Compounds useful in the synthesis of halichondrin B analogs

Abstract

In general, the invention features compounds useful for the synthesis of analogs of halichondrin B, such as eribulin or pharmaceutically acceptable salts thereof, e.g., eribulin mesylate. Exemplary compounds are of formula (I), (II), or (III): ##STR00001##

Claims

1. A method for producing eribulin or a pharmaceutically acceptable salt thereof, said method comprising: (i) reacting the compound having the formula (I): ##STR00059## wherein X is halogen; Z is a leaving group; Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; Y.sub.1 and Y.sub.2 are each independently H or a hydroxyl protecting group; and n is 1 or 2, with a compound having the formula (IV): ##STR00060## wherein Y.sub.3 and Y.sub.4, are each independently H or a hydroxyl protecting group, under NHK coupling conditions to produce the compound having the formula (II): ##STR00061## wherein X is halogen; Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; n is 1 or 2; Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently H or a hydroxyl protecting group; T is OY.sub.5; and Y.sub.5 is H or a hydroxyl protecting group, or Y.sub.5, together with the oxygen atom to which it is bound, is a leaving group; (ii) reacting the product of step (i) under Vasella fragmentation conditions to produce a compound having the formula (III): ##STR00062## wherein Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; n is 1 or 2; Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently H or a hydroxyl protecting group; U is OY.sub.6; Y.sub.5 is H or a hydroxyl protecting group or Y.sub.5, together with the oxygen atom to which it is bound, is a leaving group; and Y.sub.6 is H or a hydroxyl protecting group or Y.sub.6, together with the oxygen atom to which it is bound, is a leaving group, provided that when Q is (CH.sub.2).sub.3OY.sub.1, OY.sub.6 is a leaving group, and Y.sub.1, Y.sub.3, and Y.sub.4 are protecting groups, Y.sub.5 is not H; (iii) reacting the product of step (ii) under conditions for intramolecular Williamson etherification to produce ER-804028: ##STR00063## and (iv) converting ER-804028 into eribulin or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the compound of formula (I) has formula (Ia): ##STR00064##

3. The method of claim 1, wherein Q is (CH.sub.2).sub.3OY.sub.1.

4. The method of claim 1, wherein, in the compound of formula (I), Y.sub.1, together with the oxygen to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group.

5. The method of claim 1, wherein, in the compound of formula (I), Y.sub.1 is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p-methoxybenzyl, triphenylmethyl, tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl.

6. The method of claim 1, wherein Z is halogen or (C1-C6)alkylsulfonate.

7. The method of claim 1, wherein Z is triflate, iodide, or bromide.

8. The method of claim 1, wherein the compound of formula (I) has formula (Ib): ##STR00065## wherein Y.sub.1 is H, pivaloyl, benzoyl, p-bromobenzoyl, 1-naphthoyl, 2-naphthoyl, p-methoxybenzoyl, or o-phthaloyl or a salt thereof.

9. The method of claim 1, wherein the compound of formula (II) has formula (IIa): ##STR00066##

10. The method of claim 1, wherein the compound of formula (II) has formula (IIb): ##STR00067##

11. The method of claim 1, wherein, in the compound of formula (II), Q is (CH.sub.2).sub.3OY.sub.1; Y.sub.1, together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group; each of Y.sub.3 and Y.sub.4 is, independently and together with the oxygen atom to which it is bound, an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group, or Y.sub.3 and Y.sub.4 together with the oxygen atoms to which they are bound are a cyclic carbonate, cyclic boronate, or cyclic silylene hydroxyl protecting group, or Y.sub.3 and Y.sub.4 together are acetal, ketal, or 1,1,3,3-tetraisopropylsiloxanediyl; and Y.sub.5, together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group.

12. The method of claim 1, wherein, in the compound of formula (II), Y.sub.1 is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p-methoxybenzyl, triphenylmethyl, tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl.

13. The method of claim 1, wherein, in the compound of formula (II), Y.sub.3 and Y.sub.4 are each independently tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl, or Y.sub.3 and Y.sub.4 are together di(C1-C6alkyl)silylene.

14. The method of claim 1, wherein, in the compound of formula (II), Y.sub.5 is acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, or o-phthaloyl.

15. The method of claim 1, wherein the compound of formula (II) has formula (IIc): ##STR00068## wherein Y.sub.1 and Y.sub.5 are as follows: TABLE-US-00003 Y.sub.1 Y.sub.5 H H benzoyl benzoyl p-bromobenzoyl p-bromobenzoyl pivaloyl H pivaloyl acetyl pivaloyl benzoyl 2-naphthoyl H 2-naphthoyl 2-naphthoyl 1-naphthoyl H 1-naphthoyl 1-naphthoyl p-methoxybenzoyl H p-methoxybenzoyl p-methoxybenzoyl o-phthaloyl or salt thereof H.

16. The method of claim 1, wherein the compound of formula (III) has formula (IIIa): ##STR00069##

17. The method of claim 1, wherein, in the compound of formula (III), Q is (CH.sub.2).sub.3OY.sub.1; Y.sub.1, together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group; Y.sub.3 and Y.sub.4 are each, independently and together with the oxygen atom to which it is bound, an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group, or Y.sub.3 and Y.sub.4 together with the oxygen atoms to which they are bound are a cyclic carbonate, cyclic boronate, or cyclic silylene hydroxyl protecting group, or Y.sub.3 and Y.sub.4 together are acetal, ketal, or 1,1,3,3-tetraisopropylsiloxanediyl; and Y.sub.5, together with the oxygen atom to which it is bound, is an ester, carbonate, carbamate, sulfonate, or ether hydroxyl protecting group.

18. The method of claim 1, wherein, in the compound of formula (III), Y.sub.1 is pivaloyl, acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, o-phthaloyl, benzyl, p-methoxybenzyl, triphenylmethyl, tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl.

19. The method of claim 1, wherein, in the compound of formula (III), Y.sub.3 and Y.sub.4 are each independently tri(C1-C6 alkyl)silyl, tri(C6-C10 aryl or C1-C6 heteroaryl)silyl, di(C6-C10 aryl or C1-C6 heteroaryl)(C1-C6 alkyl)silyl, or (C6-C10 aryl or C1-C6 heteroaryl)di(C1-C6 alkyl)silyl, or Y.sub.3 and Y.sub.4 are together di(C1-C6)alkylsilylene.

20. The method of claim 1, wherein, in the compound of formula (III), Y.sub.5 is acetyl, benzoyl, p-bromobenzoyl, p-methoxybenzoyl, 1-naphthoyl, 2-naphthoyl, or o-phthaloyl.

21. The method of claim 1, wherein, in the compound of formula (III), Y.sub.5 is H or a hydroxyl protecting group.

22. The method of claim 1, wherein, in the compound of formula (III), Y.sub.6 is H.

23. The method of claim 1, wherein, in the compound of formula (III), OY.sub.6 is a leaving group.

24. The method of claim 23, wherein, in the compound of formula (III), OY.sub.6 is (C1-C6)alkylsulfonate, (C6-C10 aryl or C1-C6 heteroaryl)sulfonate, (C6-C15)aryl(C1-C6)alkylsulfonate, or (C1-C6)heteroaryl(C1-C6)alkylsulfonate.

25. The method of claim 24, wherein, in the compound of formula (III), OY.sub.6 is mesylate, toluenesulfonate, isopropylsulfonate, phenylsulfonate, or benzylsulfonate.

