Synthesis of tetracyclines and intermediates thereto

Patent metadata

Field	Value
Publication number	US-2016002183-A1
Application number	US-201514792493-A
Country	US
Kind code	A1
Filing date	Jul 6, 2015
Priority date	Apr 30, 2009
Publication date	Jan 7, 2016
Grant date	—

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):

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, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR B ; —CH 2 OR B ; —CH 2 R B ; —CH 2 N(R B ) 2 ; ═C(R B ) 2 ; ═O; —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;
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, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR C ; —CH 2 OR C ; —CH 2 R C ; —CH 2 N(R C ) 2 ; ═C(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; 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 , 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:

12 . The compound of claim 1 of formula:

13 . The compound of claim 1 of formula:

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

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 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 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):

with a suitable base under suitable conditions and reacting it with an enone of formula (II):

wherein:
each occurrence of R Q is independently hydrogen, a 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):

wherein M is a counterion generated by the suitable base;
(b) treating the compound of formula (III) with a suitable base under suitable conditions to yield a compound of formula (IV):

(c) heating the compound (IV) in a suitable solvent to yield a compound of formula (V):

(d) de

Assignees

• Harvard College

Inventors

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

Classifications

• C07D498/04

  Ortho-condensed systems · CPC title

• C07C45/67

  by isomerisation; by change of size of the carbon skeleton · CPC title

• C07D209/58

  [b]- or [c]-condensed · CPC title

• C07D261/18

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07F7/0814

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