Asymmetric Mannich Reactions by α-Silyl Controlled Aminomethylation of Ketones

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 la-j were prepared employing the SAMP/RAMP hydrazone methodology. The cyclic 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 BF 3 .Et 2 O 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 NH 4 F-Bu 4 NF in high yields (89-99%). The acyclic α-substituted β-amino ketones 4a-e were achieved in excellent enantiomeric excesses (ce 93-≥96%). During removal of the silyl group of the cyclic α-substituted β-amino ketones 4f-j racemisation could not be totally avoided (ce 32-89%).