MACROMOLECULES COMPRISING TRIAZOLES AND RELATED COMPOUNDS

Abstract

Macromolecules comprising triazoles and related compositions and methods are provided. In some embodiments, a macromolecule may comprise one or more repeat units including a triazole and a functionalizable pendant group. The macromolecule may also comprise one or more orthogonally addressable end groups. In some embodiments, one or more repeat units may be formed by a synthetic process that allows for precise control over stereochemistry, pendant functionality, and/or the spatial relationship (e.g., distance) between groups in the repeat unit(s). Such precise control over pendant group and repeat unit structure allows for the macromolecule functionality, stereochemistry, and spacing between groups (e.g., pendant groups) to be precisely controlled. Macromolecules described herein may be used for a wide variety of applications, including the delivery of active agents.

Claims

1. A compound comprising Formula (I): ##STR00032## or a salt thereof, wherein: each Q is independently N or N.sup.+(R.sup.#) each R.sup.1 and R.sup.3 is independently O, S, optionally substituted amino, optionally substituted acylene, optionally substituted alkylene, optionally substituted carbocyclylene, optionally substituted heteroalkylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene; each R.sup.2 is independently O, OR.sup.#, S, SR.sup.190 N(R.sup.#), N(R.sup.#).sub.2, C(R*).sub.2, C(R*).sub.3, C(O)R*, C(NR.sup.#)R*, or C(S)R*; each is independently a single or double bond, provided that when is a double bond each R.sup.2 is independently O, S, N(R.sup.#), or C(R.sup.*).sub.2, and when is a single bond each R.sup.2 is independently OR.sup.#, SR.sup.#, N(R.sup.#).sub.2, C(R*).sub.3, C(O)R*, C(NR.sup.#)R*, or C(S)R*; each R.sup.4 is independently hydrogen, halo, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a metal; R.sup.5 is azide, hydroxyl, optionally substituted amino, optionally substituted thiol, optionally substituted acyl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or an electrophile; R.sup.6 is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted aryl, or optionally substituted heteroaryl; each R.sup.# is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted silyl, or optionally substituted sulfonyl; and each R.sup.* is independently hydrogen, halo, hydroxyl, optionally substituted amino, optionally substituted thiol, optionally substituted acyl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted heterocyclyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted aryl, or optionally substituted heteroaryl; each m and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n is an integer between 1 and 500.

2. The compound of claim 1, wherein each is independently a single bond.

3. The compound of claim 1, wherein each R.sup.1 and R.sup.3 is independently O, S, optionally substituted amino, optionally substituted alkylene, or optionally substituted heteroalkylene.

4. The compound of claim 1, wherein each R.sup.1 and R.sup.3 is independently O, optionally substituted amino, or optionally substituted alkylene.

5. (canceled)

6. The compound of claim 1, wherein each m and p is independently 0, 1, 2, 3, 4, or 5.

7. The compound of claim 1, wherein each m is independently 0 or 1.

8. The compound of claim 1, wherein Formula (I) has the structure: ##STR00033## or a salt thereof.

9. The compound of claim 1, wherein Formula (I) has the structure: ##STR00034## or a salt thereof.

10. The compound of claim 1, wherein Formula (I) has the structure: ##STR00035## or a salt thereof.

11. (canceled)

12. The compound of claim 1, wherein Formula (I) has the structure: ##STR00036## or a salt thereof.

13. The compound of claim 1, wherein Formula (I) has the structure: ##STR00037## or a salt thereof.

14. (canceled)

15. The compound of claim 1, wherein Formula (I) has the structure: ##STR00038## or a salt thereof.

16. The compound of claim 1, wherein Formula (I) has the structure: ##STR00039## or a salt thereof.

17. The compound of claim Jany preceding claim, wherein Formula (I) has the structure: ##STR00040## or a salt thereof.

18-23. (canceled)

24. The compound of claim 1, wherein at least one R.sup.2 is C(R*).sub.3 and wherein the at least one C(R*).sub.3 has the structure:
C(R*.sub.2)(R.sup.a).sub.t(R.sup.b)R.sup.c wherein: each R.sup.a is independently optionally substituted alkylene, optionally substituted alkenylene, or optionally substituted alkynylene; R.sup.b is O, N(R), or S; R.sup.c is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted silyl, or optionally substituted sulfonyl; R is hydrogen or optionally substituted alkyl; and t is 0, 1, 2, 3 ,4 ,5, 6, 7, 8, 9, or 10.

