Process for preparing Ezetimibe intermediate by enantioselective CBS catalyzed ketone reduction with BH3–DEA prepared in situ

Bertrand, B.; Durassier, Sonia; Frein, Stéphane; Burgos, Alain

doi:10.1016/j.tetlet.2007.01.118

Cited by 18 publications

(9 citation statements)

References 5 publications

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“…1) [7,8]. Enantioselective reduction of FOP dione to (S)-FOP alcohol has been achieved mainly by use of chemical catalysts, usually with chiral boron catalysts [9,10]. One of the main drawbacks of the chemical synthetic strategy is the formation of the diol by-product which is difficult to separate because of its instability.…”

Section: Introductionmentioning

confidence: 99%

Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate

Singh

Basit

Banerjee

2009

J Ind Microbiol Biotechnol

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Ezetimibe is a selective acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor used in hypercholesterolemia. Synthesis of ezetimibe requires enantiopure 3-[5-(4-fluorophenyl)-5(S)-hydroxypentanoyl]-4(S)-4-phenyl-1,3-oxazolidin-2-one (FOP alcohol) as a crucial intermediate which is produced by reduction of the corresponding prochiral ketone (FOP dione). A new biocatalyst from acclimatized soil was screened for bioreduction of the above prochiral ketone. The microorganism was identified by 16S mRNA sequencing, as Burkholderia cenocepacia. Various physicochemical conditions were optimized to increase cellmass and enzyme activity. The overall increase in cellmass concentration and enzyme activity was 2.06 and 1.85-fold, respectively. Various reaction conditions, for example pH, temperature, agitation, and cellmass concentration, were optimized for maximum product yield (chiral alcohol) with excellent enantioselectivity. Best reduction was achieved in phosphate buffer (50 mM, pH 8.0) at 40 degrees C (200 rpm) and the yield of enantiopure alcohol from the corresponding prochiral ketone was 54%. This biocatalyst was also used for the reduction of various other prochiral ketones.

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Section: Introductionmentioning

confidence: 99%

Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate

Singh

Basit

Banerjee

2009

J Ind Microbiol Biotechnol

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“…The traditional chemical synthesis of ( S )‐ET‐5 requires expensive noble metal catalyst and harsh reaction conditions (ultra‐low temperature, −80 to −75°C), which results in low overall yield, high production cost, poor security, and contaminant discharge 6,7 . To explore for the synthesis approaches which meet the concepts of green chemistry is of great value 8 …”

Section: Introductionmentioning

confidence: 99%

“…6,7 To explore for the synthesis approaches which meet the concepts of green chemistry is of great value. 8 Recently, biocatalyst has attracted more and more attention due to its wide range of natural sources, mild reaction conditions, high catalytic efficiency, excellent stereoselectivity, and environmental friendship. 9 Carbonyl reductases (CRs, EC 1.1.1.148) are a type of nicotinamide coenzyme-dependent oxidoreductases which catalyze the reduction of a carbonyl group to the corresponding chiral alcohol, in the present of the reduced form of the cofactor, NAD[P]H. 7,10,11 CRs have been employed as a valuable biocatalyst for ezetimibe synthesis.…”

Section: Introductionmentioning

confidence: 99%

Efficient production of an ezetimibe intermediate using carbonyl reductase coupled with glucose dehydrogenase

Zhang

Zhou

et al. 2020

Biotechnology Progress

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Ezetimibe is a top-selling hypolipidemic drug for the treatment of cardiovascular diseases. Biosynthesis of (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one ((S)-ET-5) using carbonyl reductase has shown advantages including high catalytic efficiency, excellent stereoselectivity, mild reaction conditions, and environmental friendness, and was considered as the key step for ezetimibe production. The regeneration efficiency of the cofactor, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is one of the main restricted factor. Recombinant Escherichia coli strain (smCR125) coexpressing carbonyl reductase (CR125) and glucose dehydrogenase were successfully constructed and applied for the production of (S)-ET-5 for the first time. Without extra addition of the coenzyme NADPH, the yield of 99.8% and the enantiomeric excess (e.e.) of 99.9% were achieved under ET-4 concentration of 200 g/L. Using a substrate fed-batch strategy, under the optimal conditions, the substrate ET-4 concentration was increased to 250 g/L with the yield of 98.9% and the e.e. of 99.9% after 12 hr reaction. The space-time yield of 494.5 g L −1 d −1 and the space-time yield per gram biocatalyst of 24.7 g L −1 d −1 g −1 DCW were achieved, which were higher than ever reported for the biosynthesis of the ezetimibe intermediate.

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“…It is a strong cholesterol absorption inhibitor reducing LDL concentration. Despite the fact that a number of synthetic approaches have been developed for its preparation, there are still other pathways that have not been explored yet. In this respect we envisioned that a stereoselective synthesis of Ezetimibe could be based on cross-metathesis (CM) reaction as depicted in retrosynthesis in Scheme .…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-β-Lactams

et al. 2016

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Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding α-alkylidene-β-aryl-β-lactams in good isolated yields (41-83%) with exclusive Z-selectivity. The developed protocol was successfully applied for stereoselective preparation of Ezetimibe, the commercial cholesterol absorption inhibitor.

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Process for preparing Ezetimibe intermediate by enantioselective CBS catalyzed ketone reduction with BH3–DEA prepared in situ

Cited by 18 publications

References 5 publications

Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate

Burkholderia cenocepacia: a new biocatalyst for efficient bioreduction of ezetimibe intermediate

Efficient production of an ezetimibe intermediate using carbonyl reductase coupled with glucose dehydrogenase

Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α-Methylidene-β-Lactams

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