[3+2]环加成/Mannich反应策略对马钱属生物碱的合成研究

This project develop an intramolecular [3+2] cycloaddition/Mannich reaction strategy to construct the pentacyclic skeleton of strychnine type complex indole alkaloids from tryptamine propargylic ester derivatives. Based on this strategy, reasonable synthetic routes are designed to carry out the total synthesis of strychnine, strynuxline B, tsilanine, rosibiline, leuconicine A/B, cyclostrychnine and melohenine A, etc. Furthermore, an inter-/intra-molecular double [3+2] cycloaddition/Mannich reaction strategy is designed for the total synthesis of indole alkaloid bisnordihydrotoxiferine. Tandem cyclization reactions involving the key [3+2] cycloaddition such as cyclopropanation/ring opening/Aldol reaction and [3+2] cycloaddition/Friedel-Crafts reaction are to be further studied. By collecting all the key intermediates synthesized in this project, a library of natural and natural-like strychnine type indole alkaloids could be established, some high activity compounds could be found, and the preliminary works of activity evaluation could be carried out.

本项目针对色胺炔丙酯衍生物发展了一个分子内[3+2]环加成/Mannich反应策略，高效地构建了士的宁等复杂吲哚生物碱的五环骨架，基于此策略设计合理的合成路线开展士的宁、strynuxline B、tsilanine、rosibiline、leuconicine A/B、cyclostrychnine和melohenine A等吲哚生物碱的全合成工作。继而又设计发展一个分子间/分子内双[3+2]环加成/Mannich反应策略，基于此可以开展双吲哚生物碱bisnordihydrotoxiferine的全合成。作为关键的[3+2]环加成反应，本项目也将继续对其进行深入研究，包括发展环丙烷化/开环/Aldol反应，[3+2]环加成/Friedel-Crafts反应等串联环化反应。利用本项目合成的关键中间体，建立士的宁类吲哚生物碱的类天然产物化合物库，寻找高活性化合物，开展初步的活性评价工作。

本项目发展了一个吲哚炔丙酯在铂或金催化剂条件下发生1,2-酰氧基迁移/分子内[3+2]环加成的串联反应，一步构建复杂多环的吲哚骨架。以该反应为基础，用色胺作为起始原料，结合关键的Mannich反应，高效地构建了士的宁等复杂吲哚生物碱的五环骨架。基于此策略设计了合理的合成路线开展士的宁等吲哚生物碱的合成工作，在尝试各种反应条件（诸如底物中保护基的选择、金催化剂配体的选择、以及后续的关环策略等）后，最终实现了士的宁的全合成。此外，利用本项目合成的关键中间体，建立了一个超过50个化合物的该类天然产物化合物库，初步开展了活性评价工作。