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Synlett 2003(3): 0341-0344
DOI: 10.1055/s-2003-37109
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (1S,2S,3R,8S,8aR)-1,2,3,8-Tetrahydroxy-6-oxa-5-thioxoindolizidine: A Stable Reducing Swainsonine Analog with Controlled Anomeric Configuration

P. Díaz-Péreza, M. I. García-Morenoa, C. Ortiz Mellet*a, J. M. García Fernández*b
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Aptdo. 553, 41071 Sevilla, Spain
Fax: +34(954)624960; e-Mail: mellet@us.es;
Instituto de Investigaciones Químicas, CSIC, Américo Vespucio s/n, Isla de la Cartuja, E-41092 Sevilla, Spain
Fax: +34(954)460565; e-Mail: jogarcia@cica.es;
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Publication History

Received 10 January 2003
Publication Date:
07 February 2003 (online)

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Abstract

The title indolizidine, a ring-modified analog of the potent mannosidase inhibitor (-)-swainsonine, has been prepared by intramolecular nucleophilic addition of the sp2-type nitrogen atom of a preformed 1,3-oxazine-2-thione heterocycle to the masked aldehyde group in a d-mannose precursor; the stereochemistry of the generated aminoacetalic stereocenter is governed by the generalized anomeric effect, the pseudoanomeric hydroxyl group adopting an axial orientation that mimics that of α-d-mannopyranoside aglycons.

Key words

carbohydrates - cyclizations - glycosidase inhibitors - indolizidines - swainsonine

9

Notice that, although the stereochemical notation at C-2 and C-8 changes from 1 to 4, the absolute stereochemistry remains identical at these centers.

13

(i)Preparation of the reducing (-)-swainsonine derivative 4 from 7. A solution of 7 (285 mg, 1.1 mmol) in MeOH (2 mL) was hydrogenated in the presence of Pd/C (10%, 110.4 mg) for 3 h to give amine 8 as a hygroscopic solid that was used in the next step without further purification. Isothiocyanation of 8 (254 mg, 1.07 mmol) by reaction with CSCl2 (84 µL, 1.1 equiv) and CaCO3 (214 mg, 2 equiv) in H2O-acetone (3:2, 3.5 mL) afforded, after column chromatography (EtOAc-hexanes, 1:4), the hydroxyiso-thiocyanate 9 (118 mg, 40%). To a solution of 9 (50 mg, 0.18 mmol) in DMF (3.5 mL) Et3N (8.5 µL) was added and the reaction mixture was stirred at 80 ºC for 30 min, and then concentrated. Column chromatography (EtOAc-hexanes, 1:2) yielded the corresponding cylic carbamate 10 (42 mg, 85%). Treatment of 10 with TFA-H2O (1:1, 3 mL) at 100 ºC for 48 h led to mixture of compounds from which the target oxaindolizidine 4 (6 mg, 18%) was isolated by column chromatography (EtOAc-EtOH-H2O, 45:5:3). Compounds 9, and 10 gave satisfactory microanalytical, NMR (1H and 13C) and FAB-mass spectral data in agreement with the proposed structures.
(ii) From 11. To a solution of 11 (138 mg, 0.67 mmol) in pyridine (3 mL) t-butyldimethylsilyl chloride (101 mg, 0.67 mmol) was added. The mixture was stirred at r.t. for 45 min, then Ac2O (2 mL) was added and the mixture stirred for an additional 1 h. Conventional work up afforded 12 (256 mg, 62%), which was reduced to the corresponding amine 13 by hydrogenation (10% Pd/C, 46 mg) in MeOH (5 mL) and used in the next step without further purification. To a heterogeneous mixture of 13 (180 mg, 0.43 mmol) and CaCO3 (97 mg, 2 equiv) in CH2Cl2-H2O (1:1, 6.6 mL) at
0 ºC CSCl2 (36 µL, 1.1 equiv) was added. The reaction mixture was vigorously stirred for 10 min, the organic phase was separated, washed with water and concentrated. Column chromatography (EtOAc-hexanes, 1:5) of the residue yielded isothiocyanate 14 (132 mg, 67%). To a solution of 14 (102 mg, 0.22 mmol) in THF (5 mL) under Ar, TBAF (1 m in THF, 0.26 mL, 1.1 equiv) was added and the mixture was adjusted to pH 7 by addition of glacial HOAc. After 45 min the solvents were removed, the residue was dissolved in dioxane (7 mL) and a catalytic amount of Et3N was added. The mixture was stirered for 45 min, concentrated and chromatographed (EtOAc-hexanes, 1:2) to give the cyclic thiocarbamate 15 (55 mg. 73%). Deacetylation of 15 with methanolic NaOMe, neutralization of the mixture with solid CO2 and purification of the resulting residue by column chromatography (EtOAc→EtOAc-EtOH-H2O, 45:5:3) afforded 4 (21 mg, 79%). Compounds 11, 12, 14, and 15 gave satisfactory microanalytical, NMR (1H and 13C) and FAB-mass spectral data in accord with the proposed structures.
Data for 4: Rf (EtOAc-EtOH-H2O, 45:5:3) 0.53; [α]D +12.5 (c 1.0, H2O); 1H NMR (500 MHz, CD3OD): δ (ppm) = 5.41 (d, 1 H, H-3), 4.32 (dd, 1 H, H-7a), 4.18 (dd, 1 H, H-1), 4.14 (ddd, 1 H, H-8), 4.08 (dd, 1 H, H-2), 3.95 (t, 1 H, H-7b), 3.64 (dd, 1 H, H-8a), J 1,2 = 4.2 Hz, J 1,8a = 2.0 Hz, J 2,3 = 6.0 Hz, J 7a,8 = 4.6 Hz, J 7b,8 = 10.3 Hz, J 8,8a = 8.5 Hz; 13C NMR (125.7 MHz, CD3OD): δ (ppm) = 189.2 (C-5), 93.8 (C-3), 80.6 (C-2), 74.1 (C-7), 72.1 (C-1), 69.0 (C-8a), 61.9 (C-8); FABMS m/z 222 (100%, [M+H]+); FABMSHR m/z 221.035640 (221.035794 Calcd for C7H11NO5S).