IP Library › Granted Patent US 8,067,616

Granted Patent B2

US 8,067,616 · App. 12/913,624 · Granted Nov 29, 2011

Total synthesis of salinosporamide A and analogs thereof

Assignee: Nereus Pharmaceuticals, Inc.

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Quick Facts

Patent No.: US 8,067,616
App. No.: 12/913,624
Granted: Nov 29, 2011
Kind: B2

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Abstract

The present invention relates to certain compounds and to methods for the preparation of certain compounds that can be used in the fields of chemistry and medicine. Specifically, described herein are methods for the preparation of various compounds and intermediates, and the compounds and intermediates themselves. More specifically, described herein are methods for synthesizing Salinosporamide A and its analogs from a compound of formula (V).

Claims (79)

1. A compound of formula (X):

wherein:

R 1 is hydrogen or substituted or unsubstituted C 1-6 alkyl;

R 3 is selected from the group consisting of substituted or unsubstituted variants of the following: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;

R 4 can be selected from the group consisting of substituted or unsubstituted variants of the following: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, salt of carboxyalkyl, alkylaminoalkyl, salt of an alkylaminoalkyl, dialkylaminoalkyl, salt of a dialkylaminoalkyl, phenyl, alkylthioalkyl, arylthioalkyl, carboxy, cyano, alkanesulfonylalkyl, alkanesulfinylalkyl, alkoxysulfinylalkyl, thiocyanoalkyl, boronic acidalkyl, boronic esteralkyl, guanidinoalkyl, salt of a guanidinoalkyl, sulfoalkyl, salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, salt of a pyridinylalkyl, salt of a heteroarylalkyl and halogenated alkyl including polyhalogenated alkyl; and

PG 1 is a protecting group moiety.

2. The compound claim 1 , wherein PG 1 is selected from the group consisting of benzyl, a substituted benzyl, an alkylcarbonyl, an arylalkylcarbonyl, a substituted methyl ether, a substituted ethyl ether, a substituted benzyl ether, a tetrahydropyranyl ether, a silyl ether, an ester, and a carbonate.

3. The compound of claim 1 , wherein R 4 is 2-cyclohexenyl.

4. The compound of claim 1 , wherein R 3 is methyl.

5. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted C 1-6 alkyl.

6. The compound of claim 1 , wherein the compound of formula (X) has the structure:

7. The compound of claim 1 , wherein the compound of formula (X) has the structure:

8. The compound of claim 1 , wherein the compound of formula (X) has the structure:

9. The compound of claim 1 , wherein the compound of formula (X) has the structure:

10. A method of forming a compound of formula (XV) from the compound of claim 1 comprising the steps of:

removing PG 1 on the acetal of the compound of formula (X), wherein PG 1 is a protecting group moiety, and reductively opening the hemiacetal using a reducing agent;

cleaving the hemiaminal ether group of a compound of formula (XXIV) or a compound of formula (XXIVp); and

forming a four membered lactone ring by performing a lactonization reaction using a compound selected from the group consisting of a compound of formula (XXVI), a compound of formula (XXVII), a compound of formula (XXVIp) and a compound of formula (XXVIIp), to form the compound of Formula (XV);

wherein the compound of formula (XV) has the following structure:

wherein the compound of formula (X) has the following structure:

wherein the compound of Formula (XXIV) has the following structure:

wherein the compound of Formula (XXIVp) has the following structure:

wherein the compound of Formula (XXVI) has the following structure:

wherein the compound of Formula (XXVII) has the following structure:

wherein the compound of Formula (XXVIp) has the following structure:

wherein the compound of Formula (XXVIIp) has the following structure:

wherein:

R 5 is selected from the group consisting of —C(=O)OR 6 , —C(=O)SR 6 , —C(=O)NR 6 R 6 and —C(=O)Z;

each R 6 is independently selected from the group consisting of hydrogen, halogen, a substituted or an unsubstituted C 1 -C 24 alkyl, a substituted or an unsubstituted acyl, a substituted or an unsubstituted alkylacyl, a substituted or an unsubstituted arylacyl, a substituted or an unsubstituted aryl, a substituted or an unsubstituted arylalkyl, p-nitrophenyl, pentafluorophenyl, pentafluoroethyl, trifluoroethyl, trichloroethyl, and a substituted or an unsubstituted heteroaryl;

Z is a halogen; and

PG 2 and PG 3 are independently a protecting group moiety.

11. The method of claim 10 , wherein the cleaving of the hemiaminal ether group is before the removal of PG 1 and reductively opening the hemiacetal, and before the formation of the four membered lactone ring.

12. The method of claim 10 , wherein the cleaving of the hemiaminal ether group is after the removal of PG 1 and reductively opening the hemiacetal, but before the formation of the four membered ring.

13. The method of claim 10 , further comprising substituting the C-13 primary hydroxy group of the compound of formula (XV) with a halogen, wherein the compound of formula (XV) has the following structure:

to form a compound of formula (XVI-A), wherein the compound of formula (XVI-A) has the following structure:

wherein X is a halogen.

14. The method of claim 10 , further comprising substituting the C-13 primary hydroxy group of the compound of formula (XV) with a halogen, wherein the compound of formula (XV) has the following structure:

to form a compound of formula (XVI-B), wherein the compound of formula (XVI-B) has the following structure:

wherein X is a halogen.

15. The method of claim 14 , further comprising the steps of:

(1) oxidizing the secondary hydroxy group of the compound of formula (XVI-B) using an oxidizing agent, wherein the compound of formula (XVI-B) has the following structure:

to form a compound of formula (XXII):

(2) reducing the keto group of the compound of formula (XXII) to form a compound of formula (XVI-A) using a reducing agent, wherein the compound of formula (XVI-A) has the following structure:

16. The method of claim 14 , further comprising the step of:

(1) inverting the stereochemistry of the secondary hydroxy carbon center of the compound of formula (XVI-B), wherein the compound of formula (XVI-B) has the following structure:

to form a compound of formula (XVI-A), wherein the compound of formula (XVI-A) has the following structure:

wherein the stereochemistry of the secondary hydroxy carbon center is inverted via a Mitsunobu transformation, or by oxidizing the C-5 secondary hydroxy group on the compound of formula (XVI-B) to a keto group with an oxidizing agent and then reducing the keto group to a hydroxy group with a reducing agent or via a selective enzyme transformation using a reducing enzyme.

17. A method of preparing the compound of claim 1 comprising adding R 4 to the compound of formula (IX) by reacting the compound of formula (IX) with an organometallic moiety containing at least one R 4 to form a compound of formula (X):

18. The method of claim 17 , wherein the organometallic moiety is 9-cyclohex-2-enyl-9-borabicyclo[3.3.1]nonane.

19. The method of claim 17 , wherein

the compound of formula (IX) has the structure: