General Methods for Synthesis of Bioactive Materials

描述（由申请人提供）：本申请中提出的研究的统一思路是开发用于构建全碳季碳中心的立体和对映体控制方法。虽然在这一领域已经取得了显着的进展，手性，全碳季中心的建设仍然是一个主要的障碍，化学合成，或修改，许多生物学上重要的分子。拟议的研究将进一步定义两个强大的方法，我们已经率先组装复杂的含季碳中心：分子内赫克插入和前手性烯醇化与手性sp3亲电体的烷基化的实用程序。含有多个吡咯烷吲哚啉亚基的复杂生物碱是我们提出的全合成努力的主要焦点。我们在这里的目的是开发一般的方法和合成策略，第一次，将允许这个大型吲哚生物碱家族的重要成员通过化学合成在有意义的规模上进行访问。多吲哚啉生物碱的总合成靶点包括霍奇金碱、idiospermuline、四线素A、C和H、communesin A和11，11 '-双脱氧轮枝青霉素。其他全合成目标是长春碱和长春碱相关的生物碱库以及复合的强心内酯哇巴因、毒毛旋花子苷和沙拐枣苷元A。我们还将合作研究，以确定多吲哚啉生物碱镇痛活性的结构基础，并评估代表性多吲哚啉生物碱的抗感染和抗肿瘤特性。

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.