Total Synthesis of Eleutherobin and Analogs and Study of Anti-Cancer Mechanism
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2002
- Accession Number
- ADB281681
Entities
People
- Samuel J. Danishefsky
- Songnian Lin
Organizations
- Memorial Sloan Kettering Cancer Center