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Enantioselective total synthesis of the unnatural enantiomer of quinine

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Abstract

A practical enantioselective total synthesis of the unnatural (+)-quinine and (−)-9-epi-quinine enantiomers, which are important organocatalysts, is reported. The key transformation is a successive organocatalytic formal aza [3 + 3] cycloaddition/Strecker-type cyanation reaction to form an optically active tetrasubstituted piperidine derivative. This organocatalytic reaction proceeded in high yield and gave excellent enantiomeric excess with only 0.5 mol% catalyst loading. In addition, an imidate group, derived from a cyano group, was incorporated in the strategy for site-selective modification of the C4-alkyl chiral piperidine ring of quinine. Furthermore, an efficient coupling between the quinuclidine precursor and dihydroquinoline unit was achieved on a gram scale. The 15-step (LLS) synthetic protocol provided both (+)-quinine and (−)-9-epi-quinine, each with 16% overall yield.

Graphical abstract: Enantioselective total synthesis of the unnatural enantiomer of quinine

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Publication details

The article was received on 05 Aug 2019, accepted on 19 Sep 2019 and first published on 27 Sep 2019


Article type: Edge Article
DOI: 10.1039/C9SC03879E
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY license
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    Enantioselective total synthesis of the unnatural enantiomer of quinine

    S. Shiomi, R. Misaka, M. Kaneko and H. Ishikawa, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC03879E

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