SYNTHESIS OF TETRAHYDROXYQUINOLIZIDINES - RING-EXPANDED ANALOGS OF THE MANNOSIDASE INHIBITOR SWAINSONINE

The indolizidine azasugar swainsonine (1) is an important inhibitor of mannosidase II and has shown antitumor and immunomodulatory activity. A comparison of the structure of swainsonine and D-mannopyranose show s that swainsonine lacks the C(4) hydroxymethine group of mannose. Rin g-expanded quinolizidine analogs 4 of swainsonine were prepared where the ''missing'' hydroxymethine group was incorporated into the pyrroli dine ring of swainsonine between C(1) and C(8a). The quinolizidine ana logs 4 resemble both D-mannopyranose and the related azasugar deoxyman nojirimycin, a selective inhibitor of the glycoprotein processing enzy me mannosidase I. D-Arabinose was converted into the omega-halo azidoa lkene 13, which was subjected to thermolysis, a strategy which had bee n successful in an earlier synthesis of swainsonine itself. Rather tha n the desired quinolizidine 4, the pyridinium ion 16 was produced. An alternate synthesis of all four C(9)/C(9a) diastereomers of 4 was deve loped which relied on the reductive double-alkylation of epoxides bear ing remote azido and chloro groups. Thus, reduction of compounds 21 al pha, 21 beta, 26, and 27 resulted in the formation of the quinolizidin es 22, 23, 28, and 29, which were deprotected to give the quinolizidin e analogs of swainsonine (9S,9aR)-4, (9R,9aS)-4, (9S,9aS)-4, and (9R,9 aR)-4, respectively. An alternate synthesis of(9R,9aR)-4 involving the reductive N-alkylation of a cyclic imine was also developed. None of the quinolizidines showed significant glycosidase activity in screens against mannosidases, glucosidases, or fucosidases. Speculation on the significance of these findings is presented.