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Axially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six‐membered aza‐acetal‐bridge‐promoted racemization followed by an imine reductase (IRED)‐catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S‐IRED‐Ss‐M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S‐IRED‐Ss‐M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules. [ABSTRACT FROM AUTHOR]

Experimentally screening catalysts for performance, selectivity, or lifetime is one of the key steps in the development and research of novel catalytic materials. Commonly, however, complications from heat or mass transport limitations, mixing, thermodynamics, or experimental designs can cloud the interpretation and differentiation of the kinetic rate behavior of catalysts. Herein, guidelines for proper equipment setups and experimental designs are presented with the hope of improving kinetic resolution of catalyst screening results for increased data fidelity. [ABSTRACT FROM AUTHOR]

This study aimed to optimize the kinetic resolution of building blocks for the synthesis of β-blockers using Candida rugosa lipases, which could be potentially used to synthesize enantiomerically pure β-blockers further. Reaction mixtures were incubated in a thermostated shaker. Qualitative and quantitative analyses of the reaction mixtures were performed using chiral stationary phases and the UPLC-IT-TOF system. Of the 24 catalytic systems prepared, a system containing lipase from Candida rugosa MY, [EMIM][BF4] and toluene as a two-phase reaction medium and isopropenyl acetate as an acetylating agent was optimal. This resulted in a product with high enantiomeric purity produced via biotransformation, whose enantioselectivity was E = 67.5. Using lipases from Candida rugosa enables the enantioselective biotransformation of the β-blockers building block. The biocatalyst used, the reaction environment, and the acetylating agent significantly influence the efficiency of performer kinetic resolutions. The studies made it possible to select an optimum system, a prerequisite for obtaining a product of high enantiomeric purity. As a result of the performed biotransformation, the (S)-enantiomer of the β-blocker derivative was obtained, which can be used to further synthesize enantiomerically pure β-blockers. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Phthalides serve as core structures pervasive in a wide array of natural products and drug molecules, which display a diverse array of biological activities. We report herein a highly efficient dynamic kinetic resolution of 3‐hydroxyphthalides by chiral isothioureas (ITUs) catalyzed asymmetric acylation, facilitating the effective synthesis of a variety of chiral phthalidyl esters with good yields and enantioselectivities. Notably, this reaction features mild reaction conditions, expansive substrate scope as well as good functional group compatibility. In addition, the practicality of this method is underscored by the large‐scale synthesis, reduced catalyst loading experiment and the synthesis of the chiral phthalidyl ester prodrug. [ABSTRACT FROM AUTHOR]

Enantioenriched 2‐substituted piperidines are very important unit for drug discovery. Ready access to a wide range of such compounds, decorated with functional handles at 2‐position with stereo‐defined centre significantly enhance the quality and diversity of chemical libraries for screening of drug discovery. The ability to control the stereochemistry of piperidine at the 2‐position remains an area of interest in organic synthesis to allow the development of novel, structurally diverse 3D molecules. Among the various ways to obtain enantioenriched 2‐substituted piperidines, asymmetric hydrogenation is widely studied. Asymmetric synthesis, Kinetic resolution, and chiral pool synthesis methodologies are also important ways to obtain the enantioenriched 2‐substituted piperidines. This review article summarized the main four ways to achieve particularly the enantioenriched substituted piperidines only at 2‐position considering the chemical routes, excluding the biocatalytic approach. 1. Introduction 2.1 Asymmetric Hydrogenation of 2‐substituted Pyridines 2.2 Asymmetric Synthesis 2.3. Kinetic resolution of racemic 2‐substituted Piperidine derivatives 2.4. Chiral pool synthesis 3. Conclusions & outlook [ABSTRACT FROM AUTHOR]

Ene‐reductases from the old yellow enzyme (OYE) family have been traditionally employed in the reduction of conjugated C═C double bonds. This study explores the underutilized oxidative potential of OYEs, demonstrating their capability to catalyze the enantioselective desaturation of carbonyl compounds. Utilizing a deprotonated tyrosine residue as a catalytic base, we developed a method to enable OYE‐catalyzed desaturation at ambient temperature and alkaline pH without the need for high‐temperature conditions. Through screening of various OYE enzymes, we identified several candidates from different genera with enhanced desaturase activity across different substrates. This work broadens the scope of biocatalytic applications for OYEs, introducing a novel approach to the synthesis of chiral α,β‐unsaturated carbonyl compounds. [ABSTRACT FROM AUTHOR]

Asymmetric kinetic resolution polymerization (AKRP) provides an ideal way to obtain highly isotactic polylactide (PLA) with superior thermal‐mechanical properties from racemic lactide (rac‐LA). However, the development of a new catalytic system with concurrent high activity and selectivity at ambient temperature remains a great callenge. Here, a series of simple and effective binary organocatalytic pairs containing axial‐chiral thioureas and commercially available phosphazene bases were designed. These chiral binary organocatalytic pairs allow for both high polymerization activity and moderate enantioselectivity for AKRP of rac‐LA at room temperature, yielding semi‐crystalline and metal‐free stereoblock PLA with a melting temperature as high as 186 °C. The highest kinetic resolution coefficient (krel) of 8.5 at 47 % conversion was obtained, and D‐LA was preferentially polymerized via kinetic resolution with a maximum selectivity factor (kD/kL) of 18.1, indicating that an enantiomorphic site control mechanism (ESC) was involved. [ABSTRACT FROM AUTHOR]

