N-primary-amine-terminal beta-turn tetrapeptides as organocatalysts for highly enantioselective aldol reaction.

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.

2,4-Dinitrophenol as an effective cocatalyst: greatly improving the activities and enantioselectivities of primary amine organocatalysts for asymmetric aldol reactions.

Seven primary amine organocatalysts 1a-g were readily prepared from natural primary amino acids via two steps and then were used to catalyze the direct asymmetric aldol reaction, but they showed very poor enantioselectivities and activities. As an effective cocatalyst, 2,4-dinitrophenol (DNP) dramatically elevated the activities and enantioselectivities of these very inefficient primary amine organocatalysts. This remedial course to the very inefficient organocatalysts by selection and employment of the optimal cocatalyst was particularly cost-effective and environment-beneficial compared with de novo development of catalysts. The highest efficient organocatalytic system that was composed of 1f and DNP showed high enantioselectivities and good to high diastereoselectivities with a broad spectrum of seven ketones. The linear ketones and cyclopentanone got predominant syn products whereas cyclohexanone mainly gave anti products.