26. The method of claim 1, wherein the compound of formula (III) is ##STR00070##

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention provides compounds and methods of their use in the synthesis of halichondrin B analogs. In particular, the compounds are useful for the synthesis of the C14-C35 portion of halichondrin B analogs. ER-804028 is a C14-C35 fragment that has been employed in the synthesis of eribulin:

(2) ##STR00017##

(3) Halichondrin B analogs, e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized from the C14-C35 fragment as described in U.S. Pat. No. 6,214,865 and International Publication No. WO 2005/118565. In one example described in these references, the C14-C35 portion, e.g., ER-804028, of the molecule is coupled to the C1-C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):

(4) ##STR00018##

(5) Lithiation of the C14-C35 sulfone fragment followed by coupling to the C1-C13 aldehyde fragment furnishes a mixture of diastereomeric alcohols (ER-804029). Additional protecting group manipulation and oxidation followed by removal of the sulfonyl group and an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction affords an intermediate, which, when oxidized and treated with tetrabutylammonium fluoride, undergoes intramolecular oxy-Michael ring closure. Pyridinium p-toluenesulfonate mediated ketal formation and conversion of the terminal alcohol to an amine furnishes eribulin.

(6) For example, as described in WO 2005/118565 (Example 6), ER-804029 is reacted to produce ER-804030; ER-804030 is reacted to produce ER-118049; ER-118049 is reacted to produce mixture ER-118047/118048; the mixture ER-118047/118048 is reacted to produce ER-118046; ER-118046 is reacted to produce ER-811475; ER-811475 is reacted to produce ER-076349; and ER-076349 is reacted to produce eribulin.

(7) Pharmaceutically acceptable salts of eribulin, e.g., eribulin mesylate, can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid. In one example, eribulin is treated with a solution of MsOH and NH.sub.4OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane, and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate, as shown in Scheme 2.

(8) ##STR00019##

(9) A scheme for producing one example of a C14-C35 fragment (ER-804028) is as follows (Scheme 3).

(10) ##STR00020## ##STR00021## ##STR00022##
Generally, ()-quinic acid is converted to Compound A through stages 1-13 as described in International Publication Nos. WO 2009/046308 and WO 2005/118565. As outlined in Scheme 3, oxidation followed by Horner-Wadsworth-Emmons (HWE) reaction of the resulting lactol, hydrogenation, and protecting group modification furnishes Compounds E and F Blaise reaction followed by methyl ketone formation, dehydration, enolization, triflation, desilylation, and iodination produces iodo-vinyl triflate, Compound O. NHK coupling of Compound O with ER-806067 furnishes Compound P. Acetylation followed by Vasella fragmentation, intramolecular Williamson etherification, and protecting group modification affords C14-C35 fragment ER-804028. This scheme is advantageous as it results in improved stereoselectivity at C27, i.e., 67:1 dr compared to 13:1 dr in previous processes. The scheme is also advantageous as the C14-C26 starting material and C14-C35 product of the NHK coupling of this scheme exhibit greater stability than the starting material and product of previous methods. The C14-C26 starting material and C14-C35 product of the NHK coupling are stable indefinitely at room temperature, allowing for a flexible manufacturing schedule.

(11) One skilled in the art would also understand that variations on the above scheme are possible. For example, the hydroxyl protecting groups employed in particular reactions may be varied. In other variations, the leaving groups employed may be altered; for example, triflate groups can be replaced with halogens such as iodine or bromine.

(12) In addition, although the scheme depicts Compound C et seq. with carbons C14-C16, the reactions leading to the addition of carbons C14 and C15 can occur at any point prior to the synthesis of ER-804028. Synthetic steps for adding carbons C14 and C15 are disclosed in WO 2009/046308. In specific examples, Compound A or Compound B can be altered as shown in Scheme 4, and the products AG and AH substituted for Compound E or F in Scheme 3.

(13) ##STR00023##

(14) In accordance with the synthetic scheme, the invention provides compounds having the formula:

(15) ##STR00024##
e.g., Compound O, Compound AI, and Compound AJ, wherein X is halogen or oxo; Z is a leaving group; Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; Y.sub.1 and Y.sub.2 are each independently H or a hydroxyl protecting group; and n is 1 or 2. When both Y.sub.1 and Y.sub.2 are present, they may be the same or different. In addition, when Y.sub.1 and Y.sub.2 are on adjacent carbons, e.g., when n=1, they may together form a divalent hydroxyl protecting group. Compounds of this formula include those having the formula:

(16) ##STR00025##
wherein Y.sub.1 is H, pivaloyl, benzoyl, p-bromobenzoyl, 1-naphthoyl, 2-naphthoyl, p-methoxybenzoyl, or o-phthaloyl (including salts such as triethylamine and potassium).

(17) The invention also provides compounds having the formula:

(18) ##STR00026##
e.g., Compound P, Compound AD, Compound AF, Compound AK, Compound AL, and Compound AM, wherein X is halogen or oxo; Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; n is 1 or 2; Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently H or a hydroxyl protecting group; T is oxo or OY.sub.5; and Y.sub.5 is H or a hydroxyl protecting group, or Y.sub.5, together with the oxygen atom to which it is bound, is a leaving group. In certain embodiments, Y.sub.3 and Y.sub.4 are together a divalent hydroxyl protecting group. In other embodiments, Y.sub.1, Y.sub.3, and Y.sub.4 are protecting groups, and Y.sub.1 is orthogonal to Y.sub.3 and Y.sub.4. In further embodiments, Y.sub.1, Y.sub.3, Y.sub.4, and Y.sub.5 are protecting groups; Y.sub.3 and Y.sub.4 are orthogonal to Y.sub.1 and Y.sub.5; and Y.sub.1 is orthogonal to Y.sub.5. Compounds of this formula include those having the formula:

(19) ##STR00027##
wherein Y.sub.1 and Y.sub.5 are as follows:

(20) TABLE-US-00002 Y.sub.1 Y.sub.5 H H benzoyl benzoyl p-bromobenzoyl p-bromobenzoyl pivaloyl H pivaloyl acetyl pivaloyl benzoyl 2-naphthoyl H 2-naphthoyl 2-naphthoyl 1-naphthoyl H 1-naphthoyl 1-naphthoyl p-methoxybenzoyl H p-methoxybenzoyl p-methoxybenzoyl o-phthaloyl H o-phthaloyl, triethylamine H salt

(21) The invention also features compounds having the formula:

(22) ##STR00028##
e.g., Compound AE, wherein Q is C(O)H, CHCHC(O)OY.sub.1, C(R)H(CH.sub.2).sub.nOY.sub.1, or C(R)HCH.sub.2C(O)OY.sub.1; R is H or OY.sub.2; n is 1 or 2; Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are each independently H or a hydroxyl protecting group; U is halogen or OY.sub.6; Y.sub.5 is H or a hydroxyl protecting group or Y.sub.5, together with the oxygen atom to which it is bound, is a leaving group; and Y.sub.6 is H or a hydroxyl protecting group or Y.sub.6, together with the oxygen atom to which it is bound, is a leaving group, provided that when Q is C(R)H(CH.sub.2).sub.nOY.sub.1 (e.g., (CH.sub.2).sub.3OY.sub.1), U is OY.sub.6, OY.sub.6 is a leaving group, and Y.sub.1, Y.sub.3, and Y.sub.4 are protecting groups, Y.sub.5 is not H. In certain embodiments, Y.sub.3 and Y.sub.4 are together a divalent hydroxyl protecting group. In other embodiments, Y.sub.1, Y.sub.3, and Y.sub.4 are protecting groups, and Y.sub.1 is orthogonal to Y.sub.3 and Y.sub.4. In further embodiments, Y.sub.1, Y.sub.3, Y.sub.4, and Y.sub.5 are protecting groups; Y.sub.3 and Y.sub.4 are orthogonal to Y.sub.1 and Y.sub.5; and Y.sub.1 is orthogonal to Y.sub.5.

