically cleaved, resulting in release of a drug comprising all or part of the drug unit and optionally part or all of the linker unit. A released drug is then free to migrate in the cytosol and induce cytotoxic or cytostatic activities. In an alternative embodiment, a conjugate compound is cleaved and a drug is released outside the target cell, and the drug subsequently penetrates the cell.

[0513] In some embodiments, a ligand unit binds to an autoimmune antigen. In some embodiments, an antigen is on the surface of a cell involved in an autoimmune condition. In some embodiments, a ligand unit binds to an autoimmune antigen which is on the surface of a cell. In some embodiments, a ligand binds to activated lymphocytes that are associated with the autoimmune disease state. In some embodiments, a provided compound kills or inhibits the multiplication of cells that produce an autoimmune antibody associated with a particular autoimmune disease.

[0514] Exemplary types of autoimmune diseases that can be treated with provided compounds or compositions include, but are not limited to, Th2 lymphocyte related disorders (e.g., atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, and graft versus host disease); Th1 lymphocyte-related disorders (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, and tuberculosis); activated B lymphocyte-related disorders (e.g., systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type I diabetes); and those selected from the group consisting of: Active Chronic Hepatitis, Addison's Disease, Allergic Alveolitis, Allergic Reaction, Allergic Rhinitis, Alport's Syndrome, Anaphlaxis, Ankylosing Spondylitis, Anti-phosholipid Syndrome, Arthritis, Ascariasis, Aspergillosis, Atopic Allergy, Atropic Dermatitis, Atropic Rhinitis, Behcet's Disease, Bird-Fancier's Lung, Bronchial Asthma, Caplan's Syndrome, Cardiomyopathy, Celiac Disease, Chagas' Disease, Chronic Glomerulonephritis, Cogan's Syndrome, Cold Agglutinin Disease, Congenital Rubella Infection, CREST Syndrome, Crohn's Disease, Cryoglobulinemia, Cushing's Syndrome, Dermatomyositis, Discoid Lupus, Dressler's Syndrome, Eaton-Lambert Syndrome, Echovirus Infection, Encephalomyelitis, Endocrine opthalmopathy, Epstein-Barr Virus Infection, Equine Heaves, Erythematosis, Evan's Syndrome, Felty's Syndrome, Fibromyalgia, Fuch's Cyclitis, Gastric Atrophy, Gastrointestinal Allergy, Giant Cell Arteritis, Glomerulonephritis, Goodpasture's Syndrome, Graft v. Host Disease, Graves' Disease, Guillain-Barre Disease, Hashimoto's Thyroiditis, Hemolytic Anemia, Henoch-Schonlein Purpura, Idiopathic Adrenal Atrophy, Idiopathic Pulmonary Fibritis, IgA Nephropathy, Inflammatory Bowel Diseases, Insulin-dependent Diabetes Mellitus, Juvenile Arthritis, Juvenile Diabetes Mellitus (Type I), Lambert-Eaton Syndrome, Laminitis, Lichen Planus, Lupoid Hepatitis, Lupus, Lymphopenia, Meniere's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pernicious Anemia, Polyglandular Syndromes, Presenile Dementia, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Psoriatic Arthritis, Raynauds Phenomenon, Recurrent Abortion, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sampter's Syndrome, Schistosomiasis, Schmidt's Syndrome, Scleroderma, Shulman's Syndrome, Sjorgen's Syndrome, Stiff-Man Syndrome, Sympathetic Ophthalmia, Systemic Lupus Erythematosis, Takayasu's Arteritis, Temporal Arteritis, Thyroiditis, Thrombocytopenia, Thyrotoxicosis, Toxic Epidermal Necrolysis, Type B Insulin Resistance, Type I Diabetes Mellitus, Ulcerative Colitis, Uveitis, Vitiligo, Waldenstrom's Macroglobulemia, and Wegener's Granulomatosis.

[0515] In some embodiments, an autoimmune disease being treated is selected from rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjagren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), osteoarthritis, autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis), autoimmune neurological disorders (such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and autoimmune polyneuropathies), renal disorders (such as, for example, glomerulonephritis, Goodpasture's syndrome, and Berger's disease), autoimmune dermatologic disorders (such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus), hematologic disorders (such as, for example, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases (such as, for example, inner ear disease andhearing loss), Behcet's disease, Raynaud's syndrome, organ transplant, and autoimmune endocrine disorders (such as, for example, diabetic-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, andautoimmune thyroid disease (e.g., Graves' disease and thyroiditis)). More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjagren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.

[0516] In some embodiments, the present disclosure provides methods for treating an autoimmune disease, comprising administering to a subject suffering therefrom an effective amount of a provided compound or composition. In some embodiments, a provided method comprises administering an effective amount of a provided compound or composition and another therapeutic agent known for treatment of an autoimmune disease. Exemplary therapeutic agents are widely known in the art, including but not limited to cyclosporine, cyclosporine A, mycophenylate mofetil, sirolimus, tacrolimus, enanercept, prednisone, azathioprine, methotrexate cyclophosphamide, prednisone, aminocaproic acid, chloroquine, hydroxychloroquine, hydrocortisone, dexamethasone, chlorambucil, DHEA, danazol, bromocriptine, meloxicam and infliximab.

[0517] In some embodiments, the present disclosure provides methods for treating an infectious disease, comprising administering to a subject suffering therefrom or susceptible thereto an effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, a provided compound or composition is useful for killing or inhibiting the multiplication of a cell that produces an infectious disease or for treating an infectious disease. A provided compound can be used in a variety of settings for the treatment of an infectious disease in a subject. In some embodiments, a provided conjugate compound is used to deliver a drug to a target cell. In one embodiment, a ligand unit binds to the infectious disease cell. In one embodiment, a provided compound kills or inhibits the multiplication of cells that produce a particular infectious disease.

[0518] Exemplary types of infectious diseases that can be treated with a provided compound include, but are not limited to: Bacterial Diseases such as Diphtheria, Pertussis, Occult Bacteremia, Urinary Tract Infection, Gastroenteritis, Cellulitis, Epiglottitis, Tracheitis, Adenoid Hypertrophy, Retropharyngeal Abcess, Impetigo, Ecthyma, Pneumonia, Endocarditis, Septic Arthritis, Pneumococcal, Peritonitis, Bactermia, Meningitis, Acute Purulent Meningitis, Urethritis, Cervicitis, Proctitis, Pharyngitis, Salpingitis, Epididymitis, Gonorrhea, Syphilis, Listeriosis, Anthrax, Nocardiosis, Salmonella, Typhoid Fever, Dysentery, Conjunctivitis, Sinusitis, Brucellosis, Tullaremia, Cholera, Bubonic Plague, Tetanus, Necrotizing Enteritis, Actinomycosis, Mixed Anaerobic Infections, Syphilis, Relapsing Fever, Leptospirosis, Lyme Disease, Rat Bite Fever, Tuberculosis, Lymphadenitis, Leprosy, Chlamydia, Chlamydial Pneumonia, Trachoma and Inclusion Conjunctivitis; Systemic Fungal Diseases such as Histoplamosis, Coccidiodomycosis, Blastomycosis, Sporotrichosis, Cryptococcsis, Systemic Candidiasis, Aspergillosis, Mucormycosis, Mycetoma and Chromomycosis; Rickettsial Diseases such as Typhus, Rocky Mountain Spotted Fever, Ehrlichiosis, Eastern Tick-Borne Rickettsioses, Rickettsialpox, Q Fever and Bartonellosis; Parasitic Diseases such as Malaria, Babesiosis, African Sleeping Sickness, Chagas' Disease, Leishmaniasis, Dum-Dum Fever, Toxoplasmosis, Meningoencephalitis, Keratitis, Entamebiasis, Giardiasis, Cryptosporidiasis, Isosporiasis, Cyclosporiasis, Microsporidiosis, Ascariasis, Whipworm Infection, Hookworm Infection, Threadworm Infection, Ocular Larva Migrans, Trichinosis, Guinea Worm Disease, Lymphatic Filariasis, Loiasis, River Blindness, Canine Heartworm Infection, Schistosomiasis, Swimmer's Itch, Oriental Lung Fluke, Oriental Liver Fluke, Fascioliasis, Fasciolopsiasis, Opisthorchiasis, Tapeworm Infections, Hydatid Disease and Alveolar Hydatid Disease; Viral Diseases such as Measles, Subacute sclerosing panencephalitis, Common Cold, Mumps, Rubella, Roseola, Fifth Disease, Chickenpox, Respiratory syncytial virus infection, Croup, Bronchiolitis, Infectious Mononucleosis, Poliomyelitis, Herpangina, Hand-Foot-and-Mouth Disease, Bornholm Disease, Genital Herpes, Genital Warts, Aseptic Meningitis, Myocarditis, Pericarditis, Gastroenteritis, Acquired Immunodeficiency Syndrome (AIDS), Human Immunodeficiency Virus (HIV), Reye's Syndrome, Kawasaki Syndrome, Influenza, Bronchitis, Viral “Walking” Pneumonia, Acute Febrile Respiratory Disease, Acute pharyngoconjunctival fever, Epidemic keratoconjunctivitis, Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), Shingles, Cytomegalic Inclusion Disease, Rabies, Progressive Multifocal Leukoencephalopathy, Kuru, Fatal Familial Insomnia, Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker Disease, Tropical Spastic Paraparesis, Western Equine Encephalitis, California Encephalitis, St. Louis Encephalitis, Yellow Fever, Dengue, Lymphocytic choriomeningitis, Lassa Fever, Hemorrhagic Fever, Hantvirus Pulmonary Syndrome, Marburg Virus Infections, Ebola Virus Infections and Smallpox.

[0519] In some embodiments, the present disclosure provides methods for treating an infectious disease, comprising administering to a subject suffering therefrom an effective amount of a provided compound or composition. In some embodiments, a provided method comprises administering an effective amount of a provided compound or composition and another therapeutic agent known for treatment of an infectious disease.

[0520] In some embodiments, a provided method for treating an infectious disease includes administering to a patient in need thereof a provided compound and another therapeutic agent that is an anti-infectious disease agent. Exemplary anti-infectious disease agents are widely known in the art, including but not limited to β-Lactam Antibiotics such as Penicillin G, Penicillin V, Cloxacilliin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin, Ampicillin, moxicillin, Bacampicillin, Azlocillin, Carbenicillin, Mezlocillin, Piperacillin and Ticarcillin; Aminoglycosides: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Streptomycin and Tobramycin; Macrolides such as Azithromycin, Clarithromycin, Erythromycin, Lincomycinand Clindamycin; Tetracyclines such as Demeclocycline, Doxycycline, Minocycline, Oxytetracycline and Tetracycline; Quinolones such as Cinoxacin and Nalidixic Acid; Fluoroquinolones such as Ciprofloxacin, Enoxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Sparfloxacin and Trovafloxicin; Polypeptides such as Bacitracin, Colistin and Polymyxin B; Sulfonamides such as Sulfisoxazole, Sulfamethoxazole, Sulfadiazine, Sulfamethizole and Sulfacetamide; Miscellaneous Antibacterial Agents such as Trimethoprim, Sulfamethazole, Chloramphenicol, Vancomycin, Metronidazole, Quinupristin, Dalfopristin, Rifampin, Spectinomycin, Nitrofurantoin; General Antiviral Agents such as Idoxuradine, Vidarabine, Trifluridine, Acyclovir, Famcicyclovir, Pencicyclovir, Valacyclovir, Gancicyclovir, Foscarnet, Ribavirin, Amantadine, Rimantadine, Cidofovir, Antisense Oligonucleotides, Immunoglobulins and Inteferons; Drugs for HIV infection such as Tenofovir, Emtricitabine, Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Nevirapine, Delavirdine, Saquinavir, Ritonavir and Indinavir, Nelfinavir.

[0521] It will be appreciated that, in certain embodiments, each variable recited is as defined above and described in embodiments, herein, both singly and in combination.

EXAMPLES

[0522] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

[0523] The present disclosure recognizes, among other things, that there is a continuing demand for compounds, compositions and methods for treating various diseases, for example, cancer. In some embodiments, the present disclosure provides such compounds, compositions and methods. In some embodiments, the present disclosure provides methods and uses for such compounds and compositions. Exemplary but non-limiting examples are described herein.

[0524] The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of compounds. In some embodiments, the present disclosure provides methods for flexible and scalable synthesis of ETP alkaloids or thiodiketopiperazines, or derivatives and analogs thereof, for example, a provided compound of formula I, II, or V.

General Procedures

[0525] All reactions were performed in oven-dried or flame-dried round-bottom flasks, modified Schlenk (Kjeldahl shape) flasks, or glass pressure vessels. The flasks were fitted with rubber septa, and reactions were conducted under a positive pressure of argon. Cannulae or gas-tight syringes with stainless steel needles were used to transfer air- or moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al..sup.11 using granular silica gel (60-Å pore size, 40-63 μm, 4-6% H.sub.2O content, Zeochem) or C.sub.18-reversed-phase silica gel (90-Å pore size, 40-63 μm, Fluka). Analytical thin layer chromatography (TLC) was performed using glass plates pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent indicator (254 nm) or basic alumina impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to short wave ultraviolet light (254 nm) and/or irreversibly stained by treatment with an aqueous solution of ceric ammonium molybdate (CAM), an ethanolic solution of phosphomolybdic acid (PMA), an aqueous solution of silver nitrate (AgNO.sub.3), Ellman's reagent (5,5′-dithiobis-(2-nitrobenzoic acid), DTNB) in dimethylformamide,.sup.12 or an aqueous solution of potassium permanganate (KMnO.sub.4), followed by heating (˜1 min) on a hot plate (˜250° C.). Organic solutions were concentrated at 30° C. on rotary evaporators capable of achieving a minimum pressure of ˜2 Torr.

Materials

[0526] Commercial reagents and solvents were used as received with the following exceptions: dichloromethane, acetonitrile, toluene, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, and methanol were purchased from J. T. Baker (Cycletainer™) or Sigma-Aldrich and were purified by the method of Grubbs et al. under positive argon pressure..sup.13 Benzene, N,N-diisopropylethylamine, and 1,2-dichloroethane were dried by distillation over calcium hydride under an inert nitrogen atmosphere. Acetone 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone was dried by distillation over calcium hydride under an inert nitrogen atmosphere. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) were purchased from Oakwood Products, Inc.; N-hydroxybenzotriazole was purchased from Aroz Technologies. LLC; silver hexafluoroantimonate was purchased from Strem Chemicals Inc.; 2,6-di-tert-butyl-4-methylpyridine was purchased from Matrix Scientific and was further purified by flash column chromatography on silica gel (eluent: hexanes). p-Methoxybenzyl thiol and carbon disulfide were purchased from Alfa Aesar. All other solvents and chemicals were purchased from Sigma-Aldrich.

Instrumentation

[0527] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were recorded with a Bruker AVANCE 600 spectrometer, a Bruker AVANCE NEO 500 spectrometer, a Varian inverse probe 500 INOVA spectrometer, a Bruker AVANCE III 400 spectrometer, or a JEOL ECZR 500 spectrometer. Chemical shifts are recorded in parts per million on the δ scale and are referenced from the residual protium in the NMR solvent (CHCl.sub.3: δ 7.26, CD.sub.2HCN: 1.94, CD.sub.2HOD: 3.31, CD.sub.3SOCD.sub.2H: 2.50, H.sub.2O: 4.79)..sup.14 Data are reported as follows: chemical shift [multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, m=multiplet, br=broad), coupling constant(s) in Hertz, integration, assignment]. Carbon-13 nuclear magnetic resonance (.sup.13C NMR) spectra were recorded with a Bruker AVANCE 600 spectrometer, a Varian 500 INOVA spectrometer, a Bruker AVANCE III 400 spectrometer, or a JEOL 500 spectrometer, are recorded in parts per million on the δ scale, and are referenced from the carbon resonances of the solvent (CDCl.sub.3: δ 77.16, CD.sub.3CN: 118.26, CD.sub.3OD: 49.00, DMSO-d.sub.6: 39.52). Infrared data were obtained with a Perkin-Elmer 2000 FTIR or a Bruker Alpha II Platinum ATR and are reported as follows: [frequency of absorption (cm.sup.−1), intensity of absorption (s=strong, m=medium, w=weak, br=broad)]. Optical Rotations were recorded on a Jasco P-1010 Polarimeter and specific rotations are reported as follows: [wavelength of light, temperature (° C.), specific rotation, concentration in grams/100 mL of solution, solvent]. High resolution mass spectra (HRMS) were recorded on a Bruker Daltonics AP EXIV 4.7 Tesla FT-ICR-MS using using electrospray (ESI) (m/z) ionization source or direct analysis in real time (DART), an Agilent 6545 Q-TOF LC/MS using electrospray (ESI) (m/z) ionization source, or a JEOL AccuTOF LC-plus 4G using direct analysis in real time (DART).

Positional Numbering System

[0528] At least three numbering systems exist for dimeric diketopiperazine alklaoids exist in the literature..sup.15 In assigning the .sup.1H and .sup.13C NMR data for all intermediates en route to the syntheses of monomeric ETP's (+)-9a, (+)-9b, (+)-9c, and (+)-9d, a uniform numbering scheme was empolyed. For ease of direct comparison, particularly between early intermediates, non-thiolated diketopiperazines, and advanced compounds, the numbering system used by Barrow for (+)-WIN-64821 (using positional numbers 1-17) is optimal and used throughout this report.

##STR00158## ##STR00159##

Cell Culture Information (HeLa, A549, HCT-116, DU-145, and MCF7)

[0529] Cells were grown in media supplemented with fetal bovine serum (FBS) and antibiotics (100 μg/mL penicillin and 100 U/mL streptomycin). Specifically, experiments were performed using the following cell lines and media compositions: HeLa (cervical adenocarcimona) and A549 (lung carcinoma) were grown in RPMI-1640+10% FBS; HCT-116 (colorectal carcinoma) was grown in DMEM+10% FBS; DU-145 (prostate carcinoma) and MCF7 (breast adenocarcinoma) were grown in EMEM+10% FBS. Cells were incubated at 37° C. in a 5% CO2, 95% humidity atmosphere.

Cell Viability Assays (HeLa, A549, HCT-116, DU-145, and MCF7)

[0530] Cells were plated at 250 cells/well into duplicate assay plates in 50 μL media into 384-well white, opaque, tissue-culture treated plates and allowed to adhere overnight at 37° C./5% CO2. Compounds were solubilized in DMSO as 1000× stocks and 100 nl was pin-transferred to cells (V&P pin tool mounted on Tecan Freedom Evo MCA96). Compounds were tested in 10-pt, 2-fold dilution with concentrations tested between 1 nM-20 μM for most compounds, except where indicated. DMSO (32 wells of 384-wells) was used as vehicle control. After 72 hours of incubation at 37° C./5% CO2, 10 μL Cell Titer-Glo (Promega) was added to each well and plates were incubated at room temperature for 10 minutes before the luminescence was read on a Tecan M1000 plate reader. Cell Titer-Glo measures ATP levels of cells as a surrogate for cell viability. All compound-treated wells was normalized to the DMSO control averages and expressed as a % of DMSO viability. IC50 values were determined from the dose curves using Spotfire (Perkin Elmer).

Jurkat, K-562, and Toledo Cell Culture Information and Viability Assays

[0531] Cells were grown in RPMI-1640+10% FBS+Pen/Strep and all are suspension cell lines. Each were plated at 250 cells per well in 50 μL of media in a 384 well plate and 50 nL of compounds was added via pin-tool (same as our usual procedure). Compounds were tested at 20 μM starting assay concentration in 20-pt, 2-fold dose in duplicate on the same assay plate. Cells were incubated with compound for 72 hours and viability was read out with CellTiter-Glo.

Detailed Description of Examples

[0532] Several subsets of natural and unnatural monomeric and dimeric ETPs exhibiting IC.sub.50 values in the low to (sub)nanomolar range have been identified (FIG. 1)..sup.3p To further enable exploration of the translational potential of ETPs, functionalized ETPs containing conjugatable chemical handles were sought. A robust means to derivatize ETPs through conjugation chemistry would permit evaluation of these biologically potent compounds in new contexts. Herein, the design and synthesis of derivatized ETPs possessing an alkyl azide moiety for conjugation to a desired coupling partner via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is described..sup.16 The CuAAC reactions of these azido ETPs proceed smoothly even in the presence of the highly sensitive epidisulfide functionality. Furthermore, the nanomolar cytotoxic activities of these designed azido ETPs across five human cancer cell lines is reported.

[0533] A recent study describing the potent cytotoxic activities of a structurally diverse collection of ETPs demonstrated the potential of this class of compounds as anti-cancer therapeutics..sup.3p Synthetic access to ETPs containing a conjugatable chemical handle may provide a powerful tool to further evaluate the biological activity of these compounds. In recent studies, bioactive small molecules have been structurally modified and used as photoaffinity labels for target identification.sup.17, in situ small molecule clickable imaging probes.sup.18, polymer-drug conjugates for improved pharmacokinetics.sup.19, and antibody-drug conjugates for targeted drug delivery.sup.20. Based on these precedents, attachment of an alkyl azide handle to ETPs may provide a robust and general method for coupling various chemical groups using CuAAC for utilization in biological applications such as those described above.

[0534] Identification of the site for attachment of an alkyl azide moiety onto the parent ETP was needed; the site should not lead to a significant loss in potency upon conjugation to a coupling partner relative to the parent compound. Previous SAR data indicated that aryl substituents at C3 were well tolerated and often led to an increase in potency relative to short chain alkyl substitutents. Additionally, it was found that N1 benzenesulfonyl substitution led to higher activities compared to the unsubstituted compounds. As such, exploration of N14 substitution beyond a methyl group was also considered. These considerations led to the design of monomeric ETP derivatives (+)-9a, (+)-9b, and (+)-9c substituted at alternative positions with an alkyl azide moiety (FIG. 2). In each case, a monomeric rather than a dimeric ETP scaffold was chosen to allow for more direct synthetic access to these compounds..sup.2f,3p During the course of these studies, it was discovered that alanine-derived ETPs are less sensitive to basic conditions than glycine-derived ETPs, thus it was sought to prepare ETP derivative (+)-9d.

[0535] As shown in Scheme 1, the synthesis of ETP (+)-9a commenced with exposure of known endo-tetracyclic bromide (+)-10 to aryl ether 11 in the presence of silver hexafluoroantimonate and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as a Brønsted acid scavenger in dichloromethane to provide the desired cis-fused Friedel-Crafts adduct in 78% yield, resulting from exclusive attack of aryl ether 11 from the para position..sup.21 Removal of the triisopropylsilyl group with tetrabutylammonium fluoride in THF at 0° C. afforded an inseparable mixture of alcohol (+)-12 and its C.sub.11 epimer (3:1, respectively) in 88% yield. Fortunately, epimerization of the base sensitive C.sub.11 stereocenter could be completely suppressed by employing hydrogen fluoride in a mixture of pyridine and THF at 23° C. for 16 h to furnish alcohol (+)-12 in 90% yield as a single diastereomer. Alcohol (+)-12 was converted into azide (+)-13 in 87% yield utilizing the Bose-Mitsunobu protocol with polymer-supported triphenylphosphine..sup.22 Treatment of azide (+)-13 with tetra-n-butylammonium permanganate (n-Bu.sub.4MnO.sub.4) in 1,2-dichloroethane gave diol (−)-14 in 63% yield as a single diastereomer..sup.23 Installation of the epidisulfide bridge was achieved by exposure of diol (−)-14 to trifluoroacetic acid in a saturated solution of hydrogen sulfide in nitroethane followed by facile oxidation of the crude bisthiol with potassium triiodide to afford azido ETP (+)-9a in 65% yield over two steps.

##STR00160##

[0536] The synthetic route to ETP (+)-9b (Scheme 2) commenced with an examination of the amide alkylation of diketopiperazine (+)-15..sup.24 In preliminary studies it was found that treatment of diketopiperazine (+)-15 with LHMDS in DMPU-THF at −30° C. followed by addition of either alkyl iodide or 3-substituted allyl bromide derivatives resulted in no reactivity or low conversions with significant amounts of epimerization at C11, respectively. To address the issue of epimerization, it was reasoned that installation of the C3 aryl group prior to the alkylation step would potentially mitigate the inductive electron withdrawing effects of the C3 bromide and thereby reduce the propensity for epimerization at C11. Further, the larger steric dimensions of an aryl group relative to bromine might also suppress epimerization. Next, in an effort to increase the reactivity of the electrophile it was hypothesized that an alkynyl bromide electrophile might offer increased reactivity relative to an allyl bromide electrophile..sup.25

##STR00161##

[0537] Based on these considerations, Friedel-Crafts arylation of bromide (+)-15 in the presence of silver hexafluoroantimonate and DTBMP in a mixture of anisole and dichloromethane (1:1) afforded C3-arylated diketopiperazine (+)-16 in 97% yield. Notably, treatment of diketopiperazine (+)-16 with LHMDS in a mixture of DMPU-THF (1:4) at −30° C. followed by addition of alkynyl bromide 17 afforded alkyne (+)-18 and the undesired C11 epimer in 60% and 14% yield, respectively.

[0538] Having developed a practical solution for amide alkylation, the hydrogenation of alkyne (+)-18 was explored. In initial experiments, exposure of alkyne (+)-18 to 5% Pd/C in ethyl acetate under an atmosphere of hydrogen gas at 23° C. for 24 h gave an equimolar mixture of alcohol (+)-19 and an intermediate product which had undergone complete reduction of the alkyne moiety but still possessed the benzyloxy group. Interestingly, changing the solvent to ethanol in order to increase the rate of hydrogenation provided alcohol (+)-19 in 67% yield accompanied by isolation of the N14-n-butyl derivative of alcohol (+)-19 in 18% yield which is postulated to have arisen from complete reduction of a putative allyl alcohol intermediate..sup.26 To exclude formation of this species, alkyne (+)-18 was subjected to 5% Pd/C in ethyl acetate over 1 atmosphere of hydrogen for 30 min which resulted in complete reduction of the alkyne moiety but preserved the benzyloxy group. Subsequently, the reaction mixture was diluted with ethanol and stirred for an additional 1 h to remove the benzyl protecting group affording alcohol (+)-19 in 93% yield. Analogous to the synthesis of ETP (+)-9a, utilization of the Bose-Mitsunobu protocol with polymer-supported triphenylphosphine transform ed alcohol (+)-19 into azide (+)-20 in 67% yield. Dihydroxylation of diketopiperazine (+)-20 with n-Bu.sub.4MnO.sub.4 in dichloromethane furnished diol (+)-21 in 48% yield. Addition of trifluoroacetic acid to a saturated solution of hydrogen sulfide and diol (+)-21 in nitroethane resulted in bisthiolation, which upon exposure to KI.sub.3 afforded azido ETP (+)-9b in 50% yield over two steps.

##STR00162##

[0539] Synthesis of the azido ETP (+)-9c (Scheme 3) began with HATU promoted amide coupling between acid (−)-22 and sarcosine methyl ester hydrochloride to afford the corresponding dipeptide in 73% yield. Deprotection of the tert-butoxycarbonyl group with trifluoroacetic acid in dichloromethane followed by treatment with morpholine in tert-butanol resulted in cyclization to diketopiperazine (−)-23 in 99% yield. Addition of molecular bromine to diketopiperazine (−)-23 in dichloromethane at 23° C. for 10 minutes effected bromocyclization to produce endo-tetracyclic bromide (+)-24 in 79% yield in >18:1 dr. Analogous to the synthesis of ETP (+)-9a, treatment of bromide (+)-24 with silver hexafluoroantimonate in the presence of anisole and DTBMP gave Friedel-Crafts adduct (+)-25 in 99% yield. Dihydroxylation of diketopiperazine (+)-25 with n-Bu.sub.4MnO.sub.4 in dichloromethane furnished diol (−)-26 in 46% yield. Addition of trifluoroacetic acid to a solution of diol (−)-26 in nitroethane saturated with hydrogen sulfide followed by mild oxidation with KI.sub.3 produced azido ETP (+)-9c in 64% yield over two steps.

[0540] With azido ETPs (+)-9a, (+)-9b, and (+)-9c synthesized, the compatibility of the epidisulfide functionality with the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was explored. Based on previous work, epidithioketopiperazines are known to be sensitive to reductive, oxidative, basic, and strongly acidic conditions..sup.3,4,5 As such, 4-ethynylanisole 27 was chosen as a representative model substrate for possible conjugation partners to demonstrate the efficiency of the CuAAC coupling strategy with designed ETPs (Scheme 4). Treatment of either ETP (+)-9a, (+)-9b, or (+)-9c with 4-ethynylanisole 27 with CuI, AcOH, and Hunig's base in dichloromethane or toluene.sup.27 at 23° C..sup.28 proceeded smoothly to provide the corresponding cycloadducts (+)-28a, (+)-28b, and (+)-28c in 94%, 85% and 57% yield, respectively.

TABLE-US-00001 Scheme 4: Conjugation of designed ETPs with model alkyne [00163] [00164] Entry ETP Product Yield 1 (+)-9a [00165] 94% 2 (+)-9b [00166] 85% 3 (+)-9c [00167] 57%

[0541] In certain contexts an amino functionality might be desirable for bioconjugation to activated acyl donors. To this end, N-Boc-propargylamine was coupled to ETP azide (+)-9a using the standard CuAAC reaction conditions to afford amino ETP (+)-29 in 89% yield. To demonstrate the competency of amino ETP (+)-29 as an acyl acceptor, N-Boc ETP (+)-29 was treated with anhydrous HCl in dioxane followed by addition of benzoyl chloride as a model acyl donor to afford ETP amide (+)-30 in 87% yield (Scheme 5).

##STR00168##

[0542] In situ monitoring of epidisulfide (+)-8 by .sup.1H NMR spectroscopy revealed a sensitivity to basic conditions in organic solvents. In the absence of base, 98% of epidisulfide (+)-8 remained after 20 hours in deuterochloroform. However, subsequent exposure to triethylamine, N,N-diisopropylethyl amine (Hunig's base), or 1,4-diazabicyclo-[2.2.2]-octane (DABCO) for 20 hours resulted in the formation of 4-6% yield of epitrisulfide 31, with 84-85% of epidisulfide (+)-8 remaining. In deuteroacetonitrile, it was directly observed the complete consumption of epidisulfide (+)-8 after 2 hours, followed by the isolation of epitrisulfide 31 (16%) and epitetrasulfide 32 (24%).

[0543] Stirring epidisulfide (+)-8 in N,N-dimethylformamide alone resulted in a cascade of color changes (pink, blue, green, then yellow) characteristic of the decomposition of epidisulfide (+)-8. When (+)-8 was exposed to triethylamine in DMF, epitrisulfide 31 (8%), epitetrasulfide 32 (11%), diketopiperazinethione 34-S (3%) corresponding hydrolyzed triketopiperazine 34-O (3%), diketopiperazinethione 35-S (16%) and its corresponding hydrolyzed triketopiperazine (5%) were isolated. One hypothesis is that H15 deprotonation of epidisulfide (+)-8 formed C11-thiol-diketopiperazine-C15-thione 33 via S—S bond scission, a reactive species that could catalytically consume the starting disulfide and ultimately give rise to the higher order polysulfanes via electrophilic sulfur transfer.

##STR00169##

[0544] To address possible concerns of C15-proton acidity of glycine-derived epidisulfide (+)-8, alanine-derived C15-methyl substituted epidisulfide (+)-42 were explored to reduce the rate of E2 elimination (Scheme 7). To minimize competetive ortho-arylation, known tetracyclic bromide (+)-36 was exposed to silver trifluoromethanesulfonate in the presence of anisole and DTBMP at −25° C. to give C3-p-methoxyphenyl diketopiperazine (+)-37 in 81% yield (d.r. 40:1). The selectivity of the permanganate-mediated dihydroxylation of diketopiperazine (+)-37 depended significantly on the permanganate counter-ion. With bis(pyridine)silver(I) permanganate (Py.sub.2AgMnO.sub.4) and n-Bu.sub.4MnO.sub.4, partial (10-15%) and significant (50%) diastereomers were observed, respectively. However, oxidation with bis(2,2′-bipyridyl)copper(II) permanganate (bipy.sub.2Cu(MnO.sub.4).sub.2) furnished diol 38 as a single diastereomer in 74% yield..sup.29

##STR00170##

[0545] The tactical conversion of diol 38 to an alcohol by monosilylation (84%) resulted in a mixture of regioisomers (1:1) with improved stability and solubility parameters, setting the stage for incorporation of sulfur atoms. Dropwise addition of either regioisomer as a solution in dichloromethane to a solution of potassium trithiocarbonate (K.sub.2CS.sub.3) in trifluoroacetic acid and dichloromethane converged to the same dithiepanethione (+)-41 in 66-73% yield..sup.30 However, due to the challenging preparation of potassium trithiocarbonate from toxic hydrogen sulfide gas and its poor solubility prior to protonation, an alternative reagent that could obviate its use was sought.

[0546] It was hypothesized that an appropriately designed alkyl trithiocarbonate could stabilize the formation of a sulfonium ion during intramolecular cyclization onto the N-acyl-imminum ion. Drawing inspiration from Lo's synthesis.sup.31 of Biotin Thioacid using bis(4-methoxyphenyl)-methanethiol as a protecting group, a known sodium benzhydryl trithiocarbonate was prepared..sup.32 Upon subjecting the mixture of regioisomers resulting from silylation of diol 38 to sodium benzhydryl trithiocarbonate and trifluoroacetic acid in dichloromethane, dithiepanethione (+)-41 was obtained in 68% yield. Monosodium trithiocarbonate 39, conveniently prepared from commercially available p-methoxybenzyl thiol, could achieve the same transformation in 60% yield under the same conditions (85% after optimization). From dithiepanethione (+)-41, access to all bioactive sulfur congeners (di-, tri-, and tetrasulfide) was obtained. Accordingly, dithiepanethione (+)-41 was deprotected via mild transcarbamation to give a bisthiol, which was oxidized to the epidisulfide (+)-42 with triiodide (91%), or converted to epitrisulfide 43 with sulfur dichloride (25%) or to epitetrasulfide 44 with disulfur dichloride (66%).

##STR00171##

[0547] Stability assays confirmed that the C.sub.15-Me substituted epidisulfide (+)-42 (Scheme 8) did not suffer from the base-catalyzed decomposition that completely consumed epidisulfide (+)-8 (Scheme 6). Monitoring in situ by .sup.1H NMR spectroscopy, 99% remaining starting material in the presence of triethylamine after 16 hours in deuteroacetonitrile was observed. These results encouraged the investigation of the thiol-disulfide exchange reactivity of model ETPs (+)-8 and (+)-42, to help gain insight into their mechanism of action.

[0548] The SAR profile of ETPs confirmed the importance of C11 and C15 sulfuration for anticancer activity, and further demonstrated that potentially labile sulfur derivatives, such as mixed bis-disulfides, also served as competent anticancer agents..sup.3p It was hypothesized that these species might act as prodrugs, being converted to their corresponding epidisulfide pharmacophores under biological conditions, which are then concentrated within the cell via a glutathione-dependent mechanism..sup.33 Given that one of the proposed mechanisms of ETP toxicity invokes reactivity with cellular thiols,.sup.2,34 the conversion of ETPs (+)-8 and (+)-42 into mixed bis-disulfides was studied.

##STR00172##

[0549] The first study involved thiol-disulfide exchange of ETPs in organic solvents using a surrogate thiol, and then transitioned to more biologically informative aqueous conditions involving glutathione (Scheme 9). Exposure of epidisulfide (+)-8 to 4-fluorobenzyl mercaptan (PFB-SH) and its corresponding disulfide (PFB-SS-PFB) indeed resulted in the formation of bisdisulfide (−)-45a. However, there were disparities between crude and isolated yields, due to continuing reactivity upon concentration in the presence of base and/or exposure to silica..sup.35 Furthermore, a reversion experiment of bisdisulfide (−)-45a resulted in a mixture of di-, tri-, and tetra-sulfides (Scheme 9). This result demonstrates possible challenges of establishing an equilibrium between epidisulfide (+)-8 and bisdisulfide (−)-45a.

