| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1346093 | Tetrahedron: Asymmetry | 2012 | 6 Pages |
3-O-α-d-Glucopyranosyl-swainsonine was originally proposed17 as a potential inhibitor of the mammalian enzyme endo-α-mannosidase, but its synthesis has not been reported. Herein we report the total synthesis of this enigmatic compound, utilizing a halide-ion catalysed glycosylation of a swainsonine lactam with a glucosyl iodide donor as the key step. The resulting inhibitor was evaluated as an inhibitor of human endo-α-mannosidase, and as a ligand for bacterial orthologs from Bacteroides thetaiotaomicron and Bacteroides xylanisolvens, including active-centre variants, although no evidence for binding or inhibition was observed. The surprising lack of binding was rationalized by using structural alignment with an endo-α-mannosidase inhibitor complex, which identified deleterious interactions with the swainsonine piperidine ring and an essential active site residue.
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(1S,2R,8R,8aR)-2,8-Bis(acetoxy)-1-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyloxy)-hexahydroindolizin-5(1H)-oneC26H35NO15[α]D23=+46.7 (c 0.50, CHCl3)Source of chirality: d-glucose and d-riboseAbsolute configuration (1S,2R,8R,8aR,1′S,2′R,3′S,4′R,5′R)
(1S,2R,8R,8aR)-2,8-Bis(benzyloxy)-1-(6-O-acetyl-2,3,4-tri-O-benzyl-α-d-glucopyranosyloxy)-hexahydroindolizin-5(1H)-oneC51H55NO10[α]D22=+24.2 (c 0.21, CHCl3)Source of chirality: d-glucose and d-riboseAbsolute configuration (1S,2R,8R,8aS,1′S,2′R,3′S,4′R,5′R)
(1S,2R,8R,8aS)-2,8-Bis(benzyloxy)-1-hydroxyhexahydroindolizin-5(1H)-oneC22H25NO4[α]D24=-20.2 (c 0.845, CHCl3)Source of chirality: d-riboseAbsolute configuration (1S,2R,8R,8aS)
(1S,2R,8R,8aS)-8-Benzyloxy-1,2-dihydroxyhexahydroindolizin-5(1H)-oneC15H19NO4[α]D24=-30.9 (c 1.1, CHCl3)Source of chirality: d-riboseAbsolute configuration (1S,2R,8R,8aS)
(3aR,9R,9aR,9bS)-9-Benzyloxy-2,2-dimethylhexahydro-[1,3]dioxolo[4,5-a]indolizin-6(9bH)-oneC18H23NO4[α]D23=-21.2 (c 1.62, CHCl3)Source of chirality: d-riboseAbsolute configuration (3aR,9R,9aR,9bS)
(1S,2R,8R,8aR)-2,8-Bis(hydroxy)-1-(α-d-glucopyranosyloxy)-octahydroindolizineC14H25ClNO8[α]D22=+44.5 (c 0.28, MeOH)Source of chirality: d-glucose and d-riboseAbsolute configuration (1S,2R,8R,8aR,1′S,2′R,3′S,4′S,5′R)
