Synthesis of Tetracyclines and intermediates thereto

Patent metadata

Field	Value
Publication number	US-9688644-B2
Application number	US-201514792493-A
Country	US
Kind code	B2
Filing date	Jul 6, 2015
Priority date	Apr 30, 2009
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

Abstract

The tetracycline class of antibiotics has played a major role in the treatment of infectious diseases for the past 50 years. However, the increased use of the tetracyclines in human and veterinary medicine has led to resistance among many organisms previously susceptible to tetracycline antibiotics. The recent development of a modular synthesis of tetracycline analogs through a chiral enone intermediate has allowed for the efficient synthesis of novel tetracycline analogs never prepared before. The present invention provides more efficient routes for preparing the enone intermediate and allows for substituents at positions 4a, 5, 5a, and 12a of the tetracycline ring system.

First claim

What is claimed is:

1. A compound of formula (VII):

or a salt thereof;
wherein:
R 3 and R 4 are each independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —CH 2 OR B ; —CH 2 R B ; —CH 2 N(R B ) 2 ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —N 3 ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; —NHSO 2 R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio; or R 3 and R 4 are taken together to form ═O or ═C(R B ) 2 ;
R 5 , R 9 , R 10 , and R 11 are each independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR C ; —CH 2 OR C ; —CH 2 R C ; —CH 2 N(R C ) 2 ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —N 3 ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; —NHSO 2 R C ; or —C(R C ) 3 ; wherein each occurrence of R C is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio; or R 5 is ═C(R C ) 2 ; and
R P is hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
provided that when R 9 is —OR C , then R 10 and R 11 are not simultaneously hydrogen.

2. The compound of claim 1 , wherein R 3 is hydrogen, halogen, —OR B , or C 1-6 alkyl.

3. The compound of claim 1 , wherein R 4 is hydrogen, halogen, —OR B , or C 1-6 alkyl.

4. The compound of claim 1 , wherein R 5 is —N(R C ) 2 or —OR C .

5. The compound of claim 1 , wherein R 9 is —OR C .

6. The compound of claim 1 , wherein R 9 is C 1-6 alkyl.

7. The compound of claim 1 , wherein R 9 is —N(R C ) 2 .

8. The compound of claim 1 , wherein R 10 is substituted or unsubstituted alkyl, —OR C , or halogen.

9. The compound of claim 1 , wherein R 11 is hydrogen or substituted or unsubstituted alkyl.

10. The compound of claim 1 , wherein R 11 is —OR C or —N(R C ) 2 .

11. The compound of claim 1 of formula:

or a salt thereof.

12. The compound of claim 1 of formula:

or a salt thereof.

13. The compound of claim 1 of formula:

or a salt thereof.

14. The compound of claim 1 , wherein R 10 is halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR C ; —CH 2 OR C ; —CH 2 R C ; —CH 2 N(R C ) 2 ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —N 3 ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; —NHSO 2 R C ; or —C(R C ) 3 .

15. A method of preparing an enone of formula (VII):

or a salt thereof;
wherein:
R 3 and R 4 are each independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —CH 2 OR B ; —CH 2 R B ; —CH 2 N(R B ) 2 ; —C(═O)R B ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —N 3 ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; —NHSO 2 R B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio; or R 3 and R 4 are taken together to form ═O or ═C(R B ) 2 ;
R 5 , R 9 , and R 11 are each independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR C ; —CH 2 OR C ; —CH 2 R C ; —CH 2 N(R C ) 2 ; —C(═O)R C ; —CO 2 R C ; —CN; —SCN; —SR C ; —SOR C ; —SO 2 R C ; —N 3 ; —NO 2 ; —N(R C ) 2 ; —NHC(O)R C ; —NHSO 2 R C ; or —C(R C ) 3 ;
R 10 is hydrogencyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
each occurrence of R C is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio;
each R P is independently hydrogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, a protecting group, substituted or unsubstituted acyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
the method comprising steps of:
(a) deprotonating an isoxazole of formula (I):

or a salt thereof; with a base and reacting the deprotonated isoxazole with an enone of formula (II):

or a salt thereof,
wherein:
each occurrence of R Q is independently hydrogen, C 1-6 alkyl, —Si(OR Z ) 3 , or —Si(R Z ) 3 , and
each occurrence of R Z is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; or a substituted or unsubstituted heteroaryl; to yield a compound of formula (III):

or a salt thereof; wherein M is a counterion generated by the base;
(b) treating the compound of formula (III) with a base

Assignees

• Harvard College

Inventors

• Myers Andrew G
• Kummer David A
• Li Derun
• Hecker Evan
• Dion Amelie
• Wright Peter M

Classifications

• C07C2601/08

  the ring being saturated · CPC title

• C07D261/20 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07C2603/66

  containing five-membered rings · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07C311/05

  to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups · CPC title