[0550] In comparison to a glycine-derived epidisulfide (+)-8, alanine-derived epidisulfide (+)-42 permitted a more robust investigation of the thiol-disulfide exchange chemistry, as it did not decompose when exposed to basic conditions (see Scheme 9). Far slower and lower conversion (˜25%) to corresponding bisdisulfide (+)-45b was observed, however the formation of trisulfide 43 or tetrasulfide 44 was not observed. By diluting aliquots of the disulfide-exchange reaction into deuterio-chloroform (Scheme 9), the equilibration between epidisulfide (+)-42 and bisdisulfide (+)-45b (3:1 in favor of epidisulfide (+)-42) was observed by .sup.1H NMR spectroscopy. Furthermore, this study demonstrated that the equilibrium could be established from both directions by reverting bisdisulfide (+)-45b to epidisulfide (+)-42..sup.36

[0551] In order to demonstrate that mixed disulfides could undergo reversion to their corresponding epidisulfide pharmacophores under biologically relevant conditions, the preparation of a water-soluble mixed disulfide was explored. Following hydride reduction of epidisulfide (+)-42, exposure of the crude bisthiol to glutathione S-Phenyl-thiosulfonate.sup.37 provided the water-soluble glutathione bisdisulfide 46 in 45% yield, which was purified using reverse-phase silica chromatography. Epidisulfide (+)-42 and bisdisulfide 46 were both soluble in a mixture of D.sub.2O and CD.sub.3CN, and addition of glutathione facilitated the quantitative reversion of bisdisulfide 46 to ETP (+)-42, in a matter of minutes with base or days without. In the absence of additional thiol or base, it was observed the same reversion of bisdisulfide 46 to epidisulfide (+)-46 in d.sub.6-DMSO, with a 1:1 ratio after a week that progressed to >15:1 ETP after 3 weeks.

[0552] The results of these thiol-disulfide exchange studies on model epidisulfides (+)-8 and (+)-42 highlight the remarkable thermodynamic stability of the ETP substructure, as ETP-derived mixed bisdisulfides (−)-45a, (+)-45b, and 46 readily revert to their respective ETPs. The application of these bisdisulfides as ETP prodrugs may find utility in the treatments of certain types of cancer with higher glutathione (GSH)/glutathione disulfide (GSSG) ratios. For example, several studies have found that invasive and metastatic colon and prostate tumors have higher extracellular thiol concentrations than healthy tissue..sup.38 Thus, it may be possible to both modulate ETP toxicity in prodrug form, and to promote ETP formation only at the local tumor environment.

[0553] Given the enhanced chemical stability of model epidisulfide (+)-42 compared to epidisulfide (+)-8, epidisulfide azide (+)-9d was prepared (Scheme 10). The C3 arylation of bromide (+)-36 proceeded by silver-mediated electrophilic activation with trapping of the benzylic carbocation by aryl ether 11 (73% yield). Following silyl ether deprotection to arrive at alcohol (+)-47, the crucial alkyl azide moiety was installed in a highly efficient two-step tosylation (96%) and azidation (89%) sequence. Oxidation of propoxyazide (+)-48 using bis(pyridine)silver(I) permanganate furnished diol 49 in 64% yield, which was then subjected to monosilylation to arrive at a regioisomeric mixture of alcohols (1.1:1) in 85% yield. As with probes (+)-9a, (+)-9b, and (+)-9c, subsequent exposure to nitroethane saturated with hydrogen sulfide gas resulted in bis-sulfidation, which gave epidisulfide (+)-9d in 42% yield upon oxidation with triiodide. To highlight the flexibility in linkers that may be attached to these ETP probes, epidisulfide probe (+)-9d was conjugated with ethylene glycol-derived alkyne 50 using an CuAAC coupling strategy to give triazolyl ETP 51 in 92% yield, which can be subjected to downstream acylation as demonstrated in Scheme 5.

##STR00173##

[0554] To evaluate the model and functionalized ETP probes as anticancer agents, fifteen derivatives were tested in culture against a panel of five human cancer cell lines (Table 1). Model monomeric and dimeric ETPs (+)-8, (+)-42, and (+)-7, designed azido ETPs (+)-9a-d, the ETP triazolyl cycloadducts (+)-28a-c, (+)-29, and 51, and bisdisulfides (−)-45a, (+)-45b, and 46 were evaluated for cytotoxic activity against cervical (HeLa), lung (A549), breast (MCF7), colorectal (HCT116), and prostate (DU-145) carcinoma cell lines. Across all five cell lines, the model and designed ETPs displayed similar patterns of potency in the form of low nanomolar cytotoxicity (Table 1).

[0555] While it was demonstrated that alanine-derived ETP (+)-42 is chemically more stable than glycine-derived ETP (+)-8 (Scheme 6 vs. 8), it was also observed that the glycine-derived ETPs were more active against the same cell lines (3.4-16 nM vs. 32-374 nM). Whereas the p-fluorobenzyl bisdisulfides (−)-45a and (+)-45b to have approximately the same activities as their parent ETPs (+)-8 and (+)-42, respectively, the water-soluble glutathione bisdisulfide 46 derived from ETP (+)-42 was significantly less active against the same cell lines.

[0556] These results indicate that ETPs possessing conjugatable chemical handles about either the C3, N14, or N1 positions retain potency, even after conjugation with several different coupling partners. In comparing model ETP (+)-8 to its functionalized derivatives azido ETPs (+)-9a-c, it was found the activity of ETP (+)-9a to be unaffected (<2-fold difference), (+)-9c to be slightly impaired (2.7- to 13.0-fold decrease), and (+)-9b to be most affected (3.2- to 18.6-fold decrease). Similarly, functionalization of model ETP (+)-42 as azido ETP (+)-9d did not impact the activity against HCT116 or MCF7 cell and gave only slightly reduced activities against A549, HeLa, and DU-145 cells (2.7-, 4.3-, and 8.6-fold decreases, respectively). Further derivatization of azide (+)-9a to triazole (+)-28a resulted in minimal (1.5- to 2.8-fold) loss of activity, whereas derivatization of azides (+)-9b-c to triazoles (+)-28b-c resulted in slight (1.9- to 4.3-fold) gain in activity. For the alanine-derived ETP (+)-42, the functionalization as azido ETP (+)-9d was unaffected for MCF7 and HCT116 cell lines, and resulted in slightly lower (2.7- to 8.6-fold) activities against A549, HeLa, and DU145 cell lines. The derivatization of azido ETP (+)-9d as triazole 51 recovered some of the lost activity, resulting in activities comparable to parent ETP (+)-42.

[0557] Detailed herein is the development of a concise synthetic route to alkyl azide functionalized ETP derivatives. Important features of this approach include stereocontrolled construction of the C3 quaternary center and stereo- and chemoselective late-stage hydroxylation and thiolation reactions. Notably, CuAAC reactions of these azido ETPs are tolerant of the sensitive epidisulfide moiety, cleanly affording the corresponding 1,2,3-triazole cycloadducts in high yields. In vitro cytotoxicity assays of ETP azide and triazole cycloadducts demonstrate that these derivatives retain high potency as anticancer agents against five human cancer cell lines. The ability to append virtually any chemical group to ETPs via CuAAC chemistry should facilitate diversification of these compounds with a wide array of chemical groups for various biological applications.

TABLE-US-00002 TABLE 1 Assessment of designed ETPs for cytotoxicity in five human cancer cell lines {HeLa (cervical carcinoma), A549 (alveolar adenocarcinoma), IMF7 (breast adenocarcinoma), HCT116 (colorectal carcinoma), and DU-145 (prostate carcinoma)}..sup.a HeLa A549 MCF7 HCT116 DU-145 Alanine-derived dimer with epipolystilfide bridge (+) −7 0.11 ± 0.14 0.46 ± 0.45 0.30 ± 0.44 0.24 ± 0.29 0.18 ± 0.18 60 6.2 19 10.9 14.6 10 Glycine-derived monomers with epipolysulfide bridges (+) −8 5.5 ± 1.7  16 ± 9.8 9.2 ± 3.1 6.9 ± 2.9 3.4 ± 4.2 (+) −9a 5.3 ± 0.2 8.8 ± 2.6 7.8 ± 3.6 5.7 ± 0.2 6.9 ± 2.1 (+) −28a 7.9 ± 3.7  25 ± 7.7 7.8 ± 5.9  11 ± 6.3  15 ± 5.6 (+) −29 61 ± 46 753 ± 13  148 ± 58  119 ± 30  80 ± 25 (+) −9b 44 ± 25 143 ± 16   51 ± 7.1 101 ± 7.5.sub.  63 ± 22 (+) −28b 14 ± 11 78 ± 15  14 ± 3.3  23 ± 1.9  22 ± 3.5 (+) −9c 15 ± 12 76 ± 35 53 ± 48 37 ± 21 44 ± 46 (+) −28c 6.3 ± 5.9 39 ± 12 19 ± 15  20 ± 8.6 16 ± 14 Glycine-derived monomer with bisdisulfide (−) −45a 4.0 ± 0.1  21 ± 1.1 5.0 ± 2.3 6.9 ± 1.6 5.4 ± 1.9 Alanine-derived monomers with epipolysulfide bridges (+) −42 32 ± 37 92 ± 87 81 ± 64 374 ± 83  36 ± 43 (+) −9d 136 ± 84  251 ± 307  86 ± 113 348 ± 442 306 ± 385 51 24 ± 29 116 ± 102  82 ± 105 148 ± 148 62 ± 75 Alanine-derived monomers with bisdisulfides (+) −45b 81 ± 26 141 ± 68  90 ± 23 141 ± 20  88 ± 50 46 508 ± 75  910 ± 324 500 ± 152 1096 ± 540  580 ± 216 * Cytoxicity IC.sub.50 values (in nM) aller 72 h of compound treatment as determined by Cell Titer-Glo (Promega) which measures ATP levels as a surrogate for cell viability. Error is standard deviation of the mean, n ≥ 2; IC.sub.50 = half maximal inhibitory concentration.

[0558] Having achieved the synthesis of ETP probes (+)-9a-d and demonstrated that they retain potency against human cancer cell lines (Table 1) in comparison to their non-functionalized analogs, the design and synthesis of a heterodimeric ETP probe based on lead compound dimeric ETP (+)-7 was next sought..sup.3p Functionalization of N14 en route to heterodimeric probe 60, allowed for a divergent synthesis from known intermediates (+)-52 and (+)-36..sup.5a As shown in Scheme 11, the latent functional handle was introduced by N-alkylation of known tetracyclic bromide 52 with propargylic iodide 53 using trisdimethylaminosulfonium trimethylsilyldifluoride (TASF) as a source of anhydrous fluoride to give alkyne 54 in 84% yield. Under these mild conditions no C11-epimerization was observed, a notable improvement over the analogous alkylation of monomeric diketopiperazine (+)-16 (Scheme 2). Hydrogenation of alkyne 54 with 5% Pd/C in ethyl acetate followed by benzyl ether cleavage with boron trichloride afforded alcohol 55 in 81% yield over two steps. Previously the C.sub.3-C.sub.3′ bond in related, homodimeric natural products was synthesized,.sup.39 reductive dimerization of alcohol 55 and reported N-methyl bromide using Co(I)C.sub.1(PPh).sub.3 furnished heterodimeric alcohol 56 in 26% yield. Conversion of the primary alcohol to the methanesulfonate followed by S.sub.N2 displacement with sodium azide secured the alkyl azide in 81% yield over two steps. Oxidation with bispyridyl silver permanganate provided tetraol 58 in 60% yield. This sensitive intermediate was tethered with dichlorodiisopropylsilane to give dioxasilane 59, which exhibited more controlled reactivity in the key thiolation step by reducing the rate of competitive elimination. Finally, bis-sulfidation using tritylhydrodisulfane provided direct access to functionalized heterodimeric ETP probe 60 in 39% yield. Heterodimeric ETP probe 60 retains low nanomolar activity against five human cancer cell lines (Table 1), making it a promising candidate for further investigations including protein target identification and antibody-drug conjugation.

##STR00174##

[0559] Additional cell viability assays were carried out with Jurkat cell lines (acute T cell leukemia), K-562 cell lines (chronic myelogenous leukemia (CML)), and Toledo cell lines (diffuse large cell lymphoma; non-Hodgkin's B cell lymphoma). Exemplary results are shown in Table 2.

TABLE-US-00003 TABLE 2 Compound Cell Line IC.sub.50 (μM) [00175] Jurkat K-562 Toledo 0.00647 0.01971 0.00829 60 [00176] Jurkat K-562 Toledo 0.41937 1.28054 1.81121 (+)-9d

Synthesis of Exemplary Compounds

[0560] ##STR00177##

Example 1: (3-Phenoxypropoxy)triisopropylsilane 11

[0561] Triisopropylsilyl chloride (5.84 mL, 27.3 mmol, 1.00 equiv) was added via syringe to a solution of 3-phenoxypropan-1-ol.sup.40 (4.16 g, 27.3 mmol, 1 equiv) and imidazole (2.42 g, 62.3 mmol, 2.30 equiv) in N,N-dimethylformamide (45 mL) at 23° C. After 18 h, the reaction mixture was diluted with ethyl acetate (300 mL) and was slowly poured into saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (2×50 mL), with water (3×50 mL), and with a saturated aqueous sodium chloride solution (40 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0-10% ethyl acetate in hexanes) to afford (3-phenoxypropoxy)triisopropylsilane 11 (4.90 g, 61.4%) as a colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.26 (app-t, J=7.9 Hz, 2H, C.sub.2′H), 6.92-6.89 (m, 3H, C.sub.1′H, C.sub.3′H), 4.08 (t, J=6.3 Hz, 2H, C.sub.5′H), 3.87 (t, J=6.0 Hz, 2H, C.sub.2′H), 1.99 (p, J=6.1 Hz, 2H, C.sub.6′H), 1.10-1.03 (m, 21H, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 159.3 (C.sub.4′), 129.6 (C.sub.2′), 120.7 (C.sub.1′), 114.7 (C.sub.3′) 64.7 (C.sub.5′), 60.1 (C.sub.7′), 32.9 (C.sub.6′), 18.2 (SiCH(CH.sub.3).sub.2), 12.2 (SiCH(CH.sub.3).sub.2). FTIR (thin film) cm.sup.−1: 2941 (s), 2865 (s), 1497 (s), 1244 (s), 1103 (s), 881 (s), 751 (s). HRMS (ESI) (m/z): calc'd for C.sub.18H.sub.33O.sub.2Si [M+H]+: 309.2244, found: 309.2266. TLC (10% ethyl acetate in hexanes), Rf: 0.39 (UV, CAM).

##STR00178##

Example 2: C.SUB.3.-Friedel-Crafts Adduct (+)—S2

[0562] Endo-tetracyclic bromide (+)-10.sup.41 (1.67 g, 3.50 mmol, 1 equiv), 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 1.81 g, 8.80 mmol, 2.51 equiv), and (3-phenoxypropoxy)triisopropylsilane 11 (2.16 g, 6.99 mmol, 2.00 equiv) were azeotropically dried by concentration from anhydrous benzene (30 mL) under reduced pressure. Dichloromethane (35 mL) was added via syringe, and silver hexafluoroantimonate (2.40 g, 6.99 mmol, 2.00 equiv) was added as a solid in one portion to the solution at 23° C. After 1 h, the reaction mixture was diluted with dichloromethane (100 mL) and was filtered through a pad of Celite. The filter cake was washed with dichloromethane (3×50 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% acetone in dichloromethane) to afford Friedel-Crafts adduct (+)—S2 (1.93 g, 78.4%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.58 (d, J=8.1 Hz, 1H, C.sub.8H), 7.46 (app-d, J=8.5 Hz, 2H, SO.sub.2Ph-o-H), 7.30 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.28-7.24 (m, 1H, C.sub.7H), 7.10 (m, 4H, SO.sub.2Ph-o-H, C.sub.5H, C.sub.6H), 6.68-6.61 (m, 4H, C.sub.2′H, C.sub.3′H), 6.13 (s, 1H, C.sub.2H), 4.39 (app-t, J=8.3 Hz, 1H, C.sub.11H), 4.10 (d, J=17.4 Hz, 1H, C.sub.15H.sub.a), 4.04 (t, J=6.3 Hz, 2H, C.sub.5′H), 3.86 (t, J=6.1 Hz, 2H, C.sub.7′H), 3.82 (d, J=17.4 Hz, 1H, C.sub.15H.sub.b), 3.06 (dd, J=7.0, 14.1 Hz, 1H, C.sub.12H.sub.a), 2.89-2.83 (m, 4H, C.sub.12H.sub.b, C.sub.17H), 1.98 (p, J=6.1 Hz, 2H, C.sub.6′H),), 1.11-1.03 (m, 21H, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.1 (C.sub.13), 165.2 (C.sub.16), 158.4 (C.sub.4′), 139.9, (C.sub.9) 138.2 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.0 (SO.sub.2Ph-p-C), 132.5 (C.sub.1′), 129.2 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 128.0 (SO.sub.2Ph-o-C), 126.0 (C.sub.6), 125.4 (C.sub.5), 117.2 (C.sub.8), 115.0 (C.sub.3′), 87.2 (C.sub.2), 64.9 (C.sub.5′), 59.8 (C.sub.7′), 59.4 (C.sub.3), 58.6 (C.sub.11), 54.5 (C.sub.15), 39.1 (C.sub.12), 33.7 (C.sub.17), 32.7 (C.sub.6′), 18.2 (SiCH(CH.sub.3).sub.2), 12.1 (SiCH(CH.sub.3).sub.2). FTIR (thin film) cm.sup.−1: 3065 (m), 2943 (s), 2868 (s), 1684 (s), 1610 (m), 1512 (m), 1253 (m), 1171 (m), 883 (m), 686 (w). HRMS (DART) (m/z): calc'd for C.sub.38H.sub.50N.sub.3O.sub.6SSi [M+H].sup.+: 704.3184, found: 704.3195. [α].sub.D.sup.23: +19 (c=0.24, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.63 (UV, CAM).

##STR00179##

Example 3: Alcohol (+)-12

[0563] A freshly prepared solution of hydrogen fluoride-pyridine (70% HF, 9 mL), pyridine (18 mL), and tetrahydrofuran (72 mL) at 0° C. was poured into a solution of Friedel-Crafts adduct (+)—S2 (1.894 g, 2.691 mmol, 1 equiv) in tetrahydrofuran (90 mL) at 0° C. contained in a 1-L polypropylene vessel. After 5 min, the ice-water bath was removed and the solution was allowed to stir and warm to 23° C. After 20 h, the reaction mixture was cooled to 0° C. and was diluted with a saturated aqueous sodium bicarbonate solution (500 mL) in portions (50 mL) over 15 min. The resulting mixture was extracted with ethyl acetate (300 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed sequentially with a saturated aqueous copper(II) sulfate solution (3×100 mL), with a saturated aqueous ammonium chloride solution (3×100 mL), and with a saturated aqueous sodium chloride solution (75 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.60% acetone in dichloromethane) to afford alcohol (+)-12 (1.33 g, 90.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.57 (d, J=8.1 Hz, 1H, C.sub.8H), 7.45 (app-d, J=9.7 Hz, 2H, SO.sub.2Ph-o-H), 7.33 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.28-7.23 (m, 1H, C.sub.7H), 7.12-7.08 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 6.65 (app-d, J=9.0 Hz, 2H, C.sub.2′H) 6.60 (app-d, J=9.0 Hz, 2H, C.sub.3′H), 6.13 (s, 1H, C.sub.2H), 4.41 (app-t, J=8.3 Hz, 1H, C.sub.11H), 4.10 (d, J=17.3 Hz, 1H, C.sub.15H.sub.a), 4.05 (t, J=6.0 Hz, 2H, C.sub.5′H), 3.84 (t, J=6.0 Hz, 2H, C.sub.7′H), 3.81 (d, J=17.7 Hz, 1H, C.sub.15H.sub.b), 3.06 (dd, J=7.0, 14.1 Hz, 1H, C.sub.12H.sub.a), 2.88-2.82 (m, 4H, C.sub.12H.sub.b, C.sub.17H), 2.02 (p, J=5.9 Hz, 2H, C.sub.6′H), 1.88 (br-s, 1H, OH). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.1 (C.sub.13), 165.3 (C.sub.16), 158.1 (C.sub.4′), 139.9 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 135.9 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 132.9 (C.sub.1′), 129.3 (C.sub.7), 128.8 (SO.sub.2Ph-m-C), 128.2 (C.sub.2′), 127.6 (SO.sub.2Ph-o-C), 126.0 (C.sub.6), 125.5 (C.sub.5), 117.2 (C.sub.8), 115.0 (C.sub.3′), 87.2 (C.sub.2), 65.8 (C.sub.5′), 60.2 (C.sub.7′), 59.4 (C.sub.3), 58.6 (C.sub.11), 54.4 (C.sub.15), 39.0 (C.sub.12), 33.7 (C.sub.17), 32.1 (C.sub.6′). FTIR (thin film) cm.sup.−1: 2954 (w), 1700 (s), 1684 (s), 1507 (m), 1362 (m), 1169 (m), 832 (w), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.29H.sub.30N.sub.3O.sub.6S [M+H].sup.+: 548.1850, found: 548.1872. [α].sub.D.sup.23: +26 (c=0.12, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.21 (UV, CAM).

##STR00180##

Example 4: Azide (+)-13

[0564] Diisopropyl azodicarboxylate (DIAD, 256 μL, 1.28 mmol, 1.50 equiv) and diphenylphosphoryl azide (DPPA, 276 μL, 1.28 mmol, 1.50 equiv) were added dropwise via syringe to a suspension of alcohol (+)-12 (466 mg, 851 μmol, 1 equiv) and resin-bound triphenylphosphine (1.31 mmol/g on 100-200 mesh polystyrene cross-linked with 1% divinylbenzene, 973 mg, 1.28 mmol, 1.50 equiv) in tetrahydrofuran (20 mL) at 0° C. After 5 min, the ice-water bath was removed and the reaction mixture was allowed to stir and warm to 23° C. After 16 h, the reaction mixture was filtered through a 1 cm pad of Celite in a 60-mL medium-porosity fritted-glass funnel. The filter cake was washed with dichloromethane (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 30% acetone in dichloromethane) to afford azide (+)-13 (425 mg, 87.2%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.58 (d, J=8.1 Hz, 1H, C.sub.8H), 7.49 (app-d, J=8.4 Hz, 2H, SO.sub.2Ph-o-H), 7.34 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.28-7.23 (m, 1H, C.sub.7H), 7.14-7.09 (m, 4H, SO.sub.2Ph-o-H, C.sub.5H, C.sub.6H), 6.68 (app-d, J=9.0 Hz, 2H, C.sub.2H) 6.62 (app-d, J=9.0 Hz, 2H, C.sub.3′H), 6.13 (s, 1H, C.sub.2H), 4.39 (app-t, J=8.2 Hz, 1H, C.sub.11H), 4.10 (d, J=17.4 Hz, 1H, C.sub.15H.sub.a), 3.99 (t, J=5.9 Hz, 2H, C.sub.5′H), 3.82 (d, J=17.4 Hz, 1H, C.sub.15H.sub.b), 3.51 (t, J=6.5 Hz, 2H, C.sub.7′H), 3.06 (dd, J=7.1, 14.2 Hz, 1H, C.sub.12H.sub.a), 2.89-2.83 (m, 4H, C.sub.12H.sub.b, C.sub.17H), 2.04 (p, J=6.2 Hz, 2H, C.sub.6′H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.1 (C.sub.13), 165.3 (C.sub.16), 157.9 (C.sub.4′), 139.9 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 133.0 (C.sub.1′), 129.3 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.2 (C.sub.2), 127.7 (SO.sub.2Ph-o-C), 126.0 (C.sub.6), 125.4 (C.sub.5), 117.2 (C.sub.8), 115.0 (C.sub.3′), 87.1 (C.sub.2), 64.7 (C.sub.5′), 59.4 (C.sub.3), 58.6 (C.sub.11), 54.4 (C.sub.15), 48.3 (C.sub.7′), 39.0 (C.sub.12), 33.7 (C.sub.17), 28.9 (C.sub.6′). FTIR (thin film) cm.sup.−1: 2929 (w), 2099 (s), 1700 (s), 1684 (s), 1512 (m), 1362 (m), 1252 (m), 1169 (m), 1091 (w), 832 (w), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.29H.sub.29N.sub.6O.sub.5S [M+H].sup.+: 573.1915, found: 573.1921. [α].sub.D.sup.23: +21.8 (c=0.22, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.55 (UV, CAM).

##STR00181##

Example 5: Diol (−)-14

[0565] Tetra-n-butylammonium permanganate.sup.42 (807 mg, 2.23 mmol, 5.05 equiv) was added as a solid to a solution of azide (+)-13 (253 mg, 442 μmol, 1 equiv) in 1,2-dichloroethane (16 mL) at 23° C. After 1 h, the reaction mixture was diluted with a saturated aqueous sodium sulfite solution (50 mL) and with ethyl acetate-hexanes (9:1, 200 mL). The resulting mixture was washed with a saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, and the organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (50 mL), with deionized water (50 mL), and with a saturated aqueous sodium chloride solution (25 mL). The combined aqueous layers were extracted with ethyl acetate-hexanes (9:1, 2×50 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.40% acetone in dichloromethane) to afford diol (−)-14 (169 mg, 63.2%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 25° C.): δ 7.43 (app-t, J=7.4 Hz, 1H, SO.sub.2Ph-p-H), 7.39-7.32 (m, 4H, SO.sub.2Ph-o-H, C.sub.7H, C.sub.8H), 7.26-7.19 (m, 3H, C.sub.11OH, C.sub.5H, C.sub.6H), 7.13 (app-t, J=7.5 Hz, 2H, SO.sub.2Ph-m-H), 7.01 (d, J=7.2 Hz, 1H, C.sub.15OH), 6.75 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.66 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.21 (s, 1H, C.sub.2H), 5.00 (d, J=6.8 Hz, 1H, C.sub.15H), 4.02 (t, J=6.0 Hz, 2H, C.sub.5′H), 3.54 (t, J=6.7 Hz, 2H, C.sub.7′H), 3.19 (d, J=14.9 Hz, 1H, C.sub.12H.sub.a), 2.77 (s, 3H, C.sub.17H), 2.66 (d, J=14.9 Hz, 1H, C.sub.12H.sub.b), 1.99 (p, J=6.3 Hz, 2H, C.sub.6′H). .sup.13C NMR (100 MHz, DMSO-d.sub.6, 25° C.): δ 166.6 (C.sub.13), 165.8 (C.sub.16), 157.1 (C.sub.4′), 139.3 (C.sub.9), 138.0 (SO.sub.2Ph-ipso-C), 137.7 (C.sub.4), 133.6 (C.sub.1′), 133.2 (SO.sub.2Ph-p-C), 128.9 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 126.7 (SO.sub.2Ph-o-C), 126.6 (C.sub.6), 125.7 (C.sub.5), 117.0 (C.sub.8), 114.5 (C.sub.3), 87.3 (C.sub.2), 86.0 (C.sub.11), 80.9 (C.sub.15), 64.6 (C.sub.5′), 57.4 (C.sub.3), 49.7 (C.sub.12), 47.7 (C.sub.7′), 30.5 (C.sub.17), 28.1 (C.sub.6′). FTIR (thin film) cm.sup.−1: 2095 (m), 1844 (m), 1734 (m), 1700 (s), 1685 (s), 1653 (s), 1559 (s), 1540 (m), 1507 (m), 1457 (m), 1055 (w), 668 (m). [α].sub.D.sup.23: −6 (c=0.16, DMSO). HRMS (DART) (m/z): calc'd for C.sub.29H.sub.29N.sub.6O.sub.7S [M+H].sup.+: 605.1813, found: 605.1814. TLC (30% acetone in dichloromethane), Rf: 0.40 (UV, CAM).

##STR00182##

Example 6: Epidithiodiketopiperazine Azide (+)-9a

[0566] A solution of diol (−)-14 (190 mg, 314 μmol, 1 equiv) in anhydrous nitroethane (13 mL) at 0° C. was sparged with hydrogen sulfide gas for 20 min by discharge of a balloon equipped with a needle extending into the reaction mixture, providing a saturated hydrogen sulfide solution. Trifluoroacetic acid (TFA, 9.8 mL) was added via syringe over 20 seconds, and the sparging with hydrogen sulfide gas was maintained for another 20 min. The ice-water bath was removed and the solution was allowed to stir and warm to 23° C. under an atmosphere of hydrogen sulfide. After 2 h, the reaction mixture was diluted with ethyl acetate (125 mL), was slowly poured into a stirring saturated aqueous sodium bicarbonate solution (50 mL), and the organic layer was washed with a saturated aqueous sodium chloride solution (35 mL). A stock solution of potassium triiodide in pyridine.sup.43 was added dropwise into the organic layer containing crude bisthiol S3 until a persistent yellow color was observed. The resulting mixture was washed with an aqueous hydrogen chloride solution (1 M, 2×35 mL), was washed with a saturated aqueous sodium chloride solution (35 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.20% ethyl acetate in dichloromethane) to afford epidithiodiketopiperazine azide (+)-9a (129 mg, 65.4%) as a beige solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments..sup.44 1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.59 (d, J=8.0 Hz, 1H, C.sub.8H), 7.40-7.34 (m, 3H, C.sub.7H, SO.sub.2Ph-o-H), 7.29 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.25-7.21 (m, 2H, C.sub.5H, C.sub.6H), 7.03 (t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.75 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.61 (app-d, J=8.9 Hz, 2H C.sub.3′H), 6.38 (s, 1H, C.sub.2H), 5.24 (s, 1H, C.sub.15H), 3.99 (t, J=6.0 Hz, 2H, C.sub.5′H), 3.62 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.51 (t, J=6.5 Hz, 2H, C.sub.7′H), 3.11 (s, 3H, C.sub.17H), 2.84 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.03 (p, J=6.1 Hz, 2H, C.sub.6′H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.2 (C.sub.13), 160.2 (C.sub.16), 158.1 (C.sub.4′), 141.3 (C.sub.9), 138.5 (SO.sub.2Ph-ipso-C), 135.9 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 131.6 (C.sub.1′), 129.9 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.2 (C.sub.6), 125.7 (C.sub.5), 119.0 (C.sub.8), 115.1 (C.sub.3′), 87.7 (C.sub.2), 74.6 (C.sub.11), 68.5 (C.sub.15), 64.7 (C.sub.5′), 59.6 (C.sub.3), 48.3 (C.sub.7′), 45.5 (C.sub.12), 32.2 (C.sub.17), 28.9 (C.sub.6′). FTIR (thin film) cm.sup.−1: 2926 (w), 2098 (m), 1717 (s), 1700 (s), 1685 (s), 1559 (m), 1507 (m), 1473 (w), 972 (w), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.29H.sub.30N.sub.7O.sub.5S.sub.3[M+NH.sub.4].sup.+: 652.1465, found: 652.1454. [α].sub.D.sup.23: +236 (c=0.10, CHCl.sub.3). TLC (20% ethyl acetate in CH.sub.2Cl.sub.2), Rf: 0.32 (UV, CAM).

##STR00183##

Example 7: Triazole (+)-28a

[0567] Copper (I) iodide (45.7 mg, 0.240 mmol, 1.50 equiv) was added as a solid to a solution of epidithiodiketopiperazine azide (+)-9a (102 mg, 0.160 mmol, 1 equiv), 4-ethynylanisole 27 (104 μL, 0.800 mmol, 5.00 equiv), acetic acid (28 μL, 0.48 mmol, 3.0 equiv), and N,N-diisopropylethylamine (84 μL, 0.48 mmol, 3.0 equiv) in dichloromethane (1.6 mL) at 23° C. After 11 h, the reaction mixture was directly purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in dichloromethane.fwdarw.100% ethyl acetate) to afford triazole (+)-28a (116 mg, 94.3%) as a yellow solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.70 (app-d, J=8.8 Hz, 2H, C.sub.11′H), 7.68 (s, 1H, C.sub.8′H), 7.57 (d, J=8.0 Hz, 1H, C.sub.8H), 7.39-7.35 (m, 3H, C.sub.7H, SO.sub.2Ph-o-H), 7.30-7.19 (m, 3H, C.sub.5H, C.sub.6H, SO.sub.2Ph-p-H), 7.03 (t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.92 (app-d, J=8.8 Hz, 2H, C.sub.12′H), 6.76 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.60 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 6.38 (s, 1H, C.sub.2H), 5.21 (s, 1H, C.sub.15H), 4.61 (t, J=6.7 Hz, 2H, C.sub.7′H), 3.94-3.91 (m, 2H, C.sub.5′H), 3.81 (s, 3H, C.sub.14′H), 3.62 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.10 (s, 3H, C.sub.17H), 2.83 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.42 (p, J=6.3 Hz, 2H, C.sub.6′H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.1 (C.sub.13), 160.1 (C.sub.16), 159.7 (C.sub.14′), 157.8 (C.sub.4′), 147.8 (C.sub.9′), 141.3 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 131.7 (C.sub.1′), 129.8 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 127.2 (SO.sub.2Ph-o-C), 127.1 (C.sub.11′), 126.2 (C.sub.6), 125.6 (C.sub.5), 123.3 (C.sub.10′), 119.3 (C.sub.8′), 118.9 (C.sub.8), 115.0 (C.sub.3′), 114.4 (C.sub.12′), 87.6 (C.sub.2), 74.6 (C.sub.11), 68.4 (C.sub.15), 64.3 (C.sub.5′), 59.5 (C.sub.3), 55.4 (C.sub.14′), 47.1 (C.sub.7′), 45.4 (C.sub.12), 32.1 (C.sub.17), 30.0 (C.sub.6′). FTIR (thin film) cm.sup.−1: 3058 (m), 2958 (w), 1700 (s), 1646 (s), 1559 (m), 1512 (s), 1458 (m), 1250 (w), 1171 (s), 1032 (w), 836 (m). HRMS (ESI) (m/z): calc'd for C.sub.38H.sub.35N.sub.6O.sub.6S.sub.3[M+H].sup.+: 767.1775, found: 767.1796. [α].sub.D.sup.23: +315 (c=0.10, CHCl.sub.3). TLC (100% ethyl acetate), Rf: 0.38 (UV, CAM).