(23) As described herein, the compounds of the invention can be used in the synthesis of ER-804028 and in turn eribulin, or a pharmaceutically acceptable salt thereof, e.g., eribulin mesylate.

Experimental Procedures

(24) Compound D

(25) The synthesis of Compound D from ()-quinic acid is described in WO 2009/046308, which is hereby incorporated by reference.

(26) Compound E

(27) ##STR00029##

(28) Compound D (3.05 g, 9.80 mmol, 1 eq) was dissolved in DMF (6.1 ml) at 22 C., and imidazole (1.00 g, 14.7 mmol, 1.5 eq) was added. Upon complete dissolution of imidazole, the mixture was cooled to 0 C., and TBSCl (1.55 g, 10.3 mmol, 1.05 eq) was added. The mixture was stirred at 0 C. for 1 h, allowed to warm to room temperature and stirred for an additional 1 h. The reaction mixture was diluted with MTBE (37 ml) and washed with water (30 ml). The organic layer was separated, further washed with water (9.2 ml), and concentrated to give Compound S:

(29) ##STR00030##
as colorless oil (4.43 g with residual solvents, theoretical 100% yield assumed). The crude product was used for the next reaction without purification. .sup.1H NMR (400 MHz, CDCl.sub.3): 4.20 (1H, m), 3.91 (1H, m), 3.85 (1H, m), 3.64 (3H, s), 3.50 (1H, d, J=10.8 Hz) 3.45 (1H, d, J=10.8 Hz), 2.90 (1H, m), 2.39 (1H, m), 2.31 (1H, m), 2.22 (1H, dd, J=14.0 Hz, 8.8 Hz), 1.77-1.90 (2H, m), 1.60-1.74 (4H, m), 1.51 (1H, m), 1.27 (3H, d, J=6.8 Hz), 1.26 (1H, m), 0.86 (9H, s), 0.02 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 174.08, 122.93, 84.86, 75.78, 73.45, 66.82, 66.31, 51.77, 41.04, 38.16, 31.44, 31.04, 26.20, 26.06 (3C), 22.51, 22.20, 18.51, 18.48, 5.12, 5.17.

(30) Compound S (4.2 g, 9.8 mmol, 1 eq) was dissolved in THF (21 ml) and cooled to 0 C. LiBH.sub.4 (2.0 M solution in THF, 12.2 ml, 24.5 mmol, 2.5 eq) was added, and the mixture was allowed to warm to 20 C. Stirring was continued at 20-23 C. overnight (16 h). Another reactor was charged with 20 wt % citric acid (aqueous solution, 25 g, 26 mmol, 2.6 eq) and MTBE (40 ml), and the mixture was cooled to 0 C. The reaction mixture was carefully/slowly poured into the pre-chilled citric acid-MTBE while maintaining T-internal <10 C. Upon complete addition, the mixture was stirred at 0-5 C. for 30 min. The organic layer was separated, sequentially washed with: 1) saturated NaHCO.sub.3 (12 g) and 2) 20 wt % NaCl (12 g), and concentrated to give crude Compound T:

(31) ##STR00031##
as colorless oil (3.32 g, 8.3 mmol, 85% yield in 2 steps). .sup.1H NMR (400 MHz, CDCl.sub.3): 4.20 (1H, m), 3.93 (1H, dd, J=6.4 Hz, 4.8 Hz), 3.80 (1H, m), 3.57 (2H, m), 3.47 (1H, d, J=10.4 Hz), 3.42 (1H, d, J=10.4 Hz), 2.88 (1H, m), 2.57 (1H, br), 2.18 (1H, dd, J=7.2 Hz, 14.4 Hz), 1.68-1.81 (2H, m), 1.45-1.68 (6H, m), 1.24 (3H, d, J=7.2 Hz), 1.22 (1H, m), 0.83 (9H, s), 0.02 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 122.90, 84.72, 76.75, 73.56, 67.14, 66.53, 62.87, 40.94, 38.18, 33.58, 29.91, 26.36, 26.04, 22.60, 22.48 (3C), 18.478, 18.43, 5.11, 5.16.

(32) Compound T (2.30 g, 5.78 mmol, 1 eq) was dissolved in CH.sub.2Cl.sub.2 (12 ml). TEA (1.6 ml, 12 mmol, 2.0 eq) was added followed by DMAP (71 mg, 0.58 mmol, 0.10 eq). The mixture was cooled to 0 C., and pivaloyl chloride (0.747 ml, 6.07 mmol, 1.05 eq) was added. The mixture was allowed to warm to 0 C., and stirring was continued at 20-22 C. for an additional 2 h. The reaction mixture was diluted with MTBE (23 ml), sequentially washed with: 1) 20 wt % citric acid (aqueous solution, 12 g, 12 mmol, 2.1 eq) and 2) saturated NaHCO.sub.3 (aqueous solution, 4.6 g, 5.5 mmol, 0.95 eq), and concentrated to give crude product as pale yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 40M (heptane-MTBE 7:3 v/v) to give Compound E as pale yellow oil (2.79 g, 5.04 mmol, 87% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 4.22 (1H, m), 4.04 (1H, d, J=6.4 Hz), 4.03 (1H, d, J=6.4 Hz), 4.93 (1H, dd, J=3.2 Hz, 6.4 Hz), 3.85 (1H, m), 3.50 (1H, d, J=10.4 Hz), 3.45 (1H, d, J=10.4 Hz), 2.92 (1H, m), 2.21 (1H, dd, J=8.4 Hz, 13.6 Hz), 1.48-1.85 (7H, m), 1.43 (1H, m), 1.29 (3H, d, J=7.6 Hz), 1.25 (1H, m), 1.17 (9H, s), 0.87 (9H, s), 0.02 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 178.78, 122.96, 84.83, 76.25, 73.45, 67.11, 66.53, 64.43, 41.00, 38.94, 37.89, 32.98, 27.42 (3C), 26.47, 26.06 (3C), 25.60, 22.60, 22.52, 18.51, 18.48, 5.09, 5.15.

