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

紫杉醇最初是从太平洋红豆杉（Taxus brevifolia）中分离出来的，在最近的临床试验中显示出治疗乳腺癌和卵巢癌的显着潜力。其结构的复杂性和有限的可用性引起了全世界对其全面综合的深入研究。利用分子力学计算，在分子设计的基础上完成了紫杉醇合成的三种有效途径：立体选择性合成了仿紫杉醇中间体12元环烯环氧化物。Lewis酸催化的跨环环化反应得到环化加合物，而环化加合物经过过度反应生成重排产物。2. 发现氰基丙烷醚的分子内烷基化反应是制备与类taxoid的b环相对应的8元环的有效方法。该方法有效地应用于紫杉烷骨架A-B-C环的合成；3. 成功地进行了制备紫杉醇体系c环的关键反应——氧化腈(3+2)-环加成反应，在c环上形成了一个立体选择完全的8 -甲基。利用该方法合成了紫杉醇体系的全功能化cd环，为紫杉醇的全合成提供了重要的合成中间体。

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.