Synthesis of C-glycosyltetrazoles related to 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP); potential inhibitors of early steps in the shikimate pathway

J. Grant Buchanan, A. P W Clelland, Trevor Johnson, R. A C Rennie, Richard H. Wightman

Research output: Contribution to journalArticle

Abstract

Treatment of 3,4,5,7-tetra-O-acetyl-2,6-anhydro-D-glycero-D-galacto-heptononitrile 16 with diazabicycloundecene (DBU) formed 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-arabino-hept-2-enononitrile 22, which on treatment with ammonium azide gave the corresponding unsaturated tetrazole 23. Stereoselective catalytic reduction of 23 and subsequent deacetylation produced 5-(2-deoxy-ß-D-arabino-hexopyranosyl) tetrazole 24, which was converted in two steps into its 6-phosphate 10. Reaction of 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-manno-heptononitrile 27 with ammonium azide, followed by deacetylation, gave 5-(2-deoxy-a-D-arabino-hexopyranosyl)tetrazole 29 (81% overall), which was converted into its 6-phosphate 11. When 4,5,7-tri-O-acetyl-2,6-anhydro-2-bromo-3-deoxy-D-gluco-heptononitrile 31 was treated with methanol and 2,6-lutidine, methyl 3,4,6-tri-O-acetyl-1-cyano-2-deoxy-ß-D-arabino-hexopyranoside 34 was obtained (40%) together with the a-anomer 35 (11%). Cycloaddition of 34 with azide ion, followed by sequential treatment with base and with acid, gave 2-deoxy-1-tetrazol-5-yl-a-D-arabino-hexopyranose 12 (54% overall). Treatment of 1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-lyxo-hexopyranose 38 with trimethylsilyl cyanide and boron trifluoride in nitromethane gave 4,5,7-tri-O-acetyl-2,6-anhydro-3-deoxy-D-talo-heptononitrile 40 (53%), together with the D-galacto-epimer 39 (17%). Cycloaddition of 39 and 40 with azide ion and subsequent deprotection gave 5-(2-deoxy-ß-D-lyxo-hexopyranosyl)tetrazole 13 and the a-D-lyxo-isomer 14 respectively in good yields. Reaction of nitrile 40 with N-bromosuccinimide formed 4,5,7-tri-O-acetyl-2,6-anhydro-2-bromo-3-deoxy-D-galacto-heptononitrile 43 (63%), which with methanol and 2,6-lutidine was converted into the methyl ß-D-glycoside 44. Cycloaddition of 44 with azide ion, deacetylation, and hydrolysis led to 2-deoxy-1-tetrazol-5-yl-a-D-lyxo-hexo-pyranose 15. None of the C-glycosyltetrazoles were strong inhibitors of dehydroquinate synthase from E. coli.

Original languageEnglish
Pages (from-to)2593-2601
Number of pages9
JournalJournal of the Chemical Society, Perkin Transactions 1
Issue number20
Publication statusPublished - 1992

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