(33) Compound G

(34) ##STR00032##

(35) Zinc dust (876 mg, 13.4 mmol, 10.0 eq) was suspended in THF (3.9 ml). MsOH (0.0087 ml, 0.13 mmol, 0.10 eq) was added, and the mixture was heated at reflux for 20 min. A mixture of Compound E (0.645 g, 1.34 mmol, 1 eq) and benzyl bromoacetate (0.315 ml, 2.01 mmol, 1.50 eq) in THF (2.6 ml+1.3 ml) was added under reflux. After 2 h, benzyl bromoacetate (0.10 ml, 0.67 mmol, 0.50 eq) was added, and heating was continued for an additional 3 h (total 5 h). After cooling down, the reaction mixture was diluted with MTBE (10 ml) and cooled to 5 C. 20 wt % citric acid (aqueous solution, 3.2 g, 3.4 mmol, 2.5 eq) was added, and vigorous stirring was continued at 5-10 C. for 10 min. The whole mixture was filtered through a pad of Celite (1.3 g). The organic layer was separated and set aside. The aqueous layer was extracted with MTBE (10 ml). All organic layers were combined, sequentially washed with: 1) saturated NaHCO.sub.3 (aqueous solution, 3.2 g) and 2) 20 wt % NaCl (aqueous solution, 3.2 g), and concentrated to give crude product as yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 3:1 & 3:2 v/v) to give Compound G as pale yellow oil (0.627 g, 0.992 mmol, 74% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.95 (1H, br), 7.24-7.37 (5H, m), 5.11 (1H, d, J=12.8 Hz), 5.07 (1H, d, J=12.8 Hz), 4.58 (1H, s), 4.10 (1H, m), 4.02 (2H, m), 3.78 (1H, dd, J=5.6 Hz, 7.2 Hz), 3.56 (1H, m), 3.54 (1H, d, J=10.4 Hz), 3.46 (1H, d, J=10.4 Hz), 2.46 (1H, m), 2.15 (1H, dd, J=8.8 Hz, 14.0 Hz), 1.35-1.82 (10H, m), 1.18 (1H, m), 1.17 (9H, s), 1.10 (3H, d, J=6.8 Hz), 0.88 (9H, s), 0.04 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 178.77, 170.63, 168.91, 137.49, 128.66 (2C), 127.99 (2C), 127.19, 84.27, 81.26, 75.91, 73.63, 67.52, 67.17, 64.71, 64.44, 42.75, 38.94, 37.03, 35.46, 33.22, 27.43 (3C), 26.08, 26.01 (3C), 25.56, 23.50, 20.06, 18.51, 5.09 (2C).

(36) Compound L

(37) ##STR00033##

(38) Compound G (0.596 g, 0.943 mmol, 1 eq) was dissolved in THF (3.0 ml)-water (1.0 ml) and cooled to 10 C. AcOH (2.0 ml, 35 mmol, 37 eq) was added, and the mixture was allowed to warm to room temperature. After 10 h, the reaction mixture was poured into a pre-chilled (0 C.) mixture of NaHCO.sub.3 (4.8 g, 57 mmol, 60 eq), water (6 ml), and MTBE (20 ml). The organic layer was separated, washed with water (6 ml), and concentrated to give crude product. The crude was azeotroped with toluene (20 ml) and purified by Biotage (Uppsala, Sweden) 25 M (heptane-EtOAc 9:1 v/v) to give Compound U:

(39) ##STR00034##
(0.493 g, 0.779 mmol, 82% yield) as colorless oil.

(40) An inert flask was charged with 10 wt % PdC(wet-type, 15 mg, 0.014 mmol, 0.050 eq). A solution of Compound U (0.182 g, 0.288 mmol, 1 eq) in EtOAc (3.6 ml) was added under N.sub.2. The internal atmosphere was replaced with H.sub.2, and stirring was continued at room temperature for 2 h. The mixture was filtered through a pad of Celite (1.0 g). The reactor and the filter cake were rinsed with EtOAc (3.6 ml). The filtrate was concentrated to give crude keto-acid Compound J as colorless film. A portion (10%) of crude Compound J was retained for analytical and stability testing. The remaining portion (90%) of Compound J was dissolved in toluene (3.0 ml). The mixture was heated at 95 C. for 15 min and then concentrated to give crude product as pale yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-EtOAc 95:5 v/v) to give Compound L (110 mg, 0.220 mmol, 85% adjusted yield) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 4.08 (1H, m), 4.00 (1H, d, J=6.8 Hz), 3.98 (1H, d, J=6.8 Hz), 3.81 (1H, t, J=5.6 Hz), 3.49 (1H, m), 3.44 (1H, d, J=10.4 Hz), 3.39 (1H, d, J=10.4 Hz), 2.73 (1H, m), 2.09 (3H, s), 1.99 (1H, dd, J=8.8 Hz, 14.0 Hz), 1.32-1.75 (10H, m), 1.16 (1H, m), 1.13 (9H, s), 1.03 (3H, d, J=7.2 Hz), 0.84 (9H, s), 0.07 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 212.79, 178.68, 84.49, 76.05, 73.52, 67.30, 66.67, 64.38, 43.45, 39.79, 39, 37.22, 32.98, 28.75, 27.37 (3C), 26.91, 26.04 (3C), 25.53, 22.85, 18.47, 17.26, 5.15, 5.20.

(41) Compound W

(42) ##STR00035##

(43) Compound L (109 mg, 0.218 mmol, 1 eq) was dissolved in THF (1.1 ml), and PhNTf.sub.2 (117 mg, 0.328 mmol, 1.50 eq) was added. Upon complete dissolution of PhNTf.sub.2, the mixture was cooled to 30 C. 0.5 M KHMDS (solution in toluene, 0.590 ml, 0.295 mmol, 1.35 eq) was added, while maintaining T-internal <25 C. Upon complete addition, stirring was continued at 25 C. for 1 h. 20 wt % NH.sub.4Cl (aqueous solution, 0.33 g, 12 mmol, 5.6 eq) was added while maintaining T-internal <20 C., and the resultant mixture was allowed to warm to 0 C. The mixture was diluted with water (0.33 g) and MTBE (2.2 ml) and then further stirred for 5 min. The organic layer was separated, washed with saturated NaHCO.sub.3 (aqueous solution, 0.54 g), and concentrated to give crude Compound V:

(44) ##STR00036##

(45) Compound V was dissolved in MeOH (1.0 ml) and treated with 6 M HCl (solution in 2-propanol, 0.25 ml, 2 mmol, 7 eq) at 20 C. After 1 h, the reaction mixture was cooled to 0 C., neutralized with saturated NaHCO.sub.3 (1.6 g) and extracted with MTBE (6 ml). The organic layer was separated, washed with 20 wt % NaCl (0.54 g), and concentrated to give crude product as pale yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 1:1 & 3:7 v/v) to give Compound W (94.1 mg, 0.182 mmol, 83% yield) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 5.09 (1H, d, J=3.6 Hz), 4.87 (1H, d, J=3.6 Hz), 4.12 (1H, m), 4.03 (1H, m), 3.84 (1H, dd, J=6.4 Hz, 8.8 Hz), 3.59 (1H, m), 3.49 (1H, d, J=11.2 Hz), 3.45 (1H, d, J=11.2 Hz), 2.68 (1H, m), 2.19 (1H, dd, J=8.8 Hz, 14.0 Hz), 2.13 (1H, br), 1.87 (1H, m), 1.40-1.75 (8H, m), 1.35 (1H, dd, J=5.6 Hz, 14.0 Hz), 1.20 (1H, m), 1.16 (9H, s), 1.13 (3H, d, J=6.8 Hz); and .sup.13C NMR (100 MHz, CDCl.sub.3): 178.75, 160.06, 120.20, 103.03, 83.76, 75.16, 73.41, 68.59, 67.83, 64.25, 40.08, 38.94, 35.47, 35.21, 33.36, 28.05, 27.39 (3C), 25.51, 24.55, 18.90.