##STR00184##

Example 8: Diketopiperazine (+)—S6

[0568] Triethylamine (47.0 mL, 337 mmol, 7.00 equiv) was added via cannula to a solution of L-tryptophan derivative (−)—S4.sup.45 (21.4 g, 48.1 mmol, 1 equiv), glycine methyl ester hydrochloride (7.86 g, 62.6 mmol, 1.30 equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrogen chloride (EDC.HCl, 21.2 g, 111 mmol, 2.30 equiv), N-hydroxybenzotriazole (HOBt, 9.76 g, 72.2 mmol, 1.20 equiv), and powdered 4 Å molecular sieves (25.0 g) in dichloromethane (500 mL) at 0° C. The ice-water bath was removed and the solution was allowed to stir and warm to 23° C. After 18 h, the reaction mixture was washed with an aqueous hydrogen chloride solution (1 M, 150 mL), the layers were separated, and the organic layer was washed sequentially with a saturated aqueous sodium bicarbonate solution (150 mL) and with a saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure to afford dipeptide (−)—S5 as an orange foam that was used in the next step without further purification..sup.46 Trifluoroacetic acid (TFA, 73 mL) was added to a solution of crude dipeptide (−)—S5 (22.8 g) in dichloromethane (365 mL) at 23° C. After 2 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in tert-butanol (335 mL) and stirred vigorously at 23° C. as morpholine (125 mL) was added via cannula. After 16 h, the reaction mixture was concentrated under reduced pressure, and the resulting orange oil was dissolved in diethyl ether (225 mL) and ethyl acetate (75 mL). The resulting solution was stirred vigorously and was diluted with an aqueous hydrogen chloride solution (1 M, 225 mL), resulting in the formation of a white precipitate. After 1 h, the solids were collected by filtration and were washed sequentially with diethyl ether (3×100 mL) and with deionized water (4×100 mL), and were dried under reduced pressure at 50° C. for 12 h to afford diketopiperazine (+)—S6 (13.6 g, 73.7% overall) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 25° C.): δ 8.26 (d, J=2.1 Hz, 1H, NH), 7.92 (s, 1H, NH), 7.92-7.89 (m, 2H, SO.sub.2Ph-o-H), 7.85 (d, J=8.2 Hz, 1H, C.sub.8H), 7.68 (app-t, J=7.4 Hz, 1H, SO.sub.2Ph-p-H), 7.63 (d, J=7.6 Hz, 1H, C.sub.5H), 7.59-7.56 (m, 3H, C.sub.2H, SO.sub.2Ph-m-H), 7.32 (app-t, J=7.7 Hz, 1H, C.sub.7H), 7.24 (app-t, J=7.5 Hz, 1H, C.sub.6H), 4.18-4.12 (m, 1H, C.sub.11H), 3.42 (dd, J=1.9, 17.6 Hz, 1H, C.sub.15H.sub.a), 3.21 (dd, J=4.6, 14.7 Hz, 1H, C.sub.12H.sub.a), 3.01 (dd, J=4.7, 14.4 Hz, 1H, C.sub.12H.sub.b), 2.86 (app-d, J=16.5 Hz, 1H, C.sub.15H.sub.b). .sup.13C NMR (100 MHz, DMSO-d.sub.6, 25° C.): δ 167.2 (C.sub.13), 165.4 (C.sub.16), 136.9 (SO.sub.2Ph-ipso-C), 134.6 (SO.sub.2Ph-p-C), 134.0 (C.sub.9), 130.8 (C.sub.4), 129.8 (SO.sub.2Ph-m-C), 126.6 (SO.sub.2Ph-o-C), 125.4 (C.sub.2), 124.8 (C.sub.7), 123.3 (C.sub.6), 120.3 (C.sub.5), 117.4 (C.sub.3), 112.9 (C.sub.8), 54.3 (C.sub.11), 43.9 (C.sub.15), 28.0 (C.sub.12). FTIR (thin film) cm.sup.−1: 3048 (m), 1664 (s), 1457 (m), 1364 (m), 1326 (m), 1274 (m), 1169 (s), 1118 (s), 976 (w), 826 (w). HRMS (DART) (m/z): calc'd for C.sub.19H.sub.18N.sub.3O.sub.4S [M+H].sup.+: 384.1013, found: 384.1014. [α].sub.D.sup.23: +13 (c=0.20, DMSO). TLC (30% acetone in dichloromethane), Rf: 0.11 (UV, CAM).

##STR00185##

Example 9: Endo-Tetracyclic Bromide (+)-15

[0569] A solution of bromine (1.0 M, 26 mL, 26 mmol, 5.0 equiv) in dichloromethane was slowly poured into a solution of diketopiperazine (+)—S6 (2.00 g, 5.22 mmol, 1 equiv) in dichloromethane (105 mL) at 23° C. After 10 min, the reaction mixture was diluted with a saturated aqueous sodium thiosulfate solution (65 mL) and was extracted with ethyl acetate (350 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (2×80 mL) and with a saturated aqueous sodium chloride solution (80 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting solid was suspended in diethyl ether (200 mL), was collected by filtration, and was washed with diethyl ether (3×50 mL) to afford a mixture of the endo-tetracyclic bromide (+)-15 and its minor exo-diastereomer (1.91 g, 79.2%, >18:1 dr) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, gHMBC, and gNOESY experiments. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 25° C.): δ 8.01 (app-d, J=4.8 Hz, 1H, N.sub.14H), 7.91 (app-d, J=8.4 Hz, 2H, SO.sub.2Ph-o-H), 7.65-7.61 (app-t, J=7.4 Hz, 1H, SO.sub.2Ph-p-H), 7.55-7.51 (m, 2H, SO.sub.2Ph-m-H), 7.47 (d, J=7.6 Hz, 1H, C.sub.5H), 7.34-7.32 (m, 2H, C.sub.7H, C.sub.8H), 7.17-7.13 (m, 1H, C.sub.6H), 6.28 (s, 1H, C.sub.2H), 4.54 (dd, J=4.2, 10.0 Hz, 1H, C.sub.11H), 3.98 (d, J=17.1 Hz, 1H, C.sub.15H.sub.a), 3.48 (dd, J=5.0, 17.1 Hz, 1H C.sub.15H.sub.b), 3.38-3.33 (m, 1H, C.sub.12H.sub.β), 2.97 (dd, J=10.2, 14.0 Hz, 1H, C.sub.12H.sub.α). .sup.13C NMR (100 MHz, DMSO-d.sub.6, 25° C.): δ 168.0 (C.sub.13), 165.9 (C.sub.16), 138.3 (C.sub.9), 138.0 (SO.sub.2Ph-ipso-C), 134.7 (C.sub.4), 134.0 (SO.sub.2Ph-p-C), 130.71 (C.sub.7), 129.1 (SO.sub.2Ph-m-C), 128.0 (SO.sub.2Ph-o-C), 125.9 (C.sub.6), 125.4 (C.sub.5), 116.5 (C.sub.8), 86.0 (C.sub.2), 61.6 (C.sub.3), 57.1 (C.sub.11), 46.3 (C.sub.15), 37.2 (C.sub.12). FTIR (thin film) cm.sup.−1: 1684 (s), 1653 (s), 1559 (m), 1540 (m), 1473 (m), 1457 (m), 1165 (s), 1090 (m), 971 (w), 948 (w), 731 (m), 683 (w), 667 (m). HRMS (DART) (m/z) calc'd for C.sub.19H.sub.17BrN.sub.3O.sub.4S [M+H].sup.+: 462.0118, found: 462.0154. [α].sub.D.sup.23: +143 (c=0.29, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.37 (UV, CAM).

##STR00186##

Example 10: Anisole Adduct (+)-16

[0570] Silver hexafluoroantimonate (2.95 g, 8.58 mmol, 2.00 equiv) was added as a solid in one portion to a solution of endo-tetracyclic bromide (+)-15 (2.00 g, 4.29 mmol, 1 equiv), 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 1.94 g, 9.44 mmol, 2.20 equiv), and anisole (22 mL) in dichloromethane (22 mL) at 23° C. After 1 h, the reaction mixture was diluted with dichloromethane (50 mL) and was filtered through a pad of Celite. The filter cake was washed with dichloromethane (3×50 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.70% acetone in dichloromethane) to afford anisole adduct (+)-16 (2.03 g, 96.6%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.56 (d, J=8.0 Hz, 1H, C.sub.8H), 7.41 (app-d, J=8.4 Hz, 2H, SO.sub.2Ph-o-H), 7.31-7.26 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.14-7.10 (m, 2H, C.sub.5H, C.sub.6H), 7.06 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H) 6.67 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.59 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.50 (d, J=4.5 Hz, 1H, N.sub.14H), 6.16 (s, 1H, C.sub.2H), 4.42 (dd, J=5.6, 9.4 Hz, 1H, C.sub.11H), 3.95 (d, J=17.3 Hz, 1H, C.sub.15H.sub.a), 3.88-3.82 (m, 1H, C.sub.15H.sub.b), 3.75 (s, 3H, C.sub.5′H), 3.10 (dd, J=5.6, 14.1 Hz, 1H, C.sub.12H.sub.a), 2.79 (dd, J=9.4, 14.1 Hz, 1H, C.sub.12H.sub.b). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 169.6 (C.sub.13), 166.1 (C.sub.16), 158.8 (C.sub.4′), 139.8 (SO.sub.2Ph-ipso-C), 138.2 (C.sub.9), 135.2 (C.sub.4), 132.9 (SO.sub.2Ph-p-C), 132.4 (C.sub.1′), 129.5 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.3 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.3 (C.sub.6), 125.3 (C.sub.5), 117.3 (C.sub.8), 114.5 (C.sub.3′), 87.3 (C.sub.2), 59.5 (C.sub.3), 58.4 (C.sub.11), 55.5 (C.sub.5′), 47.5 (C.sub.15), 37.8 (C.sub.12). FTIR (thin film) cm.sup.−1: 3254 (m), 3064 (w), 2929 (w), 1700 (s), 1654 (m), 1610 (m), 1514 (s), 1458 (m), 1362 (m), 1254 (s), 1170 (s), 1090 (m), 1033 (m), 975 (m), 833 (m), 687(m). HRMS (DART) (m/z): calc'd for C.sub.26H.sub.24N.sub.3O.sub.5S [M+H].sup.+: 490.1431, found: 490.1453. [α].sub.D.sup.23: +56 (c=0.14, CHCl.sub.3). TLC (50% acetone in dichloromethane), Rf: 0.30 (UV, CAM).

##STR00187##

Example 11: Alkyne (+)-18

[0571] Anisole adduct (+)-16 (1.94 g, 3.96 mmol, 1 equiv) was azeotropically dried by concentration from anhydrous benzene (3×50 mL) under reduced pressure. Tetrahydrofuran (70 mL) and anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 25 mL) were introduced sequentially via cannula, and the solution was cooled to −78° C. A solution of lithium bis(trimethylsilyl)amide (LHMDS, 861 mg, 5.15 mmol, 1.30 equiv) in tetrahydrofuran (28 mL) was then added via cannula, and the reaction mixture was warmed to −30° C. After 20 min, a solution of bromide 17.sup.47 (2.37 g, 9.90 mmol, 2.50 equiv, azeotropically dried by concentration from anhydrous benzene (3×10 mL) under reduced pressure) in tetrahydrofuran (2.0 mL) was added via syringe. After 4 h, the reaction mixture was diluted with a saturated aqueous ammonium chloride solution (75 mL) and with ethyl acetate (350 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5-10% acetone in dichloromethane) to afford alkyne (+)-18 (1.53 g, 59.6%) as a white foam. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.57 (d, J=8.0 Hz, 1H, C.sub.8H), 7.45 (app-d, J=7.4 Hz, 2H, SO.sub.2Ph-o-H), 7.33-7.29 (m, 5H, OCH.sub.2Ph), 7.28-7.27 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.11-7.07 (m, 4H, C.sub.5H, C.sub.6H, SO.sub.2Ph-m-H), 6.67 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.60 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.52 (s, 2H, OCH.sub.2Ph), 4.43 (dd, J=6.8, 8.8 Hz, 1H, C.sub.11H), 4.36 (dt, J=1.7, 17.4 Hz, 1H, C.sub.15H.sub.a), 4.13 (d, J=17.2 Hz, 1H, C.sub.17H.sub.a), 4.13 (app-t, J=1.8 Hz, 2H, C.sub.20H) 3.98 (d, J=17.3 Hz, 1H, C.sub.17H.sub.b), 3.93 (dt, J=1.8, 17.4 Hz, 1H, C.sub.15H.sub.b), 3.74 (s, 3H, C.sub.5′H), 3.07 (dd, J=6.7, 14.2 Hz, 1H, C.sub.12H.sub.a), 2.85 (dd, J=9.1, 14.1 Hz, 1H, C.sub.12H.sub.b). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 166.7 (C.sub.13), 165.3 (C.sub.16), 158.8 (C.sub.4′), 139.8 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 137.4 (OCH.sub.2Ph-ipso-C), 135.6 (C.sub.4), 132.9 (SO.sub.2Ph-p-C), 132.5 (C.sub.1′), 129.2 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.6 (OCH.sub.2Ph-m-C), 128.2 (OCH.sub.2Ph-o-C), 128.1 (C.sub.2′), 128.0 (OCH.sub.2Ph-p-C), 127.6 (SO.sub.2Ph-o-C), 126.0 (C.sub.6), 125.4 (C.sub.5), 117.2 (C.sub.8), 114.4 (C.sub.3′), 87.1 (C.sub.2), 81.2 (C.sub.19), 79.6 (C.sub.18), 72.0 (OCH.sub.2Ph), 59.4 (C.sub.3), 58.6 (C.sub.11), 57.5 (C.sub.20), 55.4 (C.sub.5′), 51.7 (C.sub.17), 38.7 (C.sub.12), 35.3 (C.sub.15). FTIR (thin film) cm.sup.−1: 3063 (w), 2932 (w), 1685 (s), 1609 (m), 1513 (m), 1409 (m), 1254 (m), 1171 (s), 1090 (m), 977 (w), 832 (m), 737 (m). HRMS (DART) (m/z): calc'd for 37H.sub.34N.sub.306S [M+H].sup.+: 648.2163, found: 648.2180. [α].sub.D.sup.23:+46 (c=0.14, CHCl.sub.3). TLC (10% acetone in dichloromethane), Rf: 0.65 (UV, CAM).

##STR00188##

Example 12: Alcohol (+)-19

[0572] A suspension of alkyne (+)-18 (787 mg, 1.21 mmol, 1 equiv) and palladium on activated charcoal (5% w/w, 185 mg, 84.7 μmol, 0.0700 equiv) in ethyl acetate (45 mL) at 23° C. was sparged with hydrogen gas for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture, and was then allowed to stir under an atmosphere of hydrogen gas. After 30 min, ethanol (100 mL) was added via cannula to the reaction mixture, the reaction mixture was sparged with hydrogen gas for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture, and the reaction mixture was allowed to stir under an atmosphere of hydrogen gas. After 1 h, the reaction mixture was filtered through a pad of Celite, the filter cake was washed with ethyl acetate (3×50 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 90% acetone in dichloromethane) to afford alcohol (+)-19 (634 mg, 93.2%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): 67.52 (d, J=7.5 Hz, 1H, C.sub.8H), 7.36 (app-d, J=7.5 Hz, 2H, SO.sub.2Ph-o-H), 7.29-7.21 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.14 (app-d, J=7.5 Hz, 1H, C.sub.5H) 7.08 (app-t, J=7.4 Hz, 1H, C.sub.6H), 7.02 (app-t, J=8.1 Hz, 2H, SO.sub.2Ph-m-H), 6.65 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.55 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.14 (s, 1H, C.sub.2H), 4.44 (dd, J=5.1, 9.1 Hz, 1H, C.sub.11H), 4.09 (d, J=17.1 Hz, 1H, C.sub.15H.sub.a), 3.79 (d, J=17.1 Hz, 1H, C.sub.15H.sub.b), 3.71 (s, 3H, C.sub.5′H), 3.47 (t, J=6.2 Hz, 2H, C.sub.20H), 3.41-3.34 (m, 1H, C.sub.17H.sub.a), 3.19-3.10 (m, 2H, C.sub.17H.sub.b, C.sub.12H.sub.a), 2.79 (dd, J=9.4, 14.1 Hz, 1H, C.sub.12H.sub.b), 2.50 (br-s, 1H, OH), 1.41 (app-p, J=7.2 Hz, 2H, C.sub.19H), 1.22-1.14 (m, 2H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.4 (C.sub.13), 165.8 (C.sub.16), 158.7 (C.sub.4′), 139.7 (C.sub.9), 138.1 (SO.sub.2Ph-ipso-C), 135.1 (C.sub.4), 132.8 (SO.sub.2Ph-p-C), 132.2 (C.sub.1′), 129.2 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.2 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.4 (C.sub.6), 125.2 (C.sub.5), 116.9 (C.sub.8), 114.3 (C.sub.3′), 87.2 (C.sub.2), 62.1 (C.sub.20), 59.7 (C.sub.3), 58.8 (C.sub.11), 55.4 (C.sub.5′), 52.4 (C.sub.15), 45.8 (C.sub.17), 37.8 (C.sub.12), 29.0 (C.sub.18), 23.8 (C.sub.19). FTIR (thin film) cm.sup.−1: 3440 (w), 2936 (w), 1675 (s), 1653 (m), 1559 (m), 1514 (m), 1419 (m), 1362 (s), 1255 (s), 1169 (s), 1090 (w), 981 (w), 734 (m), 686 (m), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.32N.sub.3O.sub.6S [M+H].sup.+: 562.2006, found: 562.1997. [α].sub.D.sup.23: +40 (c 0.17, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.13 (UV, CAM).

##STR00189##

Example 13: Azide (+)-20

[0573] Diisopropyl azodicarboxylate (DIAD, 526 μL, 2.67 mmol, 1.50 equiv) and diphenylphosphoryl azide (DPPA, 575 μL, 2.67 mmol, 1.50 equiv) were added dropwise via syringe to a suspension of alcohol (+)-19 (1.00 g, 1.78 mmol, 1 equiv) and resin-bound triphenylphosphine (1.31 mmol/g on 100-200 mesh polystyrene cross-linked with 1% divinylbenzene, 1.90 g, 2.49 mmol, 1.40 equiv) in tetrahydrofuran (43 mL) at 0° C. After 5 min, the ice-water bath was removed and the reaction mixture was allowed to stir and warm to 23° C. After 14 h, the reaction mixture was filtered through a 1 cm pad of Celite in a 60-mL medium-porosity fritted-glass funnel. The filter cake was washed with dichloromethane (100 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.15% acetone in dichloromethane) to afford azide (+)-20 (697 mg, 66.7%) as a clear oil. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.56 (d, J=7.5 Hz, 1H, C.sub.8H), 7.41 (app-d, J=7.9 Hz, 2H, SO.sub.2Ph-o-H), 7.32-7.24 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.15 (d, J=7.5 Hz, 1H, C.sub.5H) 7.12-7.04 (m, 3H, C.sub.6H, SO.sub.2Ph-m-H), 6.68 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.59 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.39 (dd, J=5.2, 9.2 Hz, 1H, C.sub.11H), 4.07 (d, J=17.0 Hz, 1H, C.sub.15H.sub.a), 3.76 (d, J=16.9 Hz, 1H, C.sub.15H.sub.b), 3.75 (s, 3H, C.sub.5′H), 3.39 (dt, J=7.2, 14.0 Hz, 1H, C.sub.17H.sub.a) 3.22-3.06 (m, 4H, C.sub.17H.sub.b, C.sub.20H, C.sub.12H.sub.a), 2.82 (dd, J=9.4, 14.1 Hz, 1H, C.sub.12H.sub.b), 1.47-1.37 (m, 2H, C.sub.18H), 1.26-1.20 (m, 2H, C.sub.19H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.3 (C.sub.13), 165.4 (C.sub.16), 158.8 (C.sub.4′), 139.9 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.1 (C.sub.4), 132.9 (SO.sub.2Ph-p-C), 132.2 (C.sub.1′), 129.3 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.2 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.4 (C.sub.6), 125.2 (C.sub.5), 117.0 (C.sub.8), 114.4 (C.sub.3′), 87.2 (C.sub.2), 59.8 (C.sub.3), 58.9 (C.sub.11), 55.5 (C.sub.5′), 52.5 (C.sub.15), 51.0 (C.sub.20), 45.5 (C.sub.17), 37.9 (C.sub.12), 25.7 (C.sub.19), 24.5 (C.sub.18). FTIR (thin film) cm.sup.−1: 3063 (w), 2932 (m), 2098 (s), 1700 (s), 1684 (s), 1514 (m), 1458 (m), 1362 (m), 1255 (m), 1169 (m), 1091 (m), 756 (s), 668 (s). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.31N.sub.6O.sub.5S [M+H].sup.+: 587.2071, found: 587.2073. [α].sub.D.sup.23: +32 (c=0.17, CHCl.sub.3). TLC (10% acetone in dichloromethane), Rf: 0.43 (UV, CAM).

##STR00190##

Example 14: Diol (+)-21

[0574] Tetra-n-butylammonium permanganate.sup.42 (2.13 g, 5.90 mmol, 5.00 equiv) was added as a solid to a solution of azide (+)-20 (692 mg, 1.18 mmol, 1 equiv) in dichloromethane (43 mL) at 23° C. After 2 h, the reaction mixture was diluted with a saturated aqueous sodium sulfite solution (50 mL) and with ethyl acetate (150 mL). The resulting mixture was washed with a saturated aqueous sodium bicarbonate solution (50 mL), the layers were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were extracted with ethyl acetate (2×50 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% acetone in dichloromethane) to afford diol (+)-21 (340 mg, 47.6%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.53 (d, J=8.0 Hz, 1H, C.sub.8H), 7.30-7.14 (m, 6H, C.sub.5H, C.sub.6H, C.sub.7H, SO.sub.2Ph-o-H, SO.sub.2Ph-p-H), 6.99 (app-t, J=7.6 Hz, 2H, SO.sub.2Ph-m-H), 6.77 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.54 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.43 (s, 1H, C.sub.2H), 6.06 (d, J=6.4 Hz, 1H, C.sub.15OH), 5.67 (s, 1H, C.sub.11OH), 5.23 (d, J=6.4 Hz, 1H, C.sub.15H), 3.74 (s, 3H, C.sub.5′H), 3.57 (d, J=15.1 Hz, 1H, C.sub.12H.sub.a), 3.44-3.39 (m, 2H, C.sub.17H) 3.18 (t, J=6.8 Hz, 2H, C.sub.20H), 2.87 (d, J=15.0 Hz, 1H, C.sub.12H.sub.b), 1.66-1.48 (m, 2H, C.sub.18H), 1.40-1.28 (m, 2H, C.sub.19H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.3 (C.sub.13), 166.4 (C.sub.16), 158.7 (C.sub.4′), 139.5 (C.sub.9), 138.0 (SO.sub.2Ph-ipso-C), 136.3 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 133.0 (C.sub.1′), 129.3 (C.sub.7), 128.7 (C.sub.2′), 128.7 (SO.sub.2Ph-m-C), 127.4 (SO.sub.2Ph-o-C), 126.9 (C.sub.6), 125.9 (C.sub.5), 117.3 (C.sub.8), 114.3 (C.sub.3), 88.3 (C.sub.11), 88.3 (C.sub.2), 82.0 (C.sub.15), 58.9 (C.sub.3), 55.5 (C.sub.5′), 51.1 (C.sub.20), 47.8 (C.sub.12), 44.9 (C.sub.17), 26.0 (C.sub.19), 25.5 (C.sub.18). FTIR (thin film) cm.sup.−1: 2936 (w), 2097 (s), 1700 (s), 1684 (s), 1513 (m), 1474 (m), 1458 (m), 1362 (m), 1254 (s), 1169 (s), 1091 (w), 832 (m), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.31N.sub.6O.sub.7S [M+H].sup.+: 619.1969, found: 619.1991. [α].sub.D.sup.23: +26 (c=0.20, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.55 (UV, CAM).

##STR00191##

Example 15: Epidithiodiketopiperazine Azide (+)-9b

[0575] A solution of diol (+)-21 (259 mg, 419 μmol, 1 equiv) in anhydrous nitroethane (18 mL) at 0° C. was sparged with hydrogen sulfide gas for 20 min by discharge of a balloon equipped with a needle extending into the reaction mixture, providing a saturated hydrogen sulfide solution. Trifluoroacetic acid (TFA, 13.5 mL) was added via syringe over 20 seconds, and the sparging with hydrogen sulfide gas was maintained for another 20 min. The ice-water bath was removed, and the solution was allowed to stir and warm to 23° C. under an atmosphere of hydrogen sulfide. After 2 h, the reaction mixture was diluted with ethyl acetate (150 mL) and was slowly poured into a saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (40 mL). A stock solution of potassium triiodide in pyridine.sup.43 was added dropwise into the organic layer containing crude bisthiol S7 until a persistent yellow color was observed. The resulting mixture was washed with an aqueous hydrogen chloride solution (1 M, 2×40 mL), was washed with a saturated aqueous sodium chloride solution (40 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.15% ethyl acetate in dichloromethane) to afford epidithiodiketopiperazine azide (+)-9b (136 mg, 50.0%) as a beige solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments..sup.48 1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.61 (d, J=8.0 Hz, 1H, C.sub.8H), 7.40-7.37 (m, 1H, C.sub.7H), 7.35 (app-d, J=5.5 Hz, 2H, SO.sub.2Ph-o-H), 7.30-7.21 (m, 3H, C.sub.5H, C.sub.6H, SO.sub.2Ph-p-H, 7.02 (app-t, J=8.0 Hz, 2H, SO.sub.2Ph-m-H), 6.75 (app-d, J=6.7 Hz, 2H, C.sub.2′H), 6.61 (app-d, J=6.8 Hz, 2H, C.sub.3′H), 6.39 (s, 1H, C.sub.2H), 5.32 (s, 1H, C.sub.15H), 3.76 (s, 3H, C.sub.5′H), 3.63 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.56 (t, J=6.9 Hz, 2H, C.sub.17H), 3.30 (t, J=6.6 Hz, 2H, C.sub.20H), 2.84 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 1.85-1.67 (m, 2H, C.sub.18H), 1.65-1.58 (m, 2H, C.sub.19H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.0 (C.sub.13), 160.3 (C.sub.16), 159.0 (C.sub.4′), 141.3 (C.sub.9), 138.5 (SO.sub.2Ph-ipso-C), 135.9 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 131.3 (C.sub.1′), 129.9 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.2 (C.sub.6), 125.7 (C.sub.5), 119.0 (C.sub.8), 114.6 (C.sub.3′), 87.7 (C.sub.2), 74.9 (C.sub.11), 66.6 (C.sub.15), 59.6 (C.sub.3), 55.5 (C.sub.5′), 51.1 (C.sub.20), 45.5 (C.sub.12), 45.4 (C.sub.17), 26.2 (C.sub.19), 25.4 (C.sub.18). FTIR (thin film) cm.sup.−1: 3063 (w), 2932 (s), 2098 (s), 1717 (s), 1700 (s), 1685 (s), 1609 (m), 1514 (s), 1458 (m), 1363 (m), 1256 (s), 1171 (s), 1090 (m), 972 (m), 737 (m). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.32N.sub.7O.sub.5S.sub.3[M+NH.sub.4].sup.+: 666.1622, found: 666.1630. [α].sub.D.sup.23: +245 (c=0.22, CHCl.sub.3). TLC (20% ethyl acetate in dichloromethane), Rf: 0.61 (UV, CAM).

##STR00192##

Example 16: Triazole (+)-28b

[0576] A suspension of copper(I) iodide (5.5 mg, 29 μmol, 0.51 equiv), acetic acid (3.3 μL, 57 μmol, 1.0 equiv) and N—N-diisopropylethylamine (9.9 μL, 57 μmol, 1.0 equiv) in toluene (0.50 mL) was added via syringe to a solution of epidithiodiketopiperazine (+)-9b (37.0 mg, 57.0 mol, 1 equiv) and 4-ethynylanisole 27 (38 μL, 290 μmol, 5.1 equiv) in toluene (0.30 mL) at 23° C. After 18 h, the reaction mixture was diluted with dichloromethane (1.6 mL) and was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in dichloromethane.fwdarw.100% ethyl acetate) to afford triazole (+)-28b (37.6 mg, 84.5%) as a yellow solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.71 (app-d, J=8.8 Hz, 2H, C.sub.24H), 7.69 (s, 1H, C.sub.21H), 7.60 (d, J=8.0 Hz, 1H, C.sub.8H), 7.38 (td, J=1.8, 8.6 Hz, 1H, C.sub.7H), 7.32 (app-d, J=7.9 Hz, 2H, SO.sub.2Ph-o-H), 7.29-7.21 (m, 3H, C.sub.5H, C.sub.6H, SO.sub.2Ph-p-H), 7.01 (app-t, J=7.6 Hz, 2H, SO.sub.2Ph-m-H), 6.91 (app-d, J=8.8 Hz, 2H, C.sub.25H), 6.75 (app-d, J=6.8 Hz, 2H, C.sub.2′H), 6.61 (app-d, J=6.9 Hz, 2H, C.sub.3′H), 6.39 (s, 1H, C.sub.2H), 5.37 (s, 1H, C.sub.15H), 4.40 (t, J=6.9 Hz, 2H, C.sub.20H), 3.81 (s, 3H, C.sub.27H), 3.76 (s, 3H, C.sub.5′H), 3.66-3.51 (m, 2H, C.sub.17H), 3.63 (d, J=15.4 Hz, 1H, C.sub.12H.sub.a), 2.83 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 1.97 (p, J=7.3 Hz, 2H, C.sub.19H), 1.84-1.67 (m, 2H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 164.9 (C.sub.13), 160.2 (C.sub.16), 159.6 (C.sub.26), 158.8 (C.sub.4′), 147.7 (C.sub.22), 141.1 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 135.7 (C.sub.4), 132.9 (SO.sub.2Ph-p-C), 131.0 (C.sub.1′), 129.7 (C.sub.7), 128.5 (SO.sub.2Ph-m-C), 127.9 (C.sub.2′), 127.1 (SO.sub.2Ph-o-C), 127.1 (C.sub.24), 126.1 (C.sub.6), 125.6 (C.sub.5), 123.4 (C.sub.23), 119.0 (C.sub.21), 118.8 (C.sub.8), 114.4 (C.sub.3′), 114.2 (C.sub.25), 87.7 (C.sub.2), 74.7 (C.sub.11), 66.3 (C.sub.15), 59.4 (C.sub.3), 55.4 (C.sub.5′), 55.3 (C.sub.27), 49.6 (C.sub.20), 45.3 (C.sub.12), 44.9 (C.sub.17), 27.3 (C.sub.19), 24.9 (C.sub.18). FTIR (thin film) cm.sup.−1: 2926 (m), 1717 (s), 1700 (s), 1685 (s), 1653 (m), 1559 (m), 1457 (m), 1362 (m), 1252 (s), 1172 (m), 1032 (m), 737 (m), 668 (m). HRMS (ESI) (m/z): calc'd for C.sub.39H.sub.37N.sub.6O.sub.6S.sub.3 [M+H].sup.+: 781.1931, found: 781.1947. [α].sub.D.sup.23: +484 (c=0.06, CHCl.sub.3). TLC (100% ethyl acetate), Rf: 0.41 (UV, CAM).

##STR00193##

Example 17: Sulfonyl Chloride S9

[0577] Chlorosulfonic acid (5.20 mL, 77.9 mmol, 1.00 equiv) was added via syringe to a solution of (3-azidopropoxy)benzene.sup.49 (S7, 13.8 g, 77.9 mmol, 1 equiv) in dichloromethane (165 mL) at 0° C. After 45 min, the reaction mixture was concentrated under reduced pressure, and the resulting colorless residue was dissolved in thionyl chloride (100 mL). N,N-Dimethylformamide (250 μL, 3.2 mmol, 0.041 equiv) was added via syringe, and the reaction mixture was heated to reflux in an oil bath at 95° C. After 1.5 h, the brown solution was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (600 mL) and was washed with an aqueous sodium hydroxide solution (1.25 M, 2×100 mL) and with a saturated aqueous sodium chloride solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 25% ethyl acetate in hexanes) to afford sulfonyl chloride S9 (9.58 g, 44.6%) as a yellow oil. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.95 (d, J=9.0 Hz, 2H, C.sub.2″H), 7.03 (d, J=9.0 Hz, 2H, C.sub.3″H), 4.14 (t, J=5.9 Hz, 2H, C.sub.5″H), 3.52 (t, J=6.5 Hz, 2H, C.sub.7″H), 2.08 (p, J=6.2 Hz, 2H, C.sub.6″H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 164.1 (C.sub.4″), 136.5 (C.sub.1″), 129.8 (C.sub.2″), 115.3 (C.sub.3″) 65.6 (C.sub.5″), 48.1 (C.sub.7″), 28.6 (C.sub.6″). FTIR (thin film) cm.sup.−1: 3101 (w), 2948 (m), 2098 (s), 1594 (s), 1374 (m), 1085 (m), 833 (m). HRMS (ESI) (m/z): calc'd for C.sub.9H.sub.10ClN.sub.3NaO.sub.3S [M+Na].sup.+: 298.0024, found: 298.0040. TLC (25% ethyl acetate in hexanes), Rf: 0.44 (UV, CAM).

##STR00194##

Example 18: N-Sulfonylated Tryptophan (−)-22

[0578] N-Boc-L-tryptophan (2.76 g, 9.07 mmol, 2.00 equiv) was azeotropically dried by concentration from anhydrous benzene (3×15 mL) under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (20 mL) and cooled to −65° C. A solution of lithium hexamethyldisilazide (LHMDS, 4.55 g, 47.2 mmol, 6.00 equiv) in tetrahydrofuran (20 mL) was added via cannula over 5 min. After 1 h, sulfonyl chloride S9 (1.25 g, 4.53 mmol, 1 equiv) was added via syringe in one portion and the reaction mixture was stirred for an additional 2 h at −65° C. Excess base was quenched at this temperature by addition of a solution of acetic acid in ethyl acetate (1:1 v/v, 5 mL), then the ice-water bath was removed and the resulting mixture was allowed to stir and warm to room temperature. The mixture was then diluted with an aqueous hydrogen chloride solution (1 M, 100 mL) and was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% acetic acid, 45% hexanes, 50% dichloromethane).sup.50 to afford N-sulfonylated tryptophan (−)-22 (1.22 g, 50.8%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, DMSO-d.sub.6, 25° C.): δ 12.7 (br-s, 1H, CO.sub.2H), 7.88 (d, J=8.2 Hz, 1H, C.sub.8H), 7.84 (app-d, J=9.0 Hz, 2H, C.sub.2H), 7.60-7.58 (m, 2H, C.sub.2H, C.sub.5H), 7.35 (t, J=7.7 Hz, 1H, C.sub.7H), 7.26 (t, J=7.3 Hz, 1H, C.sub.6H), 7.17 (d, J=8.2 Hz, 1H, N—H), 7.05 (app-d, J=9.0 Hz, 2H, C.sub.3″H), 4.21-4.16 (m, 1H, C.sub.11H), 4.05 (t, J=6.0 Hz, 2H, C.sub.5″H), 3.44 (t, J=6.7 Hz, 2H, C.sub.7″H), 3.11 (dd, J=4.3, 14.8 Hz, 1H, C.sub.12H.sub.a), 2.95 (dd, J=10.1, 14.8 Hz, 1H, C.sub.12H.sub.b), 1.93 (p, J=6.4 Hz, 2H, C.sub.6″H), 1.32 (s, 9H, C(CH.sub.3).sub.3). .sup.13C NMR (100 MHz, DMSO-d.sub.6, 25° C.): δ 173.3 (C.sub.13), 162.7 (C.sub.4″), 155.4 (CO.sub.2t-Bu), 134.2 (C.sub.9), 130.5 (C.sub.4), 129.0 (C.sub.2″), 128.6 (C.sub.1″), 124.7 (C.sub.7), 124.6 (C.sub.2), 123.2 (C.sub.6), 119.6 (C.sub.5), 118.7 (C.sub.3), 115.3 (C.sub.3″), 113.2 (C.sub.8), 78.2 (C(CH.sub.3).sub.3), 65.4 (C.sub.5″), 53.3 (C.sub.11), 47.5 (C.sub.7″), 28.1 (C(CH.sub.3).sub.3) 28.1 (C.sub.6″), 27.8 (C.sub.12). FTIR (thin film) cm.sup.−1: 2931 (w), 2100 (s), 1717 (s), 1653 (m), 1595 (m), 1497 (m), 1368 (s), 1261 (s), 1167 (s), 834 (m), 746 (w), 667 (m). HRMS (DART) (m/z): calc'd for C.sub.25H.sub.33N.sub.6O.sub.7S [M+NH.sub.4].sup.+: 561.2126, found: 561.2131. [α].sub.D.sup.23: −18 (c=0.14, DMSO). TLC (5% AcOH, 5% CH.sub.3OH, 40% hexanes, 50% CH.sub.2Cl.sub.2), Rf: 0.47 (UV, CAM).

