Abstract
Iminosugars have emerged as potent inhibitors of glucosidases and glucosyltransferases, due to their transition state analogues in the enzymatic reactions. Therefore, many enantioselective syntheses of iminosugars have been reported in recent years. However, up to now, much attention has been focused on the synthesis of their D-forms. There were few reports of systematic studies of the biological properties of the L-forms of iminosugars. Herein, we report both catalytic enantioselective synthesis and biological evaluation of 1-C-alkyl-L-arabinoiminofuranose derivatives 2. We prepared iodoalkane 8 as the key intermediate for the synthesis of desired iminofuranose derivatives via asymmetric allylic aminations and ring-closing metathesis. Ni-catalyzed Negishi cross-coupling of 8 with many alkyl zinc halides proceed to give the desired products 9 in moderate yields. With 9 in hand, we have converted from coupling products into various 1-C-alkyl L-arabino-iminofuranose derivatives 2 in 3 steps (Scheme 2). Some of the synthesized iminofuranoses were found to be potent inhibitors of a-glucosidases, and their inhibitions were comparable to those of commercially available drugs such as acarbose, voglibose, and miglitol for the treatment of type 2 diabetes. Especially, 1-C-butyl-L-arabinoiminofuranose 2c showed much powerful inhibitory activity for rat intestinal sucrase. Additionally, we prepared iminosugar 12 having 1-hydroxybutyl group as 1-C-alkyl units and their inhibitory activities toward a-glucosidase were measured.
