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.