State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University , 222 Tianshui Nanlu, Lanzhou 730000, China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin 300071, China.
J Am Chem Soc. 2017 May 24;139(20):7095-7103. doi: 10.1021/jacs.7b03280. Epub 2017 May 11.
Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.
具有结构多样性和生物意义的石松生物碱一直激发着合成和药物领域越来越多的兴趣，其中对其相关生物发生关系的启发和探索通常是主要关注点之一。受合理生物发生途径的启发，将 lycojaponicumin D 作为具有结构不寻常的 C3-C13 键合支架的第一个石松生物碱成员，基于前所未有的生物启发串联断裂/Mannich 反应的设计，提出并发现了与 lycodoline 的新连接。通过在 lycodoline 的[3.3.1]双环系统中快速构建桥头杂官能化，开发了一种新型钯介导的氧化脱氢/杂迈克尔反应，用于应变驱动 C-杂原子键的形成，从而为构象刚性桥头杂季碳提供了一种新方法。目前的统一策略为 9 种天然石松生物碱和 4 种非天然 C12 差向异构体的发散全合成提供了一种方案，其中（±）-lycojaponicumin D 和 6 种 lycodoline 型生物碱已首次被合成。
