Flexible synthesis and biological activity of uronic acid-type gem-diamine1-N-iminosugars: A new family of glycosidase inhibitors

An efficient and flexible synthetic route to four gem-diamine 1-N-iminosuga rs of uronic acid-type (D-glucuronic, D-mannuronic, L-iduronic, and L-gulur onic acid), a new family of glycosidase inhibitor, from 1-galactono-1,4-lac tone have been developed in an enantiodivergent fashion through a sequence involving as the key steps (a) the formation of gem-diamine 1-N-iminopyrano se ring by the Mitsunobu reaction of an aminal and (b) the introduction of a carboxylic acid group by the Wittig reaction of a ketone, hydroboration a nd oxidation, and the Sharpless oxidation. D-Glucuronic and D-mannuronic ac id-type 1-N-iminosugars, (3S,4R,5R,6R)- and (3S,4R,5R,6S)-4,5-dihydroxy-6-t rifluoroacetamido-3-piperidinecarboxylic acid, were proven to be potent inh ibitors for beta-D-glucuronidase (IC50 6.5 x 10(-8)M) and to affect human h eparanase (endo-beta-glucuronidase).