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Cyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two‐point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety—an H‐bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold‐alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold‐catalyzed highly enantioselective cycloisomerization of 1,5‐enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The first asymmetric hydrogenation of acyclic tetrasubstituted α,β‐unsaturated amides has been achieved by using Rh/DuanPhos complex as a catalyst, delivering chiral β‐amino amides with two contiguous chiral centers in excellent yields and high enantioselectivities (up to 99% yield, 96% ee), which provides efficient and concise access to valuable β‐amino amide derivatives. The gram‐scale reaction and efficient transformation of β‐amino amide to β‐amino acid and β‐amino cyanide demonstrated the utility of this methodology. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The first asymmetric hydrogenation of acyclic tetrasubstituted α,β‐unsaturated amides has been achieved by using Rh/DuanPhos complex as a catalyst, delivering chiral β‐amino amides with two contiguous chiral centers in excellent yields and high enantioselectivities (up to 99% yield, 96% ee), which provides efficient and concise access to valuable β‐amino amide derivatives. The gram‐scale reaction and efficient transformation of β‐amino amide to β‐amino acid and β‐amino cyanide demonstrated the utility of this methodology. [ABSTRACT FROM AUTHOR]

This paper, for the first time, reports calculating molecular descripts from the combinations of catalysts and substrates, for enantioselectivity predictions in chiral phosphoric acid–catalyzed thiol addition to N‐acylimines. Ten molecular descriptors, together with random forest (RF) algorithm, were used to establish the quantitative structure–selectivity relationship (QSSR) model (RF Model I), yielding correlation coefficient of R=0.982, root mean square (rms) error of 0.604 kJ/mol (for 800 enantioselectivity ΔΔG from 32 catalysts in the training set), R=0.922, rms=1.075 kJ/mol (for 275 enantioselectivity ΔΔG from 11 new catalysts in the test set). The RF Model I was proved to be more accurate in enantioselectivity predictions, compared with the QSSR models reported in the literature and with the RF Model II and RF Model III in this work. Moreover, the RF Model I was based on simple Dragon descriptors and capable of extrapolative prediction for new catalysts. Therefore, it is reasonable deriving molecular descriptors from the combinations of catalysts and substrates (thiols and imines). This work provides a new method for the predictions of enantioselectivity ΔΔG. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Chiral 1,3‐substituted fragments are ubiquitous in pharmaceutical molecules and natural products, prompting the development of numerous methods to access these structures. Nonetheless, devising synthetic routes for complex chiral architectures in practical applications typically demands years of expertise. Herein, we developed a nickel‐catalyzed enantioselective migratory arylboration reaction of allylboronic esters using a chiral 1,2‐diamine ligand, yielding a range of chiral 1,3‐bis(boronates) with high enantioselectivity. The protocol is characterized by its use of commercially available substrates, mild reaction conditions, user‐friendly procedures, and a broad substrate compatibility. Moreover, we demonstrate the practicality and application potential of this reaction by synthesizing several key drug intermediates. [ABSTRACT FROM AUTHOR]

Epoxide hydrolases (EHs) catalyze the conversion of epoxides into vicinal diols. The epoxide hydrolase gene from P. chrysosporium was previously cloned and subjected to site-directed mutation to study its enzyme activity, but the results were unsatisfactory. This study used error prone PCR and DNA shuffling to construct a PchEHA mutation library. We performed mutation-site combinations on PchEHA based on enzyme activity measurement results combined with directed evolution technology. More than 15,000 mutants were randomly selected for the preliminary screening of PchEHA enzyme activity alongside 38 mutant strains with increased enzyme activity or enantioselectivity. Protein expression and purification were conducted to determine the hydrolytic activity of PchEHA, and three mutants increased their activity by more than 95% compared with that of the wt. After multiple rounds of screening and site-specific mutagenesis, we found that F3 offers the best enzyme activity and enantioselectivity; furthermore, the molecular docking results confirmed this result. Overall, this study uncovered novel mutants with potential value as industrial biocatalysts. [ABSTRACT FROM AUTHOR]

