ENZYMATIC CHEMICAL SYNTHESIS AND BIOLOGICAL EVALUATION OF 7-MEMBERED IMINOCYCLITOLS/

Several polyhydroxyperhydroazepines have been obtained either by chemo enzymatic or chemical synthesis. Condensation of (+/-)-3-azido-2-hydro xypropanaldehyde and dihydroxyacetone phosphate (DHAP) in the presence of a DHAP dependent aldolase followed by treatment with acid phosphat ase and an isomerase gave a 6-azido-6-deoxyaldopyranose, which upon re ductive amination afforded the title compound. The iminocyclitols can also be obtained by chemical manipulations of aldopyranoses, protected as benzyl glycosides or diisopropylidene ethers. Thus, D-galactose le ads to a meso-3,4,5,6-tetrahydroxyperhydroazepine, D-mannose to a deri vative with a C-2 symmetry axis, and N-acetylglucosamine to a 6-acetam idoiminocyclitol. Asymmetrization of the mesio azasugar was carried ou t by chemical means, to yield a 3-methoxy-4,5,6-trihydroxyazepane. An attempted enzymatic synthesis of the methoxy derivatives of these azas ugars was unsuccessful, leading, however, to both enantiomers of 1-deo xy-2-O-methylmannojirimycin. Some of these compounds display significa nt activity as glycosidase inhibitors, with K-i values from moderate t o low micromolar range. Though all these iminocyclitols do not inhibit the mechanistically related HIV protease, the 3,6-dibenzyl derivative 30 showed moderate inhibition. The X-ray structure of 7 indicates a p seudochair conformation.