25-34. (canceled)

35. The compound of claim 1, wherein at least one R.sup.4 is a metal.

36-37. (canceled)

38. The compound of claim 1, wherein R.sup.5 is an electrophile.

39-41. (canceled)

42. The compound of claim 1, wherein n is an integer between 16 and 500.

43. A compound comprising Formula (II): ##STR00041## or a salt thereof, wherein: R.sup.7, R.sup.8, and R.sup.9 are independently hydrogen, azide, or optionally substituted hydroxyl, wherein at least one of R.sup.7, R.sup.8, and R.sup.9 is azide or optionally substituted hydroxyl; and R.sup.10 is hydrogen or an alkynyl protecting group.

44. A compound comprising Formula (III): ##STR00042## or a salt thereof, wherein: R.sup.11 is independently hydrogen, azide, or optionally substituted hydroxyl; or R.sup.12 is optionally substituted hydroxyl; each R.sup.13 is independently O, S, optionally substituted amino, optionally substituted acylene, optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene; R.sup.14 is hydrogen or an alkynyl protecting group; and g is 0, 1, 2, 3 ,4 ,5, 6, 7, 8, 9, or 10.

Description

EXAMPLES

Example 1

[0208] This example describes the synthesis of a precursor molecule and a monomer, as well as the click chemistry reaction between the molecules. Scheme 1 shows the synthetic method. The precursor molecule and monomer had an enantiomeric excess of at least 99.5%.

[0209] The monomer can be used to form a macromolecule having the structure:

##STR00020##

##STR00021##

Synthesis of A2

[0210] Mg(ClO.sub.4).sub.2 (981 mg, 4.4 mmol)was added to t-BuOH (19.6 g, 265 mmol) in a 500 mL round bottom flask (RBF). The mixture was stirred until the salt was totally dissolved. A1 (11.8 g, 44 mmol) was then added dropwise to the solution and the reaction was allowed to proceed for 3 days at room temperature. Afterwards, EtOAc was added and the solution was extracted 3 times with a 50% saturated brine solution. The organic layer was collected and dried under reduced pressure. THF (150 mL), PPh.sub.3 (15.7 g, 60 mmol), and phthalimide (8.8 g, 60 mmol) were added to the crude liquid and stirred. DIAD (10.1 g, 50 mmol) was added dropwise to the solution and the reaction was left to react overnight. THF was removed under reduced pressure and EtOAc was added to the remaining material. The solution was extracted 3 times with distilled water and the organic layer was collected and concentrated under reduced pressure. Column chromatography was used to purify the desired product (16.0 g, 34 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 7.85, 7.72, 4.75, 4.58, 4.49, 4.45 3.85, 1.08, 1.03.

Synthesis of A3

[0211] A2 (10 g, 21 mmol) was dissolved in THF (100 mL). Hydrazine hydrate (2.0 g, 40 mmol) was then added dropwise and the solution was left to react overnight. EtOAc was added to the solution and the solution was extracted 3 times with a 1% AcOH acqueous solution. The crude product was concentrated under reduced pressure. To the crude product was added MeOH (100 mL), CuSO.sub.4-5H.sub.2O (249 mg, 1 mmol), and K.sub.2CO.sub.3 (5.5 g, 40 mmol). 1H-Imidazole-1-sulfonyl azide-HCl salt (5.2 g, 25 mmol) was added protionwise to the solution and the reaction was left overnight at room temperature. EtOAc was added to the reaction and the solution was then extracted 3 times with water. The crude product was concentrated under reduced pressure and was then purified by column chromatography to result in the desired product (6.2 g, 17 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.58, 4.47, 4.39, 3.85, 3.02, 1.07, 1.02.

