Enzymatic/Chemical Synthesis and Biological Evaluation of Seven-Membered Iminocyclitols

Abstract

Several polyhydroxyperhydroazepines have been obtained either by chemoenzymatic or chemical synthesis. Condensation of (±)-3-azido-2-hydroxypropanaldehyde and dihydroxyacetone phosphate (DHAP) in the presence of a DHAP dependent aldolase followed by treatment with acid phosphatase and an isomerase gave a 6-azido-6-deoxyaldopyranose, which upon reductive 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 leads to a meso-3,4,5,6-tetrahydroxyperhydroazepine, d-mannose to a derivative with a C2 symmetry axis, and N-acetylglucosamine to a 6-acetamidoiminocyclitol. Asymmetrization of the meso azasugar was carried out by chemical means, to yield a 3-methoxy-4,5,6-trihydroxyazepane. An attempted enzymatic synthesis of the methoxy derivatives of these azasugars was unsuccessful, leading, however, to both enantiomers of 1-deoxy-2-O-methylmannojirimycin. Some of these compounds display significant activity as glycosidase inhibitors, with Ki values from moderate to 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 pseudochair conformation.