(46) Compound O

(47) ##STR00037##

(48) Compound W (90.0 mg, 0.174 mmol, 1 eq) was dissolved in CH.sub.2Cl.sub.2 and cooled to 10 C. Pyridine (0.042 ml, 0.52 mmol, 3.0 eq) was added, followed by Tf.sub.2O (0.044 ml, 0.26 mmol, 1.5 eq) (T-internal <3 C.). After stirring at 5 to 0 C. for 1 h, DMF (0.45 ml) was added, followed by NaI (78 mg, 0.52 mmol, 3.0 eq). Stirring was continued at 20-22 C. for 3 h, and then the reaction mixture was poured into a pre-chilled (0 C.) mixture of MTBE (2.0 ml) and water (2.0 ml). The organic layer was separated and set aside. The aqueous layer was extracted with MTBE (2.0 ml). All organic layers were combined, washed with a mixture of water (0.4 ml) and 10 wt % Na.sub.2SO.sub.3 (0.9 g), and concentrate to give crude product as yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 85:15 v/v) to give Compound O (95.6 mg, 0.153 mmol, 87% yield from Compound W) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 5.08 (1H, d, J=3.6 Hz), 5.01 (1H, d, J=3.6 Hz), 4.18 (1H, m), 4.05 (2H, m), 3.74 (1H, dd, J=6.4 Hz, 9.2 Hz), 3.53 (1H, m), 3.44 (1H, dd, J=1.2 Hz, 10.0 Hz), 3.37 (1H, d, J=10.0 Hz), 2.84 (1H, m), 2.32 (1H, dd, J=8.8 Hz, 14.0 Hz), 1.85 (1H, m), 1.44-1.76 (9H, m), 1.22 (1H, m), 1.17 (9H, s), 1.13 (3H, d, J=6.8 Hz); and .sup.13C NMR (100 MHz, CDCl.sub.3): 178.75, 159.70, 120.20, 103.21, 81.42, 76.18, 75.51, 68.06, 64.18, 39.71, 38.96, 37.69, 35.43, 33.40, 27.94, 27.42 (3C), 25.51, 25.10, 20.10, 18.72.

(49) Compound P

(50) ##STR00038##

(51) A solution of ER-807363:

(52) ##STR00039##
(ER-807363) (4.10 g, 13.8 mmol, 3.55 eq; WO 2005/118565) in THF (34.2 ml) was purged with N.sub.2 for 1 h, and CrCl.sub.2 (1.70 g, 13.8 mmol, 3.55 eq) was added under N.sub.2. The mixture was heated to 35 C., and TEA (1.93 ml, 13.8 mmol, 3.55 eq) was added while maintaining T-internal <38 C. The mixture was heated at 30-35 C. for 1 h and cooled to 0 C. NiCl.sub.2 (75.7 mg, 0.15 eq) was added, and the mixture was purged with N.sub.2 for 3 min. A previously degassed mixture of Compound 0 (2.44 g, 3.89 mmol, 1 eq), and ER-806067:

(53) ##STR00040##
(ER-806067) (2.57 g, 4.28 mmol, 1.10 eq; WO 2005/118565) in THF (17 ml) was added. The reaction was allowed to warm to 22 C. over 30 min, and stirring was continued at 22-24 C. for 20 h. The reaction mixture was cooled to 0 C. and diluted with heptane (70 ml). A solution of ethylenediamine (2.1 ml, 31 mmol, 8.0 eq) in water (12 ml) was added while maintaining T-internal <5 C. The resultant mixture was vigorously stirred at 0 C. for 1 h and filtered through a pad of Celite (2.4 g, rinsed with 12 ml heptane). The organic layer was separated, washed with water (12 ml), and concentrated to give a green solid-oil, which was suspended in heptane (20 ml), filtered for removal of ER-807363, and re-concentrated to give crude product. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 2:1 & 1:1) to give Compound P (2.64 g, 2.44 mmol, 62% yield; C27-dr 67:1) as pale yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (2H, m), 7.64 (1H, m), 7.57 (2H, m), 5.17 (1H, s), 4.84 (1H, s), 4.12 (2H, m), 4.00 (2H, m), 3.91 (1H, m), 3.72 (4H, m), 3.53 (1H, dd, J=5.6 Hz, 10.0 Hz), 3.30-3.50 (4H, m), 3.35 (3H, s), 3.06 (2H, m), 2.55 (1H, m), 2.34 (1H, dd, J=8.8 Hz, 13.6 Hz), 2.28 (1H, m), 1.97 (1H, m), 1.88 (1H, m), 1.40-1.83 (13H, m), 1.14 (9H, s), 1.03 (3H, d, J=6.8 Hz), 0.85 (18H, s), 0.05 (6H, s), 0.01 (6H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 178.71, 156.78, 139.72, 134.26, 129.74 (2C), 128.06 (2C), 107.98, 85.78, 83.71, 81.19, 79.09, 76.36, 75.43, 73.77, 71.33, 68.86, 67.95, 64.22, 58.35, 57.65, 44.46, 44.31, 41.51, 38.92, 37.39, 33.60, 33.40, 32.31, 28.30, 27.43, 27.19, 26.20 (6C), 26.15 (3C), 25.50, 25.20, 22.65, 20.84, 18.58, 18.37, 3.89, 4.49, 5.10 (2C).
Compound AF

(54) ##STR00041##

(55) Compound P (620 mg, 0.574 mmol, 1 eq) was dissolved in pyridine (1.2 ml, 15 mmol, 27 eq). Ac.sub.2O (0.31 ml, 3.3 mmol, 5.7 eq) was added, followed by DMAP (7.0 mg, 0.057 mmol, 0.10 eq). After stirring at 20-23 C. for 3 h, the reaction mixture was diluted with toluene (12 ml) and concentrated. The same operation was repeated with toluene (12 ml2) to give crude product. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 7:3 v/v) to give Compound AF (541 mg, 0.482 mmol, 84% yield) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.93 (2H, m), 7.66 (1H, m), 7.58 (2H, m), 5.22 (1H, dd, J=3.2 Hz, 8.0 Hz), 4.98 (1H, s), 4.90 (1H, s), 4.15 (1H, m), 4.12 (2H, m), 3.82 (2H, m), 3.73 (2H, m), 3.44-3.57 (4H, m), 3.44 (1H, d, J=10.4 Hz), 3.38 (1H, d, J=10.4 Hz), 3.37 (3H, s), 3.12 (1H, dd, J=4.0 Hz, 14.0 Hz), 2.96 (1H, dd, J=10.4 Hz, 14.0 Hz), 2.63 (1H, m), 2.46 (1H, dd, J=8.8 Hz, 13.6 Hz), 2.37 (1H, dd, J=6.8 Hz, 13.6 Hz), 2.11 (1H, m), 2.04 (3H, s), 1.92 (2H, m), 1.45-1.85 (12H, m), 1.16 (9H, s), 1.01 (3H, d, J=6.8 Hz), 0.85 (18H, s), 0.06 (6H, s), 0.02 (6H, s); .sup.13C NMR (100 MHz, CDCl.sub.3): 178.74, 170.37, 152.99, 139.98, 134.14, 129.69 (2C), 128.08 (2C), 110.14, 85.58, 81.24, 81.07, 78.42, 76.39, 75.54, 73.52, 71.47, 68.96, 68.01, 64.27, 57.97, 57.56, 43.88, 43.82, 39.94, 38.94, 37.83, 33.54, 33.40, 32.72, 28.13, 27.43 (3C), 26.21 (3C), 26.17 (3C), 25.51, 25.03, 22.21, 21.56, 20.29, 18.59, 18.38, 3.87, 4.48, 5.09 (2C).