##STR00195##

Example 19: Dipeptide (+)—S10

[0579] N—N-Diisopropylethylamine (3.00 mL, 17.0 mmol, 6.00 equiv) was added via syringe to a solution of carboxylic acid (−)-22 (1.50 g, 2.83 mmol, 1 equiv), sarcosine methyl ester hydrochloride (791 mg, 5.66 mmol, 2.00 equiv), and N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl-methanaminium hexafluorophosphate N-oxide (HATU, 2.59 g, 6.80 mmol, 2.40 equiv) in N,N-dimethylformamide (25 mL) at 23° C. After 16 h, the reaction mixture was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL) and with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were extracted with ethyl acetate (2×50 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 60% ethyl acetate in hexanes) to afford dipeptide (+)—S10 (1.30 g, 73.3%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Based on the .sup.1H NMR analysis at 25° C. in CDCl.sub.3, the product exists as a 5:1 mixture of major:minor conformers. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 7.92 (d, J=8.1 Hz, 1H, C.sub.8H), 7.77 (app-d, J=8.9 Hz, 2H, C.sub.2″H), 7.54 (d, J=7.7 Hz, 1H, C.sub.5H), 7.44 (s, 1H, C.sub.2H), 7.27 (app-t, J=7.3 Hz, 1H, C.sub.7H), 7.23-7.18 (m, 1H, C.sub.6H), 6.83 (d, J=9.0 Hz, 2H, C.sub.3″H), 5.38 (d, J=8.4 Hz, 1H, N.sub.10H), 4.93 (dd, J=6.2, 13.8 Hz, 1H, C.sub.11H), 4.00 (d, J=17.2 Hz, 1H, C.sub.15H.sub.a), 3.99 (t, J=5.9 Hz, 2H, C.sub.5″H), 3.92 (d, J=17.2 Hz, 1H, C.sub.15H.sub.b), 3.71 (s, 3H, N.sub.14CH.sub.3), 3.43 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.15-3.08 (m, 1H, C.sub.12H.sub.a), 3.05-2.95 (m, 1H, C.sub.12H.sub.b), 2.77 (s, 3H, C.sub.14H), 1.98 (p, J=6.2 Hz, 2H, C.sub.6″H), 1.38 (s, 9H, C(CH.sub.3).sub.3). Minor conformer: δ 7.92 (d, J=8.1 Hz, 2H, C.sub.8H), 7.77 (app-d, J=8.9 Hz, 2H, C.sub.2″H), 7.51 (d, J=7.8 Hz, 1H, C.sub.5H), 7.39 (s, 1H, C.sub.2H), 7.27 (app-t, J=7.3 Hz, 1H, C.sub.7H), 7.23-7.18 (m, 1H, C.sub.6H), 6.83 (d, J=9.0 Hz, 2H, C.sub.3″H), 5.28 (d, J=8.8 Hz, 1H, N.sub.10H), 4.69 (dd, J=6.9, 15.1 Hz, 1H, C.sub.11H), 3.99 (t, J=5.9 Hz, 2H, C.sub.5″H), 3.87 (d, J=18.4 Hz, 1H, C.sub.15H.sub.a), 3.79 (d, J=18.3 Hz, 1H, C.sub.15H.sub.b), 3.59 (s, 3H, N.sub.14CH.sub.3), 3.43 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.15-3.08 (m, 1H, C.sub.12H.sub.a), 3.05-2.95 (m, 1H, C.sub.12H.sub.b), 2.85 (s, 3H, C.sub.14H), 1.98 (p, J=6.2 Hz, 2H, C.sub.6″H), 1.37 (s, 9H, C(CH.sub.3).sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 172.2 (C.sub.13), 169.4 (C.sub.16), 162.9 (C.sub.4″), 155.2 (N.sub.10CO.sub.2t-Bu), 135.1 (C.sub.9), 131.2 (C.sub.4), 130.2 (C.sub.1″), 129.3 (C.sub.2″), 125.0 (C.sub.2), 124.9 (C.sub.7), 123.3 (C.sub.6), 119.6 (C.sub.5), 117.3 (C.sub.3), 114.9 (C.sub.3″), 113.8 (C.sub.8), 80.0 (C(CH.sub.3).sub.3), 65.1 (C.sub.15), 52.4 (N.sub.14CH.sub.3), 50.3 (C.sub.11), 49.7 (C.sub.5″), 48.0 (C.sub.7″), 36.5 (C.sub.14), 29.0 (C.sub.12), 28.6 (C.sub.6″), 28.4 (C(CH.sub.3).sub.3). Minor conformer: δ 172.1 (C.sub.13), 169.1 (C.sub.16), 162.9 (C.sub.4″), 155.2 (N.sub.10CO.sub.2t-Bu), 135.1 (C.sub.9), 131.0 (C.sub.4), 130.2 (C.sub.1″), 129.2 (C.sub.2″), 125.0 (C.sub.2), 124.8 (C.sub.7), 123.3 (C.sub.6), 119.6 (C.sub.5), 117.6 (C.sub.3), 114.9 (C.sub.3″), 113.8 (C.sub.8), 80.1 (C(CH.sub.3).sub.3), 65.1 (C.sub.15), 52.6 (N.sub.14CH.sub.3), 51.1 (C.sub.5″), 50.1 (C.sub.11), 48.0 (C.sub.7″), 36.5 35.3 (C.sub.14), 29.1 (C.sub.12), 28.6 (C.sub.6″), 28.4 (C(CH.sub.3).sub.3). FTIR (thin film) cm.sup.−1: 3318 (w), 2933 (w), 2100 (s), 1750 (s), 1700 (s), 1653 (s), 1594 (m), 1497 (w), 1365 (s), 1260 (s), 1168 (s), 977 (w), 834 (m), 668 (m). HRMS (ESI) (m/z): calc'd for C.sub.29H.sub.36N.sub.6NaO.sub.8S [M+Na].sup.+: 651.2208, found: 651.2212. [α].sub.D.sup.23: +31 (c=0.12, CHCl.sub.3). TLC (60% ethyl acetate in hexanes), Rf: 0.56 (UV, CAM).

##STR00196##

Example 20: Diketopiperazine (−)-23

[0580] Trifluoroacetic acid (TFA, 3.5 mL) was added via syringe to a solution of dipeptide (+)—S10 (951 mg, 1.51 mmol, 1 equiv) in dichloromethane (17.5 mL) at 23° C. After 2 h, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in t-butanol (15 mL). The reaction mixture was stirred vigorously at 23° C. as morpholine (5.6 mL) was added via syringe. After 17 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and was washed with an aqueous hydrogen chloride solution (1 M, 3×50 mL) and with a saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 75% acetone in dichloromethane) to afford diketopiperazine (−)-23 (741 mg, 98.8%) as a colorless oil. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.90 (d, J=8.3 Hz, 1H, C.sub.8H), 7.78 (app-d, J=8.9 Hz, 2H, C.sub.2″H), 7.55-7.45 (m, 3H, C.sub.2H, C.sub.5H, N.sub.10H), 7.27 (app-t, J=6.7 Hz, 1H, C.sub.7H), 7.19 (app-t, J=7.6 Hz, 1H, C.sub.6H), 6.85 (app-d, J=9.0 Hz, 2H, C.sub.3″H), 4.28 (br-s, 1H, C.sub.11H), 3.98 (t, J=5.9 Hz, 2H, C.sub.5″H), 3.48-3.40 (m, 1H, C.sub.15H.sub.a), 3.42 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.29 (dd, J=5.6, 14.6 Hz, 1H, C.sub.12H.sub.a), 3.19 (dd, J=3.4, 14.4 Hz, 1H, C.sub.12H.sub.b), 2.93 (d, J=17.3 Hz, 1H, C.sub.15H.sub.b), 2.59 (s, 3H, C.sub.17H), 1.97 (p, J=6.1 Hz, 2H, C.sub.6″H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 166.3 (C.sub.13), 165.7 (C.sub.16), 163.1 (C.sub.4″), 135.0 (C.sub.9), 130.3 (C.sub.4), 129.7 (C.sub.1″), 129.4 (C.sub.2″), 126.0 (C.sub.2), 125.2 (C.sub.7), 123.5 (C.sub.6), 120.0 (C.sub.5), 116.1 (C.sub.3), 115.2 (C.sub.3″), 113.6 (C.sub.8), 65.2 (C.sub.5″), 55.2 (C.sub.11), 51.1 (C.sub.15), 48.0 (C.sub.7″), 33.8 (C.sub.17), 30.6 (C.sub.12), 28.6 (C.sub.6″). FTIR (thin film) cm.sup.−1: 3235 (w), 3103 (w), 2934 (w), 2100 (s), 1685 (s), 1653 (s), 1594 (m), 1364 (m), 1263 (s), 1167 (s), 1122 (m), 1096 (m), 978 (m), 835 (m), 694 (m). HRMS (DART) (m/z): calc'd for C.sub.23H.sub.25N.sub.6O.sub.5S [M+H].sup.+: 497.1602, found: 497.1616. [α].sub.D.sup.23: −71 (c=0.11, CHCl.sub.3). TLC (50% acetone in dichloromethane), Rf: 0.43 (UV, CAM).

##STR00197##

Example 21: Endo-Tetracyclic Bromide (+)-24

[0581] A solution of bromine (1.0 M, 6.1 mL, 6.1 mmol, 5.0 equiv) in dichloromethane was slowly poured into a solution of diketopiperazine (−)-23 (606 mg, 1.22 mmol, 1 equiv) in dichloromethane (25 mL) at 23° C. After 10 min, the solution was diluted with a saturated aqueous sodium thiosulfate solution (40 mL) and was extracted with ethyl acetate (120 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (2×40 mL), was washed with a saturated aqueous sodium chloride solution (25 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting solid was suspended in diethyl ether (120 mL), was collected by filtration, and was washed with diethyl ether (3×50 mL) to afford endo-tetracyclic bromide (+)-24 and its minor exo-diastereomer (556 mg, 79.2%, >18:1 dr) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, gHMBC, and gNOESY experiments. .sup.1H NMR (400 MHz, DMSO, 25° C.): δ 7.84 (app-d, J=9.0 Hz, 2H, C.sub.2″H), 7.48 (d, J=7.5 Hz, 1H, C.sub.5H), 7.35-7.28 (m, 2H, C.sub.7H, C.sub.8H), 7.16 (app-t, J=7.0 Hz, 1H, C.sub.6H), 7.04 (app-d, J=9.0 Hz, 2H, C.sub.3″H), 6.27 (s, 1H, C.sub.2H), 4.61 (dd, J=5.6, 9.7 Hz, 1H, C.sub.11H), 4.19 (d, J=17.1 Hz, 1H, C.sub.15H.sub.a), 4.07 (t, J=6.1 Hz, 2H, C.sub.5″H), 3.77 (d, J=17.2 Hz, 1H, C.sub.15H.sub.b), 3.47 (t, J=6.1 Hz, 2H, C.sub.7″H), 3.28 (dd, J=5.6, 14.2 Hz, 1H, C.sub.12H□), 3.01 (dd, J=10.0, 14.2 Hz, 1H, C.sub.12H□), 2.70 (s, 3H, C.sub.17H), 1.94 (p, J=6.4 Hz, 2H, C.sub.6″H). .sup.13C NMR (100 MHz, DMSO, 25° C.): δ 166.3 (C.sub.13), 165.0 (C.sub.16), 162.4 (C.sub.4″), 138.5 (C.sub.9), 135.1 (C.sub.4), 130.6 (C.sub.7), 130.4 (C.sub.2″), 129.6 (C.sub.1″), 125.9 (C.sub.6), 125.2 (C.sub.5), 116.5 (C.sub.8), 114.6 (C.sub.3″), 86.1 (C.sub.2), 65.3 (C.sub.5″), 61.5 (C.sub.3), 56.8 (C.sub.11), 53.3 (C.sub.15), 47.5 (C.sub.7″), 38.6 (C.sub.12), 32.7 (C.sub.17), 27.9 (C.sub.6″). FTIR (thin film) cm.sup.−1: 2097 (s), 1685 (s), 1653 (m), 1594 (m), 1497 (m), 1259 (m), 1073 (m), 668 (m). HRMS (DART) (m/z): calc'd for C.sub.23H.sub.24BrN.sub.6O.sub.5S [M+H].sup.+: 575.0707, found: 575.0713. [α].sub.D.sup.23: +92 (c=0.26, DMSO). TLC (50% acetone in dichloromethane), Rf: 0.65 (UV, CAM).

##STR00198##

Example 22: Anisole Adduct (+)-25

[0582] Silver hexafluoroantimonate (708 mg, 8.58 mmol, 2.00 equiv) was added as a solid in one portion to a solution of bromide (+)-24 (590 mg, 1.03 mmol, 1 equiv), 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 463 mg, 2.26 mmol, 2.20 equiv), and anisole (2.0 mL, 18 mmol, 17 equiv) in dichloromethane (8.0 mL) at 23° C. After 45 min, the suspension was diluted with dichloromethane (50 mL) and was filtered through a pad of Celite. The filter cake was washed with dichloromethane (3×50 mL) and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.30% acetone in dichloromethane) to afford anisole adduct (+)-25 (613 mg, 98.7%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.57 (d, J=8.0 Hz, 1H, C.sub.8H), 7.32 (app-d, J=9.0 Hz, 2H, C.sub.2H), 7.28-7.24 (m, 1H, C.sub.7H), 7.14-7.09 (m, 2H, C.sub.5H, C.sub.6H), 6.64 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.57 (app-d, J=9.0 Hz, 2H, C.sub.3′H), 6.49 (app-d, J=9.0 Hz, 2H, C.sub.3″H), 6.10 (s, 1H, C.sub.2H), 4.42 (dd, J=6.9, 8.9 Hz, 1H, C.sub.11H), 4.09 (d, J=17.4 Hz, 1H, C.sub.15H.sub.a), 3.95 (t, J=6.2 Hz, 2H, C.sub.5″H), 3.79 (d, J=17.5 Hz, 1H, C.sub.15H.sub.b), 3.74 (s, 3H, C.sub.5′H), 3.46 (t, J=6.6 Hz, 2H, C.sub.7″H), 3.07 (dd, J=6.7, 14.1 Hz, 1H, C.sub.12H.sub.a), 2.86-2.77 (m, 1H, C.sub.12H.sub.b), 2.83 (s, 3H, C.sub.17H), 1.99 (p, J=6.2 Hz, 2H, C.sub.6″H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.1 (C.sub.13), 165.4 (C.sub.16), 162.2 (C.sub.4″), 158.6 (C.sub.4′), 140.1 (C.sub.9), 136.0 (C.sub.4), 133.1 (C.sub.1′), 130.0 (C.sub.1″), 129.6 (C.sub.2″), 129.2 (C.sub.7), 128.1 (C.sub.2′), 126.2 (C.sub.5), 125.5 (C.sub.6), 117.5 (C.sub.8), 114.3 (C.sub.3″), 114.2 (C.sub.3′), 87.2 (C.sub.2), 64.9 (C.sub.5″), 59.4 (C.sub.3), 58.4 (C.sub.11), 55.4 (C.sub.5′), 54.4 (C.sub.15), 48.1 (C.sub.7″), 39.2 (C.sub.12), 33.6 (C.sub.17), 28.6 (C.sub.6″). FTIR (thin film) cm.sup.−1: 2936 (w), 2100 (s), 1684 (s), 1654 (m), 1457 (m), 1261 (s), 1159 (s), 830 (m), 667 (s). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.31N.sub.6O.sub.6S [M+H].sup.+: 603.2020, found: 603.2012. [α].sub.D.sup.23+23 (c=0.24, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.48 (UV, CAM).

##STR00199##

Example 23: Diol (−)-26

[0583] Tetra-n-butylammonium permanganate.sup.42 (900 mg, 2.49 mmol, 5.00 equiv) was added as a solid in one portion to a solution of anisole adduct (+)-25 (300 mg, 486 μmol, 1 equiv) in dichloromethane (20 mL) at 23° C. After 2 h, the dark purple reaction mixture was diluted with a saturated aqueous sodium sulfite solution (30 mL) and with ethyl acetate (125 mL). The resulting mixture was washed with a saturated aqueous sodium bicarbonate solution (40 mL), the layers were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution (40 mL). The combined aqueous layers were extracted with ethyl acetate (2×50 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.25% acetone in dichloromethane) to afford diol (−)-26 (146 mg, 46.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.57 (d, J=8.0 Hz, 1H, C.sub.8H), 7.32-7.27 (m, 1H, C.sub.7H), 7.19-7.15 (m, 4H, C.sub.2″H, C.sub.5H, C.sub.6H), 6.78 (app-d, J=8.7 Hz, 2H, C.sub.2′H), 6.56 (app-d, J=8.7 Hz, 2H, C.sub.3′H), 6.41 (app-d, J=8.8 Hz, 2H, C.sub.3H), 6.33 (s, 1H, C.sub.2H), 6.07 (br-s, 1H, C.sub.15OH), 5.48 (br-s, 1H, C.sub.11OH), 5.19 (d, J=5.7 Hz, 1H, C.sub.15H), 3.96-3.92 (m, 2H, C.sub.5″H), 3.75 (s, 3H, C.sub.5′H), 3.48 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.44 (m, 1H, C.sub.12H.sub.a), 3.00 (s, 3H, C.sub.17H), 2.87 (d, J=15.1 Hz, 1H, C.sub.12H.sub.b), 2.01 (p, J=6.1 Hz, 2H, C.sub.6″H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.5 (C.sub.13), 166.3 (C.sub.16), 162.3 (C.sub.4″), 158.5 (C.sub.4′), 140.0 (C.sub.9), 137.2 (C.sub.4), 133.9 (C.sub.1′), 129.8 (C.sub.1″), 129.5 (C.sub.2″), 129.3 (C.sub.7), 128.7 (C.sub.2′), 126.7 (C.sub.5), 126.2 (C.sub.6), 118.0 (C.sub.8), 114.2 (C.sub.3″), 114.1 (C.sub.3′), 88.3 (C.sub.11), 87.9 (C.sub.2), 83.1 (C.sub.15), 64.9 (C.sub.5″), 58.7 (C.sub.3), 55.4 (C.sub.5′), 49.0 (C.sub.12), 48.1 (C.sub.7″), 32.4 (C.sub.17), 28.7 (C.sub.6″). FTIR (thin film) cm.sup.−1: 3385 (m), 2936 (w), 2099 (s), 1700 (s), 1685 (s), 1595 (m), 1513 (m), 1362 (m), 1258 (s), 1163 (s), 832 (m), 667 (m). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.31N.sub.6O.sub.8S [M+H].sup.+: 635.1919, found: 635.1906. [α].sub.D.sup.23: −11 (c=0.10, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.36 (UV, CAM).

##STR00200##

Example 24: Epidithiodiketopiperazine Azide (+)-9c

[0584] A solution of diol (−)-26 (142 mg, 224 μmol, 1 equiv) in anhydrous nitroethane (9.5 mL) at 0° C. was sparged with hydrogen sulfide gas for 20 min by discharge of a balloon equipped with a needle extending into the reaction mixture, providing a saturated hydrogen sulfide solution. Trifluoroacetic acid (TFA, 7.1 mL) was added via syringe over 20 seconds, and the sparging with hydrogen sulfide was maintained for another 20 min. The ice-water bath was removed, and the solution was allowed to stir and warm to 23° C. under an atmosphere of hydrogen sulfide. After 2 h, the reaction mixture was diluted with ethyl acetate (110 mL) and was slowly poured into a saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL). A stock solution of potassium triiodide in pyridine.sup.43 was added dropwise into the organic layer containing crude bisthiol S11 until a persistent yellow color was observed. The resulting mixture was washed with an aqueous hydrogen chloride solution (1 M, 2×30 mL), was washed with a saturated aqueous sodium chloride solution (30 mL), was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% ethyl acetate in dichloromethane) to afford epidithiodiketopiperazine azide (+)-9c (93.9 mg, 64.2%) as a beige solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments..sup.51 1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.64 (d, J=8.0 Hz, 1H, C.sub.8H), 7.39 (td, J=1.6, 7.0 Hz, 1H, C.sub.7H), 7.28-7.22 (m, 2H, C.sub.6H, C.sub.5H), 7.20 (app-d, J=8.9 Hz, 2H, C.sub.2″H), 6.73 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.61 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 6.40 (app-d, J=8.9 Hz, 2H, C.sub.3″H), 6.32 (s, 1H, C.sub.2H), 5.25 (s, 1H, C.sub.15H), 3.95-3.90 (m, 2H, C.sub.5″H), 3.76 (s, 3H, C.sub.5′H), 3.58 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.48 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.10 (s, 3H, C.sub.17H), 2.82 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.00 (p, J=6.2 Hz, 2H, C.sub.6″H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.1 (C.sub.13), 162.1 (C.sub.4″), 160.0 (C.sub.16), 158.6 (C.sub.4′), 141.5 (C.sub.9), 135.8 (C.sub.4), 131.3 (C.sub.1′), 129.9 (C.sub.1′), 129.7 (C.sub.7), 129.2 (C.sub.2″), 127.9 (C.sub.2′), 126.1 (C.sub.5), 125.6 (C.sub.6), 119.3 (C.sub.8), 114.3 (C.sub.3′), 114.0 (C.sub.3″), 87.7 (C.sub.2), 74.5 (C.sub.11), 68.3 (C.sub.15), 64.7 (C.sub.5″), 59.4 (C.sub.3), 55.4 (C.sub.5′), 48.0 (C.sub.7″), 45.8 (C.sub.12), 32.0 (C.sub.17), 28.5 (C.sub.6″). FTIR (thin film) cm.sup.−1: 2930 (w), 2098 (s), 1718 (s), 1700 (s), 1685 (s), 1653 (m), 1559 (m), 1507 (m), 1457 (m), 1362 (m), 1259 (s), 1162 (s), 831 (m), 667 (m). HRMS (DART) (m/z): calc'd for C.sub.30H.sub.32N.sub.7O.sub.6S.sub.3[M+NH.sub.4].sup.+: 682.1571, found: 682.1559. [α].sub.D.sup.23: +222 (c=0.08, CHCl.sub.3). TLC (20% ethyl acetate in dichloromethane), Rf: 0.35 (UV, CAM).

##STR00201##

Example 25: Triazole (+)-28c

[0585] A suspension of copper(I) iodide (3.05 mg, 15.4 μmol, 0.500 equiv), acetic acid (1.77 μL, 30.8 μmol, 1.00 equiv), and N,N-diisopropylethylamine (5.40 μL, 30.8 μmol, 1.00 equiv) in dichloromethane (0.50 mL) was added via syringe to a solution of epidithiodiketopiperazine (+)-9c (20.5 mg, 30.8 μmol, 1 equiv) and 4-ethynylanisole (27, 20.8 μL, 0.160 mmol, 5.00 equiv) in dichloromethane (0.50 mL) at 23° C. After 36 h, the reaction mixture was directly purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in dichloromethane.fwdarw.100% ethyl acetate) to afford triazole (+)-28c (14.2 mg, 56.8%) as a yellow solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.70-7.68 (m, 3H, C.sub.8″H, C.sub.11″H), 7.61, (d, J=8.0 Hz, 1H, C.sub.8H), 7.38 (app-t, J=7.7 Hz, 1H, C.sub.7H), 7.28-7.23 (m, 2H, C.sub.6H, C.sub.5H), 7.19 (app-d, J=8.9 Hz, 2H, C.sub.2″H), 6.91 (app-d, J=8.4 Hz, 2H, C.sub.12″H), 6.72 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.59 (app-d, J=8.6 Hz, 2H, C.sub.3′H), 6.38 (app-d, J=8.8 Hz, 2H, C.sub.3″H), 6.31 (s, 1H, C.sub.2H), 5.22 (s, 1H, C.sub.15H), 4.57 (t, J=6.6 Hz, 2H, C.sub.7″H), 3.92-3.88 (m, 2H, C.sub.5″H), 3.81 (s, 3H, C.sub.14″H), 3.73 (s, 3H, C.sub.5′H), 3.57 (d, J=15.6 Hz, 1H, C.sub.12H.sub.a), 3.09 (s, 3H, C.sub.17H), 2.81 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.40 (p, J=6.2 Hz, 2H, C.sub.6″H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.2 (C.sub.13), 162.0 (C.sub.4″), 160.2 (C.sub.16), 159.8 (C.sub.13″), 158.8 (C.sub.4′), 147.9 (C.sub.9″), 141.6 (C.sub.9), 135.9 (C.sub.4), 131.5 (C.sub.1′), 130.3 (C.sub.1″), 129.9 (C.sub.7), 129.4 (C.sub.2″), 128.1 (C.sub.2′), 127.2 (C.sub.11″), 126.3 (C.sub.5), 125.8 (C.sub.6), 123.3 (C.sub.10″), 119.5 (C.sub.8″), 119.4 (C.sub.8), 114.5 (C.sub.3′), 114.5 (C.sub.12″), 114.2 (C.sub.3″), 87.9 (C.sub.2), 74.6 (C.sub.11), 68.5 (C.sub.15), 64.6 (C.sub.5″), 59.6 (C.sub.3), 55.6 (C.sub.5′), 55.5 (C.sub.14″), 47.1 (C.sub.7″), 45.9 (C.sub.12), 32.2 (C.sub.17), 30.0 (C.sub.16′). FTIR (thin film) cm.sup.−1: 2924 (w), 1717 (s), 1700 (s), 1685 (s), 1653 (m), 1559 (s), 1457 (m), 1362 (m), 1259 (s), 1162 (s), 1031 (m), 668 (m). HRMS (ESI) (m/z): calc'd for C.sub.39H.sub.37N.sub.6O.sub.7S.sub.3 [M+H].sup.+: 797.1880, found: 797.1880. [α].sub.D.sup.23: +150 (c=0.11, CHCl.sub.3). TLC (100% ethyl acetate), Rf: 0.38 (UV, CAM).

##STR00202##

Example 26: Triazole (+)-29

[0586] A suspension of copper(I) iodide (24.8 mg, 128 μmol. 0.750 equiv), acetic acid (15 μL, 260 μmol, 1.5 equiv), and DIPEA (45 μL, 260 μmol, 1.5 equiv) in toluene (1.5 mL) was introduced via syringe to a solution of epidithiodiketopiperazine (+)-9a (108 mg, 170 μmol, 1 equiv) and N-Boc-propargylamine (132 mg, 850 μmol, 5.00 equiv) in toluene (0.3 mL) at 23° C. After 15 h, the reaction mixture was diluted with dichloromethane (3 mL) and was directly purified by flash column chromatography on silica gel (eluent: 0.8%.fwdarw.2.5% methanol in dichloromethane) to afford triazole (+)-29 (119 mg, 88.8%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.68-7.50 (m, 2H, C.sub.8H, C.sub.8′H), 7.40-7.16 (m, 6H, C.sub.7H, SO.sub.2Ph-o-H, SO.sub.2Ph-p-H, C.sub.5H, C.sub.6H), 7.00 (app-t, J=7.1 Hz, 2H, SO.sub.2Ph-m-H), 6.73 (app-d, J=7.8 Hz, 2H, C.sub.2′H), 6.56 (app-d, J=6.8 Hz, 2H, C.sub.3′H), 6.37 (s, 1H, C.sub.2H), 5.30 (br-s, 2H, C.sub.15H, NH), 4.54 (br-s, 2H, C.sub.7′H), 4.36 (br-s, 2H, C.sub.10′H), 3.89 (br-s, 2H, C.sub.5′H), 3.60 (d, J=15.4 Hz, 1H, C.sub.12H.sub.a), 3.09 (s, 3H, C.sub.17H), 2.84 (d, J=15.4 Hz, 1H, C.sub.12H.sub.b), 2.34 (br-s, 2H, C.sub.6′H), 1.38 (s, 9H, C(CH.sub.3).sub.3). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 165.1 (C.sub.13), 160.2 (C.sub.16), 157.7 (C.sub.4′), 156.0 (NCO.sub.2C(CH.sub.3).sub.3), 145.8 (C.sub.9′), 141.2 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.2 (SO.sub.2Ph-p-C), 131.7 (C.sub.1′), 129.9 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 127.2 (SO.sub.2Ph-o-C), 126.2 (C.sub.6), 125.7 (C.sub.5), 122.7 (C.sub.8′), 118.9 (C.sub.8), 115.0 (C.sub.3′), 87.7 (C.sub.2), 79.8 (C(CH.sub.3).sub.3), 74.6 (C.sub.11), 68.3 (C.sub.15), 64.3 (C.sub.5′), 59.5 (C.sub.3), 47.2 (C.sub.7′), 45.4 (C.sub.12), 36.1 (C.sub.10′), 32.1 (C.sub.17), 30.0 (C.sub.6′), 28.5 (C(CH.sub.3).sub.3). FTIR (thin film) cm.sup.−1: 3391 (w), 2977 (w), 1695 (s), 1512 (m), 1363 (m), 1251 (m), 1168 (s). HRMS (ESI) (m/z): calc'd for C.sub.37H.sub.39N.sub.7NaO.sub.7S.sub.3 [M+Na].sup.+: 812.1965, found: 812.1969. [α].sub.D.sup.23: +185 (c=0.20, CHCl.sub.3). TLC (5% methanol in dichloromethane), Rf: 0.44 (UV, CAM).

##STR00203##

Example 27: Benzamide (+)-30

[0587] A solution of hydrogen chloride in 1,4-dioxane (4.0 M, 1.0 mL) was added via syringe to a solution of triazole (+)-29 (15.0 mg, 19.0 μmol, 1 equiv) in 1,4-dioxane (0.5 mL) at 23° C. After 20 min, the reaction mixture was concentrated under reduced pressure, and the resulting yellow solid was dissolved in pyridine (240 μL). A solution of benzoyl chloride (48 mM, 0.60 mL, 29 μmol, 1.5 equiv) in tetrahydrofuran was added via syringe, followed by the addition of triethylamine (40 μL, 290 μmol, 15 equiv) via syringe. After 30 min, the reaction mixture was diluted with ethyl acetate (30 mL) and was slowly poured into an aqueous hydrogen chloride solution (1 M, 5 mL). The organic layer was washed sequentially with an aqueous hydrogen chloride solution (1 M, 5 mL), with a saturated aqueous sodium bicarbonate solution (5 mL), and with a saturated aqueous sodium chloride solution (5 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 1.fwdarw.2% methanol in dichloromethane) to afford benzamide (+)-30 (13.1 mg, 86.8%) as a beige solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.77 (app-d, J=7.3 Hz, 2H, C.sub.13′H), 7.71 (br-s, 1H, C.sub.8′H), 7.57 (d, J=8.0 Hz, 1H, C.sub.8H), 7.46 (app-t, J=7.4 Hz, 1H, C.sub.15′H), 7.40-7.32 (m, 5H, SO.sub.2Ph-o-H, C.sub.14′H, C.sub.7H), 7.28-7.20 (m, 3H, SO.sub.2Ph-o-H, C.sub.5H, C.sub.6H), 7.16 (br-s, 1H, NH), 7.01 (app-t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 6.71 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.56 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 6.36 (s, 1H, C.sub.2H), 5.27 (s, 1H, C.sub.15H), 4.68 (br-s, 2H, C.sub.10′H), 4.55 (t, J=6.3 Hz, 2H, C.sub.7′H), 3.95-3.84 (m, 2H, C.sub.5′H), 3.60 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.10 (s, 3H, C.sub.17H), 2.83 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.37 (p, J=5.9 Hz, 2H, C.sub.6′H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.6 (C.sub.11′), 165.2 (C.sub.13), 160.2 (C.sub.16), 157.8 (C.sub.4′), 145.0 (C.sub.9′), 141.3 (C.sub.9), 138.4 (SO.sub.2Ph-ipso-C), 135.9 (C.sub.4), 134.0 (C.sub.12′), 133.2 (SO.sub.2Ph-p-C), 131.9 (C.sub.15′), 131.8 (C.sub.1′), 129.9 (C.sub.7), 128.8 (C.sub.14′), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2), 127.3 (SO.sub.2Ph-o-C), 127.2 (C.sub.13′), 126.3 (C.sub.6), 125.7 (C.sub.5), 123.3 (C.sub.8′), 119.0 (C.sub.8), 115.1 (C.sub.3′), 87.2 (C.sub.2), 74.6 (C.sub.11), 68.5 (C.sub.15), 64.4 (C.sub.5′), 59.6 (C.sub.3), 47.4 (C.sub.7′), 45.5 (C.sub.12), 35.5 (C.sub.10′), 32.2 (C.sub.17), 30.0 (C.sub.6′). FTIR (thin film) cm.sup.−1: 3345 (w), 3001 (w), 1695 (s), 1512 (m), 1461 (m), 1169 (m), 755 (m). HRMS (ESI) (m/z): calc'd for C.sub.39H.sub.36N.sub.7O.sub.6S.sub.3[M+H].sup.+: 794.1884, found: 794.1890. [α].sub.D.sup.23: +175 (c=0.11, CHCl.sub.3). TLC (10% methanol in dichloromethane), Rf: 0.52 (UV, CAM).

##STR00204##

Example 28: Epitrithiodiketopiperazine 31

[0588] This compound was prepared in three steps starting from diol S12.sup.52 using the methodology developed to access corresponding C3-(indol-3′-yl) epitrithiodiketopiperazine. First, the corresponding C11-thiohemiaminal was prepared from diol S12 (57.2 mg, 107 μmol) and was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.80% acetone in dichloromethane) to afford the C11-thiohemiaminal (49.2 mg, 83.5%).sup.53 as a white foam. Next, the C11-triphenylmethanetrisulfide S13 was prepared from C11-thiohemiaminal (26.4 mg, 47.9 μmol) and was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.30% ethyl acetate in dichloromethane) to afford C11-triphenylmethanetrisulfide S13 (31.2 mg, 76.0%).sup.54 as a white solid. Finally, epitrithiodiketopiperazine 31 was prepared from the C11-triphenylmethanetrisulfide S13 (29.5 mg, 34.4 μmol) and was purified by flash column chromatography on silica gel (eluent: 5-15% ethyl acetate in dichloromethane) to afford epitrithiodiketopiperazine 31 (17.0 mg, 82.7%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Based on .sup.1H NMR analysis at 25° C. degrees in CDCl.sub.3, epitrithiodiketopiperazine 31 exists as a 2.6:1 mixture of major:minor conformers. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 7.65 (app-d, J=7.4 Hz, 2H, SO.sub.2Ph-o-H), 7.57 (d, J=8.1 Hz, 1H, C.sub.8H), 7.44-7.37 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.23 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 7.21-7.09 (m, 2H, C.sub.5H, C.sub.6H), 6.86 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.69 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 4.84 (s, 1H, C.sub.15H), 3.77 (s, 3H, C.sub.5′H), 3.44 (d, J=14.8 Hz, 1H, C.sub.12H.sub.a), 3.16 (s, 3H, C.sub.17H), 3.08 (d, J=14.8 Hz, 1H, C.sub.12H.sub.b). Minor conformer: δ 7.51 (m, 3H, C.sub.8H, SO.sub.2Ph-o-H), 7.34 (app-t, J=7.4, 1H, SO.sub.2Ph-p-H), 7.30 (app-t, J=8.1 Hz, C.sub.7H), 7.21-7.09 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 6.83 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.72 (s, 1H, C.sub.2H), 6.66 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 5.18 (s, 1H, C.sub.15H), 3.78 (s, 3H, C.sub.5′H), 3.29 (d, J=14.9 Hz, 1H, C.sub.12H.sub.a), 2.98 (s, 3H, C.sub.17H), 2.98 (d, J=14.9 Hz, 1H, C.sub.12H.sub.b). .sup.13C NMR (125 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 168.0 (C.sub.13), 162.1 (C.sub.16), 159.0 (C.sub.5′), 142.9 (C.sub.9), 139.5 (SO.sub.2Ph-ipso-C), 135.0 (C.sub.4), 133.0 (SO.sub.2Ph-p-C), 131.5 (C.sub.1′), 130.2 (C.sub.7), 128.8 (SO.sub.2Ph-m-C), 127.5 (C.sub.2′), 127.1 (SO.sub.2Ph-o-C), 125.8 (C.sub.5/C.sub.6), 125.7 (C.sub.5/C.sub.6), 118.7 (C.sub.8), 114.6 (C.sub.3′), 86.2 (C.sub.2), 79.6 (C.sub.11), 67.2 (C.sub.15), 57.7 (C.sub.3), 55.5 (C.sub.5′), 50.8 (C.sub.12), 32.5 (C.sub.17). Minor conformer: δ 166.9 (C.sub.13), 161.3 (C.sub.16), 158.9 (C.sub.5′), 141.5 (C.sub.9), 138.9 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.0 (SO.sub.2Ph-p-C), 131.4 (C.sub.1′), 129.6 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 127.8 (C.sub.2′/SO.sub.2Ph-o-C), 127.5 (C.sub.2′/SO.sub.2Ph-o-C), 126.3 (C.sub.5/C.sub.6), 125.7 (C.sub.5/C.sub.6), 118.6 (C.sub.8), 114.6 (C.sub.3′), 88.1 (C.sub.2), 75.0 (C.sub.11), 71.1 (C.sub.15), 57.8 (C.sub.3), 55.5 (C.sub.5′), 48.9 (C.sub.12), 33.1 (C.sub.17). FTIR (thin film) cm.sup.−1: 3063 (w), 2837 (w), 1686 (br-s), 1609 (w), 1513 (m), 1364 (m), 1254 (m), 1168 (s), 1090 (w), 1033 (m), 832 (w), 797 (w), 736 (m), 600 (m), 575 (m). HRMS (ESI) (m/z): calc'd for C.sub.27H.sub.23N.sub.3O.sub.5S.sub.4 [M+H].sup.+: 598.0593, found: 598.0585. TLC (20% ethyl acetate in dichloromethane), Rf: 0.51 (UV, CAM).

