Granted Patent B2

US 7,750,164 · App. 11/652,383 · Granted Jul 6, 2010

Assignee: Sloan-Kettering Institute for Cancer Research

Abstract

Claims (106)

1. A method of preparing a compound having the structure:

wherein

Z is S or O;

Y is (OR 0 ) 2 , (SR 0 ) 2 , —(O—(CH 2 ) n —O)—, —(O—(CH 2 ) n —S)— or —(S—(CH 2 ) n —S)— where R O is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;

n is 2, 3 or 4;

R 1 is hydrogen or methyl;

R is linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl; and

R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

which comprises:

cross-coupling a haloolefin having the structure:

wherein X is a halogen, with a terminal hydroborane having the structure:

wherein

R* 2 B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moiety; and

under suitable conditions to form a cross-coupled compound having the structure:

2. The method of claim 1 , wherein R is acetyl; R′ is TBS; R″ is TPS; R* 2 B is derived from 9-BBN; and Y is (OMe) 2 .

3. A method of preparing an open-chain aldehyde having the structure:

which comprises:

1) preparing a compound having the structure:

wherein

Z is S or O;

Y is (OR 0 2 , (SR 0 ) 2 , —(O—(CH 2 ) n —O—, —(O—(CH 2 ) n —S)— or —(S—(CH 2 ) n —S)— where R 0 is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl;

n is 2, 3 or 4;

R 1 is hydrogen or methyl;

R is linear or branched alkyl, alkoxyalkyl, substituted or unsubstituted aryloxyalkyl, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, linear or branched acyl, substituted or unsubstituted aroyl or benzoyl; and

R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

which comprises:

cross-coupling a haloolefin having the structure:

wherein X is a halogen,

with a terminal hydroborane having the structure:

wherein

R* 2 B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moeity; and

under suitable conditions to form a cross-coupled compound having the structure:

and

2) deprotecting the cross-coupled compound under suitable conditions to form an open-chain aldehyde having the structure:

4. The method of claim 1 , wherein Z is O.

5. The method of claim 1 , wherein Z is S.

6. The method of claim 1 , wherein R 1 is hydrogen.

7. The method of claim 1 , wherein R 1 is methyl.

8. The method of claim 4 , wherein R 1 is hydrogen.

9. The method of claim 5 , wherein R 1 is methyl.

10. A method of preparing a compound having the structure:

wherein

Z is S or O;

R 1 is hydrogen or methyl;

R′ and R″ are each independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

comprising the steps of:

(a) cyclizing an open-chain aldehyde having the structure:

under suitable conditions to form a diastereomeric mixture of a protected cyclic alcohol having the structure:

said mixture comprising an α- and a β-alcohol component; and

(b) optionally isolating and oxidizing the β-alcohol formed in step (a) under suitable conditions to form a ketone and thereafter reducing the ketone under suitable conditions to form a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α-alcohol.

11. The method of claim 10 wherein R′ is TBS and R″ is TPS.

12. The method of claim 10 further comprising the step of treating the protected cyclic alcohol formed in step (a) or (b) with a deprotecting agent under suitable conditions to form a cyclic diol having the structure:

13. The method of claim 10 , wherein Z is O.

14. The method of claim 10 , wherein Z is S.

15. The method of claim 10 , wherein R 1 is hydrogen.

16. The method of claim 10 , wherein R 1 is methyl.

17. The method of claim 13 , wherein R 1 is hydrogen.

18. The method of claim 14 , wherein R 1 is methyl.

19. A method of preparing an epothilone having the structure:

wherein

Z is S or O; and

R 1 is hydrogen or methyl;

which comprises:

(a) providing a desoxyepothilone having the structure:

and

(b) epoxidizing the desoxyepothilone formed in step (a) under suitable conditions to form the epothilone.

20. The method of claim 19 , further comprising the steps of:

(i) monoprotecting the cyclic diol having the structure:

wherein R′ is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

under suitable conditions to form a cyclic alcohol having the structure:

wherein R″ is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

(ii) oxidizing the cyclic alcohol under suitable conditions to form a ketone having the structure:

and

(iii) deprotecting the ketone under suitable conditions to form a desoxyepothilone having the structure:

21. The method of claim 19 , wherein Z is O.

22. The method of claim 19 , wherein Z is S.

23. The method of claim 19 , wherein R 1 is hydrogen.

24. The method of claim 19 , wherein R 1 is methyl.

25. The method of claim 21 , wherein R 1 is hydrogen.

26. The method of claim 22 , wherein R 1 is methyl.

27. A method comprising the steps of:

(a) cross-coupling a haloolefin having the structure:

wherein

Z is S or O;

R 1 is hydrogen or methyl; and

X is a halogen;

with a terminal hydroborane having the structure:

wherein

R′ and R″ are independently hydrogen, a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

R* 2 B is a linear, branched or cyclic alkyl or substituted or unsubstituted aryl or benzyl boranyl moiety;

Y is (OR 0 ) 2 , (SR 0 ) 2 , —(O—(CH 2 ) n -O)—, —(O—(CH 2 ) n -S)— or -(S—(CH 2 ) n -S)— where R 0 is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl; and

n is 2, 3 or 4;

under suitable conditions to form a cross-coupled compound having the structure:

(b) deprotecting the cross-coupled compound formed in step (a) under suitable conditions to form an open-chain aldehyde having the structure:

(c) cyclizing the open-chain aldehyde under suitable conditions to form a-diastereomeric mixture of a protected cyclic alcohol having the structure:

said mixture comprising an α- and a β-alcohol component;

(d) optionally isolating and oxidizing the β-alcohol formed in step (c) under suitable conditions to form a ketone and thereafter reducing the ketone under suitable conditions to form a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α-alcohol;

(e) treating the protected cyclic alcohol formed in step (c) or (d) with a deprotecting agent under suitable conditions to form a cyclic diol having the structure:

(f) monoprotecting the cyclic diol under suitable conditions to form a cyclic alcohol having the structure:

wherein R is a linear or branched alkyl, substituted or unsubstituted aryl or benzyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, a linear or branched acyl, substituted or unsubstituted aroyl or benzoyl;

(g) oxidizing the cyclic alcohol under suitable conditions to form a ketone having the structure:

(h) deprotecting the ketone under suitable conditions to form a desoxyepothilone having the structure:

and

(i) epoxidizing the desoxyepothilone formed in step (h) under suitable conditions to form an epothilone having the structure:

28. The method of claim 10 , wherein in step (b) a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α-alcohol is obtained.

29. The method of claim 27 , wherein in step (d) a diastereomeric mixture of the protected cyclic alcohol comprising substantially the α-alcohol is obtained.

Assignments (1)

Continuity (15)