Concise and practical route to tri-and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from D-(+)-glucurono-γ-lactone

Abstract

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from D-(+)-glucurono-γ-lactone. Thus, D-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-D-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-D-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.