Biocatalytic Desymmetrization Research Articles

Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination

Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination

Biocatalytic Desymmetrization for the Atroposelective Synthesis of Axially Chiral Biaryls Using an Engineered Imine Reductase

The enzymatic atroposelective synthesis of biaryl compounds is relatively rare, despite considerable attention received by biocatalysis in academic and industrial sectors. Imine reductases (IREDs) are an important class of enzymes that have been applied in the asymmetric synthesis of chiral amine building blocks. In this work, two IREDs (IR140 and IR189) were identified to catalyze the efficient desymmetrization of biaryls utilizing various amine donors. Further protein engineering enabled the identification of variants (IR189 M8‐M9 and IR189 M13‐M14) that are able to catalyze the formation of both (R) and (S) atropisomers in excellent yields and atroposelectivities for up to 24 examples (up to 99% ee and yield). The absolute configuration and rotational barriers were confirmed, and the reactions were readily enlarged to allow isolation of the atropisomeric products in 99% ee and 82% isolated yields. The optically pure biaryl amines were further derivatized into various synthetically useful atropisomers. To shed light on the molecular recognition mechanisms, molecular dynamics (MD) simulations were performed, offering plausible explanations for the improved atroposelectivities and enzymatic activities. The current strategy expands the scope of IRED‐catalyzed synthesis of axially chiral biaryl amines, contributing significantly to the field of atroposelective biocatalysis.

Biocatalytic Desymmetrization for the Atroposelective Synthesis of Axially Chiral Biaryls Using an Engineered Imine Reductase.

The enzymatic atroposelective synthesis of biaryl compounds is relatively rare, despite considerable attention received by biocatalysis in academic and industrial sectors. Imine reductases (IREDs) are an important class of enzymes that have been applied in the asymmetric synthesis of chiral amine building blocks. In this work, two IREDs (IR140 and IR189) were identified to catalyze the efficient desymmetrization of biaryls utilizing various amine donors. Further protein engineering enabled the identification of variants (IR189 M8-M9 and IR189 M13-M14) that are able to catalyze the formation of both (R) and (S) atropisomers in excellent yields and atroposelectivities for up to 24 examples (up to 99% ee and yield). The absolute configuration and rotational barriers were confirmed, and the reactions were readily enlarged to allow isolation of the atropisomeric products in 99% ee and 82% isolated yields. The optically pure biaryl amines were further derivatized into various synthetically useful atropisomers. To shed light on the molecular recognition mechanisms, molecular dynamics (MD) simulations were performed, offering plausible explanations for the improved atroposelectivities and enzymatic activities. The current strategy expands the scope of IRED-catalyzed synthesis of axially chiral biaryl amines, contributing significantly to the field of atroposelective biocatalysis.

Biocatalytic desymmetrization for synthesis of chiral enones using flavoenzymes

Biocatalytic desymmetrization for synthesis of chiral enones using flavoenzymes

Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir.

In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly efficient and atom-economic process.

Reversal and Amplification of the Enantioselectivity of Biocatalytic Desymmetrization toward Meso Heterocyclic Dicarboxamides Enabled by Rational Engineering of Amidase

Reversal and Amplification of the Enantioselectivity of Biocatalytic Desymmetrization toward Meso Heterocyclic Dicarboxamides Enabled by Rational Engineering of Amidase

Highly efficient biocatalytic desymmetrization of meso carbocyclic 1,3-dicarboxamides: a versatile route for enantiopure 1,3-disubstituted cyclohexanes and cyclopentanes

Highly efficient biocatalytic desymmetrization of meso carbocyclic 1,3-dicarboxamides to enantiopure 1,3-disubstituted cyclohexanes and cyclopentanes was realized.

Biocatalytic Desymmetrization of Prochiral 3‐Aryl and 3‐Arylmethyl Glutaramides: Different Remote Substituent Effect on Catalytic Efficiency and Enantioselectivity

AbstractCatalyzed by an amidase‐containing Rhodococcus erythropolis AJ270 microbial whole cell catalyst in neutral phosphate buffer at 30 °C, desymmetric hydrolysis of a series of prochiral 3‐aryl and 3‐arylmethylglutaramides efficiently afforded 3‐substituted glutaric acid monoamides in up to 95% yield and >99.5% ee. Even far away from the reaction site, the substituents on the aryl still have a significant effect on the catalytic activity and enantioselectivity and different remote substituent effect was observed for the two types of substrates. The synthetic application of biocatalytic desymmetrization was demonstrated by the facile transformation of the obtained enantiopure (R)‐3‐substituted 4‐carbamoylbutanoic acid products to chiral dihydroquinolinone and δ‐lactone compounds.magnified image

