虎皮楠生物碱daphniyunnine C 和二萜生物碱racemulosine的全合成研究

Daphniyunnine C and racemulosine belonging to Daphniphyllum alkaloids and diterpenoid alkaloids, respectively, are architecturally complex representative of natural products. Both of two compounds contain highly congest hexacyclic ring systems and consecutive multiple stereogenic center, which pose a significant synthetic challenge. Herein, we proposed concise strategies for total synthesis of daphniyunnine C and racemulosine, based on a unified construction of [7-5-5] DEF-rings of Daphniphyllum alkaloids and [7-5-6] BCD-rings of norditerpenoid alkaloids using a gold(I)-catalyzed enyne [2+2] cycloaddition and following pinacol rearrangements as the key transformations. The other key reactions of synthetic strategies for the two molecules include intramolecular [3+2] cycloaddition of nonstabilized azometine ylide and α-vinylation of enolate to form AC-ring and B-ring of daphniyunnine C, respectively, and Au-catalyzed Conia-Ene reaction, intramolecular aziridination of primary amine and olefin, as well as radical cyclization to introduce AF-ring, E ring and B ring of racemulosine, respectively.

Daphniyunnine C和racemulosine是分别属于虎皮楠生物碱和二萜生物碱具有代表性的复杂天然产物分子。二者均具有高度合成挑战性的拥挤六环骨架和连续多个手性中心。其中racemulosine尚未有全合成报道。本申请在通过金催化分子内烯炔[2+2]环加成反应继之频哪醇重排集合式构建虎皮楠生物碱[7-5-5]DEF三环和去甲二萜生物碱[7-5-6]BCD三环核心环系的基础上，提出了针对daphniyunnine C和racemulosine的全合成路线。合成路线的关键反应涉及非稳定亚甲胺基叶立德参与的[3+2]环加成反应和羰基的α位烯基化反应用于daphniyunnine C [6-5]AC双环和六元B环的构建；金催化Conia-烯反应、分子内伯胺和烯烃的氮杂环丙烷化反应和自由基环化反应分别用于racemulosine中 [5-5]AF双环、氮杂E环和和七元B环的构建。

本研究构建了二萜生物碱和虎皮楠生物碱多个具有功能基的复杂环系的核心结构，采用了集合与发散相结合的方式对两类环系结构迥异的分子进行了多种合成策略的合成探索，实现了二萜生物碱BCD、ABEF和BCDE环系和虎皮楠生物碱DEFD’E’F’六环和BCDE独特四环的构建。基于pinacol和Wagner-Meerwein迁移重排的核心策略为该两大类重要天然产物分子的特异性合成研究提供了重要借鉴并奠定了良好基础。