Enantiomerization of 3-Carbethoxy-l,4-benzodiazepin-2-one: Combined chiral HPLC and spectroscopic study

Recently developed chiral HPLC columns CHIRIS AD1 and CHIRIS AD2 have been demonstrated to separate racemic, configurationally unstable ethyl‐7‐chloro‐2‐oxo‐5‐phenyl‐2,3‐dihydro‐1H‐1,4‐benzodiazepine‐3‐carboxylate (1) and its 3‐methyl congener 2; fast on‐column enantiomerization of configurationally unstable 1 was observed, however. Addition of 0.1% of AcOH to the eluting mixture inhibits enantiomerization, whereas the same percentage of Et3N completely precludes enantioseparation, suggesting base‐catalysis by free β‐aminoethyl groups, present in low percentage in chiral stationary phase (CSP). When both CSPs were prepared under conditions of nonexhaustive acylation by N‐DNB‐α‐aminoacids, no separation of 1 was observed. The rate of enantiomerization on CHIRIS AD2 was determined at 25°C, the mechanism is discussed, and experimental results correlated with calculated relative stabilities of the tautomers la–c. Absolute (3S) configuration of (+) enantiomers of 1 and 2 was determined by comparison of their eluation profile to that of (±)‐3 and (3S)‐(+)‐3, taking into account relative (ψa or ψe) configuration of the prevailing conformer in solution. Chirality 14:12–17, 2002. © 2002 Wiley‐Liss, Inc.