A novel synthetic route was developed for the construction of chiral cis-vicinal halohydrins derivatives through Ir/f-phamidol-catalysed asymmetric hydrogenation of corresponding α-halogenated ketones with high yields (up to 99% yield), excellent diastereoselectivities (>20 : 1 dr), enantioselectivities (up to 99% ee), and high substrate catalyst ratio (S/C = 1000). [ABSTRACT FROM AUTHOR]

Although biocatalysis has garnered widespread attention in both industrial and academic realms, the enzymatic synthesis of chiral oxetanes remains an underdeveloped field. Halohydrin dehalogenases (HHDHs) are industrially relevant enzymes that have been engineered to accomplish the reversible transformation of epoxides. In this study, a biocatalytic platform was constructed for the stereoselective kinetic resolution of chiral oxetanes and formation of 1,3‐disubstituted alcohols. HheC from Agrobacterium radiobacter AD1 was engineered to identify key variants capable of catalyzing the dehalogenation of γ‐haloalcohols (via HheC M1‐M3) and ring opening of oxetanes (via HheC M4‐M5) to access both (R)‐ and (S)‐configured products with high stereoselectivity and remarkable catalytic activity, yielding up to 49 % with enantioselectivities exceeding 99 % ee and E>200. The current strategy is broadly applicable as demonstrated by expansion of the substrate scope to include up to 18 examples for dehalogenation and 16 examples for ring opening. Additionally, the functionalized products are versatile building blocks for pharmaceutical applications. To shed light on the molecular recognition mechanisms for the relevant variants, molecular dynamic (MD) simulations were performed. The current strategy expands the scope of HHDH‐catalyzed chiral oxetane ring construction, offering efficient access to both enantiomers of chiral oxetanes and 1,3‐disubstituted alcohols. [ABSTRACT FROM AUTHOR]

A ruthenium‐catalyzed reductive amination via asymmetric transfer hydrogenation (ATH) has been used to perform an efficient dynamic kinetic resolution (DKR) of N‐aryl 2‐formyl pyrroles decorated with a phosphine moiety positioned at the ortho' position. The strategy relies on the labilization of the stereogenic axis in the substrate facilitated by a transient Lewis acid‐base interaction (LABI) between the carbonyl carbon and the phosphorus center. The reaction features broad substrate scope of aliphatic amines and N‐aryl pyrrole scaffolds, and proceeds under very mild conditions to afford P,N atropisomers in good to high yields and excellent enantioselectivities (up to 99 % ee) for both diphenyl and dicyclohexylphosphino derivatives. [ABSTRACT FROM AUTHOR]

A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)‐HyperBTM (5 mol %) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99 %, 99 : 1 er). Substitution of the aromatic core within the 3‐hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3), is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computationally, with a key substrate heteroatom donor O⋅⋅⋅acyl‐isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination. [ABSTRACT FROM AUTHOR]

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra‐substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative DKR of tetra‐substituted morpholinone and benzoxazinone‐derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di‐ and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale‐up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N−C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form. [ABSTRACT FROM AUTHOR]

Axially chiral biaryl δ‐amino acids possess significantly different conformational properties and chiral environment from centrally chiral amino acids, therefore, have drawn considerable attention in the fields of synthetic and medicinal chemistry. Herein, a novel chiral phenanthroline‐potassium catalyst has been developed by constructing a well‐organized axially chiral ligand composed of one 1,10‐phenanthroline unit and two axially chiral 1,1′‐bi‐2‐naphthol (BINOL) units. In the presence of this catalyst, good to excellent yields and enantioselectivities (up to 99 % yield, 98 : 2 er) have been achieved in the ring‐opening alcoholytic dynamic kinetic resolution of a variety of biaryl lactams, thereby providing an efficient protocol for catalytic asymmetric synthesis of unnatural axially chiral biaryl δ‐amino acid derivatives. [ABSTRACT FROM AUTHOR]

Amine dehydrogenases (AmDHs) are NAD(P)H‐dependent oxidoreductases that catalyze the reductive amination between carbonyl compounds and ammonia as the amine donor yielding valuable amines, typically with excellent enantioselectivity. While nature has provided enzymes with inherent AmDH activities, protein engineering techniques allowed researchers to expand the toolbox of available AmDHs, extend their substrate scope, improve their catalytic activities and stability under synthetically relevant conditions and even enable new reactivity concepts. The biocatalytic synthesis of amines using AmDHs has matured to a point where hundreds of aldehydes or ketones, of varying steric demands and bearing diverse functional groups, can be efficiently transformed. This review offers an overview of the available AmDHs and their substrate spectrum, covering from structural and evolutionary analyses to diverse methods employing these enzymes. Depending on the catalytic activities of other enzymes as reaction partners, AmDHs were applied in kinetic resolution (KR) and deracemization processes, cascade reactions for the amination of alcohols and alkenes or for the synthesis of amines and amino alcohols featuring multiple stereogenic centers. Moreover, the synthetic potential of AmDHs in novel pathways, such as the synthesis of secondary amines or alcohols, presents exciting opportunities for expanding their catalytic repertoire. [ABSTRACT FROM AUTHOR]

