Efficient synthesis from D -lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-L -arabinitol LABNAc, a potent pyrrolidine inhibitor of hexosaminidases J. S. Shane Rountree, a,b Terry D. Butters, a Mark R. Wormald, a Raymond A. Dwek, a Naoki Asano, c Kyoko Ikeda, c Emma L. Evinson, d Robert J. Nash d and George W. J. Fleet b, * a Oxford Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK b Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK c Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 9201181, Japan d VASTox plc, Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth, Dyfed, Wales SY23 3EB, UK Received 7 March 2007; revised 29 March 2007; accepted 5 April 2007 Available online 14 April 2007 Abstract—The synthesis from D-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol LABNAc proceeded in an overall yield of 25%; the enantiomer, 2-acetamido-1,4-imino-1,2,4-trideoxy-D-arabinitol DABNAc, was prepared from L-lyxonolac- tone. LABNAc and N-benzyl LABNAc are potent non-competitive inhibitors of D-hexosaminidase, whereas N-benzyl DABNAc exhibits weak competitive inhibition of the enzyme; this provides further evidence in support of Asano’s hypothesis that while D- imino sugar mimics inhibit D-glycohydrolases competitively, their L-enantiomers show non-competitive inhibition and in the case of iminofuranoses L-enantiomers are usually more potent inhibitors. Ó 2007 Elsevier Ltd. All rights reserved. Specific inhibition of individual D-hexosaminidases may lead to new strategies for the treatment of many dis- eases, including cancer, 1 arteriosclerosis 2 and some lyso- somal storage diseases; 3 such compounds also have potential as antifungal agents 4 and catalysts for biomass degradation. 5 Replacement of the oxygen by nitrogen in a sugar gives a broadly based class of both synthetic and naturally occurring glycosidase inhibitors. 6 Thus, replacement of the ring oxygen in glucose gives the nat- ural product deoxynojirimycin 1, which is a powerful glucosidase inhibitor; 7 derivatives of 1 have been used in the treatment of diabetes 8 and Gaucher’s disease, 9 and are antiviral compounds. 10 Pyrrolidine imino sugar 2, which is the furanose analogue of glucose, 11 is a much weaker inhibitor of glucosidases than 1; similarly, galac- tofuranose analogue 3 is a much weaker galactosidase N H CH 2 OH OH OH HO N H CH 2 OH OH OH CH 3 CONH N H HO OH 2 N H CH 2 OH HO OH 4D DAB-1 8D R=PhCH 2 9D R=H 1 5 CH 2 OH OH N H CH 2 OH HO OH 4L LAB N H HO OH 3 CH 2 OH OH N H CH 3 CONH OH 6 N R CH 2 OH CH 3 CONH OH CH 2 OH OH N R CH 2 OH CH 3 CONH OH N H CH 3 CONH OH 7 CH 2 OH OH 8L R=PhCH 2 9L R=H 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.04.041 * Corresponding author. E-mail: george.fleet@chem.ox.ac.uk Tetrahedron Letters 48 (2007) 4287–4291