INTERMEDIATES FOR INCORPORATION OF TETRAHYDROXYPIPECOLIC ACID ANALOGSOF ALPHA-D-MANNOPYRANOSE AND BETA-D-MANNOPYRANOSE INTO COMBINATORIAL LIBRARIES - UNEXPECTED NANOMOLAR-RANGE HEXOSAMINIDASE INHIBITORS - SYNTHESIS OF ALPHA-HOMOMANNOJIRIMYCIN AND BETA-HOMOMANNOJIRIMYCIN

Homoazasugars have the distinction as a class of natural products in t hat most of them have been synthesised before they were isolated. Synt heses of alpha-1 and beta-homomannojirimycin 2 rely on the stereoselec tive and chemoselective sodium cyanoborohydride reduction of a [2.2.2] bicyclic imino lactone (6) to give a single [2.2.2] bicyclic amino-la ctone (7). Methanolysis of 7 under basic conditions is accompanied by efficient epimerisation of the first formed alpha-amino-ester (8) to t he more stable beta-amino-ester(9) in which the 2,6-substitutents are equatorial. Both 7 and 9 are suitable intermediates for the incorporat ion of tetrahydroxypipecolic acid derivatives into combinatorial libra ries containing alpha- and beta-C-glycosyl analogues of aza-D-mannopyr anose, respectively. Methylamides derived from 7 and 9 are shown to be specific and potent inhibitors of two beta-N-acetylglucosaminidases b ut have no effect on an alpha-N-acetylgalactosaminidase. The synthesis of alpha-14 and beta-17 manno-pipecolic acids is also reported. (C) 1 998 Elsevier Science Ltd. All rights reserved.