Assignment of the Absolute Configuration of Natural Lentiginosine by Synthesis and Enzymic Assays of Optically Pure (+) and (-)-Enantiomers

Abstract

The structure and absolute configuration of natural lentiginosine isolated from plant sources was\ndetermined to be (lS,2S,8aS)-1,2-dihydroxyindolizidi(n(e+ )-4) on the basis of the synthesis of both\nenantiomers (+)-4 and (-)-4 and their inhibition of amyloglucosidases. Alkaloid (+)-4 was derived\nfrom (L)-(+)-tartaric acid via a highly stereo- and regioselective 1,3-dipolar cycloaddition of (3S,4S)-\n3,4-bis[(tert-butyldiphenylsilyl)oxyl-l-pyrroline N-oxide to methylenecyclopropane, followed by\nthermal rearrangement of the adduct into (1S,2S,8aS)-1,2-[(tert-butyldiphenylsilyl)oxyloctahydroindolizin-\n7-one. The enantiomer (-1-4 was derived in the same way from (D)-(-)-tartaric acid.\nBoth (+)-4 and (-1-4 displayed inhibition specificity for amyloglucosidases, being inactive toward\n17 other glycosidases. With amyloglucosidase from Aspergillus niger, synthetic (+)-4 displayed\ninhibition (Ki = 2 pM) 5 times stronger than that reported for natural lentiginosine, 35 times that\nmeasured for (-)-4, and twice that of castanospermine. Alkaloid (+)-4 is thus the most potent and\nspecific competitive inhibitor of amyloglucosidases among azasugars and their analogues.