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Flexible Synthesis and Biological Activity of Uronic Acid-Type gem-Diamine 1-N-Iminosugars:  A New Family of Glycosidase Inhibitors

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journal contribution
posted on 17.12.1999, 00:00 by Yoshio Nishimura, Eiki Shitara, Hayamitsu Adachi, Minako Toyoshima, Motowo Nakajima, Yoshiro Okami, Tomio Takeuchi
An efficient and flexible synthetic route to four gem-diamine 1-N-iminosugars of uronic acid-type (d-glucuronic, d-mannuronic, l-iduronic, and l-guluronic acid), a new family of glycosidase inhibitor, from l-galactono-1,4-lactone have been developed in an enantiodivergent fashion through a sequence involving as the key steps (a) the formation of gem-diamine 1-N-iminopyranose 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 and oxidation, and the Sharpless oxidation. d-Glucuronic and d-mannuronic acid-type 1-N-iminosugars, (3S,4R,5R,6R)- and (3S,4R,5R,6S)-4,5-dihydroxy-6-trifluoroacetamido-3-piperidinecarboxylic acid, were proven to be potent inhibitors for β-d-glucuronidase (IC50 6.5 × 10-8M) and to affect human heparanase (endo-β-glucuronidase).