Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Xu, Feng; Kosjek, Birgit; Cabirol, Fabien L.; Chen, Hai-Bin; Desmond, Richard; Park, Jeonghan; Gohel, Anupam P.; Collier, S. J.; Smith, D. J.; Liu, Zhuqing; Janey, Jacob M.; Chung, John Y. L.; Alvizo, Oscar

doi:10.1002/anie.201802791

Cited by 53 publications

(20 citation statements)

References 28 publications

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“…The use of enzymes in academy and industry, especially in the pharmaceutical and fine chemistry field, has been expanded from the use of proteases and lipases to the application of transaminases and ketoreductases, as well as complex proteins such as the cytochrome P450s . Moreover, recent developments in directed enzyme evolution and protein immobilization on inert materials have permitted to overcome several limitations in the use of enzymes in organic synthesis.…”

Section: Introductionmentioning

confidence: 99%

Dual Mechanoenzymatic Kinetic Resolution of (±)‐Ketorolac

2020

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Recently, biocatalysis mediated by mechanical energy has become a convenient strategy to obtain highly valuable products following the principles of green chemistry. In particular, mechanoenzymatic techniques have allowed the isolation of chiral drugs with high enantiomeric purity. In this regard, being aware of the preponderant anti‐inflammatory activity of Ketorolac's (S)‐isomer relative to its (R)‐enantiomer, we developed a mechanoenzymatic kinetic resolution protocol using Candida antarctica Lipase B to yield both enantiomers with high enantiopurity. The significant enantiopreference of CALB for the (R)‐isomer of Ketorolac allowed the isolation of the active (S)‐enantiomer, either by means of an enantioselective esterification of racemic Ketorolac or via enantioselective hydrolysis of suitable ester derivatives. Both techniques proceeded in short reaction times, with high enantiomeric excess (>83 %), remarkable enantiodiscrimination (E≫500) and rather good conversion (46 %). Furthermore, (R)‐Ketorolac, an effective drug for ovarian cancer management, was obtained in essentially enantiopure form (ee >99 %).

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Section: Introductionmentioning

confidence: 99%

Dual Mechanoenzymatic Kinetic Resolution of (±)‐Ketorolac

2020

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“…Enolisable racemic starting materials, for example, are a popular subject, as they allow for the generation of two chiral centres in one step [116] . An interesting example of the stereoselective reduction of α‐substituted ketones under enolising conditions was reported by Xu, Kosjek and co‐workers as a key step in the synthesis of Vibegron [117] . A ketoreductase was evolved to meet the temperature and pH requirements of the epimerisation reaction as well as to become more stereoselective.…”

Section: Reduction Of C=o Bondsmentioning

confidence: 99%

Biocatalytic Reduction Reactions from a Chemist's Perspective

2020

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Reductions play a key role in organic synthesis, producing chiral products with new functionalities. Enzymes can catalyse such reactions with exquisite stereo‐, regio‐ and chemoselectivity, leading the way to alternative shorter classical synthetic routes towards not only high‐added‐value compounds but also bulk chemicals. In this review we describe the synthetic state‐of‐the‐art and potential of enzymes that catalyse reductions, ranging from carbonyl, enone and aromatic reductions to reductive aminations.

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“…Recently, the Merck scientists established an improved, stereoselective synthesis of vibegron, featuring a diastereo‐ and enantioselective synthesis of the key vicinal amino alcohol intermediate 94 through a KRED‐catalyze DYRKR of α‐amino ketone 93 operated at a high‐temperature as well as high‐pH environment (Scheme 36). [48] Computationally and structurally aided saturation mutagenesis, followed by the combination of beneficial mutations enabled the rapid identification of the best enzyme variant KRED‐p301 with excellent catalytic capability under harsh reaction conditions. In addition to the improved specific activity and stereoselectivity, enhanced stabilization of the cofactor NADPH was revealed as another critical factor contributing to the superior performance of KRED‐p301.…”

Section: Creation Of Two Stereocenters Through Kred‐catalyzed Reductionmentioning

confidence: 99%

Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

Yang

Liu

et al. 2021

The Chemical Record

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With the rapid development of genomic DNA sequencing, recombinant DNA expression, and protein engineering, biocatalysis has been increasingly and widely adopted in the synthesis of pharmaceuticals, bioactive molecules, fine chemicals, and agrochemicals. In this review, we have summarized the most recent advances achieved (2018–2020) in the research area of ketoreductase (KRED)‐catalyzed asymmetric synthesis of chiral secondary alcohol intermediates to pharmaceuticals and bioactive molecules. In the first part, synthesis of chiral alcohols with one stereocenter through the bioreduction of four different ketone classes, namely acyclic aliphatic ketones, benzyl or phenylethyl ketones, cyclic aliphatic ketones, and aryl ketones, is discussed. In the second part, KRED‐catalyzed dynamic reductive kinetic resolution and reductive desymmetrization are presented for the synthesis of chiral alcohols with two contiguous stereocenters.

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Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Cited by 53 publications

References 28 publications

Dual Mechanoenzymatic Kinetic Resolution of (±)‐Ketorolac

Dual Mechanoenzymatic Kinetic Resolution of (±)‐Ketorolac

Biocatalytic Reduction Reactions from a Chemist's Perspective

Application of Ketoreductase in Asymmetric Synthesis of Pharmaceuticals and Bioactive Molecules: An Update (2018–2020)

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