Piperidine analogues of D-galactose as potent inhibitors of alpha-galactosidase: Synthesis by stannane-mediated hydroxymethylation of 5-azido-1,4-lactones. Structural relationships between D-galactosidase and L-rhamnosidase inhibitors

The syntheses of the polyhydroxylated piperidines deoxygalactonojirimycin 2 , homogalactonojirimycins 7 and 9, and other 2,6-iminoheptitol derivatives, including an analogue of L-altropyranose, are reported. 5-Azidoaldono-1,4- lactones undergo chain extension to afford azido lactols by the addition of a hydroxymethyllithium species 18, generated by transmetallation of a prot ected stannylmethanol derivative 17. Hydrogenation results in azide reducti on with subsequent intramolecular reductive amination to give piperidine ri ng systems. The deprotected iminogalactopyranose analogues are potent and s elective alpha-galactosidase inhibitors. Observations on the structural fea tures determining selectivity of inhibition of alpha-galactosidases over na ringinase (L-rhamnosidase) are also reported.