With the rise of machine learning (ML), the modeling of chemical systems has reached a new era and has the potential to revolutionize how we understand and predict chemical reactions. Here, we probe the historic dependence on utilizing enantiomeric excess (ee) as a target variable and discuss the benefits of using relative Gibbs free activation energies (ΔΔG≠), grounded firmly in transition‐state theory, emphasizing practical benefits for chemists. This perspective is intended to discuss best practices that enhance modeling efforts especially for chemists with an experimental background in asymmetric catalysis that wish to explore modelling of their data. We outline the enhanced modeling performance using ΔΔG≠, escaping physical limitations, addressing temperature effects, managing non‐linear error propagation, adjusting for data distributions and how to deal with unphysical predictions,in order to streamline modeling for the practical chemist and provide simple guidelines to strong statistical tools. For this endeavor, we gathered ten datasets from the literature covering very different reaction types. We evaluated the datasets using fingerprint‐, descriptor‐, and graph neural network‐based models. Our results highlight the distinction in performance among varying model complexities with respect to the target representation, emphasizing practical benefits for chemists. [ABSTRACT FROM AUTHOR]

A general phase‐transfer catalyst (PTC) mediated enantioselective alkylation of N‐acylsulfenamides is reported. Essential to achieving high selectivity was the use of the triethylacetyl sulfenamide protecting group along with aqueous KOH as the base under biphasic aqueous conditions to enable the reaction to be performed at −40 °C. With these key parameters, enantiomeric ratios up to 97.5 : 2.5 at the newly generated chiral sulfur center were achieved with an inexpensive cinchona alkaloid derived PTC. Broad scope and excellent functional group compatibility was observed for a variety of S‐(hetero)aryl and branched and unbranched S‐alkyl sulfenamides. Moreover, to achieve high selectivity for the opposite enantiomer, a pseudoenantiomeric catalyst was designed and synthesized from inexpensive cinchonidine. Given that sulfoximines are a bioactive pharmacophore of ever‐increasing interest, selected product sulfilimines were oxidized to the corresponding sulfoximines with subsequent reductive cleavage affording the free‐NH sulfoximines in high yields. The utility of the disclosed method was further demonstrated by the efficient asymmetric synthesis of atuveciclib, a phase I clinical candidate for which only chiral HPLC separation had previously been reported for isolation of the desired (R)‐sulfoximine stereoisomer. [ABSTRACT FROM AUTHOR]

A diversity-oriented total synthesis for Amaryllidaceae alkaloids incorporating the frequently found C3a-arylated hydroindole moiety was developed. Chiral-anion-induced gold(I) catalysis was employed for the cyclization of 1,4-diynes to the pyrrolidine and the installation of the all-carbon quaternary stereocenter. Both enantiomeric series of crinine-type alkaloids in high enantiopurity were accessible by this methodology. The formal synthesis of a wide range of Amaryllidaceae alkaloids is described, such as (+)-vitattine, (–)- epi -vitattine, (–)-elwesein, (–)- epi -elwesein, (–)-crinine, (–)- epi -crinine, (–)-buphanisine, (–)-flexinine, and (+)-gracilamine. [ABSTRACT FROM AUTHOR]

An efficient and practical method was developed for the synthesis of C2‐symmetric 2,2′‐bipyridine‐α,α′‐1‐t‐butyl‐diol ligands. The disclosed synthesis involves the Ullmann homocoupling of a keto bromo‐pyridine under NiCl2/Zn/PPh3 conditions, followed by the stereoselective double hydrogen transfer to the obtained 2,2′‐bipyridine‐diketone using RuII Noyori–Ikariya catalysts. This approach allowed the successful synthesis of 2,2′‐bipyridine‐α,α′‐1‐t‐butyl‐diol, i.e (S,S)‐Bolm's ligand, with a quantitative yield and an excellent stereoselectivity (ee>99.5 %, de>99.5 %), with an overall yield of 69 % from easily accessible starting materials. [ABSTRACT FROM AUTHOR]

