Carbohydrates as chiral templates: asymmetric ugi-synthesis of alpha-amino acids using galactosylamines as the chiral matrices

Abstract

In the presence of Lewis acid catalysts O-acetyl- (1) and O-pivaloyl- (2) protected β-D-galactopyranosylamines react with aldehydes, isocyanides and carboxylic acids in Ugi-four-component-condensations to give the corresponding N-galactosyl-amino acid amide derivatives 3,5 in almost quantitative yields. Zinc chloride is the most effective Lewis acid catalyst. At 0°C or even at room temperature the (2R,β-D)-diastereomers of the amino acid derivatives 3,5 are formed with high diastereoselectivity. If the sterically more demanding O-pivaloyl galactosylamine 2 is used at -78°C to -25°C the stereoselectivity often exeeds 20:1 favouring the (2R,β-D) diastereomers 5. After one recrystallisation pure (R)-amino acid derivatives 5 are obtained in yields of 80–95%. In addition to the high yields and stereoselectivity the amino acid synthesis discribed here has the further advantage that it neither requires organometallic reagents and intermediates nor exclusion of oxygen and moisture. Two step acid hydrolysis of the N-galactosylamino acid amide derivatives 5 delivers the enantiomerically pure (R)-amino-acids 8 in high yields.