(56) Compound AE

(57) ##STR00042##

(58) Zinc powder (1.54 g, 23.6 mmol, 50 eq) was suspended in water (1.1 ml) and cooled to 0 C. AcOH (0.40 ml, 7.1 mmol, 15 eq) was added at 0 C. A solution of Compound AF (530 mg, 0.473 mmol, 1 eq) in THF (2.7 ml) was added at 0 C., and the mixture was allowed to warm to 20 C. After 3 h, the reaction mixture was filtered for removal of zinc powder. The reactor was rinsed with a mixture of THF (1.1 ml) and water (1.1 ml). The filtrate was diluted with MTBE (10.6 ml), sequentially washed with: 1) 20 wt % Rochelle salt (aqueous solution, 2.7 g, 4.0 eq), 2) saturated NaHCO.sub.3 (6.0 g), and 3) 20 wt % NaCl (aqueous solution, 2.6 g), and concentrated to give crude product as colorless oil. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 1:1 v/v) to give Compound AE (393 mg, 0.394 mmol, 83% yield) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.93 (2H, m), 7.66 (1H, m), 7.58 (2H, m), 5.23 (1H, t, J=6.4 Hz), 5.05 (1H, s), 4.95 (1H, d, J=1.6 Hz), 4.88 (1H, s), 4.83 (1H, d, J=1.6 Hz), 4.33 (1H, br), 4.02 (3H, m), 3.83 (2H, m), 3.76 (1H, m), 3.60 (1H, m), 3.54 (1H, dd, J=5.6 Hz, 10.4 Hz), 3.47 (2H, m), 3.37 (3H, s), 3.15 (1H, dd, J=4.0 Hz, 14.0 Hz), 2.95 (1H, dd, J=10.0 Hz, 14.0 Hz), 2.83 (1H, d, J=5.2 Hz), 2.65 (2H, m), 2.40 (1H, m), 2.23 (1H, m), 2.03 (3H, s), 1.96-2.03 (2H, m), 1.81 (1H, m), 1.67-1.80 (3H, m), 1.40-1.67 (7H, m), 1.17 (9H, s), 1.01 (3H, d, J=6.8 Hz), 0.86 (18H, s), 0.06 (6H, s), 0.03 (6H, s); .sup.13C NMR (100 MHz, CDCl.sub.3): 178.80, 170.77, 153.18, 151.49, 139.77, 134.16, 129.67 (2C), 128.16 (2C), 109.77, 105.27, 85.84, 80.92, 80.15, 78.57, 76.97, 74.59, 71.51, 68.80, 68.05, 64.43, 58.01, 57.56, 45.21, 43.49, 39.78, 38.94, 34.58, 33.55, 32.28, 31.77, 31.74, 27.42 (3C), 26.21 (3C), 26.17 (3C), 25.49, 22.78, 21.51, 18.60, 18.39, 3.87, 4.51, 5.11 (2C).

(59) ER-804028

(60) ##STR00043##

(61) Compound AE (280 mg, 0.281 mmol, 1 eq) was dissolved in CH.sub.2Cl.sub.2 and cooled to 0 C. Pyridine (0.045 ml, 0.56 mmol, 2.0 eq) was added followed by Ms.sub.2O (58.8 mg, 0.338 mmol, 1.20 eq). The reaction was allowed to warm to room temperature, and stirring was continued for an additional 1 h. The reaction mixture was cooled to 0 C., diluted with MTBE (5.6 ml), washed with saturated NaHCO.sub.3 (0.84 g), and concentrated to give crude product as colorless film. The crude was azeotropically dried with heptane (3 ml2) and re-dissolved in THF (7.0 ml). The mixture was cooled to 0 C. and treated with 25 wt % NaOMe (0.13 ml). After 10 min, the reaction was allowed to warm to room temperature, and stirring was continued for an additional 30 min. The mixture was treated with additional 25 wt % NaOMe (0.045 ml), and stirring was continued for an additional 20 min. The reaction mixture was diluted with heptane (7.0 ml) and washed with water (1.4 ml). The organic layer was separated, sequentially washed with: 1) 20 wt % NH.sub.4Cl (0.84 g) and 2) 20 wt % NaCl (3 g), and concentrated to give crude product as brownish oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 2:3 v/v) to give ER-804028 (209 mg, 0.245 mmol, 87%) as pale yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.89 (2H, m), 7.64 (1H, m), 7.56 (2H, m), 4.85 (1H, d, J=1.6 Hz), 4.80 (1H, s), 4.72 (1H, s), 4.61 (1H, d, J=1.6 Hz), 4.23 (1H, br), 3.91 (1H, m), 3.79 (1H, m), 3.76 (2H, m), 3.63 (1H, m), 3.50-3.60 (4H, m), 3.43 (1H, dd, J=5.6 Hz, 10.0 Hz), 3.38 (3H, s), 3.32 (1H, m), 2.98 (2H, m), 2.61 (1H, br), 2.56 (1H, m), 2.50 (1H, m), 2.08-2.22 (3H, m), 1.96 (1H, m), 1.84 (1H, m), 1.78 (1H, m), 1.70 (1H, m), 1.42-1.63 (6H, m), 1.28-1.42 (2H, m), 1.01 (3H, d, J=6.8 Hz), 0.84 (18H, s), 0.05 (3H, s), 0.04 (3H, s), 0.00 (3H, s), 0.01 (3H, s); and .sup.13C NMR (100 MHz, CDCl.sub.3): 150.34, 150.75, 139.91, 134.18, 129.73 (2C), 128.14 (2C), 105.10, 85.97, 80.92, 79.72, 78.50, 77.45, 77.09, 75.53, 71.59, 68.04, 62.88, 58.27, 57.73, 43.51, 42.82, 39.16, 37.68, 35.69, 33.31, 32.41, 31.89, 31.48, 29.79, 26.21 (3C), 26.17 (3C), 18.58, 18.38, 18.13, 3.85, 4.71, 5.12 (2C).

(62) Alternate Route to Compound W

(63) Compound F

(64) ##STR00044##

(65) Compound D (0.657 g, 2.11 mmol, 1 eq) was dissolved in DMF (1.3 ml) and cooled to 0 C. Imidazole (0.287 g, 4.22 mmol, 2.00 eq) was added, followed by TBDPSCl (0.576 ml, 2.22 mmol, 1.05 eq). The mixture was stirred at 0-5 C. for 1 h and allowed to warm to room temperature. After stirring overnight (16 h), the reaction mixture was diluted with water (5.2 ml) and extracted with MTBE (5.2 ml). The organic layer was separated and set aside. The aqueous layer was extracted with MTBE (5.2 ml). All organic layers were combined, washed with water (2.6 ml), and concentrated to give crude Compound X:

(66) ##STR00045##
as pale yellow oil. Compound X (2.11 mmol assumed, 1 eq) was dissolved in toluene (4.6 ml) and cooled to 5 C. 2.0 M LiBH.sub.4 (solution in THF, 2.43 ml, 4.85 mmol, 2.30 eq) was added while maintaining T-internal <0 C. A mixture of MeOH (0.196 ml, 4.85 mmol, 2.30 eq) and toluene (0.80 ml) was added at <0 C., and then reaction was allowed to warm to 20-22 C. After 22 h, the reaction mixture was carefully/slowly poured into a pre-chilled (0 C.) mixture of 20 wt % citric acid (aqueous solution, 6.0 g, 6.2 mmol, 3.0 eq) and MTBE (20 ml) while maintaining T-internal <10 C. The organic layer was separated, sequentially washed with: 1) saturated NaHCO.sub.3 (3.0 g) and 2) water (3.0 g), and concentrated to give crude Compound Y:

