Enzymatic and chromatographic resolution procedures applied to the synthesis of the phosphoproline enantiomers

The preparation of enantiomerically pure pyrrolidine-2-phosphonic acid (phosphoproline, ProP) has been addressed through the synthesis of suitable racemates and subsequent resolution by independent enzyme-catalyzed and chiral HPLC methods. First, racemic phosphoproline derivatives bearing the necessary protecting groups have been synthesized in excellent global yields starting from inexpensive materials. Preparative HPLC resolution of the N-Cbz-protected aminophosphonate on a cellulose-based column allowed the isolation of enantiomerically pure enantiomers on a gram scale. Enzyme-catalyzed alkoxycarbonylation of the aminophosphonate was studied using different lipases, solvents, and carbonates. Candida antarctica lipase type A (CAL-A) provided the highest enantioselectivity when combined with benzyl 3-methoxyphenyl carbonate.

Figure optionsDownload as PowerPoint slide

(R)-(−)-Dimethyl N-(benzyloxycarbonyl)pyrrolidine-2-phosphonateC14H20NO5P>99.5% ee[α]D22 = −60.0 (c 0.53, CHCl3)Source of chirality: preparative HPLC resolutionAbsolute configuration: (R)

(R)-(−)-Pyrrolidine-2-phosphonic acidC4H10NO3P>99.5% ee[α]D21 = −49.8 (c 1.1, 1 M NaOH)Source of chirality: preparative HPLC resolutionAbsolute configuration: (R)

(S)-(+)-Dimethyl N-tosylpyrrolidine-2-phosphonateC13H20NO5PS94% ee[α]D20 = +76.7 (c 1.0, CHCl3)Source of chirality: enzymatic kinetic resolutionAbsolute configuration: (S)