Synthesis of Tetrahydroxyquinolizidines: Ring-Expanded Analogs of the Mannosidase Inhibitor Swainsonine

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Abstract

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 shows that swainsonine lacks the C(4) hydroxymethine group of mannose. Ring-expanded quinolizidine analogs 4 of swainsonine were prepared where the “missing” hydroxymethine group was incorporated into the pyrrolidine ring of swainsonine between C(1) and C(8a). The quinolizidine analogs 4 resemble both d-mannopyranose and the related azasugar deoxymannojirimycin, a selective inhibitor of the glycoprotein processing enzyme mannosidase I. d-Arabinose was converted into the ω-halo azidoalkene 13, which was subjected to thermolysis, a strategy which had been successful in an earlier synthesis of swainsonine itself. Rather than the desired quinolizidine 4, the pyridinium ion 16 was produced. An alternate synthesis of all four C(9)/C(9a) diastereomers of 4 was developed which relied on the reductive double-alkylation of epoxides bearing remote azido and chloro groups. Thus, reduction of compounds 21α, 21β, 26, and 27 resulted in the formation of the quinolizidines 22, 23, 28, and 29, which were deprotected to give the quinolizidine analogs of swainsonine (9S,9aR)-4, (9R,9aS)-4, (9S,9aS)-4, and (9R,9aR)-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.

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