Synthesis of Novel Glycosidase-Inhibitory Hydroxymethyl-Substituted Polyhydroxylated Indolizidines: Ring-Expanded Analogs of the Pyrrolizidine Alkaloids Alexine and Australine

The pyrrolizidine azasugars alexine ( 3 ) and australine ( 4 ) and their stereoisomers are glycosidase inhibitors of potential therapeutic use. Since the glycosidase inhibitory activity of azasugars is profoundly effected by ring size modification, the ring-expanded indolizidine analogs 7 (homoalexine), 8 (8-epihomoaustraline), 9 (homoaustraline), and 10 (8-epihomoalexine) were prepared. l -Xylose was converted into the diols 16, which were transformed into the nine-membered lactones 18 by Claisen rearrangment of the cyclic ketene acetal 17 . Transesterification of the lactones to the hydroxy esters 19 followed by azide displacement and epoxidation gave the epoxides 21 and 31 . Reductive double cyclization of these azido-epoxides followed by functional group adjustment provided the desired homologs 7 − 10 . An alternative route involving stereoselective epoxidation of the nine-membered lactones was also examined. The homologs 7 − 10 were found to be good inhibitors of amyloglucosidase ( Aspergillus niger ). The inhibitory activities of 8 and 10 are comparable to those exhibited by castanospermine ( 5 ) and the pyrrolizidines alexine ( 3 ), australine ( 4 ), and 7-epiaustraline. Indolizidines 7 − 10 do not inhibit β-glucosidase (almond) or α-glucosidase (bakers' yeast). This activity parallels that exhibited by the pyrrolizidine inhibitors alexine, australine, and 7-epiaustraline, which are generally good amyloglucosidase inhibitors but relatively weak inhibitors of α-glucosidase and β-glucosidase. However, in contrast to the pyrrolizidine inhibitors which have not been reported to possess mannosidase inhibitory activity, the indolizidines 7 − 10 were found to inhibit α-mannosidase (jack bean), albeit weakly.