(67) ##STR00046##
Compound Y (2.11 mmol assumed, 1 eq) was dissolved in CH.sub.2Cl.sub.2 (2.5 ml) at room temperature. TEA (0.441 ml, 3.16 mmol, 1.50 eq) was added followed by DMAP (26 mg, 0.21 mmol, 0.10 eq). The mixture was cooled to 0 C. and treated with pivaloyl chloride (0.272 ml, 2.22 mmol, 1.05 eq). The reaction was allowed to warm to room temperature and stirring was continued overnight (16 h). The reaction mixture was diluted with MTBE (10 ml), sequentially washed with: 1) 20 wt % citric acid (aqueous solution, 3.0 g, 1.5 eq) and 2) saturated NaHCO.sub.3 (aqueous solution, 3.0 g), and concentrated to give crude product as orange-colored oil. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 7:3 v/v) to give Compound F (0.920 g, 1.52 mmol, 72% overall yield) as colorless oil.
Compound M

(68) ##STR00047##

(69) Zinc dust (982 mg, 15.0 mmol, 10.0 eq) was suspended in THF (1.8 ml), and MsOH (0.0097 ml, 0.15 mmol, 0.10 eq) was added. The resultant mixture was heated at reflux for 30 min and then cooled to 20 C. A solution of Compound F (910 mg, 1.50 mmol, 1 eq) and t-butyl bromoacetate (0.222 ml, 15.0 mmol, 1.00 eq) in THF (4.6 ml) was added, and the mixture was heated at reflux. After 2 h, t-butyl bromoacetate (0.222 ml, 1.50 mmol, 1.00 eq) was added, and heating was continued for 4 h. t-Butyl bromoacetate (0.111 ml, 1.50 mmol, 0.50 eq) was added, and heating was continued for an additional 6 h. After cooling down, the reaction mixture was diluted with MTBE (14 ml) and cooled to 0 C. 20 wt % citric acid (aqueous solution, 7.2 g, 7.5 mmol, 5.0 eq) was added at <10 C., and vigorous stirring was continued for 10 min. The whole biphasic mixture was filtered for removal of Zn. The reactor and Zn were rinsed with MTBE (9 ml). The organic layer was separated, sequentially washed with: 1) saturated NaHCO.sub.3 (aqueous solution, 3.8 g) and 2) 20 wt % NaCl (2.7 g), and concentrated to give crude Compound I as pale yellow oil. Compound I (1.50 mmol assumed, 1 eq) was suspended in THF (2.5 ml)-water (1.5 ml) and treated with AcOH (4.5 ml, 7.9 mmol) at room temperature for 2 h. The reaction mixture was diluted with toluene (20 ml) and concentrated. The same operation was repeated with toluene (20 ml2) to give crude Compound Z:

(70) ##STR00048##
The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 4:1 v/v) to give Compound Z (1.062 g, 1.47 mmol, 97% yield) as colorless oil.

(71) Compound Z (1.00 g, 1.38 mmol, 1 eq) was dissolved in CH.sub.2Cl.sub.2 (9.0 ml) and treated with TFA (1.00 ml, 13.0 mmol) at room temperature. After 4 h, the reaction mixture was diluted with toluene (15 ml) and concentrated. The same operation was repeated with toluene (15 ml2) to give crude Compound K. Compound K was dissolved in toluene (10 ml), heated at 100 C. for 30 min, and concentrated to give crude Compound M. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 7:3 v/v) to give Compound M (775 mg, 1.24 mmol, 90% yield) as colorless oil.

(72) Compound W

(73) ##STR00049##

(74) Compound M (745 mg, 1.20 mmol, 1 eq) was dissolved in THF (4.5 ml) and PhNTf.sub.2 (641 mg, 1.79 mmol, 1.50 eq) was added at 20 C. Upon complete dissolution of PhNTf.sub.2, the mixture was cooled to 23 C. 0.5 M KHMDS (solution in toluene, 2.63 ml, 1.32 mmol, 1.10 eq) was added while maintaining T-internal <18 C., and the mixture was stirred at 18 to 20 C. for 1 h. Under vigorous stirring, 20 wt % NH.sub.4Cl (aqueous solution, 0.32 g) was added while maintaining T-internal <10 C., and then the mixture was allowed to warm to 0 C. The mixture was diluted with MTBE (7.5 ml) and water (0.74 ml), and vigorous stirring was continued for 5 min. The organic layer was separated, washed with water (1.5 ml), and concentrated to give crude Compound AA:

(75) ##STR00050##
as yellow solid-oil. Compound AA was dissolved in CH.sub.3CN (9.0 ml) and treated with 49 wt % HF (aqueous solution, 3.0 g) at room temperature for 20 h. The reaction mixture was carefully/slowly poured into a pre-chilled (0 C.) mixture of MTBE (40 ml), water (7.5 ml), and NaHCO.sub.3 (8.5 g) while maintaining T-internal <10 C. The organic layer was separated and set aside. The aqueous layer was extracted with MTBE (7.5 ml). All organic layers were combined, washed with 20 wt % NaCl (aqueous solution, 3.7 g), and concentrated to give crude Compound W as yellow solid-oil. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 1:1 & 2:3 v/v) to give Compound W (522 mg, 1.01 mmol, 84% yield) as pale yellow oil.
Alternate Route to Compound L
Compound H

(76) ##STR00051##

(77) Zinc (1.06 g, 16.2 mmol, 10 eq) was suspended in THF (2.3 ml). MsOH (0.010 ml, 0.02 mmol, 0.1 eq) was added at room temperature, and the resultant slurry was heated at reflux for 30 min. After cooling down, a mixture of Compound X (780 mg, 1.62 mmol, 1 eq) and benzhydryl bromoacetate (0.74 g, 2.4 mmol, 1.5 eq; Kume et al., Tetrahedron, 1997, 53, 1635) in THF (3.9 ml) was added, and the reaction was heated to reflux. After heating for 3 h, benzhydryl bromoacetate (0.74 g, 2.4 mmol, 1.5 eq) was added, and heating was continued for an additional 7 h. After cooling down, the mixture was diluted with MTBE (16 ml) and filtered through a pad of Celite (1.6 g). The filtrate was sequentially washed with: 1) 20 wt % citric acid (aqueous solution, 3.9 g), 2) 10 wt % NaHCO.sub.3 (aqueous solution, 3.9 g), and 3) 20 wt % NaCl (aqueous solution, 2.3 g), and concentrated to give crude product as yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 40M (heptane-MTBE 1:1 v/v) to give Compound H as pale yellow oil (770 mg, 1.08 mmol, 67% yield).

(78) Compound AB

(79) ##STR00052##

(80) Compound H (770 mg, 1.08 mmol, 1 eq) was dissolved in THF (0.77 ml) and cooled to 0 C. Water (0.38 ml) was added followed by AcOH (1.54 ml). The mixture was allowed to warm to room temperature, and stirring was continued for 8 h. The reaction mixture was diluted with toluene (15 ml) and concentrated. The residue was further azeotroped with toluene (15 ml2) and purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 2:1 v/v) to give Compound AB (716 mg, 1.01 mmol, 93% yield) as pale yellow oil.

(81) Compound L

(82) ##STR00053##

(83) Compound AB (716 mg, 1.01 mmol, 1 eq) was hydrogenated with 10 wt % PdC (wet-type, 0.11 g, 0.050 mmol, 0.05 eq), H.sub.2 (balloon), and EtOAc (7.2 ml) for 2 h. The reaction mixture was filtered, concentrated, and re-dissolved in toluene (7.2 ml). The mixture was heated at 100 C. for 15 min. After cooling down, the mixture was concentrated and purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 2:1 v/v) to give Compound L (476 mg, 0.954 mmol, 95% yield) as colorless oil.

