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Nat Chem. 2014 Jan;6(1):57-64. doi: 10.1038/nchem.1798. Epub 2013 Nov 24.

Biogenetically inspired synthesis and skeletal diversification of indole alkaloids.

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1
Division of Chemistry, Graduate School of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan.
2
1] Division of Chemistry, Graduate School of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan [2] Japan Science and Technology Agency (JST) PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan.

Abstract

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [4+2] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (±)-vincadifformine, (±)-andranginine and (-)-catharanthine.

PMID:
24345948
DOI:
10.1038/nchem.1798
[Indexed for MEDLINE]
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