Total Synthesis of the Antitumor Agent Asparagamine A

该研究的目的是开发一种抗肿瘤生物碱天冬酰胺A的对体选择性合成，天冬酰胺A已被证明对多种肿瘤细胞系具有体外抗肿瘤活性。麦克米伦最近开发了第一个有机催化，不对称的迈克尔加成吡咯与α， β -不饱和醛。本文提出了一种新颖的扩展，允许在催化循环中干预氮杂环-普林斯环化的一种离子中间体。这将允许一步合成与天冬酰胺a和相关生物碱stemofoline共同的核心桥接吡咯烷结构。所提出的综合既新颖又简洁。此外，拟议的路线将允许构建可能具有重要药用价值的天然产物的类似物。

The goal of the proposed research is to develop an enantioselective synthesis of the antitumor alkaloid asparagamine A, which has been shown to have antitumor activity in vitro against a variety of tumor cell lines. MacMillan has recently developed the first organocatalytic, asymmetric Michael additions of pyrroles with alpha, beta- unsaturated aldehydes. Proposed herein is a novel extension to allow for the intervention of an aza-Prins cyclization of an iminium ion intermediate in the catalytic cycle. This will allow for a one-step synthesis of the core bridged pyrrolidine structure common to asparagamine A and stemofoline, a related alkaloid. The proposed synthesis is both novel and concise. Moreover, the proposed route will allow for the construction of analogs of the natural product that could be of significant medicinal value.