##STR00205##

Example 29: Epitetrathiodiketopiperazine 32

[0589] Sodium borohydride (2.4 mg, 63 μmol, 5.0 equiv) was added as a solid in one portion to a solution of epidithiodiketopiperazine (+)-8 (17.5 mg, 30.9 μmol, 1 equiv) in tetrahydrofuran (7.7 mL) and methanol (77 μL). After 40 min, the reaction mixture was diluted with dichloromethane (75 mL) and was washed with a saturated aqueous ammonium chloride solution (2×35 mL). The aqueous layer was extracted with dichloromethane (35 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were sparged with argon for 15 min by discharge of a balloon equipped with a needle extending into the stirring reaction mixture. The reaction mixture was then concentrated under reduced pressure to approximately 15 mL and was cooled to 0° C. Pyridine (25 μL, 0.31 mmol, 10 equiv) was added via syringe to the solution of bisthiol S.sub.14, followed by the dropwise addition of a solution of disulfur dichloride (0.50 M, 0.10 mL, 50 μmol, 1.6 equiv) in dichloromethane via syringe. The reaction mixture was removed from the ice-water bath and allowed to stir and warm to 23° C. After 30 min, the reaction was diluted with dichloromethane (35 mL) and was washed sequentially with a saturated aqueous ammonium chloride solution (2×30 mL), with deionized water (30 mL), and with a saturated aqueous sodium chloride solution (30 mL). The combined aqueous layers were extracted with a single portion of dichloromethane (50 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.10% ethyl acetate in dichloromethane) to afford the epitetrathiodiketopiperazine 32 (13.5 mg, 69.2%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.94 (app-d, J=7.8 Hz, 2H, SO.sub.2Ph-o-H), 7.53 (td, J=7.6, 1.3 Hz, 1H, SO.sub.2Ph-p-H), 7.45 (d, J=8.2 Hz, 1H, C.sub.8H), 7.42 (app-t, J=7.7 Hz, 2H, SO.sub.2Ph-m-H), 7.29-7.23 (m, 1H, C.sub.7H), 7.08 (app-t, J=7.4 Hz, 1H, C.sub.6H), 7.03 (d, J=7.6 Hz, 1H, C.sub.5H), 6.89 (app-d, J=8.3 Hz, 2H, C.sub.2′H), 6.83 (s, 1H, C.sub.2H), 6.71 (app-d, J=8.7 Hz, 1H, C.sub.3′H), 5.12 (s, 1H, C.sub.15H), 3.27 (d, J=14.5 Hz, 1H, C.sub.12H.sub.a), 3.10 (d, J=14.5 Hz, 1H, C.sub.12H.sub.b), 3.01 (s, 3H, C.sub.17H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.9 (C.sub.13), 162.7 (C.sub.16), 159.0 (C.sub.4′), 141.7 (C.sub.9), 139.2 (SO.sub.2Ph-ipso-C), 136.6 (C.sub.4), 133.5 (C.sub.1′), 133.3 (SO.sub.2Ph-p-C), 129.5 (C.sub.7), 129.1 (SO.sub.2Ph-m-C), 127.8 (SO.sub.2Ph-o-C), 127.0 (C.sub.2′), 125.5 (C.sub.6), 124.8 (C.sub.5), 116.6 (C.sub.8), 114.6 (C.sub.3′), 86.6 (C.sub.2), 76.0 (C.sub.11), 68.3 (C.sub.15), 57.2 (C.sub.3), 55.5 (C.sub.5′), 49.7 (C.sub.12), 32.3 (C.sub.17). FTIR (thin film) cm.sup.−1: 3064 (w), 2836 (w), 1692 (s), 1674 (s), 1610 (w), 1513 (m), 1383 (m), 1254 (m), 1169 (s), 1090 (w), 1032 (m), 832 (w), 796 (w), 737 (m), 597 (m), 565 (m). HRMS (ESI) (m/z): calc'd for C.sub.27H.sub.23N.sub.3O.sub.5S.sub.5 [2M+H].sup.+: 1281.0375, found: 1281.0376. TLC (20% ethyl acetate in dichloromethane), Rf: 0.53 (UV, CAM).

##STR00206##

Example 30: Bis(p-fluorobenzyl)disulfide (−)-45a

[0590] A solution of triethylamine (0.72 M, 54 μL, 39 μmol, 2.2 equiv) in tetrahydrofuran and a solution of (p-fluorophenyl)methanethiol (PFB-SH, 0.41 M, 22 μL, 9.0 mol, 0.51 equiv) in tetrahydrofuran were added dropwise via syringe to a solution of epidithiodiketopiperazine (+)-8 (10.0 mg, 17.7 μmol, 1 equiv) and 1,2-bis(p-fluorobenzyl)disulfane (PFB-SS-PFB, 15.2 mg, 54.0 mmol, 3.05 equiv) in tetrahydrofuran (0.9 mL). After 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 2.fwdarw.50% ethyl acetate in dichloromethane) to afford bisdisulfide (−)-45a (10.3 mg, 68.6%) as a white solid, epitrithiodiketopiperazine 31 (0.2 mg, 2%) as a white solid, and unreacted epidithiodiketopiperazine (+)-8 (1.7 mg, 17%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.64 (d, J=8.1 Hz, 1H, C.sub.8H), 7.59 (app-d, J=7.4 Hz, 2H, SO.sub.2Ph-o-H), 7.42-7.31 (m, 4H, C.sub.3″/3′″H, SO.sub.2Ph-p-H, C.sub.7H), 7.19-7.13 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 7.08 (dd, J=8.6, 5.4 Hz, 2H, C.sub.3″/3′″H), 7.04 (d, J=8.7 Hz, 2H, C.sub.4″/4′″H), 6.91 (t, J=8.7 Hz, 2H, C.sub.4″/4′″H), 6.74 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.63 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.59 (s, 1H, C.sub.2H), 4.91 (s, 1H, C.sub.15H), 4.21 (d, J=12.8 Hz, 1H, C.sub.1″/1′″H), 4.01 (d, J=12.8 Hz, 1H, C.sub.1″/1′″H), 3.83 (d, J=12.3 Hz, 1H, C.sub.1″/1′″H), 3.79 (d, J=12.6 Hz, 1H, C.sub.1″/1′″H), 3.77 (s, 3H, C.sub.5′H), 3.55 (d, J=14.8 Hz, 1H, C.sub.12H.sub.a), 3.12 (s, 3H, C.sub.17H), 3.06 (d, J=14.9 Hz, 1H, C.sub.12H.sub.b). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.7 (C.sub.13), 162.5 (C.sub.16), 162.4 (d, J=246 Hz, Cs.sub.5″/5′″), 162.3 (d, J=246 Hz, C.sub.5″/5′″), 158.7 (C.sub.5′), 142.1 (C.sub.9), 138.5 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 133.1 (C.sub.1′), 132.4 (d, J=3.3 Hz, C.sub.2″/2′″), 132.1 (d, J=3.1 Hz, C.sub.2″/2′″), 131.8 (d, J=8.2 Hz, C.sub.3″/3′″), 131.2 (d, J=8.1 Hz, C.sub.3″/3′″), 129.5 (C.sub.7), 128.9 (SO.sub.2Ph-m-C), 127.4 (C.sub.2), 127.4 (SO.sub.2Ph-o-C), 125.8 (C.sub.5/6), 125.4 (C.sub.5/6), 118.1 (C.sub.8), 115.6 (d, J=21.6 Hz, C.sub.4″/4′″), 115.5 (d, J=21.5 Hz, C.sub.4″/4′″), 114.4 (C.sub.3′), 87.4 (C.sub.2), 77.7 (C.sub.15), 73.9 (C.sub.11), 57.4 (C.sub.3), 55.5 (C.sub.5′), 47.1 (C.sub.12), 42.5 (C.sub.1″/1′″), 42.1 (C.sub.1″/1′″), 32.6 (C.sub.17). FTIR (thin film) cm.sup.−1: 2937 (w), 1695 (m), 1672 (m), 1509 (s), 1384 (m), 1222 (m), 1033 (w), 833 (w), 597 (w). HRMS (ESI) (m/z): calc'd for C.sub.41H.sub.36N.sub.3O.sub.5S.sub.5F.sub.2 [M+H].sup.+: 848.1221, found: 848.1223. [α].sub.D.sup.23: −49 (c=0.24, CHCl.sub.3). TLC (10% ethyl acetate in dichloromethane), Rf: 0.53 (UV, CAM).

##STR00207##

Example 31: Anisole Adduct (+)-37

[0591] Endo-tetracyclic bromide.sup.55 (+)-36 (2.01 g, 4.10 mmol, 1 equiv) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 2.11 g, 10.3 mmol, 2.51 equiv) were azeotropically dried by concentration from anhydrous benzene (2×10 mL) under reduced pressure. Dichloromethane (40 mL) and anisole (8.9 mL, 82 mmol, 20 equiv) were added sequentially, and the resulting colorless solution was cooled to −25° C. Silver trifluoromethanesulfonate (AgOTf, 2.11 g, 8.21 mmol, 2.00 equiv) was added as a solid in one portion, the reaction mixture was stirred at −25° C. for 30 min, then the cold bath was removed and the resulting mixture was allowed to stir and warm to room temperature. After 30 min, the suspension was diluted with dichloromethane (200 mL) and was washed with a mixture of deionized water, saturated aqueous sodium thiosulfate solution, and saturated aqueous sodium bicarbonate solution (2:1:1, 2×300 mL). The aqueous layers were extracted with dichloromethane (2×100 mL), and the combined organic extracts were washed sequentially with deionized water (250 mL) and with a saturated aqueous sodium chloride solution (150 mL). The combined aqueous layers were extracted with dichloromethane (100 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting foam was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.50% acetone in chloroform) to afford anisole adduct (+)-37 (1.72 g, 81.2%) as a white foam. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.61 (d, J=8.1 Hz, 1H, C.sub.8H), 7.45 (app-d, J=8.4 Hz, 2H, SO.sub.2Ph-o-H), 7.32 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.30-7.26 (m, 1H, C.sub.7H) 7.14-7.11 (m, 2H, C.sub.5H, C.sub.6H), 7.09 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.67 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.61 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.39 (dd, J=5.6, 9.0 Hz, 1H, C.sub.11H), 4.04 (q, J=7.0 Hz, 1H, C.sub.15H), 3.77 (s, 3H, C.sub.5′H), 3.14 (dd, J=6.5, 14.1 Hz, 1H, C.sub.12H.sub.a), 2.87 (dd, J=8.9, 14.0 Hz, 1H, C.sub.12H.sub.b), 2.85 (s, 3H, C.sub.17H), 1.58 (d, J=7.1 Hz, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 167.9 (C.sub.16), 158.7 (C.sub.4′), 139.9 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.7 (C.sub.4), 132.8 (SO.sub.2Ph-p-C, C.sub.1′), 129.2 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.0 (C.sub.5), 125.3 (C.sub.6), 117.2 (C.sub.8), 114.4 (C.sub.3′), 87.3 (C.sub.2), 59.4 (C.sub.3), 58.8 (C.sub.11), 57.1 (C.sub.15), 55.4 (C.sub.5′), 39.0 (C.sub.12), 29.6 (C.sub.17), 14.5 (C.sub.18). FTIR (thin film) cm.sup.−1: 2994 (w), 1677 (s), 1513 (m), 1253 (m), 1169 (s), 1031 (w), 832 (w), 757 (w), 602 (m). HRMS (ESI) (m/z): calc'd for C.sub.28H.sub.28N.sub.3O.sub.5S [M+H].sup.+: 519.1775, found: 519.1775. [α].sub.D.sup.23: +58 (c=0.30, CHCl.sub.3). TLC (20% acetone in chloroform), Rf: 0.26 (UV, CAM).

##STR00208##

Example 32: Diol 38

[0592] Bis(2,2′)-bipyridyl)copper(II) permanganate.sup.56 (1.61 g, 2.62 mmol, 2.70 equiv) was added as a solid to solution of anisole adduct (+)-37 (502 mg, 0.970 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C. After 50 min, the reaction mixture was diluted with dichloromethane (100 mL) and was poured into an aqueous sodium bisulfite solution (1 M, 200 mL). The layers were separated, and the organic layer was washed sequentially with an aqueous sodium bisulfite solution (1 M, 75 mL), with a mixture of a saturated aqueous copper(II) sulfate solution and deionized water (1:1, 100 mL), with a saturated aqueous ammonium chloride solution (100 mL), and with a saturated aqueous sodium chloride solution (100 mL). The aqueous layers were separately extracted with dichloromethane (2×75 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting light blue foam was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.30% acetone in dichloromethane) to afford diol 38 (393 mg, 74%) as a white foam. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ7.61 (d, J=8.1 Hz, 1H, C.sub.8H), 7.34-7.26 (m, 4H, C.sub.7H, SO.sub.2Ph-p-H, SO.sub.2Ph-o-H), 7.22-7.15 (m, 2H, C.sub.5H, C.sub.6H), 7.02 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.78 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.55 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.35, (s, 1H, C.sub.2H), 5.62 (br-s, 1H, OH), 5.24 (br-s, 1H, OH), 3.76 (s, 3H, C.sub.5′H), 3.38 (d, J=15.1 Hz, 1H, C.sub.12aH), 2.99 (s, 3H, C.sub.17H), 2.92 (d, J=15.1 Hz, 1H, C.sub.12bH), 1.81 (s, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 168.2 (C.sub.13), 166.8 (C.sub.16), 158.4 (C.sub.4′), 140.0 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 137.7 (C.sub.4), 133.9 (C.sub.1′), 132.9 (SO.sub.2Ph-p-C), 129.1 (C.sub.7), 128.6 (SO.sub.2Ph-m-C/C.sub.2′), 128.5 (SO.sub.2Ph-m-C/C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.5 (C.sub.5), 126.1 (C.sub.6), 118.0 (C.sub.8), 114.3 (C.sub.3′), 88.7 (C.sub.2), 87.4 (C.sub.11), 85.8 (C.sub.15), 58.1 (C.sub.3), 55.4 (C.sub.5′), 49.6 (C.sub.12), 28.2 (C.sub.17), 22.8 (C.sub.18). FTIR (thin film) cm.sup.−1: 3375 (br), 3067 (w), 1687 (m), 1512 (m), 1361 (m), 1252 (m), 1169 (s), 832 (w), 737 (w), 600 (m), HRMS (ESI) (m/z): calc'd for C.sub.48H.sub.59N.sub.9O.sub.17S.sub.5 [M+H].sup.+: 550.1642, found: 550.1640. TLC (20% acetone in dichloromethane), Rf: 0.22 (UV, CAM).

##STR00209##

Example 33: O-TBS Protected Monoalcohols S.SUB.15 .and S.SUB.16

[0593] Diol 38 (1.00 g, 1.82 mmol, 1 equiv) was azeotropically dried by concentration from anhydrous dichloromethane (2.5 mL) and anhydrous benzene (9.0 mL) under reduced pressure. The flask was charged with 4-(dimethylamino)pyridine (DMAP, 10.2 mg, 83.5 μmol, 0.0459 equiv), and the solids were dissolved in N,N-dimethylformamide (18 mL). Triethylamine (0.76 mL, 5.45 mmol, 3.00 equiv) was then added via syringe followed immediately by tert-butyldimethylsilyl chloride (352 mg, 2.34 mmol, 1.29 equiv) as a solid in one portion. After 90 min, the white suspension was diluted with ethyl acetate-hexanes (4:1, 125 mL) and was washed with a saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with ethyl acetate-hexanes (4:1, 2×60 mL), and the combined organic extracts were washed sequentially with deionized water (3×100 mL) and with a saturated aqueous sodium chloride solution (100 mL). The combined aqueous layers were extracted with a single portion of ethyl acetate-hexanes (3:1, 100 mL), and the organic extract was washed sequentially with deionized water (3×50 mL) and with a saturated aqueous sodium chloride solution (50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting white foam was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.30% acetone in hexanes) to afford a mixture of regioisomeric O-TBS protected monoalcohols S.sub.15 and S.sub.16 (1.01 g, 84%, 1.1:1) as a white foam. Analytical samples of O-TBS protected monoalcohols S.sub.15 and S.sub.16 were obtained by flash column chromatography on silica gel (eluent: 0.fwdarw.10% diethyl ether in dichloromethane). Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments.

Example 34: Monoalcohol S15

[0594] .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.60 (d, J=8.0 Hz, 1H, C.sub.8H), 7.33-7.23 (m, 4H, C.sub.7H, SO.sub.2Ph-p-H, SO.sub.2Ph-o-H), 7.20-7.15 (m, 2H, C.sub.5H, C.sub.6H), 6.99 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.71 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.56 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.42 (s, 1H, C.sub.2H), 3.82 (s, 1H, C.sub.15OH), 3.78 (s, 3H, C.sub.5′H.sub.3), 3.53 (d, J=15.0 Hz, 1H, C.sub.12H.sub.a), 2.93 (s, 3H, C.sub.17H), 2.78 (d, J=15.1 Hz, 1H, C.sub.12H.sub.b), 1.65 (s, 3H, C.sub.18H), 0.97 (s, 9H, SiC(CH.sub.3).sub.3), 0.23 (s, 3H, SiCH.sub.3), 0.09 (s, 3H, SiCH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.3 (C.sub.16), 166.3 (C.sub.13), 158.6 (C.sub.4′), 139.9 (C.sub.9), 138.6 (SO.sub.2Ph-ipso-C), 136.9 (C.sub.4), 133.4 (C.sub.1′), 132.7 (SO.sub.2Ph-p-C), 129.2 (C.sub.7), 128.5 (SO.sub.2Ph-m-C), 128.3 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.4 (C.sub.5), 125.9 (C.sub.6), 118.0 (C.sub.8), 114.3 (C.sub.3′), 89.2 (C.sub.11), 88.2 (C.sub.2), 85.2 (C.sub.15), 58.3 (C.sub.3), 55.5 (C.sub.5′), 50.7 (C.sub.12), 27.9 (C.sub.17), 25.8 (SiC(CH.sub.3).sub.3) 24.2 (C.sub.18), 18.4 (SiC(CH.sub.3).sub.3), −3.3 (SiCH.sub.3), −4.6 (SiCH.sub.3). FTIR (thin film) cm.sup.−1: 3450 (br-w), 2956 (w), 2931 (w), 1677 (m), 1513 (m), 1254 (s), 1170 (s), 829 (m), 687 (w), 601 (m). HRMS (ESI) (m/z): calc'd for C.sub.34H.sub.42N.sub.3O.sub.7SSi [M+H].sup.+: 664.2507, found: 665.2508. TLC (40% acetone in hexanes), Rf: 0.43 (UV, CAM). TLC (7% diethyl ether in dichloromethane), Rf: 0.26 (UV, CAM).

Example 35: Monoalcohol S16

[0595] .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.61 (d, J=8.1 Hz, 1H, C.sub.8H), 7.31-7.25 (m, 4H, C.sub.7H, SO.sub.2Ph-p-H, SO.sub.2Ph-o-H), 7.17-7.14 (m, 2H, C.sub.5H, C.sub.6H), 7.00 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.74 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.58 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.30 (s, 1H, C.sub.2H), 4.84 (s, 1H, C.sub.11OH), 3.78 (s, 3H, C.sub.5′H.sub.3), 3.37 (d, J=15.1 Hz, 1H, C.sub.12H.sub.a), 2.97 (s, 3H, C.sub.17H), 2.84 (d, J=15.1 Hz, 1H, C.sub.12H.sub.b), 1.83 (s, 3H, C.sub.18H), 0.92 (s, 9H, SiC(CH.sub.3).sub.3), 0.33 (s, 3H, SiCH.sub.3), 0.32 (s, 3H, SiCH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.9 (C.sub.13), 164.8 (C.sub.16), 158.4 (C.sub.4′), 140.1 (C.sub.9), 138.4 (SO.sub.2Ph-ipso-C), 137.7 (C.sub.4), 134.1 (C.sub.1′), 132.8 (SO.sub.2Ph-p-C), 129.0 (C.sub.7), 128.5 (SO.sub.2Ph-m-C, C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.4 (C.sub.5), 125.9 (C.sub.6), 117.9 (C.sub.8), 114.2 (C.sub.3′), 88.9 (C.sub.2), 87.9 (C.sub.15), 87.3 (C.sub.11), 58.0 (C.sub.3), 55.4 (C.sub.5′), 49.2 (C.sub.12), 28.1 (C.sub.17), 25.7 (SiC(CH.sub.3).sub.3), 23.5 (C.sub.18), 18.2 (SiC(CH.sub.3).sub.3), −2.3 (SiCH.sub.3), −3.4 (SiCH.sub.3). FTIR (thin film) cm.sup.−1: 3415 (br-w), 2930 (w), 2859 (w), 2102 (w), 1714 (w), 1513 (w), 1365 (m), 1253 (s), 1171 (s), 833 (m), 601 (w). HRMS (ESI) (m/z): calc'd for C.sub.34H.sub.42N.sub.3O.sub.7SSiNa [M+H].sup.+: 664.2507, found: 664.2499. TLC (40% acetone in hexanes), Rf: 0.43 (UV, CAM). TLC (7% diethyl ether in dichloromethane), Rf: 0.53 (UV, CAM).

##STR00210##

Example 36: Sodium p-methoxybenzyl trithiocarbonate 39

[0596] A suspension of sodium hydride (60% dispersion, 1.03 g, 25.8 mmol, 1 equiv) in diethyl ether (125 mL) at 0° C. was sparged with argon for 20 min by discharge of a balloon equipped with a needle extending into the reaction mixture. p-Methoxybenzyl thiol (4.5 mL, 33 mmol, 1.3 equiv) was added dropwise via syringe over 2 min, the solution was stirred for 5 min, then the ice-water bath was removed and the reaction mixture was allowed to stir and warm to 23° C. After 1 h, the light-gray suspension was cooled to 0° C., and carbon disulfide (2.0 mL, 33 mmol, 1.3 equiv) was added dropwise via syringe over 3.5 min. The ice-water bath was removed and the reaction mixture was allowed to stir and warm to 23° C. After 2 h, a yellow precipitate was collected by filtration of the yellow suspension through a 350-mL medium-porosity fritted-glass funnel. The yellow precipitate was washed with hexanes (2×50 mL) and was dried under reduced pressure to afford sodium p-methoxybenzyl trithiocarbonate 39 (5.76 g, 88.4%) as a yellow solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, DMSO-d.sub.6, 25° C.): δ 7.20 (d, J=8.6 Hz, 2H, C.sub.4H), 6.81 (d, J=8.6 Hz, 2H, C.sub.5H), 4.29 (s, 2H, C.sub.2H), 3.70 (s, 3H, OCH.sub.3). .sup.13C NMR (125 MHz, DMSO-d.sub.6, 25° C.): δ 239.0 (C.sub.1), 157.8 (C.sub.6), 130.9 (C.sub.3), 129.8 (C.sub.4), 113.6 (C.sub.5), 55.0 (OCH.sub.3), 44.6 (C.sub.2). FTIR (thin film) cm.sup.−1: 1507 (w), 1248 (w), 1229 (w), 1177 (w), 1003 (s), 833 (m), 539 (m). HRMS (DART-TOF) (m/z): calc'd for C.sub.9H.sub.9OS.sub.3 [M-Na].sup.−: 228.9821, found: 228.9813.

##STR00211##

Example 37: Dithiepanethione (+)-41

[0597] A mixture of regioisomeric O-TBS protected monoalcohols S.sub.15 and S.sub.16 (1.1:1, 956 mg, 1.44 mmol, 1 equiv) was azeotropically dried by concentration from dichloromethane (5 mL) and anhydrous benzene (50 mL) under reduced pressure. The resulting white foam was dissolved in acetonitrile (100 mL) via cannula, and trithiocarbonate 39 (1.82 g, 7.21 mmol, 5.01 equiv) was added as a solid. Trifluoroacetic acid (TFA, 50 mL) was poured rapidly into the reaction mixture over 15 seconds, resulting in a homogeneous yellow solution. After 1 h, the dark orange solution was diluted with ethyl acetate-hexanes (9:1, 100 mL), was slowly poured into a saturated aqueous sodium bicarbonate solution (650 mL), and the biphasic mixture was stirred vigorously for 30 min. The aqueous layer was extracted with ethyl acetate-hexanes (9:1, 2×100 mL), and the combined organic extracts were washed sequentially with deionized water (200 mL) and with a saturated aqueous sodium chloride solution (150 mL). The combined aqueous layers were extracted with a single portion of ethyl acetate-hexanes (4:1, 100 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.7.5% diethyl ether in dichloromethane) to afford dithiepanethione (+)-41 (766 mg, 85.0%) as a yellow foam. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.55 (d, J=8.1 Hz, 1H, C.sub.8H), 7.43 (app-d, J=7.6 Hz, 2H, SO.sub.2Ph-o-H), 7.30-7.21 (m, 2H, C.sub.7H, SO.sub.2Ph-p-H), 7.30-7.21 (m, 2H, C.sub.5H, C.sub.6H), 7.13 (app-t, 2H, J=7.9 Hz, SO.sub.2Ph-m-H), 6.87 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.68 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 6.59 (s, 1H, C.sub.2H), 3.78 (s, 3H, C.sub.5′H), 3.53 (d, J=15.3 Hz, 1H, C.sub.12H.sub.a), 3.06 (s, 3H, C.sub.17H), 3.05 (d, J=15.2 Hz, 1H, C.sub.12H.sub.b), 1.92 (s, 3H, C.sub.18). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): 215.7 (CS.sub.3), 164.7 (C.sub.13), 160.5 (C.sub.16), 159.0 (C.sub.4′), 141.5 (C.sub.9), 138.9 (SO.sub.2Ph-ipso-C), 134.9 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 131.4 (C.sub.1′), 130.1 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 127.5 (C.sub.2′), 126.8 (SO.sub.2Ph-o-C), 126.4 (C.sub.6), 125.5 (C.sub.5), 118.7 (C.sub.8), 114.6 (C.sub.3′), 87.8 (C.sub.2), 75.0 (C.sub.11), 73.5 (C.sub.15), 57.8 (C.sub.3), 55.5 (C.sub.5′), 48.7 (C.sub.12), 28.4 (C.sub.17), 19.8 (C.sub.18). FTIR (thin film) cm.sup.−1: 3002 (w), 1713 (s), 1685 (s), 1476 (w), 1362 (s), 1169 (s), 1034 (m), 999 (m), 895 (w), 737 (m), 599 (m). HRMS (ESI) (m/z): calc'd for C.sub.29H.sub.26N.sub.3O.sub.5S.sub.4[M+H].sup.+: 624.0750, found: 624.0747. [α].sub.D.sup.23: +148 (c=0.61, CHCl.sub.3). TLC (5% diethyl ether in dichloromethane), Rf: 0.31 (UV, CAM).

##STR00212##

Example 38: Epidithiodiketopiperazine (+)-42

[0598] A yellow solution of dithiepanethione (+)-41 (374 mg, 0.600 mmol, 1 equiv) in acetone (15 mL) at 23° C. was sparged with argon for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture. Ethanolamine (3.75 mL) was added via syringe over 30 seconds, resulting in a nearly colorless solution. After 1 h, the reaction mixture was diluted with ethyl acetate-hexanes (9:1, 100 mL) and was washed with an aqueous hydrogen chloride solution (1 M, 150 mL). The aqueous layer was extracted with ethyl acetate-hexanes (9:1, 2×50 mL), and the combined organic extracts were washed with a saturated aqueous sodium chloride solution (100 mL). A stock solution of potassium triiodide in pyridine.sup.43 was added dropwise into the organic layer containing crude bisthiol until a persistent yellow color was observed. The resulting mixture was washed sequentially with an aqueous hydrogen chloride solution (1 M, 2×75 mL), with a mixture of deionized water and a saturated aqueous sodium thiosulfate solution (3:1, 100 mL), with deionized water (100 mL), and with a saturated aqueous sodium chloride solution (100 mL). The aqueous layers were separately extracted with a single portion of ethyl acetate-hexanes (9:1, 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 15% dichloromethane, 0.fwdarw.7.5% isopropanol in hexanes) to afford epidithiodiketopiperazine (+)-42 (304 mg, 87.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments..sup.57 1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.65 (d, J=8.0 Hz, 1H, C.sub.8H), 7.40 (app-t, d, J=7.1, 1.5 Hz, 1H, C.sub.7H), 7.34 (dd, J=8.5, 1.2 Hz, 2H, SO.sub.2Ph-o-H), 7.31-7.22 (m, 3H, SO.sub.2Ph-p-H, Hs, H.sub.6), 7.02 (app-t, J=7.5 Hz, 2H, SO.sub.2-m-H), 6.74 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.62 (app-d, J=8.7 Hz, 2H, C.sub.3′H), 6.42 (s, 1H, C.sub.2H), 3.79 (s, 3H, C.sub.5′H), 3.67 (d, J=15.6 Hz, 1H, C.sub.12H.sub.a), 3.05 (s, 3H, C.sub.17H), 2.88 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 1.97 (s, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.8 (C.sub.13), 161.4 (C.sub.16), 158.8 (C.sub.4′), 141.2 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 132.9 (SO.sub.2Ph-p-C), 131.4 (C.sub.1′), 129.7 (C.sub.7), 128.5 (SO.sub.2Ph-m-C), 127.9 (C.sub.2′), 127.2 (SO.sub.2Ph-o-C), 126.1 (C.sub.6), 125.6 (C.sub.5), 119.0 (C.sub.8), 114.5 (C.sub.3′), 88.0 (C.sub.2), 73.9 (C.sub.11), 73.5 (C.sub.15), 59.1 (C.sub.3), 55.5 (C.sub.5′), 46.1 (C.sub.12), 27.6 (C.sub.17), 18.2 (C.sub.18). FTIR (thin film) cm.sup.−1: 2951 (br), 2359 (w), 1679 (s), 1514 (s), 1457 (m), 1341 (s), 1249 (s), 1163 (s), 1028 (m), 905 (m), 730 (s). HRMS (ESI) (m/z): calc'd for C.sub.28H.sub.26N.sub.3O.sub.5S.sub.3[M+H].sup.+: 580.1029, found: 580.1032. [α].sub.D.sup.23: +293 (c=0.57, CHCl.sub.3). TLC (15% dichloromethane and 15% isopropanol in hexanes), Rf: 0.42 (UV, CAM).

##STR00213##

Example 39: Epitrithiodiketopiperazine 43

[0599] A yellow solution of dithiepanethione (+)-41 (30.2 mg, 48.4 μmol, 1 equiv) in acetone (1.6 mL) at 23° C. was sparged with argon for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture. Ethanolamine (0.4 mL) was added via syringe over 30 seconds, resulting in a nearly colorless solution. After 25 min, the reaction mixture was diluted with dichloromethane (30 mL) and was washed with an aqueous hydrogen chloride solution (1 M, 2×30 mL). The combined aqueous layers were extracted with dichloromethane (30 mL), and the combined organic extracts were washed with a saturated aqueous sodium chloride solution (30 mL). The aqueous layer was extracted with dichloromethane (15 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were sparged with argon for 15 min by discharge of a balloon equipped with a needle extending into the stirring reaction mixture. The reaction mixture was then concentrated under reduced pressure to approximately 25 mL and was cooled to 0° C. Pyridine (25 μL, 310 μmol, 6.4 equiv) was added via syringe to the crude bisthiol solution, followed by the dropwise addition of a solution of monosulfur dichloride (0.39 M, 0.50 mL, 0.20 mmol, 4.1 equiv) in dichloromethane via syringe over 30 seconds. The reaction mixture was removed from the ice-water bath and allowed to stir and warm to 23° C. After 30 min, the reaction mixture was washed sequentially with a saturated aqueous sodium bicarbonate solution (2×30 mL) and with a saturated aqueous ammonium chloride solution (2×40 mL). The aqueous layers were separately extracted with a single portion of dichloromethane (20 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue.sup.58 was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% ethyl acetate in dichloromethane) to afford epitrithiodiketopiperazine 43 (7.4 mg, 22%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. Based on .sup.1H NMR analysis at 25° C. in CDCl.sub.3, the product exists as a 3.5:1 mixture of major:minor conformers. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 7.60 (m, 3H, SO.sub.2Ph-o-H, C.sub.8H), 7.48-7.36 (m, 2H, SO.sub.2Ph-p-H, C.sub.7H), 7.23-7.12 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 6.85 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.67 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 6.47 (s, 1H, C.sub.2H), 3.77 (s, 3H, C.sub.5′H), 3.41 (d, J=14.7 Hz, 1H, C.sub.12H.sub.a), 3.18 (s, 3H, C.sub.17H), 3.12 (d, J=14.7 Hz, 1H, C.sub.12H.sub.b), 1.84 (s, 3H, C.sub.18H). Minor conformer: δ 7.31 (m, 2H), 7.10-7.04 (m, 1H), 6.80 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.72 (s, 1H, C.sub.2H), 6.64 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 3.78 (s, 3H, C.sub.5′H), 3.28 (d, J=14.9 Hz, 1H, C.sub.12H.sub.a), 3.03-2.95 (m, 4H, C.sub.17H, C.sub.12H.sub.b), 1.93 (s, 3H, C.sub.18H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): Major conformer: δ 168.8 (C.sub.13), 163.8 (C.sub.16), 159.0 (C.sub.4′), 143.2 (C.sub.9), 139.6 (SO.sub.2Ph-ipso-C), 135.0 (C.sub.4), 133.0 (SO.sub.2Ph-p-C), 131.7 (C.sub.1′), 130.2 (C.sub.7), 128.8 (SO.sub.2Ph-m-C), 127.5 (C.sub.2′), 127.1 (SO.sub.2Ph-o-C), 125.8 (C.sub.5), 125.8 (C.sub.6), 118.9 (C.sub.8), 114.6 (C.sub.3′), 86.8 (C.sub.2), 79.9 (C.sub.11), 72.2 (C.sub.15), 57.2 (C.sub.3), 55.5 (C.sub.5′), 51.7 (C.sub.12), 28.5 (C.sub.18), 21.8 (C.sub.17). Minor conformer: δ 167.2 (C.sub.13), 141.6 (C.sub.9), 138.7 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 129.6, 129.2, 128.6, 127.8, 127.6, 126.3, 125.5, 118.8 (C.sub.8), 88.8 (C.sub.2), 75.7 (C.sub.5/6), 75.5 (C.sub.5/6), 57.5 (C.sub.3), 49.8 (C.sub.12), 29.2 (C.sub.17), 24.1 (C.sub.18). FTIR (thin film) cm.sup.−1: 2936 (br-w), 1682 (s), 1513 (m), 1350 (s), 1167 (s), 1033 (m), 896 (w), 687 (w), 577 (m). HRMS (ESI) (m/z): calc'd for C.sub.28H.sub.26N.sub.3O.sub.5S.sub.4[M+H].sup.+: 612.0750, found: 612.0748. TLC (10% ethyl acetate in dichloromethane), Rf: 0.42 (UV, CAM).