The hydrolase-catalyzed kinetic resolution of fluorinated racemates of 3-arylcarboxylic acids is described. Hydrolysis of ethyl esters of fluorinated acids by esterases and hydrolases in all cases resulted in the formation of hydrolyzed (S)-carboxylic acids and unreacted (R)-esters in high yields and high enantiomeric purity. The influence of separation conditions on the efficiency and enantioselectivity of biocatalytic conversion was also studied. The reactions were carried out under normal conditions (stirring with a magnetic stirrer at room temperature) and microwave irradiation in the presence of hydrolases. Amano PS showed excellent selectivity and good yields in the hydrolysis of fluorinated aromatic compounds. The absolute configuration of the resulting compounds was based on biokinetic studies and the use of chiral HPLC. A molecular modeling of the kinetic resolution of carboxylic acid esters was carried out. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Chiral BINAM‐derived selenide/achiral acid co‐catalyzed atroposelective electrophilic sulfenylation of pyrrole derivatives has been realized for the first time. A variety of C—N axially chiral sulfur‐containing pyrrole derivatives were readily obtained in moderate to good yields with moderate to excellent enantioselectivities. This catalytic system involves sequential desymmetrization and kinetic resolution. [ABSTRACT FROM AUTHOR]

[Display omitted] Understanding the structure-function relationships encoded on chiral catalysts is important for investigating the fundamental principles of catalytic enantioselectivity. Herein, the synthesis and self-assembly of naphthalene substituted bis - l / d -histidine amphiphiles (bis - l / d - NapHis) in DMF/water solution mixture is reported. The resulting supramolecular assemblies featuring well-defined P/M nanoribbons (NRs). With combination of the (P/M)-NR and metal ion catalytic centers (M n+ = Co2+, Cu2+, Fe3+), the (P)-NR-M n+ as chiral supramolecular catalysts show catalytic preference to 3,4-dihydroxy- S -phenylalanine (S -DOPA) oxidation while the (M)-NR-M n+ show enantioselective bias to R -DOPA oxidation. In contrast, their monomeric counterparts bis - l / d - NapHis-M n+ display an inverse and dramatically lower catalytic selectivity in the R/S -DOPA oxidation. Among them, the Co2+-coordinated supramolecular nanostructures show the highest catalytic efficiency and enantioselectivity (select factor up to 2.70), while the Fe3+-coordinated monomeric ones show nearly racemic products. Analysis of the kinetic results suggests that the synergistic effect between metal ions and the chiral supramolecular NRs can significantly regulate the enantioselective catalytic activity, while the metal ion-mediated monomeric bis - l / d - NapHis were less active. The studies on association constants and activation energies reveal the difference in catalytic efficiency and enantioselectivity resulting from the different energy barriers and binding affinities existed between the chiral molecular/supramolecular structures and R/S -DOPA enantiomers. This work clarifies the correlation between chiral molecular/supramolecular structures and enantioselective catalytic activity, shedding new light on the rational design of chiral catalysts with outstanding enantioselectivity. [ABSTRACT FROM AUTHOR]

Chirality transformation is a basic, attractive, and important strategy for obtaining enantioenriched products with desired chiral elements. The reported chirality conversion reaction often involves the process from one type of chirality to another one. To better utilize the chirality transformation strategy for obtaining two or more products with different chiral elements in a single reaction, a new method of kinetic resolution accompanied by a chirality transformation protocol is proposed and successfully realized in this study. This process is used for the asymmetric oxidation of phenol compounds along with the kinetic resolution of oxaziridines. A wide scope of products, including axially chiral phenols, oxaziridines, and α-hydroxyl cyclic ketones were smoothly obtained in high levels of yields and enantioselectivities in the developed method. These products can be readily used for the synthesis of various types of chiral ligands, which are potential choices for other catalytic asymmetric reactions. [ABSTRACT FROM AUTHOR]

An enzymatic approach for the synthesis of intermediate alcohol of the drug tegoprazan in 99% ee at 20 °C in hexane has been developed utilizing commercially available immobilized Thermomyces lanuginosus lipase (TL lipase) as a biocatalyst and vinyl acetate as a acyl donor. This method involves the enantioselective esterification of (RS)-5,7-difluorochroman-4-ol with vinyl acetate using TL Lipase. This enzymatic approach provides the (S)-chiral alcohol in 44% yield with 99% enantiomeric excess (ee) and the (R)-acetate in 43% yield and >99% ee. It is a sustainable approach for the synthesis of enantiopure tegoprazan intermediate, contributing to the advancement of green chemistry. The recovered TL lipase was reused in 13 subsequent runs without loss of activity. [ABSTRACT FROM AUTHOR]

Biosynthetic enzymes have enormous potential for the chemoenzymatic synthesis of natural products and other bioactive compounds. Methyltransferases are promising tools for the selective enzymatic modification of complex structures. This paper describes the production, purification and biochemical characterization of the O‐methyltransferase JerF, which catalyzes unique 4‐methoxy‐5,6‐dihydropyranone formation in jerangolid A biosynthesis. Isolation problems had hitherto prevented detailed studies on JerF and were solved by the fusion to maltose‐binding protein. The differentiation of JerF between styryl‐substituted dihydropyrandion enantiomers was investigated. In combination with a spontaneous racemization occurring with this type of substrates, a new enzymatic dynamic kinetic resolution was observed, which was used for the enantioselective chemoenzymatic synthesis of kavalactone natural products and new derivatives. In combination with an HMT‐based SAM regeneration system, (+)‐kavain, (+)‐11,12‐dimethoxykavain and (+)‐12‐fluorokavain were prepared in 3–4 steps on a 100 μmol scale with overall yields of 37–57 % and ees of 70–86 %. A mutational study based on an AlphaFold 2 model provided indications for active site residues with an influence on the performance of the enzyme that could be targeted for engineering in the future. This example illustrates how the exceptional enzymatic activities and specificities of biosynthetic enzymes can be exploited for the development of new synthesis approaches. [ABSTRACT FROM AUTHOR]