Synthesis of A4

[0212] A2 (5.5 g, 11.6 mmol) was dissolved in THF (33 mL) in a 500 mL RBF. A 1M THF solution of TBAF (12.0 mL) was then added dropwise to the solution and left to react over 1 hour. EtOAc was added to the solution which was then extracted 3 times with water. The crude product A4 (3.46 g, 11 mmol) was concentrated under reduced pressure and used crude for further reactions. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 7.84, 7.73, 4.76, 4.57, 4.49, 3.83, 2.49, 1.08.

Synthesis of A5

[0213] 1,4-Dioxane (2 mL) and Cp*RuCl(COD) (2.2 mg, 0.0057 mmol) were added to a mixture of A3 (100 mg, 0.27 mmol) and A4 (90 mg, 0.29 mmol). The reaction was stirred for 4 hours and then DCM was removed under reduced pressure. The crude reaction mixture was then purified by column chromatography resulting in A4 (150 mg, 0.22 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): H 7.85, 7.76, 7.56, 4.81, 4.76, 4.74, 4.59, 4.48, 3.82, 3.65, 1.10, 1.08, 1.02.

Example 2

[0214] This example describes the synthesis of a precursor molecule and a monomer, as well as the click chemistry reaction between the molecules. Scheme 2 shows the synthetic method. The precursor molecule and monomer had an enantiomeric excess of at least 99.5%.

[0215] The monomer can be used to form a macromolecule having the structure:

##STR00022##

##STR00023##

Synthesis of B1

[0216] Ethynyltrimethylsilane (53.0 g, 540 mmol), was added to anhydrous THF (540 mL) in a dry 1000 mL RBF. The solution was cooled to 78 C. and a 2.5M Hexanes solution of n-BuLi (216 mL) was added dropwise to the solution. The reaction was left at 78 C. for 15 minutes before BF.sub.3 etherate (76.64 g, 540 mmol) was added to it dropwise. After another 15 minutes, (S)-Epichlorohydrin (25 g, 270 mmol) was added dropwise the the solution. The reaction was left at 78 C. for 2 hours and allowed to warm to 0 C. and reacted a further 2 hours. AcOH (25 mL) was added to quench the reaction. EtOAc was then added and the solution was extracted 3 times with water. The crude product B1 (44.4 g, 233 mmol) was concentrated under reduced pressure and used without further purification. .sup.1NMR (300 MHz, CDCl.sub.3, ppm): H 3.93, 3.73, 3.64, 2.46, 2.41, 0.15.

Synthesis of B2

[0217] CHCl.sub.3 (120 mL) and DIPEA (59 g, 460 mmol) was added to B1 (44 g, 231 mmol)) in a 500 mL RBF. MOMC1 (37.0 g, 460 mmol) was then added dropwise to the solution and it was left to react for 36 hours at 35 C. Water was then added to quench the reaction and the organic phase was extracted 3 times with water. The organic layer was concentrated under reduced pressure and the resulting product was used without further purification. MeOH (400 mL) and KF (58 g, 1 mol) were added to the product and the resulting solution was heated to 45 C. and left to react for 4 hours. MeOH was then removed under reduced pressure and EtOAc was added. The organic solution was extracted 3 times with water and then concentrated under reduced pressure. The crude product was then purified by column chromatography to result in B2 (27.2 g, 168 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.76, 3.98, 3.75, 3.67, 3.45, 2.51, 2.47, 1.98.

Synthesis of B3

[0218] B2 (15.0 g, 93 mmol) was added to anhydrous THF (300 mL) in a dry 1000 mL RBF. The solution was cooled to 78 C. and a 2M solution of NaHMDS (50 mL) was added dropwise. After 15 minutes, TESC1 (18.1 g, 120 mmol) was added dropwise and the solution was then allowed to warm to room temperature. AcOH (15 mL) was added dropwise to quench the reaction and THF was then removed under reduced pressure. EtOAc was added and the solution was extracted 3 times with water. The organic layer was then concentrated under reduced pressure and the crude product was used without further purification. To the crude product was added DMSO (500 mL) and NaN.sub.3 (19.5 g, 300 mmol) and heated to 45 C. After 2 days, EtOAc was added to the reaction mixture and extracted 3 times with a 2% w/w LiCl acqueous solution. EtOAc was removed under reduced pressure and the crude product was purified by column chromatography resulting in B3 (17.5 g, 62 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.76, 3.89, 3.35, 3.33, 3.29, 2.48, 2.42, 0.98, 0.15.

