General Methods for Synthesis of Bioactive Materials

描述(申请人提供)：本申请中提出的研究的统一思路是开发立体和对映体控制的方法来构建全碳季碳中心。尽管在这一领域已经取得了显著的进展，但构建手性、全碳的四元中心仍然是许多具有生物意义的分子化学合成或修饰的主要障碍。这些研究将进一步确定我们开创的两种组装含有季碳中心的复杂骨架的有效方法：分子内Heck插入和前手性烯醇酸酯与手性SP3亲电体的烷基化。含有多个吡咯烷吲哚亚基的复杂生物碱是我们建议的总合成努力的主要焦点。我们在这里的目标是开发通用的方法和合成策略，第一次使这个庞大的吲哚生物碱家族中具有重要药理意义的成员能够通过化学合成在有意义的规模上获得。多吲哚生物碱的总合成目标包括虎杖碱、二氢胡萝卜素、四氢杨梅素A、C和H、香豆素A和11，11‘-二脱氧轮枝菌素。其他总的合成目标是长春花碱和长春花碱相关的生物碱库，以及复杂的卡宾内酯哇巴因、花托花青素和丹参素A。我们还将合作进行研究，以确定聚吲哚生物碱镇痛活性的结构基础，并评价具有代表性的聚吲哚生物碱的抗感染和抗肿瘤性能。

DESCRIPTION (provided by applicant): The unifying thread of the research proposed in this application is the development of stereo- and enantiocontrolled methods for constructing all-carbon quaternary carbon centers. Although notable progress has been achieved in this area, the construction of chiral, all-carbon quaternary centers remains a major hurdle for chemical synthesis, or modification, of numerous biologically significant molecules. The proposed studies will further define the utility of two powerful methods that we have pioneered for assembling complex skeleta containing quaternary carbon centers: intramolecular Heck insertions and alkylations of prochiral enolates with chiral sp3 electrophiles. Complex alkaloids that contain multiple pyrrolidinoindoline subunits are a major focus of our proposed total synthesis endeavors. Our aim here is to develop general methods and synthesis strategies that, for the first time, will allow pharmacologically significant members of this large indole alkaloid family to be accessed on meaningful scales by chemical synthesis. Polyindoline alkaloid total synthesis targets include hodgkinsine, idiospermuline, quadrigemines A, C and H, communesin A, and 11,11'- dideoxyverticillin. Other total synthesis targets are vincorine and vincorine-related alkaloid libraries and the complex cardenolides ouabain, strophanthidin and sarmentosigenin A. We will also collaborate in studies to define the structural basis of the analgesic activity of polyindoline alkaloids and evaluate the antiinfective and antitumor properties of representative polyindoline alkaloids.