Studies towards the synthesis of (1R,2S)- and (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonates and (1S,2S)- and (1R,2S)-2,3-epoxy-1-hydroxypropylphosphonates

The trans-configured fosfomycin analogue, diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonate, was synthesised by the intramolecular Williamson reaction of diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate. The cis-analogue was obtained as O-ethyl or O,O-diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonates, when (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonate or its 3-O-trityl derivative were used as starting materials, respectively. The intramolecular Williamson cyclisations of diethyl (1S,2R)- and (1R,2S)-1-benzyloxy-3-hydroxy-2-mesyloxypropylphosphonates led to diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, respectively, with the concomitant formation of diethyl (E)-1-benzyloxy-3-hydroxyprop-1-en-1-phosphonate. From diethyl (1S,2S)- and (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonates, enantiomerically pure diethyl (1S,2S)- and (1R,2S)-1,2-dihydroxypropylphosphonates were obtained by catalytic hydrogenation, while diethyl (1S,2S)- and (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonates were produced after epoxide ring opening with dibenzylamine, acetylation and hydrogenolysis.

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Diethyl (1R,2S)-1,2-epoxy-3-hydroxypropylphosphonateC7H15O5PEe = 100%[α]D20=+11.7 (c 0.8, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1R,2S)

Diethyl (1S,2S)-1,2-epoxy-3-hydroxypropylphosphonateC7H15O5PEe = 100%[α]D20=-24.7 (c 0.8, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1S,2S)

O-Ethyl (1R,2S)-1,2-epoxy-3-trityloxypropylphosphonateC5H11O5PEe = 100%[α]D20=+12.2 (c 0.08, H2O)Source of chirality: d-mannitolAbsolute configuration: (1R,2S)

Diethyl (1R,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonateC8H19O8PSEe = 100%[α]D20=+4.7 (c 0.97, CH3OH)Source of chirality: d-mannitolAbsolute configuration: (1R,2R)

Diethyl (1S,2R)-1,3-dihydroxy-2-mesyloxypropylphosphonateC8H19O8PSEe = 100%[α]D20=+10.9 (c 1.0, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1S,2R)

Diethyl (1R,2S)-2,3-epoxy-1-benzyloxypropylphosphonateC14H21O5PEe = 100%[α]D20=-19.7 (c 1.0, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1R,2S)

Diethyl (1S,2S)-2,3-epoxy-1-benzyloxypropylphosphonateC14H21O5PEe = 100%[α]D20=-20.6 (c 4.0, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1S,2S)

Diethyl (1S,2S)-3-acetamido-1,2-dihydroxypropylphosphonateC9H20NO6PEe = 100%[α]D20=-16.4 (c 1.45, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1S,2S)

Diethyl (1R,2S)-3-acetamido-1,2-dihydroxypropylphosphonateC9H20NO6PEe = 100%[α]D20=+72.2 (c 1.1, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1R,2S)

Diethyl (1S,2S)-1,2-dihydroxypropylphosphonateC7H17O5PEe = 100%[α]D20=+10.3 (c 1.4, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1S,2S)

Diethyl (1R,2S)-1,2-dihydroxypropylphosphonateC7H17O5PEe = 100%[α]D20=-4.4 (c 1.4, CHCl3)Source of chirality: d-mannitolAbsolute configuration: (1R,2S)