Abstract
Optically active ethyl (R)-2-hydroxy-4-phenylbutyrate [(R)-HPBE] is an important chiral building block for the synthesis of angiotensin-converting enzyme (ACE) inhibitors. It is reported that microbial or enzymatic reduction of ethyl 2-oxo-4-phenyl-butyrate (OPBE) is an attractive way to produce optically active (R)-HPBE. The asymmetric reduction of OPBE to synthesize optically active (R)-HPBE with a newly isolated Rhodotorula mucilaginosa CCZU-G5 as catalyst was investigated in an aqueous/organic solvent biphasic system. R. mucilaginosa CCZU-G5 showed a good tolerance (the metabolic activity retention >80%) in the biphasic system composed of aqueous buffer and organic solvent with a log P value over 4.6. Isooctane was found to be the most suitable organic phase solvent. In the biphasic system, the volumetric phase ratio, OPBE concentration, cell concentration, reaction temperature, and buffer pH were optimized. Under the optimum conditions (volumetric phase ratio: 1/1, OPBE concentration: 100 mM, cell concentration: 0.075 g/mL, pH 7.5, 35°C), the final yield and the optical purity of (R)-HPBE reached 98.3% and >99.0% enantiomeric excess (ee), respectively, after 12 h of reaction. All the results suggested that the OPBE-reducing enzymes in a newly isolated R. mucilaginosa cells possess highly stable and excellent stereoselectivity by establishing an aqueous/organic biphasic system.
Highlights
Active ethyl (R)-2-hydroxy-4-phenylbutyrate [(R)-HPBE] is an important chiral building block for the synthesis of angiotensin-converting enzyme (ACE) inhibitors
Several biocatalysts have been used in the synthesis of (R)-HPBE, including the hydrolysis and transesterification catalyzed by lipase [5] and the reduction of OPBE catalyzed by isolated dehydrogenase [6] and whole cells [7,8]
Analytical methods The concentrations of OPBE and HPBE were determined with a gas chromatography. (GC-950, Shanghai Haixin Chromatographic Instrument Co., Ltd., Shanghai, China) equipped with a flame ionization detector and a SE-30 capillary column (30 m, i.d. 0.5 mm)
Summary
Active ethyl (R)-2-hydroxy-4-phenylbutyrate [(R)-HPBE] is an important chiral building block for the synthesis of angiotensin-converting enzyme (ACE) inhibitors. It is reported that microbial or enzymatic reduction of ethyl 2-oxo-4-phenyl-butyrate (OPBE) is an attractive way to produce optically active (R)-HPBE. Active ethyl (R)-2-hydroxy-4-phenylbutyrate [(R)-HPBE] is an important chiral building block for the synthesis of angiotensin-converting enzyme (ACE) inhibitors such as benazepril, enalapril, and lisinopril [1]. Various chemical and biological approaches for (R)-HPBE preparation have been reported, mainly in two ways: kinetic resolution and synthesis. Microbial or enzymatic reduction of ethyl 2-oxo-4phenyl-butyrate (OPBE) is an attractive way to produce optically active (R)-HPBE, since OPBE can be synthesized and is relatively cheap. Several biocatalysts have been used in the synthesis of (R)-HPBE, including the hydrolysis and transesterification catalyzed by lipase [5] and the reduction of OPBE catalyzed by isolated dehydrogenase [6] and whole cells [7,8]. Since the reduction reaction requires stoichiometric amounts of nicotinamide cofactors, whole cells rather than isolated enzymes were used preferentially to avoid enzyme purification and cofactor addition [9]
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