Total Synthesis of the Antitumor Agent Asparagamine A

这项研究的目标是开发一种抗癌生物碱天冬酰胺A的对映选择性合成方法，该生物碱已被证明在体外对多种肿瘤细胞具有抗肿瘤活性。麦克米伦最近开发了第一个有机催化的不对称Michael加成反应，即吡咯与α，β-不饱和醛的加成反应。这里提出了一种新的扩展，以允许在催化循环中干预亚胺离子中间体的氮杂-普林斯环化。这将允许一步合成天冬酰胺A和stemofoline(一种相关生物碱)共同的核心桥联吡咯烷结构。所提出的合成方法既新颖又简洁。此外，拟议的路线将允许建造可能具有重大药用价值的天然产品的类似物。

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.