Synthesis of tetracyclines and intermediates thereto

Patent metadata

Field	Value
Publication number	US-9073829-B2
Application number	US-201013266788-A
Country	US
Kind code	B2
Filing date	Apr 30, 2010
Priority date	Apr 30, 2009
Publication date	Jul 7, 2015
Grant date	Jul 7, 2015

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 thought 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:

or a pharmaceutically acceptable salt thereof;
wherein:
---- represents a single or double bond;
R 1 and R 2 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 A ; —CH 2 OR A ; —CH 2 R A ; —CH 2 N(R A ) 2 ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —N 3 ; —NO 2 ; —N(R A ) 2 ; —NHC(O)R A ; —NHSO 2 R A ; or —C(R A ) 3 ; wherein each occurrence of R A 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 1 and R 2 are taken together to form ═O or ═C(R A ) 2 ;
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 ;
each R 7 is independently 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 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 ;
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;
R 6 and R 8 are absent if the dashed line between the carbon atoms which R 6 and R 8 are attached to represents a bond, or are each independently hydrogen, halogen, substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, haloaliphatic, substituted or unsubstituted alkoxy, —OH, —CN, —SCN, —SH, alkylthio, —N 3 ; —NO 2 , amino, alkylamino, or dialkylamino;
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; and
n is an integer in the range of 0 to 8, inclusive.

2. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof, wherein n is an integer in the range of 0 to 4, inclusive.

3. The compound of claim 1 of formula:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 1 is hydrogen or C 1-6 alkyl.

5. The compound of claim 1 , wherein R 2 is hydrogen, —OR A , or C 1-6 alkyl.

6. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof; wherein R C is hydrogen or C 1 -C 6 alkyl; and n is an integer in the range of 0 to 3, inclusive.

7. The compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

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

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

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

13. The compound of claim 1 , wherein R 6 and R 8 are absent, and ---- represents a double bond.

14. The compound of claim 1 , wherein each R 7 is independently selected from the group consisting of —OR C , —SR C , —N(R C ) 2 , —NHC(O)R C , —C(R C ) 3 , —CH 2 R C , and halogen.

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

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

17. The compound of claim 1 , wherein R 11 is hydrogen.

18. The compound of claim 1 , wherein the compound is selected from the group consisting of:

Assignees

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

Inventors

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

Classifications

• C07C311/05 Primary

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

• C07D261/20 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• C07C49/637

  the condensed ring system containing ten carbon atoms · CPC title

• C07D295/15

  to an acyclic saturated chain · CPC title

• C07F7/0814

  said ring is substituted at a C ring atom by Si · CPC title