In this work, we describe an efficient and modular method for enantiodivergent accessing P(V)‐stereogenic molecules by utilizing the catalytic atroposelective Catellani‐type C−H arylation/desymmetric intramolecular N‐arylation cascade reaction. The enantioselectivity of this protocol was proved to be tuned by the polarity of the solvent, thus providing a wide range of both chiral P(V)‐stereogenic enantiomers in moderate to good yields with good to excellent enantiomeric excesses. Noteworthy is that the strategy developed herein represents an unprecedented example of solvent‐dictated inversion of the enantioselectivity of P(V)‐stereogenic compounds. [ABSTRACT FROM AUTHOR]

Chiral pincer complexes, characterized by their rigid tridentate coordination framework, have emerged as powerful catalysts in asymmetric synthesis. This review provides a comprehensive overview of recent advancements in the development of chiral pincer-type ligands and their corresponding transition metal complexes. We highlight the latest progress in their application across a range of catalytic asymmetric reactions, including the (transfer) hydrogenation of polar and non-polar bonds, hydrophosphination, alkynylation, Friedel-Crafts reactions, enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones, enantioselective hydrosilylation, as well as Aza–Morita–Baylis–Hillman reactions. The structural rigidity and tunability of chiral pincer complexes enable precise control over stereoselectivity, resulting in high enantioselectivity and efficiency in complex molecular transformations. As the field advances, innovations in ligand design and the exploration of new metal centers are expected to expand the scope and utility of these catalysts, bearing significant implications for the synthesis of enantioenriched compounds in pharmaceuticals, materials science, and beyond. [ABSTRACT FROM AUTHOR]

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition‐metal‐catalyzed asymmetric C−H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt‐catalyzed enantioselective C−H activation reaction enabled by visible‐light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96 % to >99 % ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step. [ABSTRACT FROM AUTHOR]

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The implementation of divergent protein engineering on the natural transaminase Vf‐ω‐TA led to the development of two effective mutants (M2 and M8), enabling the enzymatic synthesis of chiral amine precursors of Rivastigmine and Apremilast, respectively. The evolution of the enzymes was guided by crystal structures and a focused mutagenesis strategy, allowing them to effectively address the challenging ketone substrates with significant steric hindrance. Under the optimized reaction parameters, transamination proceeded smoothly in good conversions and with perfect stereochemical control (> 99% ee). These processes utilize inexpensive α‐methylbenzylamine as an amine donor and avoid the continuous acetone removal and costly LDH/GDH/NADH systems. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The implementation of divergent protein engineering on the natural transaminase Vf‐ω‐TA led to the development of two effective mutants (M2 and M8), enabling the enzymatic synthesis of chiral amine precursors of Rivastigmine and Apremilast, respectively. The evolution of the enzymes was guided by crystal structures and a focused mutagenesis strategy, allowing them to effectively address the challenging ketone substrates with significant steric hindrance. Under the optimized reaction parameters, transamination proceeded smoothly in good conversions and with perfect stereochemical control (> 99% ee). These processes utilize inexpensive α‐methylbenzylamine as an amine donor and avoid the continuous acetone removal and costly LDH/GDH/NADH systems. [ABSTRACT FROM AUTHOR]

Geometrically defined allylic alcohols with SE, SZ, RE and RZ stereoisomers serve as valuable intermediates in synthetic chemistry, attributed to the stereoselective transformations enabled by the alkenyl and hydroxyl functionalities. When an ideal scenario presents itself with four distinct stereoisomers as potential products, the simultaneous control vicinal stereochemistry in a single step would offer a direct pathway to any desired stereoisomer. Here, we unveil a metallaphotoredox migration strategy to access stereodefined allylic alcohols through vinylic C−H activation with aldehydes. This method harnesses a chiral nickel catalyst in concert with a photocatalyst to enable a 1,4‐Ni migration by using readily accessible 2‐vinyl iodoarenes as starting materials. The efficacy of this methodology is highlighted by the precise construction of all stereoisomers of allylic alcohols bearing analogous substituents and the efficient synthesis of key intermediates en route to Myristinin family. Experimental and computational studies have shed light on pivotal aspects including the synergy of metal catalysis and photocatalysis, the driving forces behind the migration, and the determination of absolute configuration in the C−H addition process. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Chiral α‐tertiary aminonitriles are valuable synthetic intermediates. They are also found in various structures of biologically active molecules. Therefore, numerous reports of catalytic asymmetric synthesis of chiral α‐aminonitriles continuously emerged during the past few decades. Great strides have been made for the synthesis of chiral α‐aryl and α‐branched alkyl aminonitriles. However, efficient methods for catalytic asymmetric synthesis of chiral α‐linear alkyl aminonitriles remain limited. We herein report a new synthetic approach to chiral α‐tertiary alkyl aminonitriles via catalytic asymmetric isomerization of cyanoketimines. The synthetic value of this method was illustrated by application to a concise catalytic asymmetric synthesis of vildagliptin. [ABSTRACT FROM AUTHOR]

