Asymmetric Mannich Reactions by α-Silyl Controlled Aminomethylation of Ketones

Dieter Enders; Johannes Adam; Stefan Oberbörsch; David Ward

doi:10.1055/s-2002-35998

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Asymmetric Mannich Reactions by α-Silyl Controlled Aminomethylation of Ketones

Dieter Enders*, Johannes Adam, Stefan Oberbörsch, David Ward
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: enders@rwth-aachen.de;

Abstract

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Abstract

An efficient, regio- and enantioselective synthesis of α-substituted β-amino ketones has been developed. Starting from simple ketones, enantiomerically pure α-silyl ketones 1a-j were prepared employing the SAMP/RAMP hydrazone methodology. The acyclic α-silyl ketones 1a-e were selectively converted to the silyl enol ethers (Z)-2a-e, whereas the cyclic α-silyl ketones 1f-j were obtained exclusively as the silyl enol ethers (E)-2f-j. In all cases the yields were virtually quantitative. Diastereoselective α-silyl controlled Mannich reaction with BF₃·Et₂O activated N,N-dibenzyl-N-methoxymethylamine afforded the α′-substituted β-amino ketones 3a-j in high yields (93-96%) and in one case good otherwise excellent diastereoselectivities (de 65, ≥96%). The configuration of the new stereogenic center follows from mechanistic considerations and was unambigously determined by NOE experiments with the major diastereoisomer (S,R)-3g and by X-ray crystal structure analysis of compound (S,R)-3c. Finally, the silyl group was removed with NH₄F-Bu₄NF in high yields (89-99%). The acyclic α-substituted β-amino ketones 4a-e were achieved in excellent enantiomeric excesses (ee 93-≥96%). During removal of the silyl group of the cyclic α-substituted β-amino ketones 4f-j racemisation could not be totally avoided (ee 32-89%).

Key words

asymmetric synthesis - aminomethylation - ketones - enols - silicon - Mannich bases

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