Enantioselective synthesis of 2-substituted-1,4-diketones from (S)-mandelic acid enolate and α,β-enones

An approach for the synthesis of chiral non-racemic 2-substituted-1,4-diketones from (S)-mandelic acid and alpha,beta-enones has been developed. The reaction of lithium enolate of the 1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde with alpha,beta-unsaturated carbonyl compounds proceeds readily to give the corresponding Michael adducts in good yields and with high diastereoselectivities. The addition of HMPA (3 equiv) reverses and strongly enhances the diastereoselectivity of the reaction. A change in the reaction mechanism from a lithium catalyzed to the one where catalysis has been suppressed by coordination of HMPA to lithium is proposed to explain these results. Subsequent basic hydrolysis of the 1,3-dioxolan-4-one moiety yields the corresponding a-hydroxy acids (in hemiacetal form), which after decarboxylation with oxygen in the presence of pivalaldehyde and the Co(III)Me(2)opba complex as catalyst give chiral 2-substituted 1 4-dicarbonyl compounds with very high enantiomeric excesses. In this approach, (S)-mandelic acid acts as an umpoled chiral equivalent of the benzoyl anion. (c) 2006 Elsevier Ltd. All rights reserved.