A novel and simple method for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids: phosphonic acid analogues of proline

A simple and convenient method has been developed for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids. The thermal reaction of proline with diethyl phosphite in the presence of benzaldehyde gave an N-benzyl derivative of diethyl pyrrolidine-2-phosphonate, which was transformed into two diastereomeric amides by sequential debenzylation and acylation with (+)-dibenzoyl-l-tartaric anhydride. The two diastereomeric amides were separated by column chromatography and the structure of one of them was determined by X-ray crystallographic analysis. Hydrolysis of the amides in the usual manner afforded (R)- and (S)-pyrrolidine-2-phosphonic acids. The advantages of the present method are that it is easy, rapid, and prepares both enantiomers of pyrrolidine-2-phosphonic acids.

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(2R,3R)-Bis(benzoyloxy)-4-[2(S)-(diethoxyphosphoryl)pyrrolidin-1-yl]-4-oxabutanoic acidC26H30NO10P[α]D20=-12.6 (c 0.1, MeOH)Source of chirality: (+)-dibenzoyl-l-tartaric anhydrideAbsolute configuration: (2S) (pyrrolidine moiety)

(2R,3R)-Bis(benzoyloxy)-4-[2(R)-(diethoxyphosphoryl) pyrrolidin-1-yl]-4-oxabutanoic acidC26H30NO10P[α]D20=-64.1 (c 0.1, MeOH)Source of chirality: (+)-dibenzoyl-l-tartaric anhydrideAbsolute configuration: (2R) (pyrrolidine moiety)

(R)-Pyrrolidin-2-ylphosphonic acidC4H11NO3P[α]D20=+62.6 (c 1, 1 M NaOH)Absolute configuration: (R)