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 s tereoisomers are glycosidase inhibitors of potential therapeutic use. Since the glycosidase inhibitory activity of azasugars is profoundly e ffected by ring size modification, the ring-expanded indolizidine anal ogs 7 (homoalexine), 8 (8-epihomoaustraline), 9 (homoaustraline), and 10 (8-epihomoalexine) were prepared. L-Xylose was converted into the d iols 16, which were transformed into the nine-membered lactones 18 by Claisen rearrangment of the cyclic ketene acetal 17. Transesterificati on of the lactones to the hydroxy esters 19 followed by azide displace ment and epoxidation gave the epoxides 21 and 31, Reductive double cyc lization of these azido-epoxides followed by functional group adjustme nt provided the desired homologs 7-10. An alternative route involving stereoselective epoxidation of the nine-membered lactones was also exa mined. The homologs 7-10 were found to be good inhibitors of amylogluc osidase (Aspergillus niger). The inhibitory activities of 8 and 10 are comparable to those exhibited by castanospermine (5) and the pyrroliz idines alexine (3), australine (4), and 7-epiaustraline, Indolizidines 7-10 do not inhibit beta-glucosidase (almond) or alpha-glucosidase (b akers' yeast). This activity parallels that exhibited by the pyrrolizi dine inhibitors alexine, australine, and 7-epiaustraline, which are ge nerally good amyloglucosidase inhibitors but relatively weak inhibitor s of alpha-glucosidase and beta-glucosidase. However, in contrast to t he pyrrolizidine inhibitors which have not been reported to possess ma nnosidase inhibitory activity, the indolizidines 7-10 were found to in hibit alpha-mannosidase (jack bean), albeit weakly.