Design and Synthesis of Taxol Skeleton on the Basis of Molecular Mechanics Calculations

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Taxol, originally isolated from the Pacific yew (Taxus brevifolia), has shown remarkable potential in recent clinical trials for the treatment of breast and ovarian cancer. Its structural complexity and the limited availability have engendered world-wide intensive studies toward its total synthesis. We accomplished the three efficient approaches toward the synthesis of taxol on the basis of molecular design using molecular mechanics calculations : 1. Stereoselective synthesis of 12-membered ring enepoxide that is a biomimetic taxol intermediate was achieved. Lewis acidcatalyzed transannular cyclization gave cyclized adduct which, however, underwent over reaction leading to a rearrangement product. 2. intramolecular alkylation of the cyanohydrin ether was found to be an efficient method preparing an 8-membered ring corresponding to the B-ring of taxoid system. This method was efficiently applied to the synthesis of A-B-C rings of taxane skeleton ; 3. (3+2) -cycloaddition of nitrile oxide that is a key reaction preparing the C-ring of taxol system was successfully carried out forming an 8beta-methyl group on the C-ring with complete stereoselection. This method was utilized in the synthesis of fully functionalized CD-rings of the taxane system leading to a very important synthetic intermediate toward the total synthesis of taxol.