Herein, we describe an innovative approach to the asymmetric electrochemical α‐alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α‐alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C−H/C−H oxidative α‐alkylation of aldehydes in a highly chemo‐ and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio‐induction. [ABSTRACT FROM AUTHOR]

The significance and necessity of separating enantiomers in food, pharmaceuticals, pesticides, and other samples remains constant and unrelenting. The successful chiral separation usually includes the application of a chiral auxiliary compound, known also as a chiral selector (CS), that forms complexes with enantiomers of different physicochemical properties, enabling efficient separation. While both native and substituted cyclodextrins (CDs) are commonly used as CSs, β-CD is undoubtedly the most popular one among them. This review includes recent advancements in the application of β-CD as a CS. While the theoretical background behind the enantioseparation is also part of this work, the main emphasis is put on the factors that affect the efficacy of this process such as temperature, pH, solvent, and the choice of other additives. Also, the different analytical methods: Nuclear Magnetic Resonance (NMR) spectroscopy, Capillary Electrophoresis (CE), fluorescence spectroscopy (FS), High-Performance Liquid Chromatography (HPLC), Isothermal Titration Calorimetry (ITC), and UV–vis spectroscopy, used for enantioseparation with the aid of β-CD as CS, are thoroughly compared. Also, since some of the chiral compounds have been studied in the context of their enantioseparation more than once, those works are compared and critically analyzed. In conclusion, while β-CD can be in most cases used as CS, the choice of the experimental conditions and method of analysis is crucial to achieve the success. [ABSTRACT FROM AUTHOR]

Transition‐metal‐catalyzed asymmetric α‐allylation of ketones is a particularly useful tool for constructing stereocenters via C−C bond formation. However, this type of reaction often necessitated the use of activated ketones or pre‐prepared enol intermediates as substrates. In this study, we developed a nickel‐catalyzed α‐allylation of unactivated cycloketones with allylic alcohols to synthesize chiral cycloketones with an α‐quaternary carbon center. The reaction affords the products with 42–97% yields, 72–86% ee, and no additive is needed, and the only by‐product is water. [ABSTRACT FROM AUTHOR]

Different from the reported work focusing on the construction of single P‐ or C‐stereocenter via hydrophosphinylation of unsaturated carbon bonds, the highly diastereo‐ and enantioselective hydrophosphinylation reaction of allenes, conjugated enynes and 1,3‐dienes is achieved via a designed Pd/Co dual catalysis and newly modified masked phosphinylating reagent. A series of allyl motifs bearing both a tertiary C‐ and P‐stereocenter are prepared in generally good yields, >20 : 1 dr, >20 : 1 rr and 99 % ee. The unprecedented diastereo‐ and enantioselective hydrophosphinylation of 1,3‐enynes is established to generate skeletons containing both a P‐stereocenter and a nonadjacent chiral axis. The first stereodivergent hydrophosphinylation reaction is also developed to achieve all four P‐containing stereoisomers. The present protocol features the use of only 3‐minutes reaction time and 0.1 % catalyst, and with the observation of up to 730 TON. A set of mechanistic studies reveal the necessity and roles of two metal catalysts and corroborate the designed synergistic process. [ABSTRACT FROM AUTHOR]

Chiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki–Hiyama–Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox‐catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements. [ABSTRACT FROM AUTHOR]

Multienzyme cascades (MECs) have gained much attention in synthetic chemistry but remain far from being a reliable synthetic tool. Here we report a four‐enzyme cascade comprising a cofactor‐independent and a cofactor self‐sustaining bienzymatic modules for the enantioselective benzylic C−H amination of arylalkanes, a challenging transformation from bulk chemicals to high value‐added chiral amines. The two modules were subsequently optimized by enzyme co‐immobilization with microenvironmental tuning, and finally integrated in a gas‐liquid segmented flow system, resulting in simultaneous improvements in enzyme performance, mass transfer, system compatibility, and productivity. The flow system enabled continuous C−H amination of arylalkanes (up to 100 mM) utilizing the sole cofactor NADH (0.5 mM) in >90 % conversion, achieving a high space‐time yield (STY) of 3.6 g ⋅ L−1 ⋅ h−1, which is a 90‐fold increase over the highest value previously reported. [ABSTRACT FROM AUTHOR]

Transition metal‐catalyzed radical‐based enantioconvergent reactions have become a powerful strategy to synthesize enantiopure compounds from racemic starting materials. However, existing methods primarily address precursors with central chirality, neglecting those with axial chirality. Herein, we describe the enantioconvergent reductive coupling of racemic allenes with aldehydes, facilitated by a photoredox, chromium, and cobalt triple catalysis system. This method selectively affords one product from sixteen possible regio‐ and stereoisomers. The protocol leverages CoIII−H mediated hydrogen atom transfer (MHAT) and Cr‐catalyzed radical‐polar crossover for efficient stereoablation of axial chirality and asymmetric addition, respectively. Supported by mechanistic insights from control experiments, deuterium labeling, and DFT calculations, our approach offers synthetic chemists a valuable tool for creating enantioenriched chiral homoallylic alcohols, promising to advance radical‐based strategies for synthesizing complex chiral molecules. [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 chirality of biopolymers remains one of the mysteries of Life. For such objects, the phenomenon of supramolecular chirality (SMC) is vital. Enantiomers can be recognized by the adsorption on surfaces with SMC. However, the mechanisms of such chiral recognition are still unknown. In this work, the adsorption kinetics of menthol test enantiomers on the surfaces of γ‐glycine and NiSO4•6H2O chiral crystals was studied. It was found that the difference in adsorption was observed in nonequilibrium state more often than in equilibrium. If the enantioselectivity in equilibrium state was observed, the enantioselectivity coefficient α at nonequilibrium conditions was higher. The maximum α in nonequilibrium state was 2.44 for γ‐glycine crystals and 2.12 for NiSO4•6H2O crystals. Even if no differences in adsorption were observed under adsorption–desorption equilibrium conditions, a significant enantioselectivity at nonequilibrium conditions was found. This has proved the possibility of chiral recognition on surfaces with SMC by the differences in adsorption rates. Such novel chiral recognition mechanism can provide enhanced enantioselectivity in adsorption, catalysis, chromatographic separation, and chemical sensing. [ABSTRACT FROM AUTHOR]

We report the detailed mechanistic insights of L-proline catalyzed, solvent-controlled, regioselective Mannich reaction. Different solvation models were employed to understand the formation of critical intermediates. The seminal difference in the nature of H-acceptor solvents and H-donor solvents leads to variation in the attachment site on the reactant molecule. Our calculations suggest that the H-acceptor solvent exhibits selective non-covalent interaction with α-hydrogen atoms of the iminium group, facilitating the reactivity at the more hindered site, which results in the formation of a branched isomer. On the other hand, the H-donor solvent preferentially binds to the carboxylate group, thus enabling the reactivity to proceed from the less hindered carbon chain, leading to a linear isomer. The above distinct interactions force a regioselective generation of enamines. Thus, the iminium ion's site-specific solvent interaction has been observed to cause a switch in the regioselectivity. These enamines subsequently react with cyclic ketone to produce Mannich base with excellent enantioselectivity (>99%ee). [ABSTRACT FROM AUTHOR]

