Multiple Component Approaches to C-Glycosyl -Amino Acids by Complementary One-pot Mannich-Type and Reformatsky-Type Reactions.

The development of new methods for the preparation of C-glycosyl b-amino acid libraries with chemical and stereochemical diversity levels was investigated and the results are described herein. Two complementary one-pot three-component Mannichtype and Reformatsky-type synthetic strategies have been developed for the construction of chiral 3-amino propanoate fragments (eventually bis-substituted at C-2) directly linked to the anomeric carbon of pyranose and furanose residues. Both methods involved as the initial step the coupling of a sugar aldehyde to p-methoxybenzylamine but differed in the nucleophile (a d2 synthon equivalent) which was successively added: a ketene silyl acetal (Mannich route) or a bromozinc enolate (Reformatsky route). Individual C-glycosyl b-amino esters were isolated as single 3R diastereoisomers in fair to excellent yield (60–90%) and their structure assigned by NMR spectroscopy (Riguera protocol) supported by X-ray crystallography. A tentative explanation of the observed stereochemical outcome based on transitionstate models is provided. A preliminary study on the synthesis of a,a-difluoro C-glycosyl b-amino acids via a more traditional Reformatsky route is also reported