##STR00214##

Example 40: Epitetrathiodiketopiperazine 44

[0600] A yellow solution of dithiepanethione (+)-41 (40.3 mg, 64.6 μmol, 1 equiv) in acetone (2.0 mL) at 23° C. was sparged with argon for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture. Ethanolamine (0.4 mL) was added via syringe over 30 seconds, resulting in a nearly colorless solution. After 70 min, the reaction mixture was diluted with dichloromethane (30 mL) and was washed with an aqueous hydrogen chloride solution (1 M, 2×30 mL). The combined aqueous layers were extracted with dichloromethane (30 mL), and the combined organic extracts were washed with a saturated aqueous sodium chloride solution (30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were sparged with argon for 15 min by discharge of a balloon equipped with a needle extending into the stirring reaction mixture. The reaction mixture was then concentrated under reduced pressure to approximately 30 mL and was cooled to 0° C. Pyridine (26 μL, 320 μmol, 5.0 equiv) was added via syringe to the stirring crude bisthiol solution, followed by the dropwise addition of a solution of disulfur dichloride (0.50 M, 0.50 mL, 250 μmol, 3.9 equiv) in dichloromethane via syringe over 30 seconds. After 15 min, the reaction mixture was washed with a saturated aqueous ammonium chloride solution (2×30 mL), and the combined aqueous layers were extracted with dichloromethane (25 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (45 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% ethyl acetate in dichloromethane) to afford epitetrathiodiketopiperazine 44 (27.6 mg, 66.3%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.96 (app-d, J=7.2 Hz, 2H, SO.sub.2Ph-o-H), 7.54 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.48-7.39 (m, 3H, C.sub.8H, SO.sub.2Ph-m-H), 7.27-7.20 (m, 1H, C.sub.7H), 7.05 (app-t, J=7.5, 1H, C.sub.6H), 6.99 (d, J=7.6, 1H, C.sub.5H), 6.89 (s, 1H, C.sub.2H), 6.84 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.70 (app-d, J=8.8 Hz, 2H, C.sub.3′H), 3.75 (s, 3H, C.sub.5′H), 3.27 (d, J=14.4 Hz, 1H, C.sub.12H.sub.a), 3.10 (d, J=14.4 Hz, 1H, C.sub.12H.sub.b), 3.05 (s, 3H, C.sub.17H), 1.98 (s, 3H, C.sub.18H). .sup.13C NMR (125 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 164.8 (C.sub.16), 158.9 (C.sub.4′), 141.7 (C.sub.9), 139.1 (SO.sub.2Ph-ipso-C), 136.8 (C.sub.4), 133.8 (C.sub.1′), 133.4 (SO.sub.2Ph-p-C), 129.4 (C.sub.7), 129.2 (SO.sub.2Ph-m-C), 127.8 (SO.sub.2Ph-o-C), 126.9 (C.sub.2′), 125.5 (C.sub.6), 124.6 (C.sub.5), 116.5 (C.sub.8), 114.5 (C.sub.3′), 87.1 (C.sub.2), 76.1 (C.sub.11), 74.4 (C.sub.15), 56.9 (C.sub.3), 55.5 (C.sub.5′), 49.9 (C.sub.12), 29.6 (C.sub.17), 22.8 (C.sub.18). FTIR (thin film) cm.sup.−1: 2930 (w), 1668 (s), 1610 (w), 1513 (m), 1354 (s), 1168 (s), 1032 (m), 899 (w), 738 (m), 565 (m). HRMS (ESI) (m/z): calc'd for C.sub.28H.sub.25N.sub.3NaO.sub.5S.sub.5 [M+Na].sup.+: 666.0290, found: 666.0289. TLC (5% ethyl acetate in hexanes), Rf: 0.35 (UV, CAM).

##STR00215##

Example 41: Bis(p-fluorobenzyl)disulfide (+)-45b

[0601] Triethylamine (70 μL, 0.50 mmol, 2.5 equiv) and (p-fluorophenyl)methanethiol (PFB-SH, 25 μL, 0.20 mmol, 1.0 equiv) were added via syringe to a solution of epidithiodiketopiperazine (+)-42 (116 mg, 0.200 mmol, 1 equiv) and 1,2-bis(p-fluorobenzyl)disulfane (PFB-SS-PFB, 552 mg, 1.95 mmol, 9.75 equiv) in tetrahydrofuran (0.5 mL) at 23° C. After 15 h, additional tetrahydrofuran (1.1 mL) was added via syringe to dissolve a white precipitate. After an additional 50 h, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.15% ethyl acetate in dichloromethane) to afford bisdisulfide (+)-45b (38.7 mg, 22.4%) as a white solid and unreacted epidithiodiketopiperazine (+)-42 (76.6 mg, 66.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): 7.67 (d, J=8.1 Hz, 1H, C.sub.8H), 7.48 (app-d, J=7.6 Hz, 2H, SO.sub.2Ph-o-H), 7.38-7.33 (m, 3H, C.sub.3″/3′″H, C.sub.7H), 7.30 (app-t, J=7.7 Hz, 1H, SO.sub.2Ph-p-H), 7.22-7.15 (m, 2H, C.sub.5H, C.sub.6H), 7.14-7.09 (m, 4H, C.sub.3″/3′″H, SO.sub.2Ph-m-H), 6.95 (app-t, J=8.7 Hz, 2H, C.sub.4″/4′″), 6.90 (app-t, J=8.6 Hz, C.sub.4″/4′″H), 6.67 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.59 (s, 1H, C.sub.2H), 6.58 (app-d, J=9.1 Hz, 2H, C.sub.3′H), 4.09 (d, J=12.9 Hz, 1H, C.sub.1″/1′″H), 3.99 (d, J=12.9 Hz, 1H, C.sub.1″/1′″H), 3.84 (d, J=14.7 Hz, 1H, C.sub.12H.sub.a), 3.83 (s, 2H, C.sub.1″/1′″H), 3.76 (s, 3H, C.sub.5′H), 3.10 (s, 3H, C.sub.17H), 2.99 (d, J=14.8 Hz, 1H, C.sub.12H.sub.b), 2.09 (s, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 167.4 (C.sub.13), 164.2 (C.sub.16), 162.3 (d, J=245.6 Hz, C.sub.5″/5′″), 162.3 (d, J=246.3 Hz, C.sub.5″/5′″), 158.6 (C.sub.4′), 142.2 (C.sub.9), 137.9 (SO.sub.2Ph-ipso-C), 135.5 (C.sub.4), 133.2 (C.sub.1′/SO.sub.2Ph-p-C), 133.1 (C.sub.1′/SO.sub.2Ph-p-C), 132.9 (d, J=3.2 Hz, C.sub.2″/2′″), 132.4 (d, J=3.3 Hz, C.sub.2″/2′″), 131.7 (d, J=8.2 Hz, C.sub.3″/3′″), 131.3 (d, J=8.2 Hz, C.sub.3″/3′″), 129.4 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 127.5 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 125.9 (C.sub.5/6), 125.7 (C.sub.5/6), 118.5 (C.sub.8), 115.5 (d, J=21.5 Hz, C.sub.4″/4′″), 115.4 (d, J=21.5 Hz, C.sub.4″/4′″), 114.3 (C.sub.3′), 88.3 (C.sub.2), 73.7 (C.sub.11), 71.1 (C.sub.15), 57.1 (C.sub.3), 55.5 (C.sub.5′), 46.9 (C.sub.12), 42.2 (C.sub.1″/1′″), 41.7 (C.sub.1″/1′″), 29.5 (C.sub.17), 22.8 (C.sub.18). FTIR (thin film) cm.sup.−1: 3485 (br), 2927 (br), 2106 (w), 1663 (m), 1600 (w), 1509 (s), 1362 (s), 833 (m), 687 (w), 599 (m). HRMS (ESI) (m/z): calc'd for C.sub.42H.sub.38F.sub.2N.sub.3O.sub.5S.sub.5[M+H].sup.+: 862.1378, found: 862.1371. [α].sub.D.sup.23: +9 (c=0.26, CHCl.sub.3). TLC (5% ethyl acetate in dichloromethane), Rf: 0.35 (UV, CAM).

##STR00216##

Example 42: Bis(L-glutathione)disulfide 46

[0602] Sodium borohydride (4.9 mg, 0.13 mmol, 4.3 equiv) was added as a solid in one portion to a solution of epidithiodiketopiperazine (+)-42 (17.3 mg, 29.8 μmol, 1 equiv) in tetrahydrofuran (4.0 mL) and methanol (30 μL). After 35 min, the reaction mixture was diluted with ethyl acetate-hexanes (9:1, 40 mL) and was washed sequentially with a saturated aqueous ammonium chloride solution (40 mL), with deionized water (30 mL), and with a saturated aqueous sodium chloride solution (20 mL). The aqueous layers were separately extracted with a single portion of ethyl acetate-hexanes (9:1, 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were sparged with argon for 15 min by discharge of a balloon equipped with a needle extending into the stirring reaction mixture. The reaction mixture was then concentrated under reduced pressure, and the resulting residue containing bisthiol was dissolved in tetrahydrofuran (0.25 mL) and added dropwise via syringe to a solution of S-(phenylsulfonyl)-L-glutathione hydrogen chloride.sup.59 (72.9 mg, 163 μmol, 5.45 equiv) and triethylamine (45 μL, 320 μmol, 11 equiv) in tetrahydrofuran (1.1 mL) and methanol (1.1 mL). The transfer was quantitated with additional tetrahydrofuran (2×0.25 mL). After 19 h, the reaction mixture was diluted with methanol and adsorbed onto Celite (0.4 g) by concentration under reduced pressure until a free-flowing powder was obtained. The Celite-absorbed crude mixture was purified by flash column chromatography on C.sub.18-reversed phase silica gel (eluent: 10.fwdarw.80% acetonitrile in water) to afford the bisdisulfide 46 (17.2 mg, 44.6%) as a white solid and recovered epidithiodiketopiperazine (+)-42 (6.0 mg, 21%). Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, 5:1 D.sub.2O:CD.sub.3CN,.sup.60 25° C.): δ 7.45 (d, J=8.2 Hz, 1H, C.sub.8H), 7.42-7.34 (m, 3H, SO.sub.2Ph-p-H, SO.sub.2Ph-o-H), 7.32 (app-t, J=7.7 Hz, 1H, C.sub.7H), 7.26 (d, J=7.6 Hz, 1H, C.sub.5H), 7.16 (app-t, J=7.5 Hz, 1H, C.sub.6H), 7.10 (app-t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 6.70 (app-d, J=8.4 Hz, 2H, C.sub.2′H), 6.59 (app-d, J=8.4 Hz, 2H, C.sub.3′H), 6.40 (s, 1H, C.sub.2H), 4.66 (dd, J=8.6, 5.1 Hz, 1H, C.sub.2″/2′″H), 4.42 (dd, J=10.0, 4.0 Hz, 1H, C.sub.2″/2′″H), 3.80-3.57 (m, 9H, C.sub.5′H, C.sub.7″H, C.sub.7′″H, C.sub.11″H, C.sub.11′″H), 3.54 (d, J=14.6 Hz, C.sub.12H.sub.a), 3.26-3.03 (m, 9H, HN.sup.+(CH.sub.2CH.sub.3).sub.3, C.sub.1″H.sub.a, C.sub.1″H.sub.b, C.sub.1′″H.sub.a), 3.03-2.93 (m, 4H, C.sub.17H, C.sub.12H.sub.b), 2.65-2.54 (m, 1H, C.sub.1′″H.sub.b), 2.42 (app-t, J=7.6 Hz, 2H, C.sub.5″/5′″H), 2.34 (app-t, J=7.7 Hz, 2H, C.sub.5″/5′″H), 2.04 (app-q, J=7.2 Hz, 2H, C.sub.6″/6′″H), 1.98 (app-q, J=7.5 Hz, 2H, C.sub.6″/6′″H), 1.89 (s, 3H, C.sub.18H), 1.17 (t, J=7.3 Hz, 9H, HN.sup.+(CH.sub.2CH.sub.3).sub.3). .sup.13C NMR (125 MHz, 5:1 D.sub.2O:CD.sub.3CN,.sup.60 25° C.): δ 174.5 (br, 2C, C.sub.12″, C.sub.12′″), 173.7 (C.sub.4″/4′″), 173.6 (C.sub.4″/4′″), 172.8 (br, 2C, C.sub.8″, C.sub.8′″), 170.5 (C.sub.9″/9′″), 170.0 (C.sub.9″/9′″), 166.6 (C.sub.13), 163.9 (C.sub.16), 157.0 (C.sub.4′), 140.3 (C.sub.9), 135.6 (SO.sub.2Ph-ipso-C), 134.7 (C.sub.4), 133.5 (SO.sub.2Ph-p-C), 132.3 (C.sub.1′), 128.8 (C.sub.7), 128.4 (SO.sub.2Ph-m-C), 126.7 (C.sub.2′), 125.9 (SO.sub.2Ph-o-C), 125.6 (C.sub.6), 125.3 (C.sub.5), 117.3 (C.sub.8), 113.7 (C.sub.3′), 87.1 (C.sub.2), 73.1 (C.sub.11), 71.5 (C.sub.15), 56.1 (C.sub.3), 54.6 (C.sub.5′), 53.3 (C.sub.7″/7′″), 53.2 (C.sub.7″/7′″), 52.1 (C.sub.2″/2′″), 51.7 (C.sub.2″/2′″), 45.8 (HN.sup.+(CH.sub.2CH.sub.3).sub.3), 44.4 (C.sub.12), 42.3 (C.sub.11″/11′″), 42.2 (C.sub.11″/11′″), 40.4 (C.sub.1″/1′″), 37.5 (C.sub.1″/1′″), 30.8 (C.sub.5″/5′″), 30.7 (C.sub.5″/5′″), 29.2 (C.sub.17), 25.5 (C.sub.6″/6″), 25.4 (C.sub.6″/6′″), 20.8 (C.sub.18), 7.4 (HN.sup.+(CH.sub.2CH.sub.3).sub.3). FTIR (thin film) cm.sup.−1: 3273 (br), 1645 (s), 1513 (s), 1253 (m), 1167 (m), 1109 (w), 1028 (w), 832 (w), 686 (m). HRMS (ESI) (m/z): calc'd for C.sub.48H.sub.57N.sub.9NaO.sub.17S.sub.5 [M+Na].sup.+: 1214.2368, found: 1214.2359. TLC (30% acetonitrile in water, Cis-reversed phase), Rf: 0.25 (UV, CAM).

##STR00217##

Example 43: C.SUB.3.—Friedel-Crafts Adduct (+)—S.SUB.17

[0603] Endo-tetracyclic bromide.sup.55 (+)-36 (1.03 g, 2.09 mmol, 1 equiv), 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 1.11 g, 5.39 mmol, 2.58 equiv), and (3-phenoxypropoxy)triisopropylsilane 11 (1.35 g, 4.37 mmol, 2.09 equiv) were azeotropically dried by concentration from anhydrous benzene (5 mL) under reduced pressure. Dichloromethane (21 mL) was added via cannula, the resulting colorless solution was cooled to −20° C., and silver trifluoromethanesulfonate (1.09 g, 4.22 mmol, 2.02 equiv) was added as a solid in one portion. After 25 min, the reaction mixture was filtered through a pad of Celite, the filter cake was washed with dichloromethane (200 mL), and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and was washed sequentially with a mixture of saturated aqueous sodium chloride solution and deionized water (1:1, 2×50 mL) and with a saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% acetone in dichloromethane) to afford Friedel-Crafts adduct (+)—S.sub.17 (1.10 g, 73.2%) as a white foam. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.61 (d, J=8.1 Hz, 1H, C.sub.8H), 7.45 (app-d, J=7.9 Hz, 2H, SO.sub.2Ph-o-H), 7.35-7.23 (m, 2H, SO.sub.2Ph-p-H, C.sub.7H), 7.15-7.05 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 6.68-6.59 (m, 4H, C.sub.2′H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.39 (dd, J=9.0, 6.6 Hz, 1H, C.sub.11H), 4.10-3.99 (m, 3H, C.sub.15H, C.sub.5′H), 3.88 (t, J=5.9 Hz, 2H, C.sub.7′H), 3.13 (dd, J=14.1, 6.6 Hz, 1H, C.sub.12H.sub.a), 2.87 (dd, J=14.1, 19.2 Hz, 1H, C.sub.12H.sub.b), 2.86 (s, 3H, C.sub.17H), 2.00 (p, J=6.1 Hz, 2H, C.sub.6′H), 1.58 (d, J=7.0 Hz, 3H, C.sub.18H), 1.15-0.99 (m, 21H, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 167.8 (C.sub.16), 158.2 (C.sub.4′), 139.9 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 135.7 (C.sub.4), 132.8 (SO.sub.2Ph-p-C), 132.5 (C.sub.1′), 129.1 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.0 (C.sub.5), 125.2 (C.sub.6), 117.2 (C.sub.8), 114.9 (C.sub.3′), 87.3 (C.sub.2), 64.8 (C.sub.5′), 59.8 (C.sub.7′), 59.3 (C.sub.3), 58.7 (C.sub.11), 57.1 (C.sub.15), 39.0 (C.sub.12), 32.6 (C.sub.6′), 29.5 (C.sub.17), 18.1 (SiCH(CH.sub.3).sub.2), 14.5 (C.sub.18), 12.0 (SiCH(CH.sub.3).sub.2). FTIR (thin film) cm.sup.−1: 2944 (m), 2866 (m), 2359 (w), 1679 (s), 1509 (s), 1457 (s), 1381 (s), 1249 (s), 1168 (s), 1092 (s), 877 (m), 754 (s). HRMS (ESI) (m/z): calc'd for C.sub.39H.sub.52N.sub.3O.sub.6SSi [M+H].sup.+: 719.3369, found: 719.3365. [α].sub.D.sup.23: +34 (c=0.39, CHCl.sub.3). TLC (10% acetone in dichloromethane), Rf: 0.45 (UV, CAM).

##STR00218##

Example 44: Alcohol (+)-47

[0604] A freshly prepared stock solution of hydrogen fluoride-pyridine (70% HF, 4.8 mL), pyridine (9.6 mL), and tetrahydrofuran (38 mL) at 0° C. was poured a solution of Friedel-Crafts adduct (+)—S.sub.17 (1.03 g, 1.44 mmol, 1 equiv) in tetrahydrofuran (48 mL) at 0° C. contained in a 1-L polypropylene vessel. After 20 min, the ice-water bath was removed and the solution was allowed to stir and to warm to 23° C. After 19 h, the reaction mixture was cooled to 0° C. and was diluted with a saturated aqueous sodium bicarbonate solution (350 mL) in portions (50 mL) over 15 min. The resulting mixture was extracted with ethyl acetate (2×100 mL), and the combined organic extracts were washed sequentially with a saturated aqueous copper(II) sulfate solution (4×50 mL) and with a saturated aqueous ammonium chloride solution (3×50 mL). The combined aqueous layers were extracted with a single portion of ethyl acetate (100 mL), and the organic extract was washed sequentially with a saturated aqueous copper(II) sulfate solution (2×25 mL) and with a saturated aqueous ammonium chloride solution (2×25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20.fwdarw.50% acetone in dichloromethane) to afford alcohol (+)-47 (775 mg, 96.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.60 (d, J=8.1 Hz, 1H, C.sub.8H), 7.44 (app-d, J=7.6 Hz, 2H, SO.sub.2Ph-o-H), 7.33 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.29-7.23 (m, 1H, C.sub.7H), 7.16-7.05 (m, 4H, SO.sub.2Ph-m-H, CsH, C.sub.6H), 6.64 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.59 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.14 (s, 1H, C.sub.2H), 4.39 (dd, J=9.0, 6.5 Hz, 1H, C.sub.11H), 4.11-4.00 (m, 3H, C.sub.15H, C.sub.5′H), 3.85 (t, J=5.9 Hz, 2H, C.sub.7′H), 3.12 (dd, J=14.1, 6.5 Hz, 1H, C.sub.12H.sub.a), 2.91-2.80 (m, 4H, C.sub.12H.sub.b, C.sub.17H), 2.15-1.99 (br-s, 1H, OH), 2.03 (p, J=6.0 Hz, 2H, C.sub.7′H), 1.56 (d, J=7.0 Hz, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 167.9 (C.sub.16), 157.9 (C.sub.4′), 139.8 (C.sub.9), 138.2 (SO.sub.2Ph-ipso-C), 135.6 (C.sub.4), 132.9 (C.sub.1′/SO.sub.2Ph-p-C), 132.8 (C.sub.1′/SO.sub.2Ph-p-C), 129.2 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 127.4 (SO.sub.2Ph-o-C), 126.0 (C.sub.5), 125.3 (C.sub.6), 117.2 (C.sub.8), 114.9 (C.sub.3′), 87.3 (C.sub.2), 65.6 (C.sub.5′), 60.1 (C.sub.7′), 59.3 (C.sub.3), 58.7 (C.sub.11), 57.1 (C.sub.15), 38.9 (C.sub.12), 32.0 (C.sub.6′), 29.5 (C.sub.17), 14.4 (C.sub.18). FTIR (thin film) cm.sup.−1: 3455 (br-w), 2951 (w), 2361 (w), 1672 (s), 1511 (m), 1386 (s), 1253 (s), 1170 (s), 1690 (s), 981 (m), 751 (s). HRMS (ESI) (m/z): calc'd for C.sub.30H.sub.32N.sub.3O.sub.6S [M+H].sup.+: 562.2006, found: 562.2007. [α].sub.D.sup.23: +52 (c=0.26, CHCl.sub.3). TLC (40% acetone in dichloromethane), Rf: 0.35 (UV, CAM).

##STR00219##

Example 45: Tosylate S18

[0605] Alcohol (+)-47 (277 mg, 0.494 mmol, 1 equiv) was azeotropically dried by concentration from anhydrous benzene (3 mL) under reduced pressure. Dichloromethane (4.9 mL) was added via syringe, followed by the addition of triethylamine (0.35 mL, 2.5 mmol, 5.1 equiv) via syringe and p-toluenesulfonic anhydride (655 mg, 1.99 mmol, 4.03 equiv) as a solid in one portion. After 17 h, the reaction mixture was diluted with dichloromethane (75 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was extracted with dichloromethane (50 mL), and the combined organic extracts were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.25% acetone in dichloromethane) to afford tosylate S18 (339 mg, 95.8%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.77 (app-d, J=8.3 Hz, 2H, C.sub.9′H), 7.61 (d, J=8.1 Hz, 1H, C.sub.8H), 7.47 (app-d, J=7.6 Hz, 1H, SO.sub.2Ph-o-H), 7.34 (app-t, J=7.4 Hz, 1H, SO.sub.2Ph-p-H) 7.31-7.24 (m, 3H, C.sub.7H, C.sub.10′H), 7.15-7.06 (m, 3H, C.sub.5H, C.sub.6H, SO.sub.2Ph-m-H), 6.66 (app-d, J=8.7 Hz, 1H, C.sub.2′H), 6.54 (app-d, J=8.7 Hz, 1H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.39 (app-t, J=7.3 Hz, 1H, C.sub.11H), 4.25 (t, J=5.8 Hz, 1H, C.sub.5′H), 4.04 (q, J=7.0 Hz, 1H, C.sub.15H), 3.95 (t, J=5.9 Hz, 1H, C.sub.7′H), 3.13 (dd, J=14.1, 6.6 Hz, 1H, C.sub.12H.sub.a), 2.93-2.83 (m, 4H, C.sub.12H.sub.b, C.sub.17H), 2.40 (s, 3H, C.sub.12′H), 2.13 (p, J=5.9 Hz, 2H, C.sub.6′H), 1.58 (d, J=7.0 Hz, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 167.9 (C.sub.16), 157.7 (C.sub.4′), 145.0 (C.sub.11′), 139.9 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.6 (C.sub.4), 133.1 (C.sub.1′), 133.0 (C.sub.8′), 133.0 (SO.sub.2Ph-p-C), 130.0 (C.sub.10′), 129.2 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 128.0 (C.sub.9′), 127.5 (SO.sub.2Ph-o-C), 126.0 (C.sub.5), 125.3 (C.sub.6), 117.2 (C.sub.8), 114.9 (C.sub.3′), 87.2 (C.sub.2), 67.0 (C.sub.5′), 63.4 (C.sub.7′), 59.3 (C.sub.3), 58.7 (C.sub.11), 57.1 (C.sub.15), 39.0 (C.sub.12), 29.6 (C.sub.17), 29.0 (C.sub.6′), 21.8 (C.sub.12′), 14.5 (C.sub.18). FTIR (thin film) cm.sup.−1: 2918 (br-w), 2361 (m), 1672 (m), 1511 (m), 1357 (m), 1256 (m), 1173 (s), 1095 (m), 938 (w), 747 (s). HRMS (ESI) (m/z): calc'd for C.sub.37H.sub.38N.sub.3O.sub.8S.sub.2[M+H].sup.+: 716.2095, found: 716.2092. TLC (10% acetone in dichloromethane), Rf: 0.30 (UV, CAM).

##STR00220##

Example 46: Azide (+)-48

[0606] Sodium azide (145 mg, 2.24 mmol, 3.99 equiv) was added as a solid in one portion to a solution of tosylate S.sub.18 (401 mg, 0.560 mmol, 1 equiv) in N,N-dimethylformamide (3.7 mL). After 23 h, the reaction mixture was diluted with ethyl acetate-hexanes (9:1, 150 mL) and was washed sequentially with a saturated aqueous sodium bicarbonate solution (2×50 mL), with deionized water (3×40 mL), and with a saturated aqueous sodium chloride solution (30 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.20% acetone in dichloromethane) to afford azide (+)-48 (292 mg, 89.0%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.62 (d, J=8.1 Hz, 1H, C.sub.8H), 7.48 (dd, J=8.5, 1.2 Hz, 2H, SO.sub.2Ph-o-H), 7.34 (tt, J=7.4, 1.2 Hz, 1H, SO.sub.2Ph-p-H), 7.31-7.25 (m, 1H, C.sub.7H), 7.15-7.08 (m, 4H, SO.sub.2Ph-m-H, C.sub.5H, C.sub.6H), 6.68 (app-d, J=8.9 Hz, 2H, C.sub.2′H), 6.62 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.15 (s, 1H, C.sub.2H), 4.38 (dd, J=8.9, 6.7 Hz, 1H, C.sub.11H), 4.04 (q, J=7.1 Hz, 1H, C.sub.15H), 4.00 (t, J=5.9 Hz, 2H, C.sub.5′H), 3.53 (t, J=6.5 Hz, 2H, C.sub.7′H), 3.13 (dd, J=14.1, 6.7 Hz, 1H, C.sub.12H.sub.a), 2.88 (dd, J=14.0, 9.0 Hz, 1H, C.sub.12H.sub.b), 2.86 (s, 3H, C.sub.17H), 2.05 (p, J=6.2 Hz, 2H, C.sub.6′H), 1.58 (d, J=7.1 Hz, 3H, C.sub.18H). .sup.13C NMR (125 MHz, CDCl.sub.3, 25° C.): δ 168.4 (C.sub.13), 167.9 (C.sub.16), 157.8 (C.sub.4′), 139.9 (C.sub.9), 138.3 (SO.sub.2Ph-ipso-C), 135.6 (C.sub.4), 133.0 (C.sub.1′), 132.9 (SO.sub.2Ph-p-C), 129.2 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.1 (C.sub.2′), 127.5 (SO.sub.2Ph-o-C), 126.0 (C.sub.5), 125.3 (C.sub.6), 117.2 (C.sub.8), 114.9 (C.sub.3′), 87.2 (C.sub.2), 64.6 (C.sub.5′), 58.8 (C.sub.11), 57.1 (C.sub.15), 48.3 (C.sub.7′), 39.0 (C.sub.12), 29.6 (C.sub.17), 28.8 (C.sub.6′), 14.5 (C.sub.18). FTIR (thin film) cm.sup.−1: 2956 (br-w), 2096 (s), 1670 (s), 1611 (w), 1476 (m), 1360 (s), 1168 (s), 1090 (m), 971 (w), 829 (w), 758 (m). HRMS (ESI) (m/z): calc'd for C.sub.30H.sub.31N.sub.6OSS [M+H].sup.+: 588.2100, found: 588.2101. [α].sub.D.sup.23: +46 (c=0.25, CHCl.sub.3). TLC (10% acetone in dichloromethane), Rf: 0.27 (UV, CAM).

##STR00221##

Example 47: Epidithiodiketopiperazine Azide (+)-9d

[0607] Bis(pyridine)silver(I) permanganate (178 mg, 0.464 mmol, 3.03 equiv) was added as a solid to a solution of azide (+)-48 (90 mg, 0.153 mmol, 1 equiv) in dichloromethane (3 mL). After 30 min, the reaction mixture was diluted with a saturated aqueous sodium bisulfite solution (10 mL) and was extracted with ethyl acetate-hexanes (9:1, 2×20 mL). The combined organic extracts were washed sequentially with deionized water (15 mL) and with a saturated aqueous ammonium chloride solution (3×30 mL). The combined aqueous layers were extracted with ethyl acetate-hexanes (4:1, 20 mL), and the organic extract was washed with a saturated aqueous ammonium chloride solution (2×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5.fwdarw.15% acetone in dichloromethane) to afford diol 49 (61.3 mg, 64.6%) as a white foam..sup.61 Diol 49 (55.0 mg, 88.9 μmol, 1 equiv) was azeotropically dried by concentration from dichloromethane (0.5 mL) and anhydrous benzene (1.5 mL) under reduced pressure. The flask was charged with 4-dimethylaminopyridine (DMAP, 1.5 mg, 12 μmol, 0.14 equiv), and the solids were dissolved in N,N-dimethylformamide (0.9 mL). Triethylamine (40 μL, 290 μmol, 3.2 equiv) was then added via syringe followed by the dropwise addition of a solution of t-butyldimethylsilyl chloride (TBSCl, 2.05 M, 88 μL, 180 μmol, 2.0 equiv) in N,N-dimethylformamide. After 2 h, the reaction mixture was diluted with ethyl acetate-hexanes (4:1, 25 mL) and with a saturated aqueous ammonium chloride solution (15 mL). The aqueous layer was extracted with ethyl acetate-hexanes (4:1, 25 mL). The combined organic extracts were washed with deionized water (3×10 mL) and with a saturated aqueous sodium chloride solution (10 mL). The organic layer was dried over anhydrous sodium sulfate, was filtered, and was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.30% acetone in hexanes) to afford a mixture of O-TBS protected monoalcohols S22 and S23 (55.4 mg, 85.0%, 1.1:1) as a white foam..sup.62 A solution of O-TBS protected monoalcohols S22 and S23 (16.5 mg, 22.5 μmol, 1 equiv) in anhydrous nitroethane (1.0 mL) at 0° C. was sparged with hydrogen sulfide gas for 20 min by discharge of a balloon equipped with a needle extending into the reaction mixture, providing a saturated hydrogen sulfide solution. Trifluoroacetic acid (TFA, 0.75 mL) was added via syringe over 20 seconds, and the sparging with hydrogen sulfide was maintained for another 20 min. The ice-water bath was removed, and the solution was allowed to stir and warm to 23° C. under an atmosphere of hydrogen sulfide. After 2 h, the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and the resulting mixture was extracted with ethyl acetate (2×10 mL). A stock solution of potassium triiodide in pyridine.sup.43 was added dropwise into the organic layer containing crude bisthiol until a persistent yellow color was observed. The resulting mixture was washed with an aqueous hydrogen chloride solution (1 M, 2×15 mL) and with a saturated aqueous sodium chloride solution (10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL), and the combined organic layers were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.10% ethyl acetate in dichloromethane) to afford the epidithiodiketopiperazine (+)-9d (7.8 mg, 53%) as a beige solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments..sup.63 1H NMR (500 MHz, CDCl.sub.3, 25° C.): 7.65 (d, J=8.5 Hz, 1H, C.sub.8H), 7.40 (app-t, J=8.3 Hz, 1H, C.sub.7H), 7.36 (app-d, J=8.1 Hz, 2H, SO.sub.2Ph-o-H), 7.33-7.22 (m, 3H, C.sub.6H, C.sub.5H, SO.sub.2Ph-p-H), 7.04 (app-t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 6.75 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.62 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.42 (s, 1H, C.sub.2H), 4.01 (t, J=5.9 Hz, 2H, C.sub.5′H), 3.67 (d, J=15.5 Hz, 1H, C.sub.12H.sub.a), 3.54 (t, J=6.5 Hz, 2H, C.sub.7′H), 3.05 (s, 3H, C.sub.17H), 2.88 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.07 (p, J=6.2 Hz, 2H, C.sub.6′H), 1.97 (s, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): 165.8 (C.sub.13), 161.4 (C.sub.16), 158.0 (C.sub.4′), 141.3 (C.sub.9), 138.5 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.0 (SO.sub.2Ph-p-C), 131.7 (C.sub.1′), 129.8 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.1 (C.sub.6), 125.6 (C.sub.5), 119.0 (C.sub.8), 115.1 (C.sub.3′), 88.0 (C.sub.2), 74.0 (C.sub.11), 73.5 (C.sub.15), 64.7 (C.sub.5′), 59.2 (C.sub.3), 48.3 (C.sub.7′), 46.1 (C.sub.12), 28.9 (C.sub.17), 27.6 (C.sub.6′), 18.3 (C.sub.18). FTIR (thin film) cm.sup.−1: 2922 (w), 2097 (s), 1712 (s), 1686 (s), 1610 (w), 1512 (s), 1251 (s), 1169 (s), 1056 (m), 895 (w), 738 (m), 601 (s). HRMS (ESI) (m/z): calc'd for C.sub.30H.sub.29N.sub.6O.sub.5S.sub.3 [M+H].sup.+: 649.1356, found: 649.1356. [α].sub.D.sup.23: +231 (c=0.06, CHCl.sub.3). TLC (15% ethyl acetate in dichloromethane), Rf: 0.38 (UV, CAM).

