SYNTHESIS OF C-GLYCOSYLTETRAZOLES RELATED TO 3-DEOXY-D-ARABINO-HEPTULOSONIC ACID 7-PHOSPHATE (DAHP) - POTENTIAL INHIBITORS OF EARLY STEPS IN THE SHIKIMATE PATHWAY

Treatment of 3,4,5,7-tetra-0-acetyl-2,6-anhydro-D-glycero-D-ga/acto-heptononitrile 16 with diaza-bicycloundecene (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-beta-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-alpha-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-beta-D-arabino-hexopyranoside 34 was obtained (40%) together with the alpha-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-alpha-D-arabino-hexopyranose 12 (54% overall). Treatment of 1,3,4,6-tetra-0-acetyl-2-deoxy-alpha-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-ta/o-heptononitrile 40 (53%), together with the D-ga/acto-epimer 39 (17%). Cycloaddition of 39 and 40 with azide ion and subsequent deprotection gave 5-(2-deoxy-beta-D-lyxo-hexopyranosyl)tetrazole 13 and the alpha-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 beta-D-glyCoside 44. Cycloaddition of 44 with azide ion, deacetylation, and hydrolysis led to 2-deoxy-1-tetrazol-5-yl-alpha-D-lyxo-hexopyranose 15. None of the C-glycosyltetrazoles were strong inhibitors of dehydroquinate synthase from E. coli.