(84) Compound AJ

(85) ##STR00054##

(86) Compound AI was synthesized from ER-806730 (WO 2005/118565, Example 2) by iodo-etherification with N-iodosuccinimide in acetonitrile.

(87) Compound AI (2.95 g, 5.44 mmol, 1 eq) was dissolved in pyridine (3.0 ml, 36 mmol, 6.7 eq) and treated with phthalic anhydride (0.846 g, 5.71 mol, 1.05 eq) at room temperature for 18 h. The reaction mixture was diluted with MTBE (200 ml), sequentially washed with: 1) 20 wt % citric acid (35 g); 2) 20 wt % citric acid (35 g); 3) water (9 g); and 4) water (9 g), and concentrated to give crude product as pale yellow oil. The crude was purified by Biotage (Uppsala, Sweden) 25M (heptane-MTBE 1:1 & MTBE 100%) to give Compound AJ as colorless oil (3.20 g, 4.63 mmol, 85% yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 7.83 (1H, m), 7.71 (1H, m), 7.53-7.59 (2H, m), 5.08 (1H, d, J=3.6 Hz), 5.01 (1H, d, J=3.6 Hz), 4.51 (1H, m), 4.27 (1H, m), 4.20 (1H, m), 3.87 (1H, dd, J=6.0 Hz, 9.2 Hz), 3.54 (1H, m), 3.50 (1H, d, J=10.8 Hz), 3.48 (1H, d, J=10.8 Hz), 2.84 (1H, m), 2.33 (1H, dd, J=8.8 Hz, 13.6 Hz), 1.83-1.94 (2H, m), 1.46-1.80 (8H, m), 1.22 (1H, m), 1.13 (3H, d, J=6.8 Hz).

(88) Compound AK

(89) ##STR00055##

(90) Compound P (0.050 g, 0.046 mmol, 1 eq) was dissolved in THF (0.30 mL) and treated with NaOMe (25 wt % solution in MeOH, 0.10 ml, 0.44 mmol, 9.4 eq) at room temperature for 1 h. The reaction mixture was diluted with MTBE (3.0 ml), sequentially washed with: 1) water (0.30 g); 2) water (0.30 g); and 3) 20 wt % NaCl (0.30 g), and concentrated to give crude product as colorless oil. The crude product was purified by preparative TLC (MTBE 100%) to give Compound AK as colorless film (33 mg, 0.033 mmol, 72% yield).

(91) Compounds AL and AM

(92) ##STR00056##

(93) Compound AK (0.175 g, 0.176 mmol, 1 eq) was dissolved in pyridine (0.56 ml, 6.9 mmol, 39 eq). 4-methoxybenzoly chloride (0.066 g, 0.39 mmol, 2.2 eq) was added at room temperature, and the mixture was stirred for 15 h. The reaction mixture was diluted with MTBE (7 ml) and washed with 20 wt % citric acid (7 g). The organic layer was separated and set aside. The aqueous layer was extracted with MTBE (7 ml). All organic layers were combined, sequentially washed with 20 wt % citric acid (3 g) and water (3 g), and concentrated to give crude product as pale yellow oil. The crude product was purified by Biotage (Uppsala, Sweden) 12M KP-Sil (heptane-MTBE 7:3 & 1:1) to give Compound AL (0.02 g, 0.02 mmol, 9% yield, colorless film) and Compound AM (0.14 g, 0.12 mmol, 70% yield, colorless oil). Compound AM: .sup.1H NMR (400 MHz, CDCl.sub.3) 7.95 (2H, d, J=8.8 Hz), 7.89 (2H, d, J=7.2 Hz), 7.65 (1H, m), 7.57 (2H, m), 6.87 (2H, d, J=8.8 Hz), 5.18 (1H, s), 4.85 (1H, s), 4.26 (2H, m), 4.20 (1H, m), 4.12 (1H, m), 3.92 (1H, m), 3.83 (3H, s), 3.70-3.80 (3H, m), 3.53 (1H, m), 3.40-3.50 (4H, m), 3.36 (3H, s), 3.08 (2H, m), 2.57 (1H, m), 2.38 (1H, dd, J=9.2 Hz, 14 Hz), 2.29 (1H, m), 1.98 (1H, m), 1.71-1.92 (7H, m), 1.52-1.68 (7H, m), 1.48 (1H, m), 1.18 (1H, m), 1.04 (3H, d, J=7.2 Hz), 0.86 (9H, s), 0.84 (9H, s), 0.05 (6H, s), 0.02 (3H, s), 0.01 (3H, s).

(94) Synthesis of Compound AD and Synthesis of Compound P from Compound AD

(95) Compound AD

(96) ##STR00057##

(97) Compound AD was prepared in the process of producing a mixture of Compound P with its C27 diastereomer. Compound P (50.2 mg, 0.0465 mmol, 1 eq) was dissolved in CH.sub.2Cl.sub.2 (0.50 ml). Dess-Martin periodinane (23.6 mg, 0.0556 mol, 1.2 eq) was added at room temperature. After 10 min, NaHCO.sub.3 (40 mg, 0.5 mmol) was added followed by isopropyl alcohol (0.014 ml, 0.19 mol, 4 eq), and stirring was continued for an additional 1 h. The mixture was diluted with MTBE (2 ml), washed with water (0.5 ml), and concentrated to give crude product as a colorless oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 7:3 & 1:1) to give Compound AD (42 mg, 0.039 mmol, 84% yield) as a colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.92 (2H, m), 7.63 (1H, m), 7.56 (2H, m), 5.96 (1H, s), 5.74 (1H, s), 4.15 (1H, m), 4.04 (2H, m), 3.94 (1H, d, J=3.2 Hz), 3.89 (2H, m), 3.75 (2H, m), 3.54 (2H, m), 3.39 (3H, s), 3.44 (1H, m), 3.43 (1H, d, J=10.4 Hz), 3.34 (1H, d, J=10.4 Hz), 3.19 (1H, m), 3.02 (1H, dd, J=10.8 Hz, 14 Hz), 2.98 (1H, dd, J=8.0 Hz, 17.2 Hz), 2.81 (1H, m), 2.42 (1H, m), 2.31 (1H, dd, J=8.8 Hz, 14 Hz), 1.98 (1H, m), 1.45-1.85 (12H, m), 1.17 (9H, s), 1.02 (3H, d, J=7.2 Hz), 0.87 (9H, s), 0.86 (9H, s), 0.07 (3H, s), 0.06 (3H, s), 0.03 (3H, s), 0.02 (3H, s).

(98) Compound P

(99) ##STR00058##

(100) Compound P can also be obtained from reduction of Compound AD, made by any means. Compound AD (33 mg, 0.031 mmol) was dissolved in toluene (0.50 ml) and cooled to 0 C. 2.0 M LiBH.sub.4 (solution in THF, 8 l) was added at 0 C., and stirring was continued at 0 C. for 10 min. 2.0 M LiBH.sub.4 (solution in THF, 8 l) was added, and stirring was continued for an additional 10 min. The reaction mixture was diluted with MTBE (1.0 ml), sequentially washed with 20 wt % citric acid (aqueous solution, 0.20 g) and saturated NaHCO.sub.3 (aqueous solution, 0.20 g), and concentrated to give crude product. The crude was purified by preparative TLC (heptane-MTBE 2:3) to give Compound P (24 mg, 72% yield, C27-dr 5:1).

Other Embodiments

(101) All publications, patents, and patent application publications mentioned herein are hereby incorporated by reference. Various modifications and variations of the described compounds of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant art are intended to be within the scope of the invention.