Scoping the Enantioselective Desymmetrization of a Poorly Water-Soluble Diester by Recombinant Pig Liver Esterase

Previously, the biocatalytic desymmetrization of dimethyl cyclohex-4-ene-cis-1,2-dicarboxylate to (1S,2R)-1-(methoxycarbonyl)cyclohex-4-ene-2-carboxylic acid, an important intermediate toward the synthesis of biologically active molecules, had been well-characterized in terms of pH and temperature optima and several aspects of process performance. Eventually this promising reaction could convert 200 mM (40 g·L–1) of substrate with >99.5% ee using the recombinant pig liver esterase, ECS-PLE06, at a scale of 8.8 L. However, the precise influence of substrate concentration and the poorly water-soluble nature of the substrate (approximately 60 mM in water at 25 °C for structurally similar dimethyl 1,4-cyclohexanedicarboxylate) remained elusive. Therefore, this work focuses on using a recently published methodology based on reaction trajectory analysis to identify mass transfer limitations in this reaction. With the constraints of mass transfer on space-time yield considered, it was possible to evaluate and improve biocatalyst yield (mass of product per mass of biocatalyst) through the use of higher substrate concentrations. Ultimately the complete conversion of approximately 75 g·L–1 substrate was achieved in 3.65 h yielding an excellent productivity of 20 g·L–1·h–1 with a biocatalyst yield of 4.36 g·gbiocat–1. This work also highlights the simplicity of applying a reaction trajectory analysis methodology and the importance of scale during reaction characterizations, and it identifies future directions for reaction improvement to address substrate supply and product inhibition/deactivation.

Enantioselective Synthesis of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) via Enzymatic Desymmetrization.

An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.

Biocatalytic Desymmetrization of Dinitriles in Organic Synthesis

In comparison with the chemical hydration and hydrolysis of nitriles, which usually involves harsh reaction condi- tions and low selectivity, biocatalytic desymmetrizations of prochiral or meso nitriles are highly efficient, highly enantioselec- tive and environmentally benign. Therefore, biocatalysis and biotransformation has offered an attractive and unique protocol for the enantioselective synthesis of polyfunctionalized organic compounds that are not readily obtainable by other methods. This review summarizes the biocatalytic desymmetrization of prochiral nitriles including glutaronitriles, malonitriles and meso cyclic dinitriles during the past two decades. Keywords desymmetrization; biotransformations; dinitriles 生物转化是利用生物催化体系(如各种细胞和酶等)

Biocatalytic Oxidative Desymmetrization of Piperidine Carboxylates

Biocatalytic Oxidative Desymmetrization of Piperidine Carboxylates

Biocatalytic desymmetrization of 3-substituted glutaronitriles by nitrilases. A convenient chemoenzymatic access to optically active (S)-Pregabalin and (R)-Baclofen

Desymmetrization of prochiral 3-substituted glutaronitriles offers a new approach to access (S)-Pregabalin and (R)-Baclofen. A number of nitrilases from diverse sources were screened with 3-isobutylglutaronitriles (1a) or 3-(4′-chlorophenyl)glutaronitriles (1b) as the substrate. Some nitrilases were found to catalyze the desymmetric hydrolysis of 1a and 1b to form optically active 3-(cyanomethyl)-5-methylhexanoic acid (2a) and 3-(4′-chlorophenyl)-4-cyanobutanoic acid (2b) with high enantiomeric excesse (ee), respectively. This cannot be achieved using traditional chemical hydrolysis. Among them, AtNIT3 generated (R)-2b, whereas BjNIT6402 and HsNIT produced the opposite (S)-enantiomer with high conversions and ee values. Not only the nitrilases showed different activities and stereoselectivities toward these 3-substituted glutaronitriles, the 3-substituent of the substrates also exerted great effect on the enzyme activity and stereoselectivity. (S)-2a and (S)-2b were prepared with high yields and ee values using BjNIT6402 and HsNIT as the biocatalysts, respectively. A straightforward Curtius rearrangement of (S)-2a and (S)-2b, followed by the acidic hydrolysis, afforded (S)-Pregabalin and (R)-Baclofen. This offers a new platform methodology for the synthesis of optically active β-substituted γ-amino acids of pharmaceutical importance.

