Synthesis of epothilones, intermediates thereto and analogues thereof

• US 6,965,034 B2
• Filed: 12/23/2002
• Issued: 11/15/2005
• Est. Priority Date: 12/03/1996
• Status: Expired due to Fees

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Harris, Christina, Zhang, Xiu-Guo, Meng, DongFang, Danishefsky, Samuel J., Bertino, Joseph R., Chou, Ting-Chao, Kamenecka, Ted, Bertinato, Peter, Sorensen, Erik J, Savin, Kenneth A., Su, Dai-Shi, Balog, Aaron, Kuduk, Scott
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/329,090
• Publication Number:
  US 20030208080A1
• Time in Patent Office: 1,058 Days
• Field of Search: 548/203, 549/448, 549/271
• US Class Current: 548/203
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 59/76 containing keto groups
• CPC Class Codes: C07C 69/007 Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• CPC Class Codes: C07C 69/738 Esters of keto-carboxylic acids or aldehydo-carboxylic acids
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 313/00 Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: C07F 7/1892 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof, useful in the treatment of cancer and cancer which has developed a multidrug-resistant phenotype. Also provided are intermediates useful for preparing said epothilones.

Claims

1. A process of making a desoxyepothilone comprising:

(a) reacting a desoxyepothilone precursor having the structure;

 

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2.4,6-trichlorobenzoyl chloride, to generate a desoxyepothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol-4-yl, 3-indolyl or 6-indolyl;

Y is H or linear or branched chain alkyl; and

X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol-4-yl, 3-indolyl or 6-indolyl;

wherein Y is H or linear or branched chain alkyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl; and

n is 2or 3.

2. The process of claim 1, wherein the reaction is performed in the presence of a tertiary amine selected from the group consisting of triethylamine, tri-n-propylamine, diisopropylethylamine, and diethylisopropylamine and optionally in the presence of pyridine or N,N-dimethylaminopyridine.

3. The process of claim 1, wherein in the desoxyepothilone precursor n is 3, and R″

is —

CCH₃═

CHX, wherein X is phenyl, 1,3-thiazol-4-yl, or 1,3-oxazol-4-yl.

4. The process of claim 1, wherein in the desoxyepothilone precursor R₀ is hydrogen and R′

is methyl.

5. The process of claim 1, wherein in the desoxyepothilone precursor R is hydrogen;

methyl;

ethyl;

n-propyl;

n-hexyl;

CO₂Et;

CH₂OH;

CH₂OR₃;

(CH₂)₃—

OH;

or (CH₂)₃—

OR₃,

wherein each occurrence of R₃ is independently hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl.

6. The process of claim 1, wherein in the desoxyepothilone precursor

R_A, R_B and R₃ are each independently hydrogen;

linear or branched, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

or linear or branched, substituted or unsubstituted alkoxycarbonyl.

7. The process of claim 1, wherein in the desoxyepothilone precursor

n is 3,

R″

is —

CCH₃═

CHX, wherein X is phenyl, 1,3-thiazol-4-yl, or 1,3-oxazol-4-yl,

R₀ is hydrogen and R′

is methyl;

R is hydrogen;

methyl;

ethyl;

n-propyl;

n-hexyl;

CO₂Et;

 

CH₂OH;

CH₂OR₃;

(CH₂)₃—

OH;

or (CH₂)₃—

OR₃; and

wherein R_A, R_B and R₃ are each independently hydrogen;

linear or branched, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl or linear or branched, substituted or unsubstituted alkoxycarbonyl.

8. The process of claim 7, wherein in the desoxyepothilone precursor R_A, R_B and R₃ are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

9. The process of claim 1,

wherein the step of reacting a desoxyepothilone precursor comprises macrolactonizing a desoxyepothilone precursor having the structure:

 

to generate a desoxyepothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl.

10. The process of claim 9, wherein in the desoxyepothilone precursor, R₀ is hydrogen and R′

is methyl.