##STR00222##

Example 48: Triazole 51

[0608] A solution of N,N-diisopropylethylamine (DIPEA, 2.7 μL, 16 μmol, 1.5 equiv) and acetic acid (AcOH, 0.90 μL, 16 μmol, 1.5 equiv) in toluene (0.2 mL) was added to a flask containing azide (+)-9d (6.8 mg, 11 μmol, 1 equiv) and alkyne.sup.64 50 (11.6 mg, 40.4 μmol, 3.67 equiv). Copper (I) iodide (0.9 mg, 5 μmol, 0.5 equiv) was added as a solid, and the suspension was sparged with argon for 2 min by discharge of balloon equipped with a needle extending into the reaction mixture. After 17 h, the reaction mixture was diluted with dichloromethane (0.5 mL) and was purified by flash chromatography on silica gel (eluent: 5.fwdarw.40% acetone in dichloromethane) to afford triazole 51 as a yellow solid. The mixture was further purified by flash column chromatography on silica gel (eluent: 0.fwdarw.4% methanol in dichloromethane) to afford triazole 51 (9.0 mg, 91.7%) as a white solid. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.68-7.60 (m, 2H, C.sub.8H, C.sub.8′H), 7.40 (app-t, J=7.6 Hz, 1H, C.sub.7H), 7.36 (app-d, J=7.9 Hz, 2H, SO.sub.2Ph-o-H), 7.31 (app-t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.29-7.22 (m, 2H, C.sub.5H, C.sub.6H), 7.05 (app-t, J=7.7 Hz, 2H, SO.sub.2Ph-m-H), 6.74 (app-d, J=8.2 Hz, 2H, C.sub.2′H), 6.59 (br-s, 2H, C.sub.3′H), 6.42 (s, 1H, C.sub.2H), 5.04 (br-s, 1H, N.sub.17′H), 4.70 (s, 2H, C.sub.10′H), 4.60 (t, J=5.7 Hz, 2H, C.sub.7′H), 3.97-3.88 (m, 2H, C.sub.5′H), 3.73-3.57 (m, 9H, C.sub.12H.sub.a, C.sub.11′H, C.sub.12′H, C.sub.13′H, C.sub.14′H), 3.53 (t, J=5.0 Hz, 2H, C.sub.15′H), 3.30 (app-q, J=5.5 Hz, 2H, C.sub.16′H), 3.05 (s, 3H, C.sub.17H), 2.88 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.40 (p, J=6.4 Hz, 2H, C.sub.6′H), 1.96 (s, 3H, C.sub.18H), 1.43 (s, 9H, C.sub.19′(CH.sub.3).sub.3). .sup.13C NMR (125 MHz, CDCl.sub.3, 25° C.): δ 165.8 (C.sub.13), 161.4 (C.sub.16), 157.7 (C.sub.4′), 156.1 (C.sub.18′), 145.45 (C.sub.9′), 141.3 (C.sub.9), 138.5 (SO.sub.2Ph-ipso-C), 135.8 (C.sub.4), 133.1 (SO.sub.2Ph-p-C), 132.0 (C.sub.1′), 129.8 (C.sub.7), 128.6 (SO.sub.2Ph-m-C), 128.0 (C.sub.2′), 127.2 (SO.sub.2Ph-o-C), 126.1 (C.sub.6), 125.5 (C.sub.5), 123.0 (C.sub.8′), 119.0 (C.sub.8), 115.0 (C.sub.3′), 87.9 (C.sub.2), 79.3 (C.sub.19′), 73.9 (C.sub.11), 73.5 (C.sub.15), 70.7 (3C, C.sub.12′, C.sub.13′, C.sub.14′), 70.4 (C.sub.15′), 69.9 (C.sub.11′), 64.8 (C.sub.10′), 64.2 (C.sub.5′), 59.1 (C.sub.3), 47.1 (C.sub.7′), 46.0 (C.sub.12), 40.5 (C.sub.16′), 30.0 (C.sub.6′), 28.6 (C.sub.19′(CH.sub.3).sub.3), 27.7 (C.sub.17), 18.2 (C.sub.18). FTIR (thin film) cm.sup.−1: 3360 (br-m), 2921 (s), 2851 (m), 1659 (m), 1632 (m), 1468 (w), 1411 (w), 1024 (w), 801 (w). HRMS (ESI) (m/z): calc'd for C.sub.44H.sub.53N.sub.7NaO.sub.10S.sub.3 [M+Na].sup.+: 958.2908, found: 958.2902. TLC (40% acetone in dichloromethane), Rf: 0.39 (UV, CAM). TLC (5% methanol in dichloromethane), Rf: 0.26 (UV, CAM).

##STR00223##

Example 49: Heterodimeric Epidithiodiketopiperazine Azide 60

[0609] A solution of heterodimeric dioxasilane 59 (14.5 mg, 12.0 μmol, 1 equiv) in dichloromethane (0.5 mL) was added via cannula to a solution of tritylhydrodisulfane (40.0 mg, 129 μmol, 10.8 equiv) in dichloromethane (1 mL). The transfer was quantitated with additional dichloromethane (0.5 mL). Boron trifluoride diethyl etherate (29 μL, 240 μmol, 20 equiv) was added via syringe, and the resulting bright yellow solution was stirred at 23° C. After 70 min, another portion of boron trifluoride etherate (29 μL, 240 μmol, 20 equiv) was added via syringe. After an additional 2 h, the reaction mixture was diluted with dichloromethane (10 mL) and was washed with a saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.10% ethyl acetate in dichloromethane). The resulting colorless residue was further purified by flash column chromatography on silica gel (eluent: 0.fwdarw.15% diethyl ether in dichloromethane) to afford heterodimeric epidithiodiketopiperazine azide 60 (4.9 mg, 39.3%) as a colorless solid. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.90-7.88 (m, 4H), 7.70-7.66 (m, 2H), 7.58-7.54 (m, 2H), 7.50-7.46 (m, 4H), 7.26-7.21 (m, 2H), 7.21-7.17 (m, 2H), 7.10-7.06 (m, 2H), 6.84 (s, 1H), 6.83 (s, 1H), 3.82-3.74 (m, 1H), 3.60-3.53 (m, 2H), 3.33-3.21 (m, 3H), 2.99 (s, 3H), 2.97-2.91 (m, 2H), 1.74-1.63 (m, 8H), 1.62-1.56 (m, 2H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 164.8, 164.4, 160.7, 160.6, 142.5 (2C), 142.3 (2C), 132.5, 130.9 (2C), 128.9 (2C), 125.8, 125.7, 125.1, 124.8, 81.9, 73.8, 73.6, 73.4, 72.0, 60.4, 51.0, 42.3, 41.6 (2C), 27.7, 26.3, 25.3, 17.9, 17.4. FTIR (thin film) cm.sup.−1: 2927 (w), 2162 (m), 2097 (w), 1716 (s), 1688 (s), 1480 (m), 1462 (m), 1348 (s), 1168 (s), 1096 (m), 1057 (m), 753 (m), 730 (m), 582 (s). HRMS (ESI) (m/z): calc'd for C.sub.45H.sub.41N.sub.9O.sub.8S.sub.6[M+H].sup.+: 1027.1409, found: 1027.1402. TLC (15% ethyl acetate in dichloromethane), Rf: 0.34 (UV, CAM).

##STR00224##

Alkyne (+)-54

[0610] Diketopiperazine bromide (+)-52 (966 mg, 2.04 mmol, 1 equiv) and propargylic iodide (Propargylic iodide was prepared using a procedure adapted from Yasuda, S.; Kawaguchi, Y.; Okamoto, Y.; Mukai, C. Chem. Eur. J. 2016, 22, 1218) 53 (11.6 g, 40.7 mmol, 20.0 equiv) were azeotropically dried by concentration from anhydrous benzene (20 mL). The resulting residue was dissolved in acetonitrile (14.8 mL). A sample of tris(dimethylamino) sulfonium difluorotrimethylsilicate (TASF, 2.00 g, 5.59 mmol, 2.75 equiv) was added at 23° C. After 20 min, the red solution was diluted with ethyl acetate (75 mL) and with a saturated aqueous sodium bicarbonate solution (75 mL). The aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (150 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10.fwdarw.50% ethyl acetate in hexanes) to afford alkyne (+)-54 (1.03 g, 80.4%) as a white foam. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.98 (d, J=8.5 Hz, 2H, SO.sub.2Ph-o-H), 7.55 (d, J=8.2 Hz, 1H, C.sub.8H), 7.54 (t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.44 (t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 7.39-7.29 (m, 7H, C.sub.5H, C.sub.7H, OCH.sub.2Ph), 7.11 (t, J=7.6 Hz, 1H, C6H), 6.26 (s, 1H, C2H), 4.72 (dt, J=17.7, 2.0 Hz, 1H, C18H.sub.a), 4.54 (s, 2H, OCH.sub.2Ph), 4.41 (dd, J=8.7, 6.5 Hz, 1H, C11H), 4.20 (q, J=7.0 Hz, 1H, C15H), 4.13 (t, J=1.9 Hz, 2H, C21H), 3.70 (dt, J=17.6, 1.9 Hz, 1H, C18H.sub.b), 3.34 (dd, J=14.4, 6.5 Hz, 1H, C12H.sub.a). 3.05 (dd, J=14.4, 8.8 Hz, 1H, C12H.sub.b), 1.69 (d, J=7.0 Hz, 3H, C17H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.9 (C16), 167.5 (C13), 138.9 (C9), 137.8 (SO.sub.2Ph-ipso-C), 137.4 (OCH.sub.2Ph-ipso-C), 133.6 (SO.sub.2Ph-p-C), 133.5 (C4), 130.9 (C7), 129.0 (SO.sub.2Ph-m-C), 128.6 (OCH.sub.2Ph-m-C), 128.3 (SO.sub.2Ph-o-C), 128.1 (2C, (OCH.sub.2Ph-p-C, OCH.sub.2Ph-o-C), 125.9 (C6), 125.0 (C5), 117.0 (C8), 87.1 (C2), 80.6 (C20), 80.0 (C19), 71.9 (OCH.sub.2Ph), 61.1 (C3), 58.4 (C11), 58.0 (C21), 57.5 (C11), 55.8 (C15), 41.2 (C12), 31.9 (C18), 14.2 (C17). FTIR (thin film) cm.sup.−1: 3065 (w), 2857 (w), 2252 (w), 1683 (s), 1496 (m), 1388 (s), 1290 (m), 1169 (s), 910 (w), 730 (s). HRMS (ESI) (m/z): calc'd for C.sub.31H.sub.28BrN.sub.3NaO.sub.5S [M+Na].sup.+: 656.0825, found: 656.0852. [α].sub.D.sup.23: +53 (c=1.4, CHCl.sub.3). TLC (20% ethyl acetate in dichloromethane), Rf: 0.60 (UV, CAM)

##STR00225##

Alcohol (+)-55

[0611] A sample of palladium on activated charcoal (10% w/w, 744 mg, 664 μmol, 0.200 equiv) was added to a solution of alkyne (+)-54 (2.11 g, 3.32 mmol, 1 equiv) in ethyl acetate (296 mL). The suspension was sparged with hydrogen gas for 10 min by discharge of a balloon equipped with a needle extending into the reaction mixture. After stirring for 1 h under an atmosphere of dihydrogen, the suspension was filtered through a pad of celite. The filter cake was washed with ethyl acetate (750 mL). The filtrate was concentrated under reduced pressure to afford benzyl ether U4 as a white foam that was used in the next step without further purification.

[0612] The sample of crude benzyl ether U4 (1 equiv) was azeotropically dried by concentration from anhydrous benzene (3×8 mL). The residue was dissolved in dichloromethane (33 mL) and cooled to −78° C. Boron trichloride (1.0 M in dichloromethane, 25.6 mmol, 8.00 equiv) was added dropwise from a pressure-equalizing addition funnel over 5 min. After 1 h, the reaction mixture was diluted with methanol-chloroform (1:9, 50 mL) and the cooling bath was removed. After warming to 23° C., the reaction mixture was diluted with a saturated aqueous sodium bicarbonate solution (200 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (200 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 10->30% acetone in dichloromethane) to afford alcohol (+)-55 (1.48 g, 81.5% over two steps) as a white foam. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.94 (d, J=7.4 Hz, 2H, SO.sub.2Ph-o-H), 7.55 (d, J=8.2, 1H, C8H), 7.51 (t, J=7.1 Hz, 1H, SO.sub.2Ph-p-H), 7.43 (t, J=8.0 Hz, 2H, SO.sub.2Ph-m-H), 7.36 (d, J=7.9 Hz, 1H, C5H), 7.28 (td, J=8.3, 7.4 Hz, 1H, C7H) 7.12 (td, J=7.6, 1.0 Hz, 1H, C6H), 6.24 (s, 1H, C2H), 4.33 (dd, J=9.0, 5.3 Hz, 1H, C11H), 4.11 (q, J=7.1 Hz, 1H, C15H), 3.55 (t, J=5.8 Hz, 2H, C21H), 3.48 (dd, J=14.2, 5.3 Hz, 1H, C12H.sub.a), 3.42-3.36 (m, 1H, C18H.sub.a), 3.33-3.26 (m, 1H, C18H.sub.b), 3.03 (dd, J=14.2, 9.0 Hz, 1H, C12H.sub.b), 1.58 (d, J=6.8 Hz, 3H, C17H), 1.44-1.30 (m, 4H, C19H, C20H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.7 (2C, C16, C13), 139.0 (C9), 138.0 (SO.sub.2Ph-ipso-C), 133.8 (C4), 133.5 (SO.sub.2Ph-p-C), 130.9 (C7), 129.0 (SO.sub.2Ph-m-C), 128.3 (SO.sub.2Ph-p-C), 125.9 (C6), 125.3 (C5), 116.9 (C8), 87.1 (C2), 62.4 (C21), 61.1 (C3), 58.5 (C11), 56.1 (C15), 42.1 (C18), 40.3 (C12), 29.3 (C19), 25.3 (C20), 13.6 (C17). FTIR (thin film) cm.sup.−1: 3399 (br-w), 2930 (w), 1713 (s), 1462 (m), 1349 (s), 1167 (s), 1096 (m), 730 (m), 582 (s). HRMS (ESI) (m/z): calc'd for C.sub.24H.sub.26BrN.sub.3NaO.sub.5S [M+Na].sup.+: 570.0669, found: 570.0689. [α].sub.D.sup.23: +102 (c=0.17, CHCl.sub.3). TLC (30% acetone in dichloromethane), Rf: 0.32 (UV, CAM).

##STR00226##

Heterodimeric Diketopiperazine Alcohol (+)-56

[0613] A sample of tris(triphenylphosphine)colbalt(I) chloride complex (4.17 g, 4.73 mmol, 3.00 equiv) was added as a solid to a solution of alcohol (+)-55 (862 mg, 1.58 mmol, 1 equiv) and N-methyl diketopiperazine bromide (Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238-241) (+)-36 (772 mg, 1.58 mmol, 1 equiv) in degassed (Ar stream, 20 min) acetone (30 mL) at 0° C. The ice-water bath was removed. After 15 min, the green suspension was diluted with ethyl acetate and was stirred vigorously for 10 min. The resulting blue solution was diluted with a saturated aqueous ammonium chloride solution (150 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×150 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (300 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 5.fwdarw.10% isopropanol, 50% dichloromethane 45.fwdarw.40% hexanes) to afford heterodimeric diketopiperazine alcohol (+)-56 (364 mg, 26.2%) as a white solid. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 8.11-8.01 (m, 4H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H), 7.63-7.59 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.56-7.52 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.36 (dd, J=7.7, 1.3 Hz, 1H, C5H/C5′H), 7.33 (dd, J=7.8, 1.3 Hz, 1H, C5H/C5′H), 7.32-7.28 (m, 2H, C7H, C7′H), 7.24-7.18 (m, 2H, C6H, C6′H), 7.08 (d, J=8.4 Hz, 1H, C8H/C8′H), 7.04 (d, J=8.1 Hz, 1H, C8H/C8′H), 6.44 (s, 1H, C2H/C2′H), 6.43 (s, 1H, C2H/C2′H), 4.60 (t, J=9.0 Hz, 1H, C11H/C11′H), 4.51 (dd, J=9.5, 7.5 Hz, 1H, C11H/C11′H), 4.03 (q, J=7.0 Hz, 1H, C15/C15′H), 3.98 (q, J=7.0 Hz, 1H, C15/15′H), 3.55 (m, 3H, C18H.sub.a, C20H), 3.09 (dt, J=14.3, 7.1 Hz, 1H, C18H.sub.b), 2.84 (s, 3H, C18′H), 2.80-2.70 (m, 2H, C12H.sub.a, C12H.sub.a′), 2.62 (dd, J=15.0, 7.5 Hz, 1H, C12H.sub.b/C12′H.sub.b), 2.55 (dd, J=15.0, 8.6 Hz, 1H, C12H.sub.b/C12′H.sub.b), 1.46-1.34 (m, 4H, C19H, C20H), 1.37 (d, J=7.0 Hz, 3H, C17H/C17′H) 1.36 (d, J=7.0 Hz, 3H, C17H/C17′H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 169.2 (2C, C16, C16′), 168.4 (C13/C13′), 168.2 (C13/C13′), 142.2 (2C, C9, C9′), 141.7 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 141.6 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 135.5 (C4/C4′), 135.0 (C4/C4′), 133.1 (2C, SO.sub.2Ph-p-C, SO.sub.2Ph′-p-C), 129.8 (C7/C7′), 129.7 (C7/C7′), 129.0 (2C, SO.sub.2Ph-m-C, SO.sub.2Ph′-m-C), 127.5 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 127.4 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 127.3 (C5/C5′), 127.1 (C5/C5′), 125.1 (2C, C6, C6′), 117.4 (C8/C8′), 117.2 (C8/C8′), 81.9 (2C, C2/C2′), 62.3 (C21), 59.7 (C3/C3′), 59.4 (C3/C3′), 57.5 (C11/C11′), 57.4 (C11/C11′), 57.1 (C15/C15′), 55.9 (C15/C15′), 42.1 (C18), 34.1 (C12/C12′), 33.4 (C12/C12′), 29.9 (C18′), 29.4 (C19), 24.8 (C20), 15.1 (C17/C17′), 14.3 (C17/C17′). FTIR (thin film) cm.sup.−1: 3408 (br-w), 3071 (w), 2249 (w), 1665 (s), 1391 (m), 1335 (m), 1159 (s), 909 (m), 727 (s), 589 (s). HRMS (ESI) (m/z): calc'd for C.sub.45H.sub.47N.sub.6O.sub.9S.sub.2 [M+H].sup.+: 879.2840, found: 879.2878. [α].sub.D.sup.23: +12 (c=1.2, CHCl.sub.3). TLC (10% isopropanol, 50% dichloromethane, 40% hexanes), Rf: 0.35 (UV, CAM).

##STR00227##

Heterodimeric Diketopiperazine Azide (+)-57

[0614] Methanesulfonyl chloride (130 μL, 1.55 mmol, 4.00 equiv) was added to a solution of heterodimeric alcohol (+)-56 (340 mg, 387 μmol, 1 equiv) and triethylamine (393 μL, 3.10 mmol, 8.00 equiv) at 23° C. After 3 h, the orange solution was diluted with dichloromethane (30 mL) and a saturated aqueous sodium bicarbonate solution (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (45 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure to provide the crude mesylate as a yellow foam, which was used directly in the next step without further purification.

[0615] A sample of sodium azide (91.3 mg, 1.42 mmol, 4.00 equiv) was added as a solid to a solution of the crude mesylate in N,N-dimethylformamide (3.78 mL) at 23° C. After 24 h, the orange suspension was diluted with a saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (2×45 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 10->15% acetone in dichloromethane) to afford heterodimeric diketopiperazine azide (+)-57 (280 mg, 80.1%) as an off-white solid. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 8.14-8.04 (m, 4H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H), 7.65-7.58 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.57-7.50 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.37 (d, J=6.7 Hz, 1H, C5H/C5′H), 7.34-7.28 (m, 3H, C5H/C5′H, C7H, C7′H), 7.22 (m, 2H, C6H, C6′H), 7.09 (d, J=8.3 Hz, 1H, C8H/C8′H), 7.04 (d, J=8.0 Hz, 1H, C8H/C8′H), 6.45 (s, 1H, C2H/C2′H), 6.43 (s, 1H, C2H/C2′H), 4.60 (t, J=9.0 Hz, 1H, C11H/C11′H), 4.55-4.45 (m, 1H, C11H/C11′H), 4.07-3.94 (m, 2H, C15H/C15′H), 3.55-3.46 (m, 1H, C18H.sub.a), 3.23-3.16 (m, 2H, C21H), 3.14-3.05 (m, 1H, C18H.sub.b), 2.84 (s, 3H, C18′H), 2.80-2.69 (m, 2H, C12H.sub.a, C12′H.sub.a), 2.63 (dd, J=15.0, 7.4 Hz, 1H, C12H.sub.b/C12′H.sub.b), 2.55 (dd, J=15.1, 8.6 Hz, 1H, C12H.sub.b/C12′H.sub.b), 1.48-1.31 (m, 10H, C19H, C20H, C17H, C17′H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 169.2 (C16/C16′), 169.0 (C16/C16′), 168.3 (C13/C13′), 168.2 (C13/C13′), 142.1 (2C, C9, C9′), 141.7 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 141.6 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 135.5 (C4/C4′), 134.9 (C4/C4′), 133.1 (2C, SO.sub.2Ph-p-C, SO.sub.2Ph′-p-C), 129.7 (2C, C7, C7′) 129.0 (2C, SO.sub.2Ph-m-C, SO.sub.2Ph′-m-C), 127.5 (C5/C5′), 127.3 (2C, C5/C5′, SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 127.1 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 125.1 (C6/C6′), 125.0 (C6/C6′), 117.4 (C8/C8′), 117.2 (C8/C8′), 81.9 (2C C2, C2′), 59.7 (C3/C3′), 59.4 (C3/C3′), 57.5 (C11/C11′), 57.4 (C11/C11′), 57.0 (C15/C15′), 55.8 (C15/C15′), 51.0 (C21), 41.7 (C18), 34.0 (C12/C12′), 33.3 (C12/C12′), 29.8 (C18′), 26.1 (C20), 25.6 (C19), 15.1 (C17/C17′), 14.3 (C17/C17′). FTIR (thin film) cm.sup.−1: 3615 (br-w), 3067 (w), 2947 (w), 2097 (m), 1676 (s), 1477 (m), 1162 (s), 731 (s), 598 (s). HRMS (ESI) (m/z): calc'd for C.sub.45H.sub.46N.sub.9O.sub.8S.sub.2[M+H].sup.+: 904.2905, found: 904.2920. [α].sub.D.sup.23: +2.0 (c=1.2, CHCl.sub.3). TLC (20% acetone in dichloromethane), Rf: 0.35 (UV, CAM).

##STR00228##

Heterodimeric Dioxasilane (+)-59:

[0616] A sample of bis(pyridine)silver(I) permanganate (102 mg, 264 μmol, 5.00 equiv) was added to a solution of heterodimeric azide (+)-57 (47.8 mg, 52.9 μmol, 1 equiv) in dichloromethane (530 μL) at 23° C. After 2 h, the thick purple suspension was diluted with a saturated aqueous sodium bisulfite solution (20 mL) and dichloromethane (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic extracts were washed with a saturated aqueous copper sulfate solution (20 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 20% acetone in dichloromethane) to afford heterodimeric tetraol 58 (26.0 mg, 50.8%) as a white solid.

[0617] A sample of 4-(dimethylamino)pyridine (DMAP, 32.9 mg, 268 μmol, 10.0 equiv) and dichlorodiisopropylsilane (20.4 μL, 107 μmol, 4.00 equiv) were sequentially added to a solution of heterodimeric tetraol 58 (25.8 mg, 26.7 μmol, 1 equiv) in N,N-dimethylformamide (650 μL). After 2 h, the reaction mixture was diluted with ethyl acetate-hexanes (1:1, 10 mL) and a saturated aqueous sodium bicarbonate solution (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate-hexanes (1:1, 2×10 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (3×10 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 10->30% ethyl acetate in hexanes) to afford heterodimeric dioxasilane (+)-59 (18.1 mg, 57.0%) as a white solid. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.80-7.72 (m, 6H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H, C5H, C5′H), 7.55-7.49 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.49-7.39 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.17-7.12 (m, 2H, C6H, C6′H), 7.13-7.03 (m, 2H, C7H, C7′H), 6.89 (m, 2H, C8H, C8′H), 6.82 (s, 1H, C2H/C2′H), 6.80 (s, 1H, C2H/C2′H), 3.84 (m, 2H, C12H.sub.a, C12′H.sub.a), 3.53 (dt, J=14.3, 8.0 Hz, 1H, C18H.sub.a), 3.25-3.10 (m, 4H, C12H.sub.b/C12′H.sub.b, C18H.sub.b C21H), 3.07 (d, J=15.0 Hz, 1H, C12H.sub.b/C12′H.sub.b), 2.93 (s, 3H, C18′H), 1.48-1.28 (m, 4H, C19H, C20H), 1.37 (app-d, J=2.7 Hz, 6H, C17H, C17′H), 1.10-1.00 (m, 14H, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2), 0.95-0.79 (m, 14H, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2, SiCH(CH.sub.3).sub.2). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 167.6 (C16/C16′), 167.2 (C16/C16′), 165.8 (C13/C13′), 165.7 (C13/C13′), 143.3 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 143.1 (SO.sub.2Ph-ipso-C/SO.sub.2Ph′-ipso-C), 141.1 (2C, C9, C9′), 132.2 (2C, C4, C4′) 132.0 (SO.sub.2Ph-p-C/SO.sub.2Ph′-p-C), 131.3 (SO.sub.2Ph-p-C/SO.sub.2Ph′-p-C), 129.7 (C7/C7′), 129.6 (C7/C7′), 128.7 (2C, SO.sub.2Ph-m-C, SO.sub.2Ph′-m-C), 126.3 (C5/C5′), 126.1 (C5/C5′), 125.7 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 125.6 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 125.2 (C6/C6′), 125.1 (C6/C6′), 115.4 (C8/C8′), 115.3 (C8/C8′), 88.9 (C11/C11′), 88.8 (C11/C11′), 87.1 (C15/C15′), 86.7 (C15/C15′), 82.4 (C2/C2′), 82.1 (C2/C2′), 60.3 (C3/C3′), 60.2 (C3/C3′), 51.1 (C21), 45.2 (C12/C12′), 44.7 (C12/C12′), 42.1 (C18), 28.3 (C18′), 26.8 (C20), 26.1 (C19), 22.6 (4C, SiCH(CH.sub.3).sub.2), 16.6 (SiCH(CH.sub.3).sub.2), 16.5 (2C, SiCH(CH.sub.3).sub.2), 16.4 (SiCH(CH.sub.3).sub.2), 16.3 (SiCH(CH.sub.3).sub.2), 16.2 (SiCH(CH.sub.3).sub.2), 13.7 (SiCH(CH.sub.3).sub.2), 13.5 (SiCH(CH.sub.3).sub.2). FTIR (thin film) cm.sup.−1: 3418 (br-w), 2925 (s), 2868 (m), 2097 (m), 1721 (m), 1462 (m), 1355 (s), 1167 (s), 979 (m), 781 (m), 584 (s). HRMS (ESI) (m/z): calc'd for C.sub.57H.sub.69N.sub.9NaO.sub.12S.sub.2Si.sub.2 [M+Na].sup.+: 1214.3943, found: 1214.3921. [α].sub.D.sup.23: +10 (c=1.38, CHCl.sub.3). TLC (30% ethyl acetate in hexanes), Rf: 0.31 (UV, CAM). Hydrogen-bonding induced signal broadening and instability of tetraol 58 complicated its full characterization by NMR. The measured HRMS was consistent with the desired product; HRMS (ESI) (m/z): calc'd for C.sub.45H.sub.45N.sub.9NaO.sub.12S.sub.2 [M+Na].sup.+: 990.2521, found: 990.2484.

##STR00229##

Alternative Synthesis of Heterodimeric Epidithiodiketopiperazine Azide 60

[0618] A solution of heterodimeric dioxasilane (+)-59 (20.8 mg, 17.4 μmol, 1 equiv) in dichloromethane (500 μL) was added via cannula to a solution of freshly prepared tritylhydrodisulfane (81.0 mg, 263 μmol, 15.1 equiv) in dichloromethane (500 μL). The transfer was quantitated with additional dichloromethane (750 μL). Boron trifluoride diethyl etherate (44.5 μL, 349 μmol, 20.0 equiv) was added at 23° C. After 4.5 h, the reaction mixture was diluted with dichloromethane (10 mL) and with a saturated aqueous sodium bicarbonate solution (30 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (30 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 0.fwdarw.15% ethyl acetate in dichloromethane) to afford heterodimeric epidithiodiketopiperazine azide (+)-60 (10.4 mg, 58.0%) as a white solid. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.90-7.86 (m, 4H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H), 7.70-7.65 (m, 2H, C8H, C8′H), 7.58-7.53 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.51-7.45 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.26-7.20 (m, 2H, C6H, C6′H), 7.19 (m, 2H, C7H, C7′H), 7.10-7.05 (m, 2H, C5H, C5′H), 6.84 (s, 1H, C2H/C2′H), 6.83 (s, 1H, C2H/C2′H), 3.78 (dt, J=15.1, 7.7 Hz, 1H, C18H.sub.a), 3.57 (dd, J=15.1, 2.4 Hz, 2H, C12H.sub.a/C12′H.sub.a), 3.32-3.20 (m, 3H, C21H, C18H.sub.b), 2.99 (s, 3H, C18′H), 2.94 (dd, J=15.2, 3.7 Hz, 2H, C12H.sub.b/C12′H.sub.b), 1.72-1.67 (m, 2H, C19H) 1.70 (s, 3H, C17H/C17′H), 1.65 (s, 3H, C17H/C17′H), 1.62-1.56 (m, 2H, C20H). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 164.8 (C16/C16′), 164.4 (C16/C16′), 160.7 (C13/C13′), 160.6 (C13/C13′), 142.5 (2C, C9, C9′), 142.3 (2C, SO.sub.2Ph-ipso-C, SO.sub.2Ph′-ipso-C), 132.5 (2C, SO.sub.2Ph-p-C, SO.sub.2Ph′-p-C), 130.9 (2C, C4, C4′), 130.4 (2C, C6, C6′), 128.9 (2C, SO.sub.2Ph-m-C, SO.sub.2Ph′-m-C), 125.8 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 125.7 (SO.sub.2Ph-o-C/SO.sub.2Ph′-o-C), 125.1 (2C, C7, C7′), 124.8 (2C, C8′C8′), 116.3 (2C, C5, C5′), 81.9 (2C, C3′C3′), 73.8 (C15/C15′), 73.6 (C11/C11′), 73.4 (C11/C11′), 72.0 (C15/C15′), 60.4 (2C, C3′C3′), 51.0 (C21), 42.3 (C18), 41.6 (2C, C12, C12′), 27.7 (C18′), 26.3 (C20), 25.3 (C19), 17.9 (C17/C17′), 17.4 (C17/C17′). FTIR (thin film) cm.sup.−1: 2927 (w), 2162 (m), 2097 (w), 1716 (s), 1688 (s), 1480 (m), 1462 (m), 1348 (s), 1168 (s), 1096 (m), 1057 (m), 753 (m), 730 (m), 582 (s). HRMS (ESI) (m/z): calc'd for C.sub.45H.sub.42N.sub.9O.sub.8S.sub.6[M+H].sup.+: 1027.1475, found: 1027.1483. [α].sub.D.sup.23: +329 (c=0.29, CHCl.sub.3). TLC (15% ethyl acetate in dichloromethane), Rf: 0.34 (UV, CAM).

##STR00230##

Epithiodiketopiperazine Triazole (+)-61

[0619] A solution of aqueous copper sulfate pentahydrate (46.1 μM, 12.5 μL, 576 nmol, 0.100 equiv), and a solution of aqueous sodium L-ascorbate (92.2 PM, 12.5 μL, 1.15 μmol, 0.200 equiv) were added sequentially via syringe to a solution of heterodimeric epithiodiketopiperazine azide (+)-60 (5.92 mg, 5.76 μmol, 1 equiv) and alkyne (Grimes, K. D.; Aldrich, C. C. Analytical Biochemistry, 2011, 417, 264-273) U12 (4.88 mg, 17.3 μmol, 3.00 equiv) in N,N-dimethylformamide-water (4:1, 250 μL) at 23° C. The reaction vessel was sealed with a Teflon-lined glass stopper. After 18 h, the reaction mixture was diluted with ethyl acetate (10 mL) and with water (10 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (10 mL), were dried over anhydrous sodium sulfate, were filtered, and were concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 20% acetone in dichloromethane.fwdarw.5% methanol in dichloromethane) to afford epithiodiketopiperzine triazole (+)-61 (5.61 mg, 74.3%) as a colorless solid. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CDCl.sub.3, 25° C.): δ 7.93-7.82 (m, 4H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H), 7.67-7.64 (m, 2H, C8H, C8′H), 7.60-7.54 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.52 (s, 1H, C22H), 7.50-7.45 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.27-7.23 (m, 2H, C6H, C6′H), 7.22-7.17 (m, 2H, C7H, C7′H), 7.12-7.06 (m, 2H, C5H, C5′H), 6.82 (m, 2H, C2H, C2′H), 5.05 (br-s, 1H, NHBoc), 4.65 (s, 2H, C24H), 4.35 (td, J=6.9, 2.6 Hz, 2H, C21H), 3.77 (dt, J=15.4, 7.7 Hz, 1H, C29H.sub.a), 3.70-3.51 (m, 12H, C12H.sub.a, C12′H.sub.a, C18H, C25H, C26H, C27H, C28H), 3.50-3.44 (m, 1H, C29H.sub.b), 3.36-3.25 (m, 2H, C30H), 2.99 (s, 3H, C18′H), 2.95-2.85 (m, 2H, C12H.sub.b, C12′H.sub.b), 1.90 (p, J=7.2 Hz, 2H, C20H), 1.70-1.64 (m, 2H, C19H), 1.67 (s, 3H, C17H/C17′H), 1.65 (s, 3H, C17H/C17′H), 1.43 (s, 9H, NCO.sub.2C(CH.sub.3).sub.3). .sup.13C NMR (150 MHz, CDCl.sub.3, 25° C.): δ 164.8 (C16/C16′), 164.6 (C16/C16′), 160.8 (C13/C13′), 160.6 (C13/C13′), 156.2 (NCO.sub.2C(CH.sub.3).sub.3), 145.4 (C23), 142.6 (2C, C9, C9′), 142.2 (2C, SO.sub.2Ph-ipso-C, SO.sub.2Ph′-ipso-C), 132.6 (2C, SO.sub.2Ph-p-C, SO.sub.2Ph′-p-C), 131.0 (C4/C4′), 130.9 (C4/C4′), 130.6 (2C, C6, C6′), 129.0 (SO.sub.2Ph-m-C/SO.sub.2Ph′-m-C), 128.9 (SO.sub.2Ph-m-C/SO.sub.2Ph′-m-C), 125.8 (2C, SO.sub.2Ph-o-C, SO.sub.2Ph′-o-C), 125.1 (2C, C7, C7′), 124.9 (2C, C8′C8′), 122.7 (C22), 116.5 (2C, C5, C5′), 81.9 (2C, C2, C2′), 79.3 (NCO.sub.2C(CH.sub.3).sub.3), 73.8 (C15/C15′), 73.6 (C11/C11′), 73.4 (C11/C11′), 73.0 (C15/C15′), 70.7 (3C, C26, C27, C28), 70.4 (C29), 69.8 (C25), 64.8 (C24), 60.3 (2C, C3′C3′), 49.6 (C21), 41.8 (C18), 41.5 (2C, C12, C12′), 40.5 (C30), 28.6 (NCO.sub.2C(CH.sub.3).sub.3), 27.8 (C18′), 27.5 (C20), 25.2 (C19), 17.9 (C17/C17′), 17.4 (C17/C17′). FTIR (thin film) cm.sup.−1: 3398 (br-w), 2930 (w), 1713 (s), 1684 (s), 1349 (s) 1167 (s), 1096 (m), 1056 (m), 753 (m), 582 (s). HRMS (ESI) (m/z): calc'd for C.sub.59H.sub.67N.sub.10O.sub.13S.sub.6[M+H].sup.+: 1315.3208, found: 1315.3200. [α].sub.D.sup.23: +231 (c 0.17, CHCl.sub.3). TLC (5% methanol in dichloromethane), Rf: 0.18 (UV, CAM).