Fungicides play a role in managing plant diseases but raise concerns about environmental impact, emphasizing the need to understand and minimize their effects on non-target ecosystems. Flutriafol is a fungicide used to combat fungal diseases in crops. It has two enantiomers that exhibit different levels of efficacy and environmental impact. This study focuses on evaluating the effects of different doses of flutriafol on soil microorganism populations and enzyme activity and the possible specificity of enantiomer interactions with soil enzymes by combining experimental and computational approaches. The effects of different doses of flutriafol on the population of microorganism and on the activity of soil enzymes were experimentally assessed. Molecular docking of the enantiomers with soil enzymes was used to assess the possible stereoselectivity of the interactions. Regardless of the dose used (normal dose recommended by the manufacturer for cereal crops, half this dose, and double dose), flutriafol had no significant impact on soil microbial communities or on catalase activity. The half dose of flutriafol produced increases in the activity of dehydrogenases (8%), phosphatases (26%), and urease (33%) during the first 7 days of incubation. Molecular docking showed that both enantiomers were able to bind to the active sites of dehydrogenases and phosphatases. The average value of the interaction energy observed for (R)-flutriafol with dehydrogenases was −7.85 kcal/mol, compared to −7.45 kcal/mol for the interaction of (S)-flutriafol with these enzymes. Similarly, the interaction energy obtained for the interaction of (R)-flutriafol with phosphatase was −9.16 kcal/mol, compared to −9.04 kcal/mol for the interaction of (S)-flutriafol with this enzyme. This study confirms the need to implement optimized application practices when using flutriafol by considering the enantiomer that is most effective on the target organism and less toxic to non-target ecosystems. [ABSTRACT FROM AUTHOR]

This study explores the reasons behind the variations in the enantioselectivity of the sulfoxidation of methyl phenyl sulfide by marine-derived vanadium-dependent haloperoxidases (VHPOs). Twelve new VHPOs of marine organisms were overexpressed, purified, and tested for their ability to oxidize sulfide. Most of these marine enzymes exhibited nonenantioselective behavior, underscoring the uniqueness of AnVBPO from the brown seaweed Ascophyllum nodosum and CpVBPO from the red seaweed Corallina pilulifera, which produce (R)- and (S)-sulfoxides, respectively. The enantioselective sulfoxidation pathway is likely due to direct oxygen transfer within the VHPO active site. This was demonstrated through molecular docking and molecular dynamics simulations, which revealed differences in the positioning of sulfide within AnVBPO and CpVBPO, thus explaining their distinct enantioselectivities. Nonenantioselective VHPOs probably follow a different oxidation pathway, initiating with sulfide oxidation to form a positively charged radical. Further insights were gained from studying the catalytic effect of VO43− on H2O2-driven sulfoxidation. This research improves the understanding of VHPO-mediated sulfoxidation and aids in developing biocatalysts for sulfoxide synthesis. [ABSTRACT FROM AUTHOR]

By employing a chiral bifunctional phosphine ligand, a gold(I)-catalyzed efficient and highly enantioselective dearomatization of phenols is achieved via versatile metal-ligand cooperation. The reaction is proven to be remarkably general in scope, permitting substitutions at all four remaining benzene positions, accommodating electron-withdrawing groups including strongly deactivating nitro, and allowing carbon-based groups of varying steric bulk including tert-butyl at the alkyne terminus. Moreover, besides N-(o-hydroxyphenyl)alkynamides, the corresponding ynoates and ynones are all suitable substrates. Spirocyclohexadienone-pyrrol-2-ones, spirocyclohexadienone-butenolides, and spirocyclohexadenone-cyclopentenones are formed in yields up to 99 % and with ee up to 99 %.