The conceptual merger of relay catalysis with dynamic kinetic resolution strategy is reported to enable regio‐ and enantioselective C(sp3)‐H bond arylation of aliphatic alcohols, forming enantioenriched β‐aryl alcohols typically with >90 : 10 enantiomeric ratios (up to 98 : 2 er) and 36–74 % yields. The starting materials bearing neighbouring stereogenic centres can be converted to either diastereomer of the β‐aryl alcohol products, with >85 : 15 diastereomeric ratios determined by the catalysts. The reactions occur under mild conditions, ensuring broad compatibility, and involve readily available aryl bromides, an inorganic base, and commercial Ru‐ and Pd‐complexes. Mechanistic experiments support the envisioned mechanism of the transformation occurring through a network of regio‐ and stereoselective processes operated by a coherent Ru/Pd‐dual catalytic system. [ABSTRACT FROM AUTHOR]

The development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N(2)‐, C(4)‐ and C(5)‐, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol %). The application of this KR method to tertiary alcohols derived directly from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s >100) is also described. The KR process is readily amenable to scale up using bench grade solvents and reagents, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O⋅⋅⋅isothiouronium interaction from substrate to acylated catalyst observed within the favoured transition state. Similarly, the effect of C(5)‐aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π–isothiouronium interaction identified as leading to reduced selectivity. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Optically active phthalides are prevalent in many natural and bioactive products. Herein, a novel dynamic kinetic resolution of isobenzofuranone derivatives through palladium‐catalyzed asymmetric allylic alkylation has been developed to synthesize phthalide derivatives bearing vicinal quaternary and tertiary stereocenters with high yields, showing excellent chemo‐, enantio‐ and diastereoselectivity. Furthermore, gram‐scale experiment underwent smoothly and the transformation of product could build a bridged bicyclic skeleton. [ABSTRACT FROM AUTHOR]

Going beyond currently reported two electron transformations that formed the core backdrop of asymmetric catalytic site‐selective carbohydrate polyol functionalizations, we herein report a seminal demonstration of an enantioconvergent copper catalyzed site‐selective etherification of minimally protected saccharides through a single‐electron radical pathway. Further, this strategy paves a rare strategy, through which a carboxamide scaffold that is present in some glycomimetics of pharmacological relevance, can be selectively introduced. In light of the burgeoning interest in chiral radical catalysis, and the virtual absence of such stereocontrol broadly in carbohydrate synthesis, our strategy showcased the unknown capability of chiral radical copper catalysis as a contemporary tool to address the formidable site‐selectivity challenge on a remarkable palette of naturally occurring saccharides. When reducing sugars were employed, a further dynamic kinetic resolution type glycosylation can be activated by the catalytic system to selectively generate the challenging β‐O‐glycosides. [ABSTRACT FROM AUTHOR]

Five- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied. 1 Introduction 2 Catalyst-Controlled Cα –H Functionalization (Approach a) 3 Decarboxylative α-AAA Reactions (Approach b) 4 Cα –X Substitution Reactions (Approach c) 5 De Novo Synthesis from Acyclic Precursors (Approach d) 6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e) 7 Kinetic Resolution and Deracemization (Approach f) 8 Conclusions [ABSTRACT FROM AUTHOR]

Vicinal halohydrins are key building blocks to produce bioactive molecules and drugs, especially if they can be obtained in enantiomerically pure form. In this study, we present a bi‐enzymatic sequence that allows to obtain vic‐halohydrins through a photochemoenzymatic olefin hydroxy halogenation followed by a lipase catalysed kinetic resolution. The absolute configuration of the resulting products was determined using Mosher's method [ABSTRACT FROM AUTHOR]

Chiral guanidine-catalyzed acylative and silylative dynamic kinetic resolutions of 6-hydroxy-2 H -pyran-3(6 H)-one were achieved. We succeeded in developing a non-enzymatic acylative dynamic kinetic resolution of 6-hydroxy-2 H -pyran-3(6 H)-one with high enantioselectivity, which could be improved by recrystallization. In contrast, the non-enzymatic silylative dynamic kinetic resolution of 6-hydroxy-2 H -pyran-3(6 H)-one was accomplished with a moderate selectivity for the first time. [ABSTRACT FROM AUTHOR]

Noncovalent interactions associated with the enzyme, enzyme-substrate complexes, and transition states have profound influences on varying the biocatalytical activity and enantioselectivity. The recent rediscovery of halogen bonds incorporating in biocatalysis has induced our motivation on introducing halogen substituents into the substrate for improving the enzyme performance. By selecting Candida antarctica lipase B (CALB)-catalyzed kinetic hydrolysis (or butanolysis) of trans-2-(p-halophenyl)cyclopropyl 1,2,4-triazolide in methyl tert-butyl ether (MTBE) as the model reaction system, (R, R)-2-(p-halophenyl)cyclopropane-1-carboxylic acid (or ester) of high-optical purity that acts as the key building block for synthesizing the corresponding (1 R, 2S)-2-(p-halophenyl)cyclopropylamine derivatives was obtainable. The thermodynamic and kinetic analysis was then employed for elucidating effects of the halogen substituent and acyl acceptor on enhancing the noncovalent interactions of the rate-limiting tetrahedral intermediate and hence CALB activity and enantioselectivity. A putative model was moreover proposed for interpreting the possible hydrogen and halogen bonding involving the halogen substituent in turning the noncovalent interactions. [ABSTRACT FROM AUTHOR]

