Intermediates for incorporation of tetrahydroxypipecolic acid analogues of α- and β-D-mannopyranose into combinatorial libraries:: unexpected nanomolar-range hexosaminidase inhibitors.: Synthesis of α- and β-homomannojirimycin

Homoazasugars have the distinction as a class of natural products in that most of them have been synthesised before they were isolated. Syntheses of alpha-1 and beta-homomannojirimycin 2 rely on the stereoselective and chemoselective sodium cyanoborohydride reduction of a [2.2.2] bicyclic imino lactone (6) to give a single [2.2.2] bicyclic amino-lactone (7). Methanolysis of 7 under basic conditions is accompanied by efficient epimerisation of the first formed alpha-amino-ester (8) to the more stable beta-amino-ester(9) in which the 2,6-substitutents are equatorial. Both 7 and 9 are suitable intermediates for the incorporation of tetrahydroxypipecolic acid derivatives into combinatorial libraries containing alpha- and beta-C-glycosyl analogues of aza-D-mannopyranose, respectively. Methylamides derived from 7 and 9 are shown to be specific and potent inhibitors of two beta-N-acetylglucosaminidases but have no effect on an alpha-N-acetylgalactosaminidase. The synthesis of alpha-14 and beta-17 manno-pipecolic acids is also reported. (C) 1998 Elsevier Science Ltd. All rights reserved.