##STR00231##

Epithiodiketopiperazine Ammonium Salt (+)-62

[0620] A solution of hydrogen chloride (3 M in CPME, 600 μL) was added via syringe to a solution of triazole (+)-61 (3.79 mg, 2.82 μmol, 1 equiv) in dichloromethane (200 μL) at 23° C. After 2 h, the heterogeneous reaction mixture was concentrated under reduced pressure. The resulting residue was filtered through a pad of silica gel (eluent: 10% methanol in dichloromethane) to afford epithiodiketopiperazine ammonium salt (+)-62 (3.48 mg, quantitative yield) as a white powder. Structural assignments were made using additional information from gCOSY, gHSQC, and gHMBC experiments. .sup.1H NMR (600 MHz, CD.sub.3OD, 25° C.): δ 7.95 (s, 1H, C22H), 7.92-7.86 (m, 4H, SO.sub.2Ph-o-H, SO.sub.2Ph′-o-H), 7.76-7.69 (m, 2H, C8H, C8′H), 7.69-7.60 (m, 2H, SO.sub.2Ph-p-H, SO.sub.2Ph′-p-H), 7.59-7.50 (m, 4H, SO.sub.2Ph-m-H, SO.sub.2Ph′-m-H), 7.32-7.23 (m, 2H, C6H, C6′H), 7.22-7.13 (m, 2H, C7H, C7′H), 7.13-7.06 (m, 2H, C5H, C5′H), 6.93-6.85 (m, 2H, C2H, C2′H), 4.60 (s, 2H, C24H), 4.43 (t, J=7.0 Hz, 2H, C21H), 3.72-3.62 (m, 14H, C12H.sub.a, C12′H.sub.a, C18H, C25H, C26H, C27H, C28H, C29H.sub.a, C29H.sub.b), 3.14-3.07 (m, 2H, C30H), 3.02-2.94 (m, 5H, C18′H, C12H.sub.b, C12′H.sub.b), 1.95-1.87 (m, 2H, C20H), 1.70-1.64 (m, 6H, C17H, C17′H), 1.61-1.56 (m, 2H, C19H). .sup.13C NMR (150 MHz, CD.sub.3OD, 25° C.): δ 166.6 (C16/C16′), 166.3 (C16/C16′), 162.4 (C13/C13′), 162.3 (C13/C13′), 145.7 (C23), 143.8 (2C, C9, C9′), 143.5 (2C, SO.sub.2Ph-ipso-C, SO.sub.2Ph′-ipso-C), 133.8 (2C, SO.sub.2Ph-p-C, SO.sub.2Ph′-p-C), 132.6 (C4/C4′), 131.1 (2C, C6, C6′), 130.0 (2C, SO.sub.2Ph-m-C/SO.sub.2Ph′-m-C), 126.94 (2C, SO.sub.2Ph-o-C, SO.sub.2Ph′-o-C), 126.5 (2C, C7, C7′), 126.0 (2C, C8′C8′), 125.2 (C22), 117.4 (2C, C5, C5′), 83.2 (2C, C2, C2′), 75.0 (C15/C15′), 74.7 (2C, C11, C11′), 74.3 (C15/C15′), 71.6 (C26/C27/C28), 71.3 (C26/C27/C28), 71.1 (C26/C27/C28), 70.5 (C29), 67.9 (C25), 64.7 (C24), 61.4 (2C, C3′C3′), 50.7 (C21), 42.8 (C18), 41.9 (2C, C12, C12′), 40.7 (C30), 28.5 (C18′), 27.8 (C20), 26.0 (C19), 17.8 (C17/C17′), 17.4 (C17/C17′). FTIR (thin film) cm.sup.−1: 2926 (w), 1717 (s), 1688 (m), 1349 (s), 1168 (s), 752 (s), 581 (m). HRMS (ESI) (m/z): calc'd for C.sub.54H.sub.59N.sub.10O.sub.11S.sub.6[M].sup.+: 1215.2684, found: 1215.2691. [α].sub.D.sup.23: +171 (c=0.27, MeOH). TLC (20% methanol in dichloromethane), Rf: 0.43 (UV, CAM).

##STR00232##

Equilibration of Epidisulfide (+)-42 and Bisdisulfide (+)-45b

[0621] As shown herein, the isolated quantities of epidisulfide (+)-42 and bisdisulfide (+)-45b suggested an equilibrium ratio of 3:1 favoring the ETP. To investigate this, aliquots of the reaction were diluted starting with epidisulfide (+)-42 (“from ETP”) in CDCl.sub.3 to analyze the composition versus an internal standard over a period of 100 h. Additionally, (+)-45b was resubjected to the same reaction conditions and monitored the reversion back to epidisulfide (“to ETP”) in an analogous experiment. In both cases, equilibration approaching 3:1 was observed. See FIGS. 3-4.

[0622] While several embodiments of the present disclosure have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present disclosure is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present disclosure.

[0623] All patent publications and non-patent publications are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All these publications are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated as being incorporated by reference.

[0624] Although the disclosure herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be

EQUIVALENTS AND SCOPE

[0625] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0626] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0627] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0628] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

REFERENCES

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R.; Cava, M. P.; Behforouz, M.; Lakshmikantham, M. V.; Zeiger, W. J. Am. Chem. Soc. 1973, 95, 7842; b) Saxton, J. E. The Alkaloids, Chem. and Biol. 1998, 51, 1. [0644] 16. (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302. (b) Berg, R.; Straub, B. F. Beilstein J. Org. Chem. 2013, 9, 2715. [0645] 17. Smith I.; Collins, I. Future Med. Chem. 2015, 7, 159. [0646] 18. Ghosh, B.; Jones, L. H. Med. Chem. Commun. 2014, 5, 247. [0647] 19. Larson, N.; Ghandehari, H. Chem. Mater. 2012, 24, 840. [0648] 20. (a) Flygare, J. A.; Pillow, T. H.; Aristoff, P. Chem. Biol. Drug Des. 2013, 81, 113. (b) Chari, R. V. J.; Miller, M. L.; Widdison, W. C. Angew. Chem. Int. Ed. 2014, 53, 3796. [0649] 21. See the Examples section for details. [0650] 22. Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1977, 18, 1977. [0651] 23. Karaman, H.; Barton, R. J.; Robertson, B. E.; Lee, D. G. J. Org. Chem. 1984, 49, 4509. [0652] 24. For the preparation of bromide (+)-15 described in the Examples section. [0653] 25. Hulce, M.; Chapdelaine, M. C. Nucleophilic Addition-Electrophilic Coupling with a Carbanion Intermediate. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: London, 1991; Vol. 4, pp 273-268. [0654] 26. (a) Okada, K.; Murakami, K.; Tanino, H.; Kakoi, H, Inoue, S. Heterocycles 1996, 43, 1735. (b) Fanning, K. N.; Sutherland, A. Tetrahedron Lett. 2007, 48, 8479. [0655] 27. Use of CH.sub.2Cl.sub.2 as solvent in the CuAAC reaction of ETP (+)-9b and 4-ethynylanisole X gave cycloadduct (+)-28b in 73% yield whereas use of toluene gave cycloadduct (+)-28b in 85% yield. [0656] 28. Shao, C.; Wang, X.; Zhang, Q.; Luo, S.; Zhao, J.; Hu, Y. J. Org. Chem. 2011, 76, 6832. [0657] 29. Firouzabadi, H.; Sardarian, A.; Naderi, M.; Vessal, B. Synth. Commun. 1984, 40(23), 5001. [0658] 30. For a procedure using potassium trithiocarbonate, see references 3p and 5a. [0659] 31. Chou, T.-H.; Hsu, Y-L.; Lo, L.-C. J. Chinese Chem. Soc. 2014, 61 (6), 707. [0660] 32. Christophersen, C.; Holm, A. Acta Chim. Scandinavia, 1971, 25, 2015. [0661] 33. (a) Bernardo, P. H.; Chai, C. L. L.; Deeble, G. J.; Liu, X.-M.; Waring, P. Bioorg. & Med. Chem. Lett., 2001, 11, 483. (b) Bernardo, P. H.; Brasch, N.; Chai, C. L. L.; Waring, P.; J. Biol. Chem. 2003, 278(47), 46549. [0662] 34. (a) Bertling, A.; Niemann, S.; Uekotter, A.; Fegeler, W.; Lass-Flörl, C.; von Eiff, C.; Kehrel, B. E. Thromb. Haemost., 2010, 104, 270. (b) Block, K. M.; Wang, H.; Szabó, L. Z.; Polaske, N. W.; Henchey, L. K.; Dubey, R.; Kushal, S.; László, C. F.; Makhoul, J.; Song, Z.; Meuillet, E. J.; Olenyuk, B. Z. J. Am. Chem. Soc., 2009, 131, 18078; (c) Kushal, S.; Wang, H.; László, C. F.; Szábo, L. Z.; Olenyuk, B. Z. Biopolymers, 2011, 95, 8. (d) Srinivasan, U.; Bala, A.; Jao, S.-C.; Starke, D. W.; Jordan, T. W.; Mieyal, J. J. Biochemistry, 2006, 45 (29), 8978. (e) Chai, C. L. L.; Waring, P. Redox Rep., 2000, 5, 257. [0663] 35. The sensitivity to concentration in the presence of base was confirmed by removing polymer-bound base from the reaction mixture by filtration prior to concentration. The reactivity upon exposure to silica is due to the presence of unidentified reactive intermediates. For example, when epidisulfide (+)-8 was exposed to PFB-SH (0.5 equiv) in CDCl.sub.3 [0.02 M], after 18 h we observed only 48% remaining epidisulfide (+)-8 and 21% of an unknown intermediate by in situ 1H NMR spectroscopy. However, upon exposure we observed the appearance of 29% epitrisulfide 31. [0664] 36. See the Examples section for further details. [0665] 37. Hart, T. W. Tet. Lett. 1985, 26 (16), 2013. [0666] 38. (a) Jonas, C. R.; Ziegler, T. R.; Gu, L. H.; Jones, D. P. Free Radical Bio. & Med. 2002, 33 (11), 1499. (b) Ramirez, A.; Ramadan, B.; Ritzenthaler, J. D.; Rivera, H. N.; Jones, D. P.; Roman, J. Am. J. Physiol. Lung Cell Mol. Physiol. 2007, 293, 972. (c) Rubartelli A.; Lotze, M. T. TRENDS in Immunology, 2007, 28(10), 429-436. (d) Chaiswing, L.; Zhong, W.; Cullen, J. J.; Oberley, L. W.; Oberley, T. D. Cancer Research, 2008, 68 (14), 5820. [0667] 39. (a) Movassaghi, M.; Schmidt, M. A.; Angew. Chem. Int. Ed. 2007, 46, 3725. (b) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A.; Angew. Chem. Int. Ed. 2008, 47, 1485. [0668] 40. Muthyala, M. K.; Choudary, S.; Pandey, K.; Shelke, G. M.; Jha, M.; Kumar, A. Eur. J. Org. Chem. 2014, 2365. [0669] 41. Boyer, N.; Movassaghi, M. Chem. Sci. 2012, 3, 1798. [0670] 42. Karaman, H.; Barton, R. J.; Robertson, B. E.; Lee, D. G. J. Org. Chem. 1984, 49, 4509. [0671] 43. Prepared from potassium iodide (200 mg, 1.20 mmol) and iodine (305 mg, 1.20 mmol) in pyridine (5 mL). [0672] 44. The relative stereochemistry of the epidisulfide (+)-9a was confirmed by key NOESY cross-peaks on the corresponding bis(methylthioether). Our assignment is supported by key NOESY signals (.sup.1H, .sup.1H) in ppm: (3.12, 7.10-7.04), (3.12, 1.88), (2.97, 6.88). This derivative was prepared in one step using our chemistry developed to access (+)-gliocladin B (Boyer, N.; Movassaghi M. Chem Sci. 2012, 3, 1798). The corresponding bis(methylthioether) of epidisulfide (+)-9a was characterized as follows: .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.86 (d, J=8.4 Hz, 2H, SO.sub.2Ph-o-H), 7.51 (d, J=8.1 Hz, 1H, C.sub.8H), 7.47 (t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.35 (t, J=8.1 Hz, 2H, SO.sub.2Ph-m-H), 7.27 (ddd, J=2.4, 6.4, 8.6 Hz, 1H, C.sub.7H), 7.10-7.04 (m, 2H, C.sub.5H, C.sub.6H), 6.88 (d, J=8.8 Hz, 2H, C.sub.2′H), 6.67 (d, J=8.8 Hz, 2H, C.sub.3′H), 6.63 (s, 1H, C.sub.2H), 4.46 (s, 1H, C.sub.15H), 3.96 (t, J=6.0 Hz, 2H, C.sub.5′H), 3.47 (t, J=6.6 Hz, 2H, C.sub.7′H), 3.12 (d, J=14.3 Hz, 1H, C.sub.12H.sub.a), 3.03 (s, 3H, C.sub.17H), 2.97 (d, J=14.3 Hz, 1H, C.sub.12H.sub.b), 2.17 (s, 3H, C.sub.15SCH.sub.3), 2.00 (p, J=6.2 Hz, 2H, C.sub.6′H), 1.88 (s, 3H, C.sub.11SCH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.1 (C.sub.13), 162.3 (C.sub.16), 158.0 (C.sub.4′), 142.4 (C.sub.9), 140.2 (SO.sub.2Ph-ipso-C), 136.7 (C.sub.4), 134.6 (C.sub.1′), 132.9 (SO.sub.2Ph-p-C), 129.1 (C.sub.7), 129.1 (SO.sub.2Ph-m-C), 127.1 (C.sub.2′), 127.0 (SO.sub.2Ph-o-C), 124.9 (C.sub.6), 123.8 (C.sub.5), 117.0 (C.sub.8), 115.0 (C.sub.3′), 85.7 (C.sub.2), 69.8 (C.sub.11), 67.6 (C.sub.15), 64.7 (C.sub.5′), 57.0 (C.sub.3), 48.3 (C.sub.7), 45.7 (C.sub.12), 32.5 (C.sub.17), 28.9 (C.sub.6′), 17.1 (C.sub.15SCH.sub.3), 15.5 (C.sub.11SCH.sub.3). HRMS (ESI) (m/z): calc'd for C.sub.31H.sub.32N.sub.6NaO.sub.5S.sub.3 [M+Na].sup.+: 687.1489, found 687.1501. [0673] 45. Movassaghi, M.; Schmidt M. A.; Ashenhurst, J. A.; Angew. Chemie. Int. Ed. 2008, 47 (18), 1485-1487. [0674] 46. An analytical sample of amide (−)—S.sub.5 was obtained by flash column chromatography on silica gel (eluent: 50% ethyl acetate in hexanes). The amide (−)—S.sub.5 was characterized as follows: .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.93 (d, J=8.3 Hz, 1H, C.sub.8H), 7.82 (d, J=7.6 Hz, 2H, SO.sub.2Ph-o-H), 7.52-7.46 (m, 2H, C.sub.5H, SO.sub.2Ph-p-H), 7.44 (s, 1H, C.sub.2H), 7.38 (t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 7.27 (t, J=7.6 Hz, 1H, C.sub.7H), 7.19 (J=7.6 Hz, 1H, C.sub.6H), 6.62 (br-s, 1H, NH), 5.20 (d, J=8.2 Hz, 1H, NHCO.sub.2C(CH.sub.3).sub.3), 4.47 (br-s, 1H, C.sub.11H), 3.97-3.84 (m, 2H, C.sub.15H), 3.67 (s, 3H, OCH.sub.3), 3.21-3.04 (m, 2H, C.sub.12H), 1.36 (s, 9H, OCCH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 171.6 (C.sub.13), 170.0 (C.sub.16), 155.6 (NHCO.sub.2C(CH.sub.3).sub.3), 138.3 (SO.sub.2Ph-ipso-C), 135.3 (C.sub.9), 133.9 (SO.sub.2Ph-p-C), 130.9 (C.sub.4), 129.4 (SO.sub.2Ph-m-C), 126.9 (SO.sub.2Ph-o-C), 125.1 (C.sub.2), 124.7 (C.sub.7), 123.5 (C.sub.6), 119.7 (C.sub.5), 118.0 (C.sub.3), 113.8 (C.sub.8), 80.6 (OC(CH.sub.3).sub.3), 54.3 (C.sub.11), 52.5 (OCH.sub.3), 41.3 (C.sub.15), 28.4 (OC(CH.sub.3).sub.3), 28.0 (C.sub.12). FTIR (thin film) cm.sup.−1: 3309 (m), 2977 (w), 1748 (m), 1662 (s), 1520 (s), 1447 (m), 1365 (s), 1278 (s), 746 (m). HRMS (ESI) (m/z): calc'd for C.sub.25H.sub.29N.sub.3NaO.sub.7S [M+Na].sup.+: 538.1618, found 538.1624. [α].sub.D.sup.23: −5.0 (c=0.20, CHCl.sub.3). TLC (100% ethyl acetate), Rf: 0.74 (UV, CAM). [0675] 47. Kern, N.; Blanc, A.; Weibel, J.-M.; Pale, P. Chem Commun., 2011, 47, 6665. [0676] 48. The relative stereochemistry of the epidisulfide (+)-9b was confirmed by key NOESY cross-peaks on the corresponding bis(methylthioether). Our assignment is supported by key NOESY signals (.sup.1H, .sup.1H) in ppm: (3.12, 7.09-7.04), (3.12, 1.88), (2.96, 6.88). This derivatized compound was prepared in one step using our methodology developed to access (+)-gliocladin B (Boyer, N.; Movassaghi M. Chem Sci. 2012, 3, 1798). The corresponding bis(methylthioether) of epidisulfide (+)-9b was characterized as follows: .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.86 (d, J=8.0 Hz, 2H, SO.sub.2Ph-o-H), 7.52 (d, J=8.2 Hz, 1H, C.sub.8H), 7.47 (t, J=7.4 Hz, 1H, SO.sub.2Ph-p-H,) 7.35 (t, J=8.0 Hz, 2H, SO.sub.2Ph-m-H), 7.27 (ddd, J=2.2, 6.5, 8.6 Hz, 1H, C.sub.7H), 7.09-7.04 (m, 2H, C.sub.5H, C.sub.6H), 6.88 (d, J=8.8 Hz, 2H, C.sub.2′H), 6.68 (d, J=8.9 Hz, 2H, C.sub.3′H), 6.63 (s, 1H, C.sub.2H), 4.49 (s, 1H, C.sub.15H), 3.73 (s, 3H, C.sub.5′H), 3.66-3.58 (m, 1H, C.sub.17H.sub.a), 3.34-3.28 (m, 1H, C.sub.17H.sub.b), 3.30 (t, J=6.7 Hz, 2H, C.sub.20H), 3.12 (d, J=14.3 Hz, 1H, C.sub.12H.sub.a), 2.96 (J=14.3 Hz, 1H, C.sub.12H.sub.b), 2.16 (s, 3H, C.sub.15SCH.sub.3), 1.88 (s, 3H, C.sub.11SCH.sub.3), 1.75-1.68 (m, 2H, C.sub.18H), 1.63-1.55 (m, 2H, C.sub.19H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.3 (C.sub.13), 162.3 (C.sub.16), 158.9 (C.sub.4′), 142.2 (C.sub.9), 140.2 (SO.sub.2Ph-ipso-C), 136.8 (C.sub.4), 134.3 (C.sub.1′), 132.9 (SO.sub.2Ph-p-C), 129.2 (C.sub.7, SO.sub.2Ph-m-C), 127.0 (C.sub.2′, SO.sub.2Ph-o-C), 124.9 (C.sub.6), 123.8 (C.sub.5), 117.0 (C.sub.8), 114.5 (C.sub.3′), 85.7 (C.sub.2), 69.8 (C.sub.11), 65.7 (C.sub.15), 57.0 (C.sub.3), 55.5 (C.sub.5′), 51.1 (C.sub.20), 45.7 (C.sub.12), 44.9 (C.sub.17), 26.3 (C.sub.19), 24.9 (C.sub.18), 17.1 (C.sub.15SCH.sub.3), 15.4 (C.sub.11SCH.sub.3). HRMS (ESI) (m/z): calc'd for C.sub.32H.sub.34N.sub.6NaO.sub.5S.sub.3 [M+Na].sup.+: 701.1645, found 701.1649. [0677] 49. Maury, J.; Feray, L.; Bertrand, M. P.; Kapat, A.; Renaud, P. Tetrahedron, 2012, 68, 9606. [0678] 50. To remove residual acetic acid, pooled fractions containing N-sulfonylated tryptophan (−)-22 were concentrated under reduced pressure to approximately 10% of the volume, then diluted with benzene (100 mL) and concentrated. This process was repeated two more times. [0679] 51. The relative stereochemistry of epidisulfide (+)-9c has been confirmed by key NOESY cross-peaks on the corresponding bis(methylthioether). Our assignment is supported by key NOESY signals (.sup.1H, .sup.1H) in ppm: (3.09-3.04, 7.10-7.06), (3.09-3.04, 1.86), (2.93, 6.82), (2.93, 6.55). This derivatized compound was prepared in one step using our methodology developed to access (+)-gliocladin B (Boyer, N.; Movassaghi M. Chem Sci. 2012, 3, 1798). The corresponding bis(methylthioether) of epidisulfide (+)-9c was characterized as follows: .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 7.67 (d, J=8.8 Hz, 2H, C.sub.2H), 7.56 (d, J=8.1 Hz, 1H, C.sub.8H), 7.29 (ddd, J=3.0, 5.8, 8.4, 1H, C.sub.7H), 7.10-7.06 (m, 2H, C.sub.6H, C.sub.5H), 6.82 (d, J=8.8 Hz, 2H, C.sub.2′H), 6.70 (d, J=8.9 Hz, 2H, C.sub.3″H), 6.65 (d, J=8.8 Hz, 2H, C.sub.3′H), 6.55 (s, 1H, C.sub.2H), 4.51 (s, 1H, C.sub.15H), 4.00 (t, J=5.9 Hz, 2H, C.sub.5″H), 3.73 (s, 3H, C.sub.5′H), 3.49 (t, J=6.5 Hz, 2H, C.sub.7″H), 3.09-3.04 (m, 4H, C.sub.12H.sub.a, C.sub.17H) 2.93 (d, J=15.5 Hz, 1H, C.sub.12H.sub.b), 2.27 (s, 3H, C.sub.15SCH.sub.3), 2.03 (p, J=6.2 Hz, 2H, C.sub.6″H) 1.86 (s, 3H, C.sub.11SCH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.2 (C.sub.13), 162.3 (C.sub.4″H or C.sub.16), 162.3 (C.sub.4″H or C.sub.16), 158.7 (C.sub.4′), 142.6 (C.sub.9), 136.6 (C.sub.4), 134.2 (C.sub.1′), 129.4 (C.sub.1″H), 129.4 (C.sub.2″H), 129.1 (C.sub.7), 127.2 (C.sub.2′), 125.0 (C.sub.6), 124.1 (C.sub.5), 117.6 (C.sub.8), 114.5 (C.sub.3′ or C.sub.3″), 114.3 (C.sub.3′ or C.sub.3″), 86.2 (C.sub.2), 69.9 (C.sub.11), 67.8 (C.sub.15), 65.0 (C.sub.5″H), 57.1 (C.sub.3), 55.5 (C.sub.5′), 48.2 (C.sub.7″H), 46.4 (C.sub.12), 32.5 (C.sub.17), 28.7 (C.sub.6″H), 17.2 (C.sub.15SCH.sub.3), 15.5 (C.sub.11SCH.sub.3). HRMS (ESI) (m/z): calc'd for C.sub.32H.sub.34N.sub.6NaO.sub.6S.sub.3 [M+Na].sup.+: 717.1594, found 717.1588. [0680] 52. For the preparation of diol S.sub.12 and the corresponding methodology, see Boyer, N.; Morrison, K. C.; Kim, J.; Hergenrother, P. J.; Movassaghi, M. Chem. Sci., 2013, 4, 1646. [0681] 53. The C11-hemithioaminal has been characterized by NMR: .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.75 (d, J=8.1 Hz, 1H, C.sub.8H), 7.47 (d, J=8.0 Hz, 2H, SO.sub.2Ph-o-H), 7.42 (t, J=8.3, C.sub.7H), 7.35 (t, J=7.4 Hz, SO.sub.2Ph-p-H), 7.29-7.22 (m, 2H, C.sub.5H, C.sub.6H), 7.11 (t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 6.69 (d, J=8.6 Hz, 2H, C.sub.2′H), 6.60 (d, J=8.4 Hz, 2H, C.sub.3′H), 6.44 (s, 1H, C.sub.2H), 5.33 (d, J=4.7 Hz, 1H, C.sub.15H), 4.64 (d, J=4.8 Hz, C.sub.15OH), 3.76 (s, 3H, C.sub.5′H), 3.39 (d, J=14.6 Hz, 1H, C.sub.12H.sub.a), 3.11 (d, J=14.7 Hz, 1H, C.sub.12H.sub.b), 3.08 (s, 3H, C.sub.17H), 2.45 (s, 1H, C.sub.11SH). .sup.13C NMR (125 MHz, CDCl.sub.3, 25° C.): δ 166.0 (C.sub.13), 165.3 (C.sub.16), 158.7 (C.sub.4), 141.6 (C.sub.9), 137.9 (SO.sub.2Ph-ipso-C), 135.3 (C.sub.4), 133.2 (SO.sub.2Ph-p-C), 132.0 (C.sub.1), 129.7 (C.sub.7), 128.7 (SO.sub.2Ph-m-C), 127.6 (C.sub.2′), 127.3 (SO.sub.2Ph-o-C), 126.2 (C.sub.5), 126.1 (C.sub.6), 118.5 (C.sub.8), 114.4 (C.sub.3′), 86.8 (C.sub.2′), 76.9 (C.sub.15), 69.3 (C.sub.11), 57.6 (C.sub.3), 55.4 (C.sub.5′), 53.45 (C.sub.12), 29.0 (C.sub.17). TLC (25% acetone in dichloromethane), Rf: 0.23 (UV, CAM, AgNO.sub.3). [0682] 54. The C.sub.11-triphenylmethanetrisulfide S.sub.13 has been characterized by NMR: .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.59 (d, J=8.1 Hz, 1H, C.sub.8H), 7.48 (d, J=7.4 Hz, 2H, SO.sub.2Ph-o-H), 7.35 (t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.30-7.22 (m, 9H, Ph-m-H, Ph-p-H), 7.18-7.13 (m, 6H, Ph-o-H), 7.11 (t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 7.05 (d, J=7.0 Hz, 1H, C.sub.5H), 6.98 (t, J=7.4 Hz, 1H, C.sub.6H), 6.62 (d, J=8.9 Hz, 2H, C.sub.2′H), 6.56 (d, J=8.9 Hz, 2H, C.sub.3′H), 6.44 (s, 1H, C.sub.2H), 5.36 (d, J=4.0 Hz, 1H, C.sub.15H), 4.23 (d, J=4.0 Hz, 1H, C.sub.15OH), 3.75 (s, 3H, C.sub.5′H), 3.21 (d, J=15.1 Hz, 1H, C.sub.12H.sub.a), 3.11 (d, J=15.1 Hz, 1H, C.sub.12H.sub.b), 3.02 (s, 3H, C.sub.17H). .sup.13C NMR (100 MHz, CDCl.sub.3, 25° C.): δ 165.7 (C.sub.16), 163.7 (C.sub.13), 158.7 (C.sub.4′), 143.0 (C(Ph-ipso-C).sub.3), 141.5 (C.sub.9), 138.1 (SO.sub.2Ph-ipso-C), 135.4 (C.sub.4), 133.2 (SO.sub.2Ph-p-C), 132.6 (C.sub.1′), 130.3 (C(Ph-m-C).sub.3), 129.5 (C.sub.7), 128.8 (SO.sub.2Ph-m-C), 128.1 (C(Ph-o-C).sub.3), 127.5 (C.sub.2′), 127.5 (C(Ph-p-C).sub.3), 127.3 (SO.sub.2Ph-o-C), 125.9 (C.sub.5), 125.9 (C.sub.6), 118.1 (C.sub.8), 114.4 (C.sub.3′), 87.0 (C.sub.2), 77.0 (C.sub.15), 75.9 (C.sub.11), 73.6 (C(Ph).sub.3), 57.5 (C.sub.3), 55.5 (C.sub.5′), 49.2 (C.sub.12), 29.6 (C.sub.17). TLC (10% acetone in dichloromethane), Rf: 0.38 (UV, CAM, AgNO.sub.3, Ellman's Reagent). [0683] 55. Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science, 2009, 324, 238-241. [0684] 56. Firouzabadi, H.; Naderi, M.; Sardarian, A.; Vessal, B. Synth. Commun. 1983, 13, 611. [0685] 57. The relative stereochemistry of epidisulfide (+)-42 was confirmed by key NOESY cross-peaks on the corresponding bis(methylthioether). Our assignment is supported by key NOESY signals (.sup.1H, .sup.1H) in ppm: (2.07, 3.18), (3.18, 7.11-7.03), (2.95, 6.70), (2.95, 6.76). This derivatized compound was prepared in one step using our methodology developed to access (+)-gliocladin B (Boyer, N.; Movassaghi M. Chem Sci. 2012, 3, 1798). The corresponding bis(methylthioether) of epidisulfide (+)-42 was characterized as follows: .sup.1H NMR (400 MHz, CDCl.sub.3, 25° C.): δ 6 7.94 (d, J=7.3 Hz, 2H, SO.sub.2Ph-o-H), 7.61 (d, J=8.2 Hz, 1H, C.sub.8H), 7.52 (t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.40 (t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 7.33-7.25 (m, 2H, C.sub.7H), 7.11-7.03 (m, 2H, C.sub.5H, C.sub.6H), 6.76 (d, J=8.9 Hz, 2H, C.sub.2′H), 6.70 (s, 1H, C.sub.2H), 6.65 (d, J=8.9 Hz, 2H, C.sub.3′H), 3.74 (s, 2H, C.sub.5′H), 3.18 (d, J=14.1 Hz, 1H, C.sub.12H.sub.a), 3.07 (s, 3H, C.sub.17H), 2.95 (d, J=14.2 Hz, 1H, C.sub.12H.sub.b), 2.07 (s, 3H, C.sub.11SCH.sub.3), 1.91 (s, 3H, C.sub.15SCH.sub.3), 1.84 (s, 3H, C.sub.18H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 165.7 (C.sub.13), 163.3 (C.sub.16), 158.7 (C.sub.4′), 142.6 (C.sub.9), 139.7 (SO.sub.2Ph-ipso-C), 136.7 (C.sub.4), 134.8 (C.sub.1′), 133.0 (SO.sub.2Ph-p-C), 129.2 (SO.sub.2Ph-m-C), 129.0 (C.sub.7), 127.1 (SO.sub.2Ph-o-C), 126.9 (C.sub.2′), 124.7 (C.sub.5/6), 123.8 (C.sub.5/6), 116.7 (C.sub.8), 114.4 (C.sub.3′), 86.1 (C.sub.2), 70.0 (C.sub.11), 67.4 (C.sub.15), 56.7 (C.sub.3), 55.4 (C.sub.5′), 46.2 (C.sub.12), 29.3 (C.sub.17), 23.7 (C.sub.18), 15.8 (C.sub.15SCH.sub.3), 14.4 (C.sub.11SCH.sub.3). HRMS (ESI) (m/z): calc'd for C.sub.30H.sub.31N.sub.3NaO.sub.5S.sub.3 [M+Na].sup.+: 632.1318, found 632.1315. [0686] 58. As measured by crude .sup.1H NMR (CDCl.sub.3) analysis, the ratio of tetrasulfide 44:trisulfide 43:disulfide (+)-42 epithiodiketopiperazines was 1:2:1.2 before chromatography. [0687] 59. Hart, T. Tetrahedron Lett. 1985, 26, 2013-2016. [0688] 60. When pure D.sub.2O was used, signal broadening was observed. [0689] 61. Diol 49 has been characterized by .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C.): δ 7.62 (d, J=8.1 Hz, 1H, C.sub.8H), 7.36-7.27 (m, 4H), 7.22-7.14 (m, 2H), 7.02 (t, J=7.8 Hz, 2H, SO.sub.2Ph-m-H), 6.78 (app-d, J=8.8 Hz, 2H, C.sub.2′H), 6.55 (app-d, J=8.9 Hz, 2H, C.sub.3′H), 6.35 (s, 1H, C.sub.2H), 5.65-5.40 (br-s, OH), 3.99 (t, J=5.9 Hz, 2H, C.sub.5′H), 3.54 (t, J=6.5 Hz, 2H, C.sub.7′H), 3.37 (d, J=15.1 Hz, 1H, C.sub.12H.sub.a), 3.00 (s, 3H, C.sub.17H), 2.92 (d, J=15.2 Hz, 1H, C.sub.12H.sub.b), 2.10-2.01 (m, 2H, C.sub.6′H), 1.82 (s, 3H, C.sub.18H). TLC (20% acetone in dichloromethane), Rf: 0.34 (UV, CAM). [0690] 62. O-TBS protected monoalcohols S22 and S23 have been characterized by .sup.1H NMR (500 MHz, CDCl.sub.3, 25° C., 1.1:1 mixture of regioisomers): δ 7.63-7.57 (m), 7.34-7.29 (m), 7.31-7.24 (m), 7.22-7.13 (m), 7.05-6.96 (m), 6.77-6.69 (m), 6.57 (t, J=9.2 Hz), 6.42 (s), 6.30 (s), 4.01 (t, d, J=5.9, 2.4 Hz), 3.85 (s), 3.57-3.52 (m), 3.51 (s), 3.37 (dd, J=15.2, 1.5 Hz), 2.97 (s), 2.93 (s), 2.85 (d, J=14.6 Hz), 2.78 (d, J=15.1 Hz), 2.06 (p, J=6.1 Hz), 1.83 (s), 1.65 (s), 0.97 (s), 0.92 (s, 3H), 0.33 (s), 0.32 (s), 0.24 (s), 0.23 (s). TLC (40% acetone in hexanes), Rf: 0.51 and 0.58 (UV, CAM). [0691] 63. The relative stereochemistry of the epidithiodiketopiperazine (+)-9d was confirmed by key NOE correlations on the corresponding bis(methylthioether). Our assignment is supported by key NOE signals (.sup.1H, .sup.1H) in ppm: (7.34, 3.29), (3.29, 1.88), (6.94, 3.03). This derivatized compound was prepared in one step using our methodology developed to access (+)-gliocladin B (Boyer, N.; Movassaghi M. Chem Sci. 2012, 3, 1798). The corresponding bis(methylthioether) of epidithiodiketopiperazine (+)-9d was characterized as follows: .sup.1H NMR (500 MHz, acetone-d.sub.6) δ 8.00 (d, J=7.3 Hz, 2H, SO.sub.2Ph-o-H), 7.69 (t, J=7.5 Hz, 1H, SO.sub.2Ph-p-H), 7.56 (t, J=7.9 Hz, 2H, SO.sub.2Ph-m-H), 7.52 (d, J=8.1 Hz, 1H, C.sub.8H), 7.34 (d, J=7.6 Hz, 1H, C.sub.5H), 7.30 (t, J=7.8 Hz, 1H, C.sub.7H), 7.10 (t, J=7.9 Hz, 1H, C.sub.6H), 6.94 (d, J=8.8 Hz, 2H, C.sub.2′H), 6.77 (d, J=8.8 Hz, 2H, C.sub.3′H), 6.75 (s, 1H, C.sub.2H), 4.05 (t, J=6.0 Hz, 2H, C.sub.5′H), 3.54 (t, J=6.7 Hz, 2H, C.sub.7′H), 3.29 (d, J=14.1 Hz, 1H, C.sub.12H.sub.β), 3.03 (d, J=14.1 Hz, 1H, C.sub.12H.sub.α), 2.99 (s, 3H, C.sub.17H), 2.06-2.03 (m, 2H, C.sub.6′H), 2.02 (s, 3H, C.sub.18H), 1.88 (s, 3H, C.sub.11SCH.sub.3), 1.80 (s, 3H, C.sub.15SCH.sub.3). [0692] 64. Grimes, K. D.; Aldrich, C. C. Analytical Biochemistry, 2011, 417 (2), 264-273.