Asymmetric cyanosilylation serves as an important tool to convert easily available ketones into cyanohydrins of diverse reactivity. Whereas a large library of organocatalysts and transition-metal catalysts have been identified for monoketones, cyanosilylation of more-complex substrates, particularly those giving enantioenriched vicinal stereocenters, is underexplored in comparison. Here, a pair of recently published kinetic resolution and desymmetrization methods are highlighted for their success in constructing complex vicinal stereocenters by cyanosilylation using tailored aluminum and magnesium catalysts, respectively. 1 Introduction 2 Kinetic Resolution of α-Branched Ketones 3 Desymmetrization of 1,3-Diketones 4 Conclusion [ABSTRACT FROM AUTHOR]

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo‐ and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene‐based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity. [ABSTRACT FROM AUTHOR]

Isotactic polythioesters (PTEs) that are thioester analogs to natural polyhydroxyalkanoates (PHAs) have attracted growing attention due to their distinct properties. However, the development of chemically synthetic methods for preparing isotactic PTEs has long been an intricate endeavour. Herein, we report the successful synthesis of perfectly isotactic PTEs via stereocontrolled ring‐opening polymerization. This binaphthalene‐salen aluminium (SalBinam‐Al) catalyst promoted a robust polymerization of rac‐α‐substituted‐β‐propiothiolactones (rac‐BTL and rac‐PTL) with highly kinetic resolution, affording perfectly isotactic P(BTL) and P(PTL) with Mn up to 276 kDa. Impressively, the isotactic P(BTL) formed a supramolecular stereocomplex with improved thermal property (Tm=204 °C). Ultimately, this kinetic resolution polymerization enabled the facile isolation of enantiopure (S)‐BTL, which could efficiently convert to an important pharmaceutical building block (S)‐2‐benzyl‐3‐mercapto‐propanoic acid. Isotactic P(PTL) served as a tough and ductile material comparable to the commercialized polyolefins. This synthetic system allowed to access of isotactic PTEs, establishing a powerful platform for the discovery of sustainable plastics. [ABSTRACT FROM AUTHOR]

The (R,R)-Teth-TsDPEN-Ru(II) complex promoted the one-pot double C=O reduction of α-alkyl-β-ketoaldehydes through asymmetric transfer hydrogenation/dynamic kinetic resolution (ATH-DKR) under mild conditions. In this process, ten anti-2-benzyl-1-phenylpropane-1,3-diols (85:15 to 92:8 dr) were obtained in good yields (41–87%) and excellent enantioselectivities (>99% ee for all compounds). Notably, the preferential reduction of the aldehyde moiety led to the in situ formation of 2-benzyl-3-hydroxy-1-phenylpropan-1-one intermediates. These intermediates played a crucial role in enhancing both reactivity and stereoselectivity through hydrogen bonding. [ABSTRACT FROM AUTHOR]

While simultaneously proceeding reactions are among the most fascinating features of biosynthesis, this concept of tandem processes also offers high potential in the chemical industry in terms of less waste production and improved process efficiency and sustainability. Although examples of one‐pot chemoenzymatic syntheses exist, the combination of completely different reaction types is rare. Herein, we demonstrate that extreme "antipodes" of the "worlds of catalysis", such as syngas‐based high‐pressure hydroformylation and biocatalyzed reduction, can be combined within a tandem‐type one‐pot process in water. No significant deactivation was found for either the biocatalyst or the chemocatalyst. A proof‐of‐concept for the one‐pot process starting from 1‐octene was established with >99 % conversion and 80 % isolated yield of the desired alcohol isomers. All necessary components for hydroformylation and biocatalysis were added to the reactor from the beginning. This concept has been extended to the enantioselective synthesis of chiral products by conducting the hydroformylation of styrene and an enzymatic dynamic kinetic resolution in a tandem mode, leading to an excellent conversion of >99 % and an enantiomeric ratio of 91 : 9 for (S)‐2‐phenylpropanol. The overall process runs in water under mild and energy‐saving conditions, without any need for intermediate isolation. [ABSTRACT FROM AUTHOR]

Owing to its associated advantages such as the generation of two stereocenters in 100% maximum theoretical yield, mild reaction conditions and environmentally friendliness, ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) is a versatile and appealing synthetic approach to access valuable chiral alcohols containing two or more stereocenters. Despite the considerable progress that has been made in this research field, previous studies mostly focused on ketone substrates with relatively simple structures. In the present study, ketoreductases YDR368w and YGL039w were identified through enzyme screening and applied to the KRED-catalyzed DYRKR of sterically hindered 2-aryl-1,5-benzothiazepin-3,4(2H,5H)-diones (1). Eleven structurally diverse chiral cis-(2S,3S)-2,3-dihydro-3-hydroxy-2-aryl-1,5-benzothiazepin-4(5H)-ones (cis-(2S,3S)-2), including the critical synthetic intermediates to the calcium channel blockers diltiazem and clentiazem, were prepared in 50–90% isolated yields with excellent stereoselectivities (all >20 : 1 dr and ≥99% ee). Finally, the successful execution of a gram scale synthesis and the demonstrated excellent recyclability of the immobilized ketoreductase (up to 20 cycles) both underscored the good application potential of the currently established DYRKR method. [ABSTRACT FROM AUTHOR]

An efficient RuPHOX−Ru catalyzed asymmetric cascade hydrogenation of 3‐substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3‐substituted chromanols in high yields with excellent enantio‐ and diastereoselectivities (up to 99 % yield, >99 % ee and >20 : 1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3‐substituted chromanols and their derivatives. [ABSTRACT FROM AUTHOR]