Comprehensive Summary: Transition metal‐catalyzed asymmetric hydrogenation is an efficient and direct synthetic method to access chiral compounds, which features simplicity, easy working‐up process, and high atomic economy. It typically relies on precious transition metal catalytic systems, including ruthenium, rhodium, iridium and palladium, which always face the difficulties of limited resources, high cost, and environmental contamination. Therefore, great efforts were made to apply earth‐abundant, low (non‐)toxic, and environmentally friendly transition metals, such as iron, cobalt, nickel and copper, to the asymmetric hydrogenation in the past decades, and some considerable breakthroughs have been obtained. In this review, we mainly summarized some recent research progress of nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. And continuous development of chiral nickel catalytic systems and the application of them into challenging asymmetric hydrogenation is prospected in the future. Key Scientists: Transition metal‐catalyzed asymmetric hydrogenation has been regarded as an important and direct approach to access chiral molecules. The first example of homogeneous catalytic asymmetric hydrogenation was developed by Knowles and Horner in 1968, respectively. In 1971, Kagan developed privileged chiral DIOP ligand for asymmetric hydrogenation. Halpern and Brown made deep studies on the Rh‐catalyzed asymmetric hydrogenation in 1977, respectively. Noyori developed a powerful and privileged chiral BINAP ligand in 1980. Owing to Knowles and Noyori's great contribution in the field of catalytic asymmetric hydrogenation, they were awarded the Nobel Prize in Chemistry in 2001. In 1984, Ohkubo developed pioneering earth‐abundant transition metal Ni‐catalyzed asymmetric hydrogenation of ethyl α‐methylcrotonate. A great many scientists made tremendous contribution to the development of chiral privileged ligands, such as, Bosnich, Kumada, Giongo, Takaya, Miyashima, Achiwa, Burk, Pflaltz, Chan, X. Zhang, Imamoto, Zhou, Genet, Sannicolo, Ding, Hoge, W. Zhang, Z. Zhang, Tang, these ligands owned wide application in the catalytic asymmetric hydrogenation. In addition, Zhou, Fan made deep investigation on the asymmetric hydrogenation of challenging aromatic heterocyclic compounds. Owing to the great importance of the development of the asymmetric (transfer) hydrogenation promoted by cheap transition metal catalytic systems, some researchers, such as Hamada, Gao, J. S. Zhou, Chirik, X. Zhang, Y.‐G. Zhou, W. Zhang, Lv, Dong, Fu, Deng, and Hou, made great efforts to the development of earth‐abundant nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. In addition, there are some other scientists that have also made great contribution to the development of catalytic asymmetric hydrogenation and Ni‐catalyzed asymmetric transformation, with too limited space to list all of them. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Transition metal‐catalyzed asymmetric hydrogenation is an efficient and direct synthetic method to access chiral compounds, which features simplicity, easy working‐up process, and high atomic economy. It typically relies on precious transition metal catalytic systems, including ruthenium, rhodium, iridium and palladium, which always face the difficulties of limited resources, high cost, and environmental contamination. Therefore, great efforts were made to apply earth‐abundant, low (non‐)toxic, and environmentally friendly transition metals, such as iron, cobalt, nickel and copper, to the asymmetric hydrogenation in the past decades, and some considerable breakthroughs have been obtained. In this review, we mainly summarized some recent research progress of nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. And continuous development of chiral nickel catalytic systems and the application of them into challenging asymmetric hydrogenation is prospected in the future. Key Scientists: Transition metal‐catalyzed asymmetric hydrogenation has been regarded as an important and direct approach to access chiral molecules. The first example of homogeneous catalytic asymmetric hydrogenation was developed by Knowles and Horner in 1968, respectively. In 1971, Kagan developed privileged chiral DIOP ligand for asymmetric hydrogenation. Halpern and Brown made deep studies on the Rh‐catalyzed asymmetric hydrogenation in 1977, respectively. Noyori developed a powerful and privileged chiral BINAP ligand in 1980. Owing to Knowles and Noyori's great contribution in the field of catalytic asymmetric hydrogenation, they were awarded the Nobel Prize in Chemistry in 2001. In 1984, Ohkubo developed pioneering earth‐abundant transition metal Ni‐catalyzed asymmetric hydrogenation of ethyl α‐methylcrotonate. A great many scientists made tremendous contribution to the development of chiral privileged ligands, such as, Bosnich, Kumada, Giongo, Takaya, Miyashima, Achiwa, Burk, Pflaltz, Chan, X. Zhang, Imamoto, Zhou, Genet, Sannicolo, Ding, Hoge, W. Zhang, Z. Zhang, Tang, these ligands owned wide application in the catalytic asymmetric hydrogenation. In addition, Zhou, Fan made deep investigation on the asymmetric hydrogenation of challenging aromatic heterocyclic compounds. Owing to the great importance of the development of the asymmetric (transfer) hydrogenation promoted by cheap transition metal catalytic systems, some researchers, such as Hamada, Gao, J. S. Zhou, Chirik, X. Zhang, Y.‐G. Zhou, W. Zhang, Lv, Dong, Fu, Deng, and Hou, made great efforts to the development of earth‐abundant nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. In addition, there are some other scientists that have also made great contribution to the development of catalytic asymmetric hydrogenation and Ni‐catalyzed asymmetric transformation, with too limited space to list all of them. [ABSTRACT FROM AUTHOR]

