Dihydropyridine C-glycoconjugates by Hantzsch cyclocondensation. Synthesis of a C(6)-glycosylated nifedipine analogue

Abstract

The use of glycosylated reagents in Hantzsch-type cyclocondensation reactions leading to C-glycosylated dihydropyridines (DHPs) has been investigated. A three-component approach with an anomeric sugar aldehyde (galacto, manno, and ribo derivatives), a β-keto ester, and an aminocrotonate afforded C(4)-glycosylated DHPs in high yield (70-90%). A two-component cyclocondensation approach based on different glycosylated β-amino acrylates (sugar enamines) and an enone derived from the Knoevenagel condensation between benzaldehyde and ethyl acetoacetate was followed for the preparation of C(6)-glycosylated 4-phenyl-substituted DHPs in fair yields (60-70%). The latter compounds were obtained as mixtures of diastereoisomers owing to the asymmetric induction of the sugar moiety in the formation of the C(4)-stereogenic center of the DHP ring. The diastereomer excess of the major products varied from 30 to 60%. The structure of selected compounds was determined by X-ray crystallography and by chiroptical measurements. The two-component cyclocondensation method was also employed for the preparation of a C(6)-ribofuranosyl-containing analogue of the well-known hypotensive agent nifedipine.