Metal‐enzyme integrated catalysts (MEICs) that combine metal and enzyme offer great potential for sustainable chemoenzymatic cascade catalysis. However, rational design and construction of optimal microenvironments and accessible active sites for metal and enzyme in individual nanostructures are necessary but still challenging. Herein, Pd nanoparticles (NPs) and Candida antarctica lipase B (CALB) are co‐immobilized into the pores and surfaces of covalent organic frameworks (COFs) with tunable functional groups, affording Pd/COF‐X/CALB (X = ONa, OH, OMe) MEICs. This strategy can regulate the microenvironment around Pd NPs and CALB, and their interactions with substrates. As a result, the activity of the COF‐based MEICs in catalyzing dynamic kinetic resolution of primary amines is enhanced and followed COF‐OMe > COF‐OH > COF‐ONa. The experimental and simulation results demonstrated that functional groups of COFs modulated the conformation of CALB, the electronic states of Pd NPs, and the affinity of the integrated catalysts to the substrate, which contributed to the improvement of the catalytic activity of MEICs. Further, the MEICs are prepared using COF with hollow structure as support material, which increased accessible active sites and mass transfer efficiency, thus improving catalytic performance. This work provides a blueprint for rational design and preparation of highly active MEICs. [ABSTRACT FROM AUTHOR]

Asymmetric desymmetrization through the selective reduction of one double bond of prochiral 2,5-cyclohexadienones is highly challenging. A novel method has been developed for synthesizing chiral cyclohexenones by employing an ene-reductase (Bacillus subtilis YqjM) enzyme that belongs to the OYE family. Our strategy demonstrates high substrate scope and enantioselectivity towards substrates containing all-carbon as well as heteroatom (O, N)-containing quaternary centers. The mechanistic studies (kH/D = ∼1.8) indicate that hydride transfer is probably the rate-limiting step. Mutation of several active site residues did not affect the stereochemical outcomes. This work provides a convenient way of synthesizing various enantioselective γ,γ-disubstituted cyclohexanones using enzymes. [ABSTRACT FROM AUTHOR]

To enrich 'epoxide hydrolase (EH) tool cabinet' for preparing enantiopure epoxides and 1,2-diols, a novel microbial EH, Sf EH2, was identified from Streptomyces fradiae SF-2. Bioinformatics analysis indicated that Sf EH2 has typical structural characteristics of α/β-hydrolase fold superfamily. Its coding gene, sfeh 2, was then codon-optimized and amplified. A recombinant (re) Sf EH2-expressing E. coli BL21(DE3) strain (E. coli / sfeh 2) was constructed through DNA manipulations. Substrate spectrum assay including fifteen common racemic (rac -) epoxides by E. coli / sfeh 2 showed that re Sf EH2 displayed the highest and best complementary regioselectivities (regioselectivity coefficients, α R = 89.7% and β S = 91.4%) towards rac - 14a , as well as the highest enantioselectivity (enantiomeric ratio, E = 15.3) in S -type towards rac - 15a. Molecular docking simulation revealed that Sf EH2 preferentially attacked C α of (R)- 14a and C β of (S)- 14a geometrically. In kinetic parameter analysis, the K m R (5.74 mM) of purified re Sf EH2 for (R)- 15a was 1.76-fold lower than K m S (10.09 mM) for (S)- 15a. At last, using 50 mg dry cell weight/mL E. coli / sfeh 2, the scale-up enantioconvergent hydrolysis of 100 mM rac - 14a at 30 °C for 6.0 h afforded (S)- 14b with 80.9% ee p and 90.1% yield, while the kinetic resolution of 150 mM rac - 15a retained (S)- 15a with >99.0% ee s and 42.2% yield. [Display omitted] • A novel epoxide hydrolase, Sf EH2, is identified and characterized. • Sf EH2 displays desired regioselectivity for racemic 4-methylphenyl glycidyl ether. • Sf EH2 displays desired enantioselectivity for racemic benzyl glycidyl ether phenyl. • Space-time yield of (S)-3-aryloxy-1,2-propanediol by Sf EH2 is the highest. • Space-time yield of (S)-benzyl glycidyl ether phenyl by Sf EH2 is the highest. [ABSTRACT FROM AUTHOR]

The synthesis of enantiomerically pure tertiary alcohols is an important issue in organic synthesis of a range of pharmaceuticals including molecules such as the anti‐HIV drug Efavirenz. A conceptually elegant approach to such enantiomers is the dynamic kinetic resolution of racemic tertiary alcohols, which, however, requires efficient racemization strategies. The racemization of tertiary alcohols is particularly challenging due to various side reactions that can occur because of their high tendency for elimination reactions. In the last few years, several complementary catalytic concepts for racemization of tertiary alcohols have been developed, characterized by efficient racemization and suppression of unwanted side‐reactions. Besides resins bearing sulfonic acid moieties and a combination of boronic acid and oxalic acid as heterogeneous and homogeneous Brønsted‐acids, respectively, immobilized oxovanadium and piperidine turned out to be useful catalysts. The latter two catalysts, which have already been applied to different types of substrates, also have proven good compatibility with lipase, thus leading to the first two examples of chemoenzymatic dynamic kinetic resolution of tertiary alcohols. In this review, the difficulties in racemizing tertiary alcohols are specifically described, and the recently developed complementary concepts to overcome these hurdles are summarized. [ABSTRACT FROM AUTHOR]

