Synthesis of acetal-αḡlucosides. A stereoselective entry into a new class of compounds

Abstract

Acetal-glycosides are a new class of compounds, which became of special interest as enzyme inhibitors and cytostatics for the treatment of cancer. In a highly stereoselective glucosidation, acetyl-protected acetal-α-glucosides such as methoxymethyl 2,3,4,6-tetra- O-acetal-α- d-glucopyranoside ( 5a) were obtained in 60–80% yield by treatment of 2,3,4,6-tetra- O-acetyl-1- O-trimethylsilyl-α- d-glucopyranose ( 1) with acetals, e.g. dimethoxymethane ( 3a) in the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate ( 4) at −70°> The glucosidation involves a new principle, where the reaction does not take place at the anomeric carbon, but with retention at the oxygen of the trimethylsilyloxy group on C-1. The trimethylsilyl derivative 1 may be used as a pure anomer or prepared by in situ anomerisation from a mixture of 1 and its β anomer 26. The yields in the glucosidation can be increased by the addition of acetone or the aldehydes that correspond to the acetals (except formaldehyde). In a one pot synthesis, the reaction of phenylacetaldehyde ( 23e), trimethylsilyl methyl ether ( 14a), and 1 at −70° in the presence of 4 led directly to 1-methoxy-2-phenylethyl 2,3,4,6-tetra- O-acetyl-α- d-glucopyranoside ( 5e). O-Deacetylation of the obtained acetyl-protected acetal-α-glucosides gave the free acetal-α-glucosides in excellent yield. Thus 5e afforded 1-methoxy-2-phenylethyl α- d-glucopyranoside ( 6e). Since the acetal-α-glucosides can be cleaved by enzymic hydrolysis to the corresponding aldehydes under mild conditions, glucose may be used as a protective group for the CHO function. Similarly, 2,3,4,6,-tetra- O-benzyl-1- O-trimethylsilyl-α- d-glucopyranose ( 2) was used to afford benzyl-protected acetal-α-glucosides.