Stereoselective oxygenation of a double bond: Design and synthesis of azasugar inhibitors of glucoconjugate processing enzymes.

Abstract

A novel methodology for the synthesis of amino sugars and aza-sugars, important inhibitors of glycosidases, is described. This is accomplished via the intermediacy of N-diphenylmethylene-protected a-amino esters. This methodology can be divided into three major phases. First, the reduction-alkenylation reaction with DIBAL-TRIBAL and oxygenated alkenyllithium nucleophiles provides unsaturated 1,2-amino alcohols with excellent threo-selectivity (>20: 1). Second, optimization of catalytic osmylation conditions with regards to chemical yield, stereoselectivity, and osmium content is described. A mixture of 1.2 mol% of osmium tetroxide in the presence of 3 eq. of potassium ferricyanide (K₃Fe(CN)₆) as an oxidant, 3 eq. of K₂CO₃ and 3 mol% of (DHQ)₂PHAL chiral ligand represents optimized dihydroxylation conditions. Depending upon the substrate, good to excellent antiselectivities are observed. The separation of diastereomeric mixtures of protected amino tetrols is accomplished by flash chromatography on silica gel. Thus, four contiguous chiral centers are established efficiently in two steps. The third stage involves manipulation of the protecting groups and subsequent cyclization. Deprotection of the silyl protecting group in the presence of acyl groups is complicated by migration. The cyclization is accomplished via the reductive amination of acyclic amino aldehydes with NaBH3CN. D-N-methyl-fucosamine is prepared from protected L-serine. Depending on the order of osmylation and cyclization steps, this methodology provides either Lazafucose or L-azagulose from protected L-alanine in 8 steps. Furthermore, 1-cyano-L-azafucose is prepared via treatment of acyclic amino aldehydes with HCN (Strecker reaction).