Hantzsch-Type Three-Component Approach to a New Family of Carbon-Linked Glycosyl Amino Acids. Synthesis of C-Glycosylmethyl Pyridylalanines,

Abstract

C-Glycosylmethyl pyridylalanines reported in this paper constitute a novel family of glycosyl amino acids that contain a pyridine ring linking the carbohydrate and amino acid residues. These amino acids may serve to prepare nonnatural glycopeptides displaying firmly bound carbohydrate fragments through a rigid and highly stable tether. A viable route to these new hybrid molecules has been opened via thermally induced Hantzsch-type cyclocondensation using an aldehyde-ketoester-enamino ester system. To one of these reagents was attached a C-glycosyl residue, while to another was bound an amino acid fragment. In a one-pot optimized methodology, the dihydropyridine was not isolated while its purification was carried out by removal of unreacted material and side products using polymer-supported scavengers. Then the dihydropyridine (mixture of diastereoisomers) was oxidized by a polymer-bound oxidant to give the target pyridine bearing the two bioactive residues. In this way a range of eight compounds (58-68% yield) was prepared in which the elements of diversity were (i) the gluco and galacto configurations of the pyranose ring, (ii) the alpha- and beta-configurations at the anomeric center, and (iii) the positions of the carbohydrate and amino acid sectors in the pyridine ring. The orthogonal functional group protection in these amino acids allowed their easy incorporation into oligopeptides via sequential amino and carboxylic group coupling.