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

Abstract Homoazasugars have the distinction as a class of natural products in that most of them have been synthesised before they were isolated. Syntheses of α- 1 and β-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 α-amino-ester ( 8 ) to the more stable β-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 α- and β-C-glycosyl analogues of aza- d -mannopyranose, respectively. Methylamides derived from 7 and 9 are shown to be specific and potent inhibitors of two β-N-acetylglucosaminidases but have no effect on an α-N-acetylgalactosaminidase. The synthesis of α- 14 and β- 17 manno-pipecolic acids is also reported.