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.