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

Journal article

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. ©The Royal Society of Chemistry 1999.

Authors: Shilvock, J; Wheatley, JR; Nash, R; Watson, A; Griffiths, R

• Publication status: Published
• Journal: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1
• Issue: 19
• Pages: 2735-2745
• Publication date: 1999-10-07
• DOI: 10.1039/a904064a
• EISSN: 1364-5463
• ISSN: 0300-922X
• Language: English