Synthesis of homorhamnojirimycins and related trihydroxypipecolic acid derivatives via divergent bicyclic amino lactone intermediates: Inhibition of naringinase (L-rhamnosidase) and dTDP-rhamnose biosynthesis

Abstract

A series of homorhamnojirimycins and related compounds are prepared from two epimeric [2.2.2] bicyclic amino lactones 6 and 7 via the 2-azidoheptono-1,5-lactone 8, itself derived from L-rhamnose. Aminolysis and deprotection of the bicyclic lactones provides an efficient route to trihydroxypipecolic acid amide analogues of 5-epi-L-rhamnopyranose 12a–d and L-rhamnopyranose 14a–d. Some of the L-rhamnopyranose analogues display inhibitory activity against naringinase (L-rhamnosidase) and dTDP-rhamnose biosynthesis and are potentially useful as tools for investigating cell wall biosynthesis of Mycobacterium tuberculosis, the causative agent of tuberculosis. The synthesis of other homoiminosugar analogues including epi-homorhamnojirimycin (HRJ) 3 is also reported. Methanolysis of the bicyclic lactone 7 possessing a configuration corresponding to α-L-rhamnopyranose under basic conditions affords both α- and β-methyl 2,6-iminoheptonates 16 and 17. Reduction and subsequent deprotection affords the 2,6-iminoheptitols, α-homorhamnojirimycin (α-HRJ) 1 and β-homorhamnojirimycin (β-HRJ) 2, potent inhibitors of L-rhamnosidase and α-galactosidase, respectively. The crystal-structure determination of the bicyclic lactone 7 is also reported.