Madin Andrew, O'Donnell Christopher J, Oh Taeboem, Old David W, Overman Larry E, Sharp Matthew J
Department of Chemistry, University of California, Irvine, 516 Rowland Hall, Irvine, California 92697-2025, USA.
J Am Chem Soc. 2005 Dec 28;127(51):18054-65. doi: 10.1021/ja055711h.
Intramolecular Heck reactions of alpha,beta-unsaturated 2-haloanilides derived from azatricyclo[4.4.0.0(2,8)]decanone 5 efficiently install the congested spirooxindole functionality of gelsemine. Depending upon the Heck reaction conditions and the nature of the beta-substituent, either products having the natural or unnatural configuration of the spirooxindole group are formed predominantly. Efforts to elaborate the hydropyran ring of gelsemine from the endo-oriented nitrile substituent of pentacyclic Heck product 18 were unsuccessful. Important steps in the ultimately successful route to (+/-)-gelsemine (1) are as follows: (a) intramolecular Heck reaction of tricyclic beta-methoxy alpha,beta-unsaturated 2-iodoanilide 68 in the presence of silver phosphate to form pentacyclic product 69 having the unnatural configuration of the spirooxindole fragment, (b) formation of hexacyclic aziridine 80 from the reaction of cyanide with intermediate 79 containing an N-methoxycarbonyl-beta-bromoethylamine fragment, (c) introduction of C17 by ring-opening of the aziridinium ion derived from aziridine 80, and (d) base-promoted skeletal rearrangement of pentacyclic equatorial alcohol 82 to form the oxacyclic ring and invert the spirooxindole functional group to provide hexacyclic gelsemine precursor 83.
由氮杂三环[4.4.0.0(2,8)]癸烷-5衍生的α,β-不饱和2-卤代苯胺的分子内Heck反应有效地构建了钩吻素的拥挤螺环氧化吲哚官能团。根据Heck反应条件和β-取代基的性质，主要形成具有螺环氧化吲哚基团天然或非天然构型的产物。从五环Heck产物18的内向腈取代基对钩吻素的氢化吡喃环进行修饰的尝试未成功。最终成功合成(±)-钩吻素(1)的重要步骤如下：(a) 三环β-甲氧基α,β-不饱和2-碘代苯胺68在磷酸银存在下进行分子内Heck反应，形成具有螺环氧化吲哚片段非天然构型的五环产物69；(b) 氰化物与含有N-甲氧基羰基-β-溴乙胺片段的中间体79反应生成六环氮丙啶80；(c) 通过由氮丙啶80衍生的氮丙啶离子开环引入C17；(d) 五环赤道醇82在碱促进下进行骨架重排，形成氧杂环并使螺环氧化吲哚官能团构型翻转，得到六环钩吻素前体83。
