N-Primary-Amine-Terminal β-Turn Tetrapeptides as Organocatalysts for Highly Enantioselective Aldol Reaction

Abstract

Tetrapeptides, containing a terminated primary amine and conformationally restricted D-Pro-Gly or D-Pro-Aib (2-aminoisobutanoic acid) segment as a strongly beta-turn-nucleating element, were designed and synthesized with condensation of N-module dipeptides with C-module dipeptides in solution. They were first applied to catalyze aldol reactions, and were found to be effective catalysts for the transformations. The tetrapeptide Val-D-Pro-Gly-Leu-OH (1g) was the optimal organocatalyst. It was shown that the intensive beta-turn conformation, indicated by CD and NOESY spectra, contributed to the (R)-aldol and high enantioselectivity of the reaction of acetone in MeOH, whereas the sharply varied conformation should contribute to the low enantioselectivity and (S)-product of the reaction in 1,2-dichloroethane (DCE). The asymmetric induction in the reaction of hydroxyacetone was not affected by solvents, and predominant anti products were achieved by 1g in MeCN with the additive (S)-BINOL.