Synthesis of tetracyclines and intermediates thereto

摘要

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.

主权项

1. A compound of formula:or a pharmaceutically acceptable salt thereof;wherein:
---- represents a single or double bond; R1 and R2 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; —ORA; —CH2ORA; —CH2RA; —CH2N(RA)2; —C(═O)RA; —CO2RA; —CN; —SCN; —SRA; —SORA; —SO2RA; —N3; —NO2; —N(RA)2; —NHC(O)RA; —NHSO2RA; or —C(RA)3; wherein each occurrence of RA 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 R1 and R2 are taken together to form ═O or ═C(RA)2; R3 and R4 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; —ORB; —CH2ORB; —CH2RB; CH2N(RB)2; —C(═O)RB; —CO2RB; —CN; —SCN; —SRB; —SORB; —SO2RB; —N3; —NO2; —N(RB)2; —NHC(O)RB; —NHSO2RB; or —C(RB)3; wherein each occurrence of RB 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 R3 and R4 are taken together to form ═O or ═C(RB)2; R5, R9, and R11 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; —ORC; —CH2ORC; —CH2RC; —CH2N(RC)2; —C(═O)RC; —CO2RC; —CN; —SCN; —SRC; —SORC; —SO2RC; —N3; —NO2; —N(RC)2; —NHC(O)RC; —NHSO2RC; or —C(RC)3; each R7 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; —ORC; —CH2ORC; —CH2RC; —CH2N(RC)2; —C(═O)RC; —CO2RC; —CN; —SCN; —SRC; —SORC; —SO2RC; —N3; —NO2; —N(RC)2; —NHC(O)RC; —NHSO2RC; or —C(RC)3; R10 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; —ORC; —CH2ORC; —CH2RC; —CH2N(RC)2; —C(═O)RC; —CO2RC; —CN; —SCN; —SRC; —SORC; —SO2RC; —N3; —NO2; —N(RC)2; —NHC(O)RC; —NHSO2RC; or —C(RC)3; each occurrence of RC is independently hydrogen, halogen, azido, a protecting group, aliphatic, heteroaliphatic, haloaliphatic, acyl, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio; R6 and R8 are absent if the dashed line between the carbon atoms which R6 and R8 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, —N3; —NO2, amino, alkylamino, or dialkylamino; each RP 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.