A pair of enantiopure [6]‐azairidahelicenes incorporating chirality at the metal center and on the helicenic ligand were synthesized by dynamic kinetic resolution (dkr) of a configurationally labile [4]‐helicenic ligand (4‐(2‐pyridyl)‐benzo[g]phenanthrene, L1H) using bis‐cyclometalated chiral‐at‐metal only iridium(III) precursors as chiral inductors. The origin of the observed dkr is attributed to the different conformation and stability of diastereomeric reaction intermediates formed during the cyclometalation process. The isolated enantiomers exhibited circularly polarized phosphorescence (CPP), with |gphos| values of 1.8×10−3. [ABSTRACT FROM AUTHOR]

The catalytic access of silicon‐stereogenic organosilanes remains a big challenge, and largely depends on the desymmetrization of the symmetric precursors with two identical substitutes attached to silicon atom. Here we report the construction of silicon‐stereogenic organosilanes via catalytic kinetic resolution of racemic monohydrosilanes with good to excellent selectivity factors. Both Si‐stereogenic dihydrobenzosiloles and Si‐stereogenic monohydrosilanes could be efficiently accessed in one single operation via Rh‐catalyzed enantioselective intramolecular hydrosilylation, employing (R,R)‐Et‐DuPhos as the optimal ligand. This catalytic protocol features mild conditions, a low catalyst loading (0.1 mol % [Rh(cod)Cl]2), high stereoinduction (S factor up to 152), and excellent scalability. Moreover, further derivatizations led to the efficient synthesis of uncommon middle‐size (7‐ and 8‐membered) Si‐stereogenic silacycles. Preliminary mechanistic study indicates this reaction might undergo a modified Chalk–Harrod mechanism. [ABSTRACT FROM AUTHOR]

This document discusses the development of an efficient method for the kinetic resolution of ¿-allenols using a commercially available immobilized lipase, Lipozyme TL-IM. The study found that the method had high enantioselectivity, with an S-factor of over 1000. The researchers also found that the method was compatible with a wide range of substrates, including those with electron-withdrawing and electron-donating groups on the benzene ring. This method provides a valuable approach for synthesizing chiral oxycycles. [Extracted from the article]

This document provides a summary of various methods for the synthesis of tetrasubstituted axially chiral alkenes. The methods discussed include urea group-directed organocatalytic dihalogenation, Rh(III)-catalyzed C-H activation and directing group migration, cationic rhodium(I)/H8-BINAP-catalyzed chelation-controlled cycloaddition, Cu/Pd dual catalysis for arylboration, nickel-catalyzed cross-electrophile trans-aryl-benzylation, palladium-catalyzed C-H functionalization, Pd(II)-catalyzed thioether-directed alkenyl C-H olefination, Suzuki-Miyaura cross-coupling, asymmetric N-alkylation, chiral phosphoric acid catalyzed kinetic resolution, and asymmetric allylic substitution-isomerization. The methods demonstrate broad substrate scope and high enantioselectivities, but further research is needed to explore stereodivergent synthesis and applications in pharmaceutical chemistry. [Extracted from the article]

Enzyme‐catalyzed acylative kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic primary and secondary alcohols have been widely reported to produce esters with high enantiomeric purity. In contrast, similar KRs of tertiary alcohols have been reported for only a limited range of substrates and require prolonged reaction times of several days. To gain deeper insight into the substrate scope and increase the process efficiency, we examined the reaction conditions using commercially available immobilized lipase A from Candida antarctica and found that the addition of the heterogeneous, inorganic base sodium carbonate significantly increased the reaction rate while maintaining high enantioselectivity. The use of vinyl hexanoate as the acyl donor provided esters that were stable during chromatography purification. The optimized reaction conditions were then successfully applied to a range of cyclic tertiary alcohols containing tetralin, dihydroindene, chromane, and thiochromane skeletons having, in part, a substituent on the aromatic ring. In this study on the structure–reactivity relationship of enzymatic KR‐type reactions, we achieved >30 % conversion for various tertiary alcohols in 24 h at 25 °C, producing optically active esters with 88–99 % ee. [ABSTRACT FROM AUTHOR]

Kinetic resolution of racemates with lipases is the preferred method for producing bioactive compounds. One strategy for obtaining highly enantioselective lipases that are stable in the organic media that are often used in these reactions is to improve existing lipases by protein engineering. In this work, we engineered the lipase LipC12, which has good stability in organic media, but only moderate enantioselectivity. Molecular docking with LipC12 identified V261 as a key position influencing, first, enantioselectivity in the transesterification of (RS)-1-phenylethanol and, second, activity in the hydrolysis of p-nitrophenyl octanoate. Variants were then obtained by site-directed mutagenesis, expressed in Escherichia coli, and their performance in these reactions was evaluated. Enzymes immobilized on Immobead 150 were used in the transesterification while free enzyme was used in the hydrolysis reaction. It was not possible to increase the hydrolytic activity and enantioselectivity simultaneously: some variants had increased enantioselectivity but lower hydrolytic activity, and others had increased hydrolytic activity but lower enantioselectivity. The best result for enantioselectivity was obtained for LipC12V261Q, with an increase of the E-value (for (R)-1-phenylethanol) from 46 to 110, however, its hydrolytic activity decreased 4-fold in comparison to LipC12wt. The highest hydrolytic activity was obtained for LipC12V261F, with a value almost 6-fold higher than that of LipC12wt. This variant also had an inverted enantiopreference (i.e. for (S)-1-phenylethanol), but with a very low E-value of only 4. [ABSTRACT FROM AUTHOR]

