Synthesis of four enantiomerically pure 4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acids

CuCl-catalysed cycloaddition of methyl propiolate to O,O-diisopropyl (1S,2R,3S)- and (1R,2R,3S)-, or O,O-dibenzyl (1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-4-azido-1,2,3-trihydroxy-2,3-O-isopropylidenebutylphosphonates followed by methylation of HO–C-1, ammonolysis of methoxycarbonyl groups and hydrolysis of isopropylidene acetals led to diisopropyl (1S,2R,3S)- and (1R,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonates or, after hydrogenolytic removal of benzyl groups, to (1S,2R,3S)-, (1R,2R,3S)-, (1S,2R,3R)- and (1R,2R,3R)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acids.

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(1R,2R,3R)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acidC8H15N4O7PEe = 100%[α]D20=+7.7 (c 0.83, water)Source of chirality: d-isoascorbic acidAbsolute configuration: (1R,2R,3R)

(1R,2R,3S)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acidC8H15N4O7PEe = 100%[α]D20=-19.6 (c 1.01, water)Source of chirality: diethyl l-tartrateAbsolute configuration: (1R,2R,3S)

(1S,2R,3R)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acidC8H15N4O7PEe = 100%[α]D20=+12.4 (c 0.84, water)Source of chirality: d-isoascorbic acidAbsolute configuration: (1S,2R,3R)

(1S,2R,3S)-4-(4-Carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonic acidC8H15N4O7PEe = 100%[α]D20=-64.6 (c 0.89, water)Source of chirality: diethyl l-tartrateAbsolute configuration: (1S,2R,3S)

Diisopropyl (1S,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonateC14H27N4O7PEe = 100%[α]D20=+6.8 (c 1.1, CH3OH)Source of chirality: diethyl l-tartrateAbsolute configuration: (1S,2R,3S)

Diisopropyl (1R,2R,3S)-4-(4-carbamoyl-1,2,3-triazol-1-yl)-2,3-dihydroxy-1-methoxybutylphosphonateC14H27N4O7PEe = 100%[α]D20=-1.1 (c 1.8, CHCl3)Source of chirality: diethyl l-tartrateAbsolute configuration: (1R,2R,3S)