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

紫杉醇最初从太平洋紫杉（短叶红豆杉）中分离出来，在最近的临床试验中显示出治疗乳腺癌和卵巢癌的巨大潜力。由于其结构的复杂性和可利用性的有限性，世界范围内对其进行了广泛的研究。我们在分子设计的基础上，利用分子力学计算，实现了紫杉醇合成的三条有效途径：1。实现了仿生紫杉醇中间体12元环环氧化合物的立体选择性合成。刘易斯酸催化的环化反应生成环化加成物，但环化加成物反应过度，生成重排产物。2.发现氰醇醚的分子内烷基化是制备对应于紫杉烷系统的B-环的八元环的有效方法。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C-环的关键反应--氧化腈的（3+2）-环加成反应，在C-环上形成了完全立体选择性的8 β-甲基。该方法被用于合成紫杉烷体系的完全官能化的CD环，从而成为紫杉醇全合成的一个非常重要的合成中间体。

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.