Synthesis of B4

[0219] 1,4-Dioxane (2 mL) and Cp*RuCl(COD) (2.5 mg, 0.0064 mmol) were added to a mixture of B2 (50 mg, 0.31 mmol) and B3 (90 mg, 0.32 mmol). The reaction was stirred for 4 hours and then DCM was removed under reduced pressure. The crude reaction mixture was then purified by column chromatography resulting in B4 (112 mg, 0.25 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): H 7.40, 5.15, 4.99, 4.89, 4.87, 3.57, 3.45, 3.38, 3.28, 2.55, 2.51, 0.95, 0.55.

Example 3

[0220] This example describes the synthesis of a precursor molecule and a monomer, as well as the click chemistry reaction between the molecules. Scheme 3 shows the synthetic method. The precursor molecule and monomer had an enantiomeric excess of at least 99.5%.

[0221] The monomer can be used to form a macromolecule having the structure:

##STR00024##

##STR00025## ##STR00026##

Synthesis of C1

[0222] Mg(ClO.sub.4).sub.2 (12.1 g, 54 mmol)was added to t-BuOH (160 g, 2.16 mol) in a 500 mL round bottom flask (RBF). The mixture was stirred until the salt was totally dissolved. (S)-Epichlorohydrin (50 g, 540 mmol) was then added dropwise to the solution and the reaction was allowed to proceed for 3 days at room temperature. Afterwards, EtOAc was added and the solution was extracted 3 times with a 50% saturated brine solution. The organic layer was collected and dried under reduced pressure. DMF (250 mL) and Imidazole (68 g, 1 mol) were added to the crude liquid. After 15 minutes of stirring, TMSCl (108 g, 1 mol) was added to the reaction mixture and the reaction was left to react for 8 hours. At this point, DMF and other volatile compounds were removed under reduced pressure. Diethyl ether was added to the leftover concentrated material and the mixture was stirred for an hour. The mixture was then extracted with water 3 times and the organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product Cl (90.7 g, 380 mmol) was used without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 3.91, 3.63, 3.49, 3.36, 1.18, 0.16.

Synthesis of C2

[0223] Ethynyltrimethylsilane (43.5 g, 440 mmol), was added to anhydrous THF (220 mL) in a dry 1000 mL RBF. The solution was cooled to 78 C. and a 2.5M Hexanes solution of n-BuLi (176 mL) was added dropwise to the solution. The reaction was left at 78 C. for 15 minutes before the reaction mixture was allowed to warm to room temperature. Cl (50 g, 209 mmol) and DMSO (150 mL) were then added to the solution. After four hours of reaction, MeOH (40 mL) was added dropwise to quench the reaction. The product was concentrated under reduced pressure and then EtOAc was added and the resulting solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and then concentrated under reduced pressure to yield product C2 (23.1 g, 152 mmol), which was used without further purification. .sup.lEINMR (300 MHz, CDCl.sub.3, ppm): H 3.88, 3.50, 3.38, 3.36, 2.53, 2.49, 1.96 1.21.

Synthesis of C3

[0224] DCM (300 mL), 4-DMAP (23.2 g, 190 mmol), and TEA (22.1 g, 219 mmol) were added to C3 (22 g, 146 mmol) and stirred together until homogenous. Tosyl chloride (27.8 g, 146 mmol) was then added portionwise and the reaction was left to react overnight. Water was added and the solution was extracted 1 time with water and 2 times with 1% AcOH. The organic layer was isolated and dried with Na.sub.2SO.sub.4 and then concentrated under reduced pressure to yield C3 (48.4 g, 136 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3 , ppm): H 7.83, 7.37, 4.59, 3.54, 3.52, 2.61, 2.46, 2.35, 1.99.

