Preparation of dimethyl (R)- and (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonate derived from salicylaldehyde via resolution using (S)-methoxyphenylacetic acid (MPA)

The efficient preparation of both enantiomers of dimethyl δ,β-dihydroxyethylphosphonate 2 has been achieved from salicylaldehyde as a starting material, through the resolution of dimethyl (±)-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonate 4 using (S)-methoxyphenylacetic acid (MPA). The absolute configuration was assigned by the Dale and Mosher approach using extended Newman projections and ab initio calculations.

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Dimethyl (S)-2-(2-O-benzylphenyl)-2-[(S)-O-methylmandelate]ethylphosphonateC26H29O7PDe >98%[α]D = +26.9 (c 1.8, CHCl3)Source of chirality: chemical resolutionAbsolute configuration: (S,S)

Dimethyl (R)-2-(2-O-benzylphenyl)-2-[(S)-O-methylmandelate]ethylphosphonateC26H29O7PDe >98%[α]D = +27.2 (c 1.7, CHCl3)Source of chirality: chemical resolutionAbsolute configuration: (R,S)

Dimethyl (S)-2-(2-O-benzylphenyl)-2-hydroxyethylphosphonateC17H21O5PEe >98%[α]D = +46.8 (c 1.23, CHCl3)Source of chirality: chemical resolutionAbsolute configuration: (S)

Dimethyl (S)-2-(2-hydroxyphenyl)-2-hydroxyethylphosphonateC17H21O5PEe >98%[α]D = −0.3 (c 3.0, CHCl3)Source of chirality: chemical resolutionAbsolute configuration: (S)