Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids

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.

石松生物碱（Lycopodium alkaloids）兼具结构多样性与生物学活性，日益受到合成化学与药物研发领域的关注，其中探究其生源合成关联并从中获得研究灵感，向来是该领域的核心研究方向之一。基于首个具有罕见C3-C13连接骨架结构的石松生物碱——日本石松碱D（lycojaponicumin D）的合理生源合成途径，研究人员通过设计前所未有的仿生级联碎裂/曼尼希反应，提出并发现了其与石松灵碱（lycodoline）之间的全新生源关联。以快速构建石松灵碱的[3.3.1]双环体系桥头杂官能化为起始步骤，我们开发了一种新型钯介导的氧化脱氢/杂迈克尔级联反应，通过张力驱动形成碳-杂原子键，为构建构象刚性的桥头杂季碳中心提供了全新方法。本研究提出的统一合成策略可实现9种天然石松生物碱与4种非天然C12位差向异构体的发散式全合成，其中(±)-日本石松碱D与6种石松灵碱型生物碱均为首次实现全合成。