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

John P. Shihock, Joseph R. Wheatley, Robert J. Nash, Alison A. Watson, Rhodri C. Griffiths, Terry D. Butters, Mathias Müller, David J. Watkin, David A. Winkler, George W J Fleet

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A series of homorhamnqjirimycins and related compounds are prepared from two epimeric [2.2.2] bicyclic amino lactones 6 and 7 via the 2-azidoheptono-l,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 S-epi-L-rhamndpyranose 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 e/7/-homorhamnojirimycin (HRJ) 3 is also reported. Methanolysis of the bicyclic lactone 7 possessing a configuration corresponding to a-L-rhamnopyranose under basic conditions affords both a- and β-methyl 2,6-iminoheptonates 16 and 17. Reduction and subsequent deprotection affords the 2,6-iminoheptitols, a-homorhamnojirimycin (a-HRJ) 1 and β-homorhamnojirimycin (β-HRJ) 2, potent inhibitors of L-rhamnosidase and a-galactosidase, respectively. The crystal-structure determination of the bicyclic lactone 7 is also reported. 

Original languageEnglish
Pages (from-to)2735-2745
Number of pages11
JournalJournal of the Chemical Society, Perkin Transactions 1
Issue number19
Publication statusPublished - 1999
Externally publishedYes

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