Total Synthesis of Eleutherobin and Analogs and Study of Anti-Cancer Mechanism
Annual summary rept. 1 Apr 1999-30 Apr 2002
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
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The first total syntheses of protesome inhibitors TMC-95A B have been achieved. Highlights of the synthesis include a venturesome application of the Suzuki biaryl construction, a diastereofacial dihydroxylation reaction taking advantage of the Garner method, and a macrolactamization. A new chemistry to accomplish stereo-specific cis-propenamide formation was discovered inspired by goal system. The completion of the total synthesis program paves the way to the development of TMC-95 family compounds as new anti-cancer drug leads. In addition to the total syntheses of TMC-95A B, the first total chemical synthesis of diterpene natural product guanacastepene A and its epimers at carbon 5 and carbon 13 position has also been successful accomplished. Thus, the diminished natural source for guanacastepene A has been replaced with this replenishable source. Highlights of the synthesis include a stereo- and regio-selective installation of a alpha-acetoxyl group via Rubottom-type oxidation, a diastereoselective reduction of ester to hydroxyl group and a subsequent inversion of stereo-chemistry by Mitsunobu reaction, and a chemo-selective oxidation of the primary alcohol in the presence of a secondary alcohol. The synthesis will greatly facilitate the biological study of guanacastepne family compounds, including their potential uses as anticancer agents.
- Medicine and Medical Research
- Physical Chemistry