Issue 19, 1999

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.

Supplementary files

Article information

Article type
Paper

J. Chem. Soc., Perkin Trans. 1, 1999, 2735-2745

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

J. P. Shilvock, J. R. Wheatley, R. J. Nash, A. A. Watson, R. C. Griffiths, T. D. Butters, M. Müller, D. J. Watkin, D. A. Winkler and G. W. J. Fleet, J. Chem. Soc., Perkin Trans. 1, 1999, 2735 DOI: 10.1039/A904064A

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