Stereodivergent Evolution of Artificial Enzymes for the Michael Reaction

Garrabou, Xavier; Macdonald, Duncan Stuart; Wicky, Basile I. M.; Hilvert, Donald

doi:10.1002/ange.201712554

Cited by 9 publications

(3 citation statements)

References 35 publications

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“…reported, these generally involve the use of readily enolizable Michael donors for which no additional activation step is required. 6,[27][28][29] Here, we used the much less reactive ketone 1-(1-methyl-1H-imidazol-2-yl)-2-phenylethan-1-one (1a) as Michael donor. This ketone does not enolize spontaneously under the reaction conditions, but this can be achieved by binding to a Lewis acidic metal complex.…”

Section: Resultsmentioning

confidence: 99%

Synergistic catalysis in an artificial enzyme by simultaneous action of two abiological catalytic sites

2020

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Section: Resultsmentioning

confidence: 99%

Synergistic catalysis in an artificial enzyme by simultaneous action of two abiological catalytic sites

2020

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“…Iron (II)-porphyrin, also known as hemoprotein, which is present in cytochrome P450 and hemoglobin, was reported by Brustad and colleagues 70 to be a biocatalyst that can be used for the cyclopropanation of active alkenes (39) such as styrene with ethyl diazoacetate (38). In their subsequent report, 71 the stereodivergent synthesis of four stereoisomers of ethyl 2-phenylcyclopropane-1-carboxylate (40) and its derivatives could be accomplished under the catalysis of P450 BM3 variant from B. megaterium as well as other cytochrome enzymes (Scheme 16).…”

Section: Preparation Of Ethyl 2-substituted Cyclopropane-1carboxylatesmentioning

confidence: 99%

Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

Ding

Huang

et al. 2022

Pharmaceutical Fronts

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Multiple stereoisomers can be found when a substance contains chiral carbons in its chemical structure. To obtain the desired stereoisomers, asymmetric synthesis was proposed in the 1970s and developed rapidly at the beginning of this century. Stereodivergent synthesis, an extension of asymmetric synthesis in organic synthesis with the hope to produce all stereoisomers of chiral substances in high conversion and selectivity, enriches the variety of available products and serves as a reference suggestion for the synthesis of their derivatives and other compounds. Since biocatalysis has outstanding advantages of economy, environmental friendliness, high efficiency, and reaction at mild conditions, the biocatalytic reaction is regarded as an efficient strategy to perform stereodivergent synthesis. Thus, in this review, we summarize the stereodivergent synthesis catalyzed by enzymes or chemo-enzymes in cases where a compound contains two or three chiral carbons, i.e., at most four or eight stereoisomers are present. The types of reactions, including reduction of substituent ketones, cyclization reactions, olefin addition, and nonredox transesterification reactions, are also discussed for the understanding of the progress and application of biocatalysis in stereodivergent synthesis.

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“…Hilvert and co-workers reported the directed evolution of an artificial retro-aldolase which was engineered for promiscuous Michael reactions leading optionally to four stereocomplementary products with 80−85% selectivities. 19 In this interesting process, CH-acidic Michael donors such as cyano acetic acid ethyl ester undergo rapid racemization prior to addition to prochiral α,βunsaturated ketones.…”

Section: ■ Introductionmentioning

confidence: 99%

Stereodivergent Protein Engineering of a Lipase To Access All Possible Stereoisomers of Chiral Esters with Two Stereocenters

et al. 2019

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Enzymatic stereodivergent synthesis to access all possible product stereoisomers bearing multiple stereocenters is relatively undeveloped, although enzymes are being increasingly used in both academic and industrial areas. When two stereocenters and thus four stereoisomeric products are involved, obtaining stereodivergent enzyme mutants for individually accessing all four stereoisomers would be ideal. Although significant success has been achieved in directed evolution of enzymes in general, stereodivergent engineering of one enzyme into four highly stereocomplementary variants for obtaining the full complement of stereoisomers bearing multiple stereocenters remains a challenge. Using Candida antarctica lipase B (CALB) as a model, we report the protein engineering of this enzyme into four highly stereocomplementary variants needed for obtaining all four stereoisomers in transesterification reactions between racemic acids and racemic alcohols in organic solvents. By generating and screening less than 25 variants each isomer, we achieved >90% selectivity for all of the four possible stereoisomers in the model reaction. This difficult feat was accomplished by developing a strategy dubbed "focused rational iterative site-specific mutagenesis" (FRISM) at sites lining the enzyme's binding pocket. The accumulation of single mutations by iterative site-specific mutagenesis using a restricted set of rationally chosen amino acids allows the formation of ultra-small mutant libraries requiring minimal screening for stereoselectivity. The crystal structure of all stereodivergent CALB variants, flanked by MD simulations, uncovered the source of selectivity.

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Stereodivergent Evolution of Artificial Enzymes for the Michael Reaction

Cited by 9 publications

References 35 publications

Synergistic catalysis in an artificial enzyme by simultaneous action of two abiological catalytic sites

Synergistic catalysis in an artificial enzyme by simultaneous action of two abiological catalytic sites

Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

Stereodivergent Protein Engineering of a Lipase To Access All Possible Stereoisomers of Chiral Esters with Two Stereocenters

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