Synthesis of both RP and SP enantiomers of unsymmetrical methylphosphonates based on a new approach utilizing a P-ester bond with α-hydroxyacids

Condensation of methyl methylphosphonochloridate with the dilithium salt of 2-methyllactic acid gave P-racemic methylphosphonates which unexpectedly contained two units of α-hydroxyacid linked via carboxylic ester bond. The racemic mixture was chromatographically separated via diastereomeric salts with quinine or cinchonine to give, based on the X-ray analysis, pure (RP)-(+) and (SP)-(−) enantiomers. Both enantiomers were immobilized on the ArgoGel®–OH solid support. Condensation of methyl methylphosphonochloridate with α-hydroxyacid methyl esters [2-methyllactate, (SC)-(−)-lactate, methyl (SC)-(+) and (RC)-(−)-mandelates] gave chromatographically inseparable 1:1 mixtures of diastereomers in 63–69% yields. A basic hydrolysis of the latter resulted in a selective and unexpected cleavage of the P–OMe group in a quantitative yield [(SC)-(+) and (RC)-(−)-mandelates, (SC)-(−)-lactate] or simultaneous cleavages of P–OMe and C(O)OMe groups (2-methyllactate).

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(RP)-(+)-2-(2-(Methoxy(methyl)phosphoryloxy)-2-methylpropanoyloxy)-2-methylpropanoic acidC10H19O7P[α]D25=+12.3 (c 0.46, CHCl3)Source of chirality: resolution of racemic mixtureAbsolute configuration: (RP)

(S)-(−)-Methyl 2-(diphenylphosphoryloxy)propanoateC16H17O4P[α]D22=-7.4 (c 2.79, CH2Cl2)Source of chirality: chiral substrateAbsolute configuration: (S)