A study on the racemization step in the synthesis of pyrrolidinols via cyclic α-hydroxyimides

Analytical HPLC methods for the determination of the enantiomeric excess of N-protected malimides 1 as well as the corresponding pyrrolidinol 5 and tartarimides 2 and 3 have been established. On this basis, a study to reveal the racemization step in the synthesis of pyrrolidinols from α-hydroxyacids, via chiral cyclic α-hydroxyimides, has been undertaken. It was confirmed that the known, one-step method for the synthesis of the N-protected chiral cyclic imides from α-hydroxydiacids proceeded with little racemization, and partial racemization has been proven to occur during the reduction of the resultant imide 1a with LAH to yield the corresponding pyrrolidinol 5. Conditions have been defined in order to avoid racemization in the LAH reduction step.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(S)-N-BenzylmalimideC11H11NO3[α]D25=-43.0 (c 1.0, MeOH)Source of chirality: (S)-malic acidAbsolute configuration: (S)

(S)-N-Benzylpyrrolidin-3-olC11H15NO[α]D25=-5.3 (c 0.5, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (S)

(R)-4-Hydroxy-1-(4-methoxybenzyl)pyrrolidine-2,5-dioneC12H13NO4[α]D25=+69.2 (c 0.8, MeOH)Source of chirality: (R)-malic acidAbsolute configuration: (R)

(3S,4S)-3,4-Dihydroxy-1-(4-methoxybenzyl)pyrrolidine-2,5-dioneC12H13NO5[α]D25=-97.4 (c 1.0, MeOH)Source of chirality: d-tartaric acidAbsolute configuration: (2S,3S)

(3R,4R)-3,4-Dihydroxy-1-benzylpyrrolidine-2,5-dioneC11H11NO4[α]D25=+121.3 (c 1.0, MeOH)Source of chirality: l-tartaric acidAbsolute configuration: (2R,3R)