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Keywords:

  • Aldol reaction;
  • Prolinethioamides;
  • Asymmetric synthesis;
  • Organocatalysis;
  • Imidazolidinethione

Abstract

L-Prolinethioamides have been found to be active catalysts for direct aldol reactions of acetone with aromatic aldehydes, affording aldol products in good yields and with good enantioselectivities. They were prepared from L-proline and simple aliphatic and aromatic amines in optically pure form and in good overall yields. Studies employing ten catalysts allowed us to unequivocally establish the basic principles governing the outcome of the L-prolinethioamide-catalysed aldol reaction. In particular, the catalyst prepared from L-proline and (S)-phenylethylamine catalysed the reaction of acetone with 4-cyanobenzaldehyde in 57 % yield and 93 % ee (100 % ee at –78 °C). Most importantly, we found that steric interaction between the catalyst and a donor or an acceptor is crucial for the stereoselectivity of the aldol addition, while the unwanted formation of imidazolidinethione (from the catalyst and acetone or an aldehyde) was shown to decrease both the ee and the yield. The influence of the amine moiety (–CSNHR), different solvents and temperatures were studied, and we also found that there is a linear correlation between the optical purity of the catalyst and the ee of the aldol product, which supports the hypothesis that the reaction proceeds by the enamine–imine mechanism, involving only one molecule of the catalyst in the transition state. For the first time, the formation of 1,5-dihydroxypentan-3-one products (double addition products) was studied in detail. By precise optimisation we were able to show that the courses of the reactions of acetone with highly reactive aromatic aldehydes could be manipulated to give either the aldol products or 1,5-dihydroxypentan-3-one derivatives as the major product in moderate ee. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)