The resolution of racemic phenylalanine esters with esterases has been reexamined in relation to the development of a continuous process based on the use of hollow fiber/liquid membrane (SLM) reactors. The requirement for high enantioselectivity was met by phenylalanine isopropyl ester, whose (R)‐enantiomer was found refractory to the action of subtilisin Carlsberg, in water, pH 7.5, at 25 °C. The continuous feeding of (R, S)‐Phe‐O‐iPr‐HCl at 2 mm/h to 0.7 g/L subtilisin resulted in steady‐state reaction conditions that gave (S)‐Phe‐OH of 95% enantiomeric excess (ee) at the theoretical rate. The unreacted (R)‐Phe‐O‐iPr, which permeated out continuously, had 80% ee and was racemized quantitatively by heating with a salicylaldehyde catalyst in refluxing toluene. Doubling the feeding rate (4 mm/h) created excessive accumulation of (R)‐Phe‐O‐iPr in the reactor, which inhibited the enzyme through nonproductive binding, lowering the (S)‐Phe‐OH resolution rate to 68% of the theoretical rate. Similar experiments with (R, S)‐Phe‐OMe‐HCl gave (S)‐Phe‐OH of 9–48% ee, due to the enzymatic hydrolysis of (R)‐Phe‐OMe experienced during the runs. When α‐chymotrypsin was used for the continuous hydrolysis of (R, S)‐Phe‐O‐iPr, the isolated (S)‐Phe‐OH showed 67% ee, indicating that substantial hydrolysis of the (‐R)‐ester had occurred.
Am. Chem. SOC., 86,3364 (1964).(IO) in order to exist as stable. separable, cis and trans conformers, a substituent(s). able to markedly inhibit the rate of inversion or provide a steric barrier to the process, would be required. However, no such substituent is known.The synthesis and some anomalous reactions of the title compound (4) are discussed. Treatment of 4 with hydroxylamine caused oxazoline ring opening to form the amidoxime 5. When the diester 4 was saponified, the 0benzoyl zwitterion 6 crystallized from solution in excellent yield. The structure of 6 was secured by its rearrangement into DL-threo-Nbenzoyl-P-hydroxyaspartic acid (10) and its conversion into DL-threo-P-hydroxyaspartic acid dimethyl ester, In contrast, the oxazoline ring in monoester 2 (R = H; R' = CHS) is stable to both hydroxylamine and alkali.
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