A palladium/chiral N,N′-disulfonyl bisimidazoline (Bim)-catalyzed asymmetric addition of arylboronic acids to isoquinoline-1,3,4-trione-derived ketimines is reported, leading to the generation of a series of functionalized isoquinoline-1,3(2H,4H)-diones bearing one quaternary carbon-amino functionality in good to excellent yields with ≥95% ee in most cases. The reaction has remarkable compatibility with both substrate scopes, providing a highly enantioselective entry to chiral heterocyclic α-tertiary amines.

Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates without substituents on the carbon–carbon double bond have remained a formidable challenge. To address this limitation, we report herein the asymmetric bromolactonization of 5-hexenoic acid derivatives catalyzed by a BINOL-derived chiral bifunctional sulfide.

Abstract Regioselective and enantioselective hydroxylation of propargylic C-H bonds are useful reactions but often lack appropriate catalysts. Here a green and efficient asymmetric hydroxylation of primary and secondary C–H bonds at propargylic positions has been established. A series of optically active propargylic alcohols were prepared with high regio- and enantioselectivity (up to 99% ee) under mild reaction conditions by using P450tol, while the C≡C bonds in the molecule remained unreacted. This protocol provides a green and practical method for constructing enantiomerically chiral propargylic alcohols. In addition, we also demonstrated that the biohydroxylation strategy was able to scaled up to 2.25 mmol scale with the production of chiral propargyl alcohol 2a at a yield of 196 mg with 96% ee, which’s an important synthetic intermediate of antifungal drug Ravuconazole. Graphical Abstract

Transition‐metal‐catalyzed hydroamination of unsaturated hydrocarbons is an appealing synthetic tool for the construction of high value‐added chiral amines. Despite significant progress in the asymmetric hydroamination of alkenes, allenes, and 1,3‐dienes, asymmetric hydroamination of 1,6‐enynes or 1,7‐enynes remains rather limited due to the enormous challenges in controlling the chemoselectivity and stereoselectivity of the reaction. Herein, we report a Ni‐catalyzed chemo‐ and enantioselective reductive cyclization/amidation and amination of 1,6‐enynes and 1,7‐enynes using dioxazolones or anthranils as nitrene‐transfer reagents. This mild, modular, and practical protocol provides rapid access to a variety of enantioenriched 2‐pyrrolidone and 2‐piperidone derivatives bearing an aminomethylene group at the 4‐position in good yields (up to 83 %) with excellent enantioselectivities (46 examples, up to 99 % ee). Mechanistic experiments and density functional theory calculations indicate that the reaction is initiated by hydronickelation of alkynes followed by migratory insertion into alkenes, rather than by a [2+2+1] oxidative addition process of nickel to alkenes and alkynes. [ABSTRACT FROM AUTHOR]

Sulfinamidines are promising aza‐SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N−H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 °C in solution and show remarkable stability against organic acids and bases under non‐aqueous conditions. We also demonstrate a one‐pot, three‐component, enantioselective synthesis of sulfinamides using N−H oxaziridine reagents. [ABSTRACT FROM AUTHOR]

Development of catalytic systems using nontoