Journal article

Total, asymmetric synthesis of methyl 3-deoxy-3-(1 ',2 ',6 '-trideoxy-2 ',6 '-imino-D-galactitol-1-yl)-alpha-D-manno-pyranoside (A C-linked imino disaccharide): Conformational analysis and glycosidase inhibition

The lithium enolate 16 derived in 5 steps from the Diels-Alder adduct of furan to 1-cyanovinyl (1S)-camphanate [(+)-12: a "naked sugar" of the first generation] was reacted with (+)(1R,4S,5S,6S)-6-endo-chroro-3-methylidene-5-exo-phenylseleno-7-oxabic yclo[2.2.1]. heptan-2-one [(+)-8] to give a unique product of Michael addition after acidic quenching. This adduct (-)-18 was transformed into branched long-chain carbohydrate derivatives such as benzyl 5-deoxy-5-[(5"-O-acetyl-3"-deoxy-2"-O-methoxymethyl-D-manno-furanurono-6 , 1-lactone-3''-yl)methyl]- (tert-butyl)dimethylsilyl-2,3-di-O-methoxymethyl-alpha and beta-L-gulo-furanosideuronate [(-)-27]. Hydrogenolysis, followed by a Curtius rearrangement permitted to construct the corresponding branched 5-amino-5,6-dideoxydodecose derivative (-)-30 which was converted into 5-O-acetyl-3- [ 5'-N-(benzyloxy)carbonyl-2',3'-di-O-methoxymethyl-alpha and beta-D-manno-furanose]-2-O-methoxymethyl-D-manno-furanurono-6, 1-lactone [(-)-31] and then into methyl 3-deoxy-3-(1',2',6'-trideoxy-2',6'-imino-D-galactitol-1'-yl)-alpha-D-man no-pyranoside [(-)-1]. Its H-1 NMR spectrum measured at variable temperature demonstrated that (-)-1 exist as a double equilibrium involving two pairs of rotamers about the sigma C(1')-C(2') and sigma C(1')-C(3) bond [CH2 bridge linking beta-C(I) of the I,5-dideoxy-1,5-imino-D-lyxitol unit at C(3) of methyl alpha-D-manno-pyranoside]. Rotamers B' in which C(3) is gauche with respect to C(3') is preferred to conformers C' in which C(3) is anti with respect to C(3'). An equilibrium constant K (B' = C') congruent to 0.35 (25 degrees C) was evaluated. Rotamers B [C(2) gauche with respect to C(2')] and C [C(2) anti with respect to C(2')] are equally populated. Disaccharide mimetic (-)-1 is a moderate inhibitor of alpha-L-fucosidases from bovine liver (K-i = 100 mu M) and human placenta.


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