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US 2014/0179929 A1Published application
Synthesis of enone intermediate
AssigneePresident and Fellows of Harvard College
InventorsAndrew G. Myers, Jason D. Brubaker
Life of this patent
Estimating the term…
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 a more efficient route for preparing the enone intermediate.
Claims22
1-48. (canceled)
A method of preparing a compound of formula (III):
- wherein:
- R3 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;
- —ORC;
- —C(═O)RC;
- —CO2RC;
- —CN;
- —SCN;
- —SRC;
- —SORC;
- —SO2RC;
- —NO2;
- —N(RC)2;
- —NHC(O)RC;
- or —C(RC)3;
- wherein each occurrence of RC is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- R4 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;
- —ORD;
- —C(═O)RD;
- —CO2RD;
- —CN;
- —SCN;
- —SRC;
- —SORD;
- —SO2RD;
- —NO2;
- —N(RD)2;
- —NHC(O)RD;
- or —C(RD)3;
- wherein each occurrence of RD is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- R5 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;
- —ORE;
- —CN;
- —SCN;
- —SRE;
- or —N(RE)2;
- wherein each occurrence of RE is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- and
- P is hydrogen or an oxygen-protecting group;
- the method comprising:
- substituting the hydroxyl group of alcohol of formula (Ha):
- with a nucleophile under suitable conditions to yield the compound of formula (III):
80 more elements
A method of preparing a compound of formula (III):
- wherein:
- R3 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;
- —ORC;
- —C(═O)RC;
- —CO2RC;
- —CN;
- —SCN;
- —SRC;
- —SORC;
- —SO2RC;
- —NO2;
- —N(RC)2;
- —NHC(O)RC;
- or —C(RC)3;
- wherein each occurrence of RC is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- R4 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;
- —ORD;
- —C(═O)RD;
- —CO2RD;
- —CN;
- —SCN;
- —SRD;
- —SORD;
- —SO2RD;
- —NO2;
- —N(RD)2;
- —NHC(O)RD;
- or —C(RD)3;
- wherein each occurrence of RD is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- R5 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;
- —ORE;
- —CN;
- —SCN;
- —SRE;
- or —N(RE)2;
- wherein each occurrence of RE is independently hydrogen, a protecting group, aliphatic, heteroaliphatic, acyl;
- aryl;
- heteroaryl;
- alkoxy;
- aryloxy;
- alkylthio;
- arylthio;
- amino, alkylamino, dialkylamino, heteroaryloxy;
- or heteroarylthio;
- and
- P is hydrogen or an oxygen-protecting group;
- the method comprising:
- substituting the hydroxy group of alcohol of formula (IIb):
- wherein P′ is hydrogen or an oxygen-protecting group;
- with a nucleophile under suitable conditions to yield the compound of formula:
81 more elements
61-102. (canceled)
Dependencies are inferred from the claim text.