Chemo-enzymatic synthesis of ethyl (R)-2-hydroxy-4-phenylbutyrate

A new biocatalytic strategy to obtain the ethyl (R)-2-hydroxy-4-oxo-4-phenylbutyrate precursor of ethyl (R)-2-hydroxy-4-phenylbutyrate, an important intermediate in the synthesis of a variety of ACE inhibitors, has been set up. Starting from ethyl 2,4-dioxo-4-phenylbutyrate, a screen of microorganisms has been performed in order to find the best catalyst able to reduce the keto group in the α-position with high chemo- and enantioselectivity. The biotransformation catalyzed by Pichia pastoris CBS 704 gave the best results in terms of conversion and enantioselectivity. The addition of adsorbing resins in the fermentation medium is effective in controlling substrate and product concentration in the medium, thus improving both conversion and enantioselectivity of the biotransformation. Preliminary experiments in a continuous batch reactor with growing culture of P. pastoris will be also presented.

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Ethyl (R)-2-hydroxy-4-oxo-4-phenylbutyrateC12H14O4[α]D25=+11.7 (12 mg/mL, ethanol, 25 °C)Absolute configuration: (R)Source of chirality: microbial reduction

Ethyl (R)-2-hydroxy-4-phenylbutyrateC12H16O3[α]D25=-9.3 (neat, 25 °C)Absolute configuration: (R)Source of chirality: ethyl (R)-2-hydroxy-4-oxo-4-phenylbutyrate