Synthesis of C4

[0225] DMSO (450 mL) and NaN.sub.3 (20.1 g, 309 mmol) were added to C3 (32 g, 103 mmol), and the resulting solution was heated to 50 C. and left to react for 24 hours. EtOAc was added and the solution was extracted 3 times with 1% w/w LiCl acqueous solution. The organic phase was isolated, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude material was then purified by column chromatography to yield a clear oil. Anhydrous THF (400 mL) was added to this oil and the solution was cooled to 78 C. 2M NaHMDS in THF (30 mL) was added dropwise to the solution, and after 15 minutes TESC1 (10.6 g, 70 mmol) was added dropwise to the solution. After another 15 minutes the reaction was warmed to room temperature and AcOH (10 mL) was added to quench the reaction. The reaction mixture was concentrated under reduced pressure and then EtOAc was added. The solution was extracted with 3 times with water and the organic layer was isolated, dried with Na.sub.2SO.sub.4, and concentrated. The product was purified by column chromatography to yield C.sub.4 as a clear oil (15.7 g, 53 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 41 7.84, 3.91, 3.63, 3.49, 3.36, 1.18, 0.16.

Synthesis of C5

[0226] A 1:1 mixture of TFA and DCM (200 mL) was added to C4 (15 g, 50.8 mmol) and reacted at 35 C. for 1 hour. TFA and DCM were removed by reduced pressure and the product was purified by column chromatography. The purified product was then added to a solution of DCM (150 mL), 4-DMAP (2.44 g, 20 mmol), and TEA (6.06 g, 60 mmol). Isobutyric anhydride (7.9 g, 50 mmol) was then added and left to react for 15 minutes.

[0227] Volatile compounds were removed under reduced pressure and the desired product C5 (11.4 g, 37 mmol) was isolated by column chromatography. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.32, 4.18, 3.79, 2.63, 2.60, 1.22, 1.01, 0.60.

Synthesis of C6

[0228] A 1:1 mixture of TFA and DCM (200 mL) was added to C3 (16 g, 52 mmol) and reacted at 35 C. for 1 hour. TFA and DCM were removed by reduced pressure and the product was purified by column chromatography. The purified product was then added to a solution of DCM (150 mL), 4-DMAP (2.44 g, 20 mmol), and TEA (6.06 g, 60 mmol). Isobutyric anhydride (7.9 g, 50 mmol) was then added and left to react for 15 minutes. Volatile compounds were removed under reduced pressure and the desired product C6 (13.6 g, 42 mmol) was isolated by column chromatography. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 41 7.83, 7.37, 4.79, 4.30, 4.22, 2.63, 2.48, 2.46, 2.01, 1.14.

Synthesis of C7

[0229] 1,4-Dioxane (1 mL) and Cp*RuCl(COD) (1.2 mg, 0.0031 mmol) were added to a mixture of C5 (50 mg, 0.16 mmol) and C6 (50 mg, 0.15 mmol). The reaction was stirred for 4 hours and then DCM was removed under reduced pressure. The crude reaction mixture was then purified by column chromatography resulting in C7 (82 mg, 0.13 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3, ppm):7.78, 7.58, 7.26, 4.90, 4.80, 4.65, 4.20, 4.01, 3.12, 2.89, 2.57, 2.44, 2.29, 1.09, 0.95, 0.56.

EXAMPLE 4

[0230] This example describes the synthesis of a precursor molecule and a monomer, as well as the click chemistry reaction between the molecules. Scheme 4 shows the synthetic method. The precursor molecule and monomer had an enantiomeric excess of at least 99.5%.