11. The process of claim 9, wherein in the desoxyepothilone precursor R is hydrogen;

methyl;

ethyl;

n-propyl;

n-hexyl;

CO₂Et;

CH₂OH;

CH₂OR₃;

(CH₂)₃—

OH;

or (CH₂)₃—

OR₃,

wherein each occurrence of R₃ is hydrogen, or substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl.

30. The process of claim 1, 9, 12, 21, 23, 24, or 25, wherein the macrolactonization reagent is 2,4,6-trichlorobenzoyl chloride in the presence of a tertiary amine selected from the group consisting of triethylamine, tri-n-propylamine, diisopropylethylamine, and diethylisopropylamine and optionally reacting in the presence of pyridine or N,N-dimethylaminopyridine.

31. The process of claim 9, wherein in the desoxyepothilone precursor, R₀ is hydrogen, R′

is methyl, and R is selected from the group consisting of hydrogen or methyl.

12. A process of making a desoxyepothilone comprising:

(a) reacting a desoxyepothilone precursor having the structure;

 

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2,4,6-trichlorobenzoyl chloride, to generate a desoxyepothilone having the structure;

 

wherein R is hydrogen, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl.

13. The process of claim 12, wherein in the desoxyepothilone precursor R_A, R_B and R₃ are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

14. The process of claim 12, wherein in the desoxyepothilone precursor R is substituted or unsubstituted, linear or branched chain alkyl;

R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

15. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, fluorine, cyclic acetal, or NR₁R₂, wherein R₁ and R₂ are each independently H, phenyl, benzyl, or linear or branched chain alkyl;

R_A, R_B and R₃ are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

16. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl substituted by fluorine;

R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

17. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl substituted by hydroxy or OR₃;

R_A, R_B and R₃ are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

18. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl substituted by NR₁R₂, wherein R₁ and R₂ are both hydrogen;

R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

19. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl substituted by cyclic acetal;

R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

20. The process of claim 12, wherein in the desoxyepothilone precursor R is linear or branched chain alkyl substituted by a substituted carboxy group;

R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

21. A process of making a desoxyepothilone comprising:

reacting a desoxyepothilone precursor having the structure;

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2,4,6-trichlorobenzoyl chloride, to generate a desoxyepothilone having the structure;

wherein R is hydrogen;

methyl;

ethyl;

n-propyl;

n-hexyl;

CO₂Et;

 

CH₂OH;

CH₂OR₃;

(CH₂)₃—

OH;

or (CH₂)₃—

OR₃; and

R_A, R_B, and R₃ are each independently hydrogen;

linear or branched, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl or linear or branched, substituted or unsubstituted alkoxycarbonyl.

22. The process of claim 21, wherein in the desoxyepothilone precursor, R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

23. The process of claim 21, wherein the step of reacting the desoxyepothilone precursor comprises macrolactonizing a desoxyepothilone precursor having the structure:

to generate a desoxyepothilone having the structure;

wherein R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

24. The process of claim 21, wherein the step of reacting the desoxyepothilone precursor comprises macrolactonizing a desoxyepothilone precursor having the structure:

to generate a desoxyepothilone having the structure;

wherein R₃, R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

25. The process of claim 21, wherein the step of reacting the desoxyepothilone precursor comprises macrolactonizing a desoxyepothilone precursor having the structure:

to generate a desoxyepothilone having the structure;

wherein R_A and R_B are each independently hydrogen, t-butyldimethylsilyl, t-butyldiphenylsilyl, triethylsilyl or 2,2,2-trichloroethoxycarbonyl.

26. The process of claim 23, wherein the macrolactonization reagent is acetic anhydride.

27. The process of claim 23, wherein the macrolactonization reagent is pentafluorophenol.

28. The process of claim 23, wherein the macrolactonization reagent is 2,4-dichlorobenzoyl chloride.

29. The process of claim 23, wherein the macrolactonization reagent is 2,4,6-trichlorobenzoyl chloride.

32. A process of making an epothilone comprising:

(a) reacting an epothilone precursor having the structure;

 

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2,4,6-trichlorobenzoyl chloride, to generate an epothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol-4-yl, 3-indolyl or 6-indolyl;

Y is H or linear or branched chain alkyl; and

X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol-4-yl, 3-indolyl or 6-indolyl;

wherein Y is H or linear or branched chain alkyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl; and

n is 2or 3.