Layered double hydroxides (LDHs) are brucite-like nanomaterials that have been used to immobilize several enzymes. However, layered hydroxide salts (LHSs), another group of brucite-like nanomaterials, have not yet been used for enzyme immobilization. In this work, we prepared two types of layered hydroxide salts, zinc hydroxide nitrate (ZHN: Zn5(OH)8(NO3)2.2H2O) and zinc hydroxide chloride (ZHC: Zn5(OH)8Cl2.H2O) and used them to immobilize Pseudomonas cepacia lipase (LipPS). The best protein loading for both ZHN and ZHC was 162.5 mg g−1 of LHS, which gave high values of triolein-hydrolyzing activity in organic medium (103 U g−1 for LipPS-ZHN and 105 U g−1 for LipPS-ZHC), immobilization efficiencies above 90% and activity retentions above 170%. In the kinetic resolution of (R,S)-1-phenylethanol, LipPS-ZHN gave better results, with 50% conversion being obtained in 2 h and an ees of 99%. With LipPS-ZHC, the conversion at 2 h was 40% and the ees, was lower, only 73%. For both immobilized materials, the eep was higher than 99% and E was higher than 200. The immobilized materials were stable after 5 cycles of reuse in successive 2-h kinetic resolutions. These results demonstrate that the layered hydroxide salts ZHN and ZHC have good potential as supports for the immobilization of lipases. [ABSTRACT FROM AUTHOR]

Despite the significance of chiral allene skeletons in catalysis, organic synthesis and medicinal chemistry et al. there is a scarcity of reports on axially chiral allenyl phosphorus compounds. Here, we disclosed an efficient and straightforward cascade reaction between ethynyl ketones and phosphine oxides, resulting in a broad array of trisubstituted allenes incorporating a phosphorus moiety in high yields with excellent stereoselectivities facilitated by peptide‐mimic phosphonium salt (PPS) catalysis, Additionally, comprehensive series of mechanistic experiments have been conducted to elucidate that this cascade reaction proceeds via an asymmetric Pudovik addition reaction followed by a subsequent phospha‐Brook rearrangement that occurs concomitantly with kinetic resolution, representing a stereospecific rearrangement and protonation process facilitating central‐to‐axial chirality transfer in a cascade manner. We anticipate that our research will pave the way for a promising exploration of novel stereo‐induction pattern in the Pudovik addition/phospha‐Brook rearrangement cascade reaction. [ABSTRACT FROM AUTHOR]

Upgrading CO2 to value‐added chiral molecules via catalytic asymmetric C−C bond formation is a highly important yet challenging task. Although great progress on the formation of centrally chiral carboxylic acids has been achieved, catalytic construction of axially chiral carboxylic acids with CO2 has never been reported to date. Herein, we report the first catalytic asymmetric synthesis of axially chiral carboxylic acids with CO2, which is enabled by nickel‐catalyzed dynamic kinetic asymmetric reductive carboxylation of racemic aza‐biaryl triflates. A variety of important axially chiral carboxylic acids, which are valuable but difficult to obtain via catalysis, are generated in an enantioconvergent version. This new methodology features good functional group tolerance, easy to scale‐up, facile transformation and avoids cumbersome steps, handling organometallic reagents and using stoichiometric chiral materials. Mechanistic investigations indicate a dynamic kinetic asymmetric transformation process induced by chiral nickel catalysis. [ABSTRACT FROM AUTHOR]

P‐stereogenic benzo‐fused heterocycles is a privileged skeleton due to their outstanding catalytic properties and bioactivities. However, their enantioselective synthesis is still underdeveloped. Here we demonstrate the use of easily accessible racemic H−P(O) compounds as starting materials and commercial chiral N1, N2‐dimethyl‐1,2‐diphenylethane‐1,2‐diamine ligand in combination with Cu(I) catalysts to enable an attractive dynamic kinetic C(sp2)−P cross‐coupling reaction. This protocol not only exhibits a broad substrate scope but also provides general access to a diverse range of useful P‐stereogenic five‐, six‐, seven‐ and eight‐membered benzo‐fused O, P‐ containing heterocycles with good to high yields and enantioselectivities. [ABSTRACT FROM AUTHOR]

Chirality constitutes an inherent attribute of nature. The catalytic asymmetric synthesis of molecules with central, axial, and helical chirality is a topic of intense interest and is becoming a mature field of research. However, due to the difficulty in synthesis and the lack of a prototype, less attention has been given to planar chirality arising from the destruction of symmetry on a single planar ring. Herein, we report the catalytic asymmetric synthesis of planar-chiral dianthranilides, a unique class of tub-shaped eight-membered cyclic dilactams. This protocol is enabled by cinchona alkaloid-catalyzed (dynamic) kinetic resolution. Under mild conditions, various C2- or C1-symmetric planar-chiral dianthranilides have been readily prepared in high yields with excellent enantioselectivity. These dianthranilides can serve as an addition to the family of planar-chiral molecules. Its synthetic value has been demonstrated by kinetic resolution of racemic amines via acyl transfer, enantiodivergent synthesis of the natural product eupolyphagin, and preliminary antitumor activity studies. Chirality has long fascinated chemists, but asymmetric synthesis has largely focused on central, axial, and helical chirality to date. Here, the authors synthesize dianthranilides with planar chirality, via cinchona alkaloid-catalyzed (dynamic) kinetic resolution. [ABSTRACT FROM AUTHOR]