[0231] The monomer can be used to form a macromolecule having the structure:

##STR00027##

##STR00028## ##STR00029##

Synthesis of D1

[0232] Mg(ClO.sub.4).sub.2 (12.1 g, 54 mmol)was added to t-BuOH (160 g, 2.16 mol) in a 500 mL round bottom flask (RBF). The mixture was stirred until the salt was totally dissolved. (S)-Epichlorohydrin (50 g, 540 mmol) was then added dropwise to the solution and the reaction was allowed to proceed for 3 days at room temperature. Afterwards, EtOAc was added and the solution was extracted 3 times with a 50% saturated brine solution. The organic layer was collected and dried under reduced pressure. DMF (250 mL) and NaI (223 g, 1.5 mol) were added to the crude liquid, and this reaction mixture was heated to 100 C. for 2 hours. EtOAc was added to the solution, which was then extracted 3 times with water. The organic layer was then isolated, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude liquid was used without further purification in the next step. DMF (200 mL) and Imidazole (68 g, 1 mol) were added to the crude liquid. After 15 minutes of stirring, TMSC1 (108 g, 1 mol) was added to the reaction mixture and the reaction was left to react for 8 hours. At this point, DMF and other volatile compounds were removed under reduced pressure. Diethyl ether was added to the leftover concentrated material and the mixture was stirred for an hour. The mixture was then extracted with water 3 times and the organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product D1 (134 g, 400 mmol) was used without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 3.79, 3.56, 3.33, 3.28, 0.19.

Synthesis of D2

[0233] t-Butyl(dichloromethyl)dimethylsilane (82 g, 410 mmol) was added to anhydrous THF (1.2 L) in a dry RBF. The solution was cooled to 78 C. and 2M LDA in THF (205 mL) was added dropwise. After 1 hour, the solution was kept at 78 C. and D1 (66.4 g, 200 mmol) was added dropwise to the solution. The reaction was left at 78 C. for 8 hours at which point the reaction was quenched with water. EtOAc was added and the solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product D2 (55.3 g, 166 mmol, contaminated with starting material and evaluated by NMR) was used without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 61-1 4.63, 3.75, 3.67, 3.33, 2.59, 2.36, 1.05, 1.01, 0.25.

Synthesis of D3

[0234] D2 (50 g, 150 mmol) was dissolved in THF (450 mL) and 1M TBAF in THF (450 mL) was added dropwise to the solution. After 15 minutes, EtOAc was added and the solution was extracted 3 times with water. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. DMF (50 mL) and imidazole (13.6 g, 200 mmol) were then added to the resulting crude liquid. TMSCl (22 g, 200 mmol) was then added and the reaction was left at room temperature for 8 hours, and then DMF and other volatiles were removed under reduced pressure. Diethyl ether was added and the mixture was stirred for 1 hour. The solution was then extracted 3 times with water, the organic layer was dried with Na.sub.2SO.sub.4, and the crude product was concentrated under reduced pressure to yield D3 (26.1 g, 89 mmol) which was used without further purification. .sup.1 H NMR (300 MHz, CDCl.sub.3, ppm): H 5.80, 4.08, 3.49, 3.42, 2.48, 2.43, 0.89.

Synthesis of D4

[0235] DMSO (480 mL) was added to D3 (23.5 g, 80 mmol) and the mixture was stirred until homogenous. KOtBu (26.9 g, 240 mmol) was then added to the solution and the reaction was left at room temperature for 2 hours. EtOAc was added to the solution, which was then extracted 3 times with water. The organic layer was isolated, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure. The resulting oil was purified with column chromatography to yield D4 (6.4 g, 45 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3 , ppm): H 4.46, 3.54, 3.45, 2.63, 2.45, 1.22.

Synthesis of D5

[0236] D4 (3.0 g, 20.8 mmol) was dissolved in Acetonitrile (50 mL), and TMSBr (6.12 g, 40 mmol) was then added to the solution. After 1 hour, 1% AcOH in water (10 mL) was added and all volatiles were removed under reduced pressure. Acetonitrile (20 mL), vinyl acetate (20 mL), and lipase B (250 mg) were then added and the reaction was left over night to react. Volatile compounds were removed under reduced pressure and the crude mixture was purified by column chromatography to yield D5 (1.98 g, 14.3 mmol) as a clear liquid. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.86, 4.69, 4.30, 2.63, 2.13.