33. The process of claim 32,

wherein the step of reacting an epothilone precursor comprises macrolactonizing an epothilone precursor having the structure:

 

to generate an epothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl.

34. The process of claim 32,

wherein the step of reacting an epothilone precursor comprises macrolactonizing an epothilone precursor having the structure:

 

to generate an epothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl.

35. The process of claim 34, wherein in the epothilone precursor R is methyl.

36. The he process of claim 34, wherein in the epothilone precursor R is hydrogen.

37. A process of making a desoxyepothilone comprising:

(a) reducing a desoxyepothilone precursor having the structure;

 

to generate a desoxyepothilone precursor having the structure;

(b) hydrolyzing a desoxyepothilone precursor having the structure;

 

to generate a desoxyepothilone precursor having the structure;

(c) reacting a desoxyepothilone precursor having the structure;

 

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2,4,6-trichlorobenzoyl chloride, to generate a desoxyepothilone having the structure;

wherein R, R₀ and R′

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol-4-yl, 3-indolyl or 6-indolyl;

Y is H or linear or branched chain alkyl; and

X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol4-yl, 3-indolyl or 6-indolyl;

wherein Y is H or linear or branched chain alkyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl;

R_C is tertiary alkyl;

P is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl or triarylsilyl; and

n is 2or 3.

39. The process of claim 37 or 38, wherein R₀ is hydrogen, R′

is methyl, R is hydrogen or methyl;

n is 3, and R″

is —

CH₃—

CHX, wherein X is 1,3-thiazol4-yl or 1,3-oxazol-4-yl.

38. A process of making a desoxyepothilone comprising:

(a) reducing a desoxyepothilone precursor having the structure;

 

to generate a desoxyepothilone precursor having the structure;

(b) reducing a desoxyepothilone precursor having the structure;

 

to generate a desoxyepothilone precursor having the structure;

(c) etherifying and hydrolyzing a desoxyepothilone precursor having the structure;

 

to generate a desoxyepothilone precursor having the structure;

(d) reacting a desoxyepothilone precursor having the structure;

 

with a macrolactonization reagent, wherein the macrolactonization reagent is selected from the group consisting of acetic anhydride, pentafluorophenol, 2,4-dichlorobenzoyl chloride, and 2,4,6-trichlorobenzoyl chloride, to generate a desoxyepothilone having the structure;

wherein R, R₀ and R″

are independently H, linear or branched chain alkyl, optionally substituted by hydroxy, OR₃, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR₁R₂, N-hydroximino, or N-alkoxyimino, wherein R₁ and R₂ are independently H, phenyl, benzyl, linear or branched chain alkyl; and

R₃ is hydrogen, substituted or unsubstituted trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, or triarylsilyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-3-oxazol-4-yl, 3-indolyl or 6-indolyl;

Y is H or linear or branched chain alkyl; and

X is H, linear or branched chain alkyl, phenyl, 2-methyl-1,3-thiazol-4-yl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 2-methyl-1,3-oxazol4-yl, 3-indolyl or 6-indolyl;

wherein Y is H or linear or branched chain alkyl;

R_A is hydrogen or a linear or branched alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R_B is hydrogen, substituted or unsubstituted alkoxycarbonyl, t-butyloxycarbonyl, amyloxycarbonyl, (trialkylsilyl)alkyloxycarbonyl, (dialkylarylsilyl)alkoxycarbonyl, benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, a linear or branched acyl, or substituted or unsubstituted aroyl or benzoyl;

R_C is tertiary alkyl;

P is a linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl or triarylsilyl; and

n is 2 or 3.