(1S,2S,7R,8AS)-TRIHYDROXYOCTAHYDROINDOLIZINE AND (1S,2S,7S,8AS)-TRIHYDROXYOCTAHYDROINDOLIZINE - 2 NEW GLYCOSIDASE INHIBITORS BY NITRONE CYCLOADDITION STRATEGY

The two new epimeric (1S,2S,7R,8aS)- and 1S,2S,7S,8aS)-1,2,7-trihydrox yoctahydroindolizines 4 and 5 have been synthesized via methylenecyclo propane-nitrone cycloaddition-rearrangement methodology employing an e nantiomerically pure L-tartaric acid derived nitrone 7b. Highly stereo selective reductions of the intermediate indolizidinone 10b and final deprotection furnished the two title indolizidinetriols 4 and 5, the i nhibiting abilities of which toward 24 commercially available glycosid ases were tested. Both 4 and 5 are good competitive inhibitors of amyl oglucosidases with K-i values of ca. 6 and 75 mu M, respectively. Comp ared with (+)-lentiginosine 3, 4 and 5 are less powerful inhibitors bu t, in contrast to 3, the (7R)-hydroxy analogue 4 possesses a weak inhi biting activity toward alpha-L-fucosidase from bovine epididymis. A mo del to rationalize the structure-activity relationship of (+)-lentigin osine and the two new 7-hydroxylentiginosines toward glucoamylases is proposed on the basis of their structural comparison with known inhibi tors and with the natural enzyme's substrate amylose. Copyright (C) 19 96 Elsevier Science Ltd