Synthesis of D6

[0237] CHCl.sub.3 (20 mL) and DIPEA (3.53 g, 27.4 mmol) was added to D5 (1.9 g, 13.7 mmol) in a 500 mL RBF. MOMCl (2.21 g, 27.4 mmol) was then added dropwise to the solution and it was left to react for 36 hours at 35 C. Water was then added to quench the reaction and the organic phase was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. MeOH (30 mL) and K.sub.2CO.sub.3 (4.15 g, 30 mmol) were then added to the resulting oil and the mixture was heated to 45 C. for 1 hour. MeOH was then removed under reduced pressure, EtOAc was added and the solution was extracted 3 times with water. The organic layer was isolated, dried with Na.sub.2SO.sub.4, and concentrated under reduced pressure. This crude mixture was purified with column chromatography resulting in D6 (1.42 g, 10 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.98, 4.84, 3.58, 3.47, 3.40, 2.71.

Synthesis of D7

[0238] D6 (1.0 g, 7.0 mmol) was added to anhydrous THF (50 mL) in a dry RBF. The solution was cooled to 78 C. and 2M NaHMDS in THF (7.2 mL) was added dropwise. After 15 minutes, TESCl (2.71 g, 18 mmol) was added dropwise and after 1 hour, the reaction was allowed to warm up to room temperature. AcOH (7 mL) was added to quench the reaction. EtOAc was added and the solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. A 9:1 mixture of Acetone/H.sub.2O (20 mL) and PPTS (251 mg, 1 mmol) added. The reaction was heated to 60 C. for 4 hours. Acetone was removed under reduced pressure and EtOAc was added and the solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. DCM (20 mL), 4-DMAP (366 mg, 3.0 mmol), and TEA (1.0 g, 10 mmol) was then added and the mixture was stirred until homogenous. Tosyl chloride (1.52g, 8 mmol) was then added and the reaction was left to react overnight. DCM was removed under reduced pressure and EtOAc was added and the solution was extracted 1 time with water and 2 times with 1% AcOH in water. The organic layer was dried with Na.sub.2SO4 and concentrated under reduced pressure. DMSO (28 mL) and NaN.sub.3 (910 mg, 14 mmol) were then added and the solution was heated to 45 C. for 24 hours, after which EtOAc was added. The solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting liquid was then purified by column chromatography to yield D7 (1.16 g, 4.1 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): H 4.98, 4.84, 3.39, 3.30, 3.25, 1.05, 0.15.

Synthesis of D8

[0239] DCM (10 mL), 4-DMAP (122 mg, 1 mmol), and TEA (400 mg, 4 mmol) was added to D6 (400 mg, 2.8 mmol) and the mixture was stirred until homogenous. Tosyl chloride (572 mg, 3.0 mmol) was then added and the reaction was left to react overnight. DCM was removed under reduced pressure and EtOAc was added and the solution was extracted 1 time with water and 2 times with 1% AcOH in water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure leaving the product D8 (810 mg, 2.7 mmol) which ws used without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 61-1 7.83, 7.30, 4.98, 4.91, 3.92, 3.78, 3.42, 2.71, 2.55.

Synthesis of D9

[0240] 1,4-dioxane (1 mL) and Cp*RuCl(COD) (1.4 mg, 0.0036 mmol) were added to a mixture of D7 (50 mg, 0.18 mmol) and D8 (50 mg, 0.17 mmol). The reaction was stirred for 4 hours and then DCM was removed under reduced pressure. The crude reaction mixture was then purified by column chromatography resulting in D9 (89 mg, 0.15 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): 61-1 7.89, 7.60, 7.25, 5.30, 5.11, 4.97, 4.84, 3.92, 3.84, 3.73, 3.50, 3.41, 1.07, 0.18.

Example 5

[0241] This example describes the synthesis of a precursor molecule and a monomer, as well as the click chemistry reaction between the molecules. Scheme 3 shows the synthetic method. The precursor molecule and monomer had an enantiomeric excess of at least 99.5%.

