Synthesis of polyhydroxy 7- and N-alkyl-azepanes as potent glycosidase inhibitors

An effective synthetic method for polyhydroxylated azepanes that contain an alkyl group (Me or Bu) at either the 7- or N-positions is developed. The synthetic routes are accomplished in eight to ten steps from D-(-)-quinic acid. Among the compounds synthesized, the polyhydroxy 7-butyl azepane (compound 3), which possessed the R-configuration at C-7 position, is shown to give potent inhibition against beta-galactosidase (IC50 = 3 mu M). Preliminary biological data indicate that the length of alkyl groups along with the proper stereochemistry at the C-7 position is essential for acquiring extra binding affinity. Using similar synthetic routes, the polyhydroxy N-methyl and N-butyl azepanes are synthesized for the comparison of their biological activities. (C) 2010 Elsevier Ltd. All rights reserved.