Prolinamides carrying a thiourea group as new catalysts for the asymmetric aldol reaction

Abstract

At the beginning of the 21st century, organocatalysis has emerged as a new powerful methodology for the synthesis of enantiopure organic compounds. The breakthrough of proline-catalyzed asymmetric direct aldol reaction together with the pioneering work on catalytic thioureas and imidazolidinones opened new directions in asymmetric catalysis. The five-membered secondary amine structure of proline is considered as a“privileged” structure able to activate carbonyl compounds through the formation of enamine intermediates. In an attempt to develop new organocatalysts, we thought of combining a thiourea group with prolinamide or an α-amino acid amide unit. Thiourea group is a well known double hydrogen bond donor and recently we have shown that chiral thioureas based on tert-butyl esters of α- amino acids are excellent catalysts for the asymmetric Michael reaction.1 In the present work, we describe the synthesis of various α-amino acid amides based on a chiral diamine carrying a thiourea group (general structure 1). The catalytic efficiency of the new organocatalysts was evaluated in the aldol reaction between acetone and 4-nitrobenzaldehyde. Prolinamide derivative was more efficient than the valinamide and the threonine amide derivatives. The catalyst based on (S)-proline and (1S,2S)-diphenylethylenediamine proved to be an excellent catalyst providing the products between ketones and aromatic aldehydes in high to quantitative yield and high stereoselectivities