[0242] The monomer can be used to form a macromolecule having the structure:

##STR00030##

##STR00031##

Synthesis of E1

[0243] THF (30 mL), PPh.sub.3 (1.05 g, 4 mmol), and phthalimide (559 mg, 3.8 mmol) were added to D4 (540 mmol, 3.3 mmol) and stirred. DIAD (728 mg, 3.6 mmol) was added dropwise to the solution and the reaction was left to react overnight. THF was removed under reduced pressure and EtOAc was added to the remaining material. The solution was extracted 3 times with distilled water and the organic layer was collected and concentrated under reduced pressure. Column chromatography was used to purify the desired product El (823 mg, 3.0 mmol). .sup.1 HNMR (300 MHz, CDCl.sub.3, ppm): H 7.85, 7.72, 5.16, 4.31, 4.23, 2.39, 1.09.

Synthesis of E2

[0244] E1 (325 mg, 1.3 mmol) was added to anhydrous THF (10 mL) in a dry RBF. The solution was cooled to 78 C. and 2M NaHMDS in THF (0.7 mL) was added dropwise. After 15 minutes, TESCl (226 mg, 1.5 mmol) was added dropwise and after 1 hour, the reaction was allowed to warm up to room temperature. AcOH (1 mL) was added to quench the reaction. EtOAc was added and the solution was extracted 3 times with water. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. THF (10 mL) and Hydrazine hydrate (75 mg, 1.5 mmol) were then added and left to react for 1 hour at room temperature. EtOAc was added and the solution was extracted 3 times with saturated bicarbonate solution. To the crude product was added MeOH (10 mL), CuSO4-5H.sub.2O (12 mg, 0.05 mmol), and K.sub.2CO.sub.3 (249 mg, 1.8 mmol). 1H-Imidazole-1-sulfonyl azide-HCl salt (219 mg, 1.05 mmol) was added protionwise to the solution and the reaction was left overnight at room temperature. EtOAc was added to the reaction and the solution was then extracted 3 times with water. The crude product was concentrated under reduced pressure and was then purified by column chromatography to result in the desired product E2 (307 mg, 0.95 mmol). .sup.1H NMR (300 MHz, CDCl.sub.3, ppm): 41 4.35, 4.28, 4.12, 1.12, 1.06.

Synthesis of E3

[0245] 1,4-dioxane (1 mL) and Cp*RuCl(COD) (0.81 mg, 0.0021 mmol), were added to a mixture of E1 (29 mg, 0.11 mmol) and E2 (30 mg, 0.11 mmol). The reaction was stirred for 4 hours and then DCM was removed under reduced pressure. The crude reaction mixture was then purified by column chromatography resulting in E3 (48 mg, 0.081 mmol). .sup.1H NMR (400 MHz, CDCl.sub.3, ppm): 41 7.86, 7.74, 7.44, 5.61, 5.25, 4.40, 4.35, 4.25, 1.12, 1.09, 1.04.

[0246] While several embodiments of the present invention 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 invention. 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 invention 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 invention 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 invention may be practiced otherwise than as specifically described and claimed. The present invention 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 invention. The indefinite articles a and an, as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean at least one.

[0247] The phrase and/or, as used herein in the specification and in the claims, should be understood to mean either or both of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the and/or clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to A and/or B, when used in conjunction with open-ended language such as comprising can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0248] As used herein in the specification and in the claims, or should be understood to have the same meaning as and/or as defined above. For example, when separating items in a list, or or and/or shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as only one of or exactly one of, or, when used in the claims, consisting of, will refer to the inclusion of exactly one element of a number or list of elements. In general, the term or as used herein shall only be interpreted as indicating exclusive alternatives (i.e. one or the other but not both) when preceded by terms of exclusivity, such as either, one of, only one of, or exactly one of Consisting essentially of, when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0249] As used herein in the specification and in the claims, the phrase at least one, in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase at least one refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, at least one of A and B (or, equivalently, at least one of A or B, or, equivalently at least one of A and/or B) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0250] In the claims, as well as in the specification above, all transitional phrases such as comprising, including, carrying, having, containing, involving, holding, and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases consisting of and consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.