Production of (+)‐(S)‐Ethyl 3‐Hydroxybutyrate and (‐)‐(R)‐Ethyl 3‐Hydroxybutyrate by Microbial Reduction of Ethyl Acetoacetate

Abstract

SummaryThe production of (S)-ethyl 3-hydroxybutyrate (2) from ethyl acetoacetate (1) in higher yields and with higher optical purity than with the usual procedures was achieved by continuous addition of the substrate 1 and sucrose to an aerated suspension of bakers' yeast. The microbial reduction of 1 by the fungus Geotrichum candidum LINK yields -for the first time -the antipode 3.

Synthesis and Structure of Linear and Cyclic Oligomers of 3-Hydroxybutanoic Acid with Specific Sequences of (R)- and (S)-Configurations

“…This method was improved by Leuenberger et al, who added the substrate very slowly and so, by continuously starving the yeast, reached enantiomer ratios (e.r.) of up to 98.5 : 1.5 in favor of the (S)-isomer ent-2f 8 ) [25]. By Scheme 2 8 ) Helvetica Chimica Acta ± Vol.…”

Influence of the ethanol and glucose supply rate on the rate and enantioselectivity of 3‐oxo ester reduction by baker's yeast

“…These numbers are significantly higher than 0.05 mol glucose.kg dw −1 .h −1 or 0.15 mol EtOH.kg dw −1 .h −1 , which is sufficient according to our results. In an industrial reduction process, not only the electron donor supply must be controlled, it is also recommended to feed the substrate ethyl 3-oxobutanoate to keep its concentration low and thus achieve high enantiomenc purities of the product (Chen et al, 1984;Kometani, 1993Kometani, , 1994Rohner et al, 1984;Wipf et al, 1983). For an efficient industrial process the use of higher yeast concentrations and also its re-use is recommended to speed up the reduction and to minimize as much as possible the environmental burden.…”

“…To obtain high q EOB values at otherwise comparable conditions, electron donor supply rates in optimized literature procedures for ethyl 3-oxobutanoate were calculated to be ∼1.0 mol EtOH.kg dw −1 .h −1 (Kometani et al, 1993) and, using a combined electron donor supply, ∼0.14 mol glucose.kg dw −1 .h −1 plus ∼0.9 mol EtOH.kg dw −1 .h −1 (Wipf et al, 1983). These numbers are significantly higher than 0.05 mol glucose.kg dw −1 .h −1 or 0.15 mol EtOH.kg dw −1 .h −1 , which is sufficient according to our results.…”

“…Even if such protocols are described in sufficient detail to be reproduced, quantitative understanding of the results and scaling-up is difficult because several process parameters change simultaneously. In only a few publications, optimization of the reduction of ethyl 3-oxobutanoate while controlling and measuring the most important param- eters has been reported (Kometani et al, 1993(Kometani et al, , 1994Rohner et al, 1990;Wipf et al, 1983). From these publications a useful protocol for controlled EOB addition, leading to high enantiomeric excess values of the product can be obtained.…”

Substâncias enantiomericamente puras (SEP): a questão dos fármacos quirais

“…Como resultado desta tendência, as substân-cias de natureza sintética passam a predominar no arsenal terapêutico em substituição aos produtos naturais, constituindo-se hoje em dia em cerca de 75% do seu total. Exceção feita aos fármacos semi-sintéticos, produzidos a partir de matérias-primas naturais (antibióticos 18 , hormônios esteroidais 19 , glicosídeos cardíacos 20 ), a maioria entre os demais fármacos foram produzidos, estudados e licenciados para a venda em suas formas racêmicas 21 , visto que os métodos de Síntese Assimétrica disponíveis até então não eram muito eficientes e os custos para a resolução de racematos eram altos e oneravam substancialmente a produção industrial. Assim, durante décadas, a questão da quiralidade e conseqüentemente da pureza ótica foi um fator negligenciado pela comunidade científica e pela indústria farmacêutica.…”