To formulate a potentially general approach generating a collection of skeletally diverse scaffolds without simplifying a structural property of natural products, we devised a bioinspired artificial assembly line of indole alkaloids. Getting inspiration from dehydrosecodine (2), a biosynthetic branching point of terpenoid indole alkaloids, dihydropyridine-diene (3) composed of a 1,6-dihydropyridine conjugated with carbonyl moiety was designed as a “multipotent intermediate” for the divergent cyclizations. The sensitive dihydropyridine ring in the vicinity of indole and unsaturated ester was constructed by newly developed copper catalyzed cyclization protocol. By harnessing a versatile reactivity of the multipotent intermediate (3), three types of bioinspired [4+2] cycloadditions as well as two types of oxidation-triggered cyclizations were successfully carried out generating five distinct scaffolds involving iboga-(4), aspidosperma-(5), andranginine-(6) and ngouniensine-(7) type skeletons and non-natural tetracyclic framework (8) within 6-9 steps from tryptamine (1). Furthermore, simple manipulations of the scaffolds 4-6 allowed total synthesis of (-)-catharanthine, (±)-vincadifformine and (±)-andranginine, demonstrating a relevance of our approach to the biosynthetic assembly line of natural products.

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids

250th National Meeting (2015)

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