(1S,2S,7R,8aS)- and (1S,2S,7S,8aS)-Trihydroxyoctahydroindolizine: Two New Glycosidase Inhibitors by Nitrone Cycloaddition Strategy

The two new epimeric (1S,2S,7R,8aS)- and (1S,2S,7S, SaS)-I,2,7- trihydroxyoctahydroindolizines 4 and 5 have been synthesized via methylenecyclopropanenitrone eycloaddition-rearrangement methodology employing an enantiomerically pure L-tartaric acid derived nitrone 7b. Highly stereoselective reductions of the intermediate indolizidinone 10b and final deprotection furnished the two title indolizidinetriols 4 and 5, the inhibiting abilities of which toward 24 commercially available glycosidases were tested. Both 4 and $ are good competitive inhibitors of amyloglucosidases with K i values of ca. 6 and 75 ~M, respectively. Compared with (+)-lentiginosine 3, 4 and 5 are less powerful inhibitors but, in contrast to 3, the (7R)-hydroxy analogue 4 possesses a weak inhibiting activity toward ct-Lfucosidase from bovine epididymis. A model to rationalize the structure-activity relationship of (+)-lentiginosine and the two new 7-hydroxylentiginosines toward glucoamylases is proposed on the basis of their structural comparison with known inhibitors and with the natural enzyme's substrate amylose.