Correction to Synthesis and Application of Enantioenriched Functionalized α-Tetrasubstituted α-Amino Acids from Biocatalytic Desymmetrization of Prochiral α-Aminomalonamides

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Synthesis and Application of Enantioenriched Functionalized α-Tetrasubstituted α-Amino Acids from Biocatalytic Desymmetrization of Prochiral α-AminomalonamidesLi-Bin Zhang, De-Xian Wang, Liang Zhao, and Mei-Xiang Wang*Cite this: J. Org. Chem. 2012, 77, 20, 9434Publication Date (Web):September 28, 2012Publication History Published online28 September 2012Published inissue 19 October 2012https://doi.org/10.1021/jo302041hCopyright © 2012 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views555Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (109 KB) Get e-Alerts Get e-Alerts

Synthesis and Application of Enantioenriched Functionalized α-Tetrasubstituted α-Amino Acids from Biocatalytic Desymmetrization of Prochiral α-Aminomalonamides

Catalyzed by Rhodococcus erythropolis AJ270, an amidase-containing microbial whole cell catalyst in neutral phosphate buffer at 30 °C, a number of prochiral α-substituted α-aminomalonamides underwent highly efficient and enantioselective hydrolytic desymmetrization to afford functionalized α-tetrasubstituted α-amino acids in 74-98% chemical yields and 94.0 to >99.5% ee. The presence of a free α-amino (NH(2)) substituent in the substrates was deemed important to ensure high biocatalytic efficiency and enantioselectivity. The synthetic application of biocatalytic desymmetrization was demonstrated by practical chemical transformations of (R)-2-amino-2-carbamoylpent-4-enoic acid to α-substituted serine analogues and a bioactive diamino alcohol derivative.

Enantioselective Biotransformations of Racemic and Meso Pyrrolidine-2,5-dicarboxamides and Their Application in Organic Synthesis

In this paper, we report the amidase-catalyzed hydrolysis of pyrrolidine-2,5-dicarboxamides and their application in organic synthesis. Catalyzed by Rhodococcus erythropolis AJ270, an amidase containing microbial whole cell catalyst, racemic trans-pyrrolidine-2,5-carboxamide was kinetically resolved into (2S,5S)-pyrrolidine-2,5-dicarboxamide and (2R,5R)-5-carbamoylpyrrolidine-2-carboxylic acid in high yields and excellent enantioselectivity. Biocatalytic desymmetrization of meso cis-pyrrolidinedicarboxamide afforded enantiomerically pure (2R,5S)-5-carbamoylpyrrolidine-2-carboxylic acid in an almost quantitative yield. In both kinetic resolution and desymmetrization, the amidase always exhibited excellent 2R-enantioselectivity, although its catalytic efficiency was influenced dramatically by the steric effect of the substituent on the nitrogen atom of pyrrolidine ring. The synthetic potential of biotransformation was demonstrated by the scalable preparation of (2R,5R)- and (2R,5S)-5-carbamoylpyrrolidine-2-carboxylic acids and their conversions to aza-nucleoside analogues and druglike pyrroline-fused diazepin-11(5H)-one compounds.

Practical biocatalytic desymmetrization of meso-N-heterocyclic dicarboxamides and their application in the construction of aza-sugar containing nucleoside analogs

Amidase-catalyzed desymmetrization of meso-N-heterocyclic dicarboxamides under very mild conditions provided a highly efficient and practical method for the preparation of enantiomerically pure carbamoyl-substituted heterocyclic amino acids that were unique and versatile platforms for the construction of both antipodes of aza-sugar containing nucleoside analogs.

ChemInform Abstract: A Highly Efficient Synthesis of Telaprevir by Strategic Use of Biocatalysis and Multicomponent Reactions.

AbstractA short and efficient synthesis of the important drug candidate telaprevir (IX), featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps is presented.

ChemInform Abstract: Asymmetric Synthesis of Synthetic Alkaloids by a Tandem Biocatalysis/Ugi/Pictet—Spengler‐Type Cyclization Sequence.

Abstract3,4‐cis‐substituted imines, such as (I), prepared via biocatalytic desymmetrization as reported earlier, are used as imine components in an Ugi‐type multicomponent reaction.

ChemInform Abstract: Highly Stereoselective Synthesis of Substituted Prolyl Peptides Using a Combination of Biocatalytic Desymmetrization and Multicomponent Reactions.

Abstract3,4‐Disubstituted 1‐pyrrolines (I) and (V) generated from the corresponding meso‐pyrrolidines by biocatalytic desymmetrization with monoamine oxidase N, react with carboxylic acids (II) and isocyanides (III) in a highly diastereoselective Ugi‐type multicomponent reaction to give substituted prolyl peptides (IV) and (VI) with high enantioselectivities.