Mannich-type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of
Vladislav G Lisnyak1, Tessa Lynch-Colameta1, Scott A Snyder1
1Department of Chemistry, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL, 60637, USA.
Abstract:
Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using β-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of β-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (-)-lobeline and (-)-sedinone.
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