β-amino acid catalyzed asymmetric michael additions: Design of organocatalysts with catalytic acid/base dyad inspired by serine proteases

10.1021/jo2011413Journal of Organic Chemistry76187399-7405JOCE

A Highly Efficient Solvent-Free Asymmetric Direct Aldol Reaction Organocatalyzed by Recoverable (s)-Binam-L-Prolinamides. ESI-MS Evidence of the Enamine-Iminium Formation

Recoverable (Sa)-binam-l-prolinamide in combination with benzoic acid is used as catalysts in the direct aldol reaction between cycloalkyl, alkyl, and α-functionalized ketones and aldehydes under solvent-free reaction conditions. Three different methods are assayed: simple conventional magnetic stirring, magnetic stirring after previous dissolution in THF and evaporation, and ball mill technique. These procedures allow one to reduce not only the amount of required ketone to 2 equiv but also the reaction time to give the aldol products with regio-, diastereo-, and enantioselectivities comparable to those in organic or aqueous solvents. Generally anti-isomers are mainly obtained with enantioselectivities up to 97%. The reaction can be carried out under these conditions also using aldehydes as nucleophiles, yielding after in situ reduction of the aldol products the corresponding chiral 1,3-diols with moderate to high enantioselectivities mainly as anti-isomers. The aldol reaction has been studied by the use of positive ESI-MS technique, providing the evidence of the formation of the corresponding enamine−iminium intermediates.This work was financially supported by the Dirección General de Investigación of the Ministerio de Educación y Ciencia of Spain (Grant CTQ2004-00808/BQU, CTQ2007-62771/BQU and Consolider Ingenio 2010 CSD2007-00006), the Generalitat Valenciana (Grants CTIOIB/2002/320, GRUPOS03/134, and GV05/157), and the University of Alicante (GRJ06-05)