Syntheses of tetrahydroxyazepanes from chiro-inositols and their evaluation as glycosidase inhibitors

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Two pairs of C2-symmetric tetrahydroxyazepanes [(−), (+)-1 and (−), (+)-2] have been synthesized from the enantiomeric chiro-inositols and evaluated as glycosidase inhibitors. Alternative syntheses of ido-tetrahydroxyazepanes (−)- and (+)-2 from myo-inositol were also developed. The key synthetic transformations were glycol fission and cyclization of the derived dialdehydes by double reductive amination. The d-manno-tetrahydroxyazepane [(−)-1] showed selective inhibition of α-l-fucosidase and β-d-galactosidase, while the enantiomer [(+)-1] was a selective inhibitor of an α-d-galactosidase. In contrast, the l-ido-tetrahydroxyazepane (+)-2 was a broad spectrum hexosidase inhibitor, but showed none of the reported hexosaminidase inhibition. Its enantiomer (−)-2 is a poor hexosidase inhibitor.