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Synthesis 2006(3): 496-508  
DOI: 10.1055/s-2006-926281
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Reactivity of Halogenated 1,2,4-Triazole Nucleoside Analogues with High Potential for Chemical Modifications

Stefanie Libnow, Susanne Wille, Andrea Christiansen, Martin Hein, Helmut Reinke, Martin Köckerling, Ralf Miethchen*
Universität Rostock, Institut für Chemie, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: ralf.miethchen@uni-rostock.de;
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Publikationsverlauf

Received 26 June 2005
Publikationsdatum:
11. Januar 2006 (online)

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Abstract

1,2,4-Triazole nucleoside analogues bonded at N-1 of the base were synthesized by addition of N-halo-3,5-dibromo-1,2,4-triazoles to 1,2-unsaturated carbohydrate derivatives (glycals). Examples are given for 1,5-anhydro-3,4,6-tri-O-acetyl-2-deoxy-d-arabino-hex-1-enitol (tri-O-acetyl-d-glucal), and 1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-d-arabino-hex-1-enitol (tri-O-benzyl-d-glucal), respectively. The graduated reactivity of the three halogens [C-5 (triazole) > C-2 (sugar) > C-3 (triazole)] in the addition products allows subsequent regioselective replacement and deprotection reactions like hydrodehalogenations, nucleophilic substitutions (by methoxide, hydrazine, benzylamine, thiophenolate), deacetylations, and debenzylations, respectively. Thus, the paper opens a new synthetic approach to triazole nucleoside analogues of 2-deoxy-sugars. X-ray analyses support the structures of nine products.

Key words

nucleoside analogues - 1,2,4-triazoles - additions to d-glucals - nucleophilic substitutions - hydrodehalogenations

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3

Unlike 3,5-dibromo-1,2,4-triazole itself, which is deprotonated and so deactivated by sodium hydroxide, the corresponding N-alkyl derivative reacts with this reagent via 3-bromo-5-hydroxy-1-methyl-1,2,4-triazole to the tautomeric 3-bromo-1-methyl-1,2,4-triazolone-(5). The reaction stops at this stage, because the 3-bromo-1-methyl-1,2,4-triazolone-(5) is now likewise deactivated by deprotonation: Miethchen, R.; Kröger, C.-F. unpublished results.

23

The use of solvents like CHCl3 and NMP gave only low yields of the desired compounds. THF proved to be unsuitable, because it was attacked by 1,3,5-tribromo-1,2,4-triazole (1) resulting in ring-opening and insertion of the 1-oxy-tetramethylene chain between the glycosidic position and N-1 of the triazole ring. The diastereomeric O-glyco­-sides (54%) were formed along with about 26% of the desired products: Christiansen, A.; Miethchen, R. unpublished results.

24

Tribromo derivative 5, EtMgCl/[Fe(acac)3] in THF/NMP gave 1-(3,4,6-tri-O-acetyl-2-deoxy-α-d-mannopyranosyl)-3-bromo-1H-1,2,4-triazole along with dibromo compound 13.

27

Crystallographic data for the structures in this paper have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 265777 (11), 265778 (17), 276274 (5), 276275 (6), 276276 (7), 276277 (8), 276278 (13), 276279 (14), and 276280 (30). Copies of these data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk or via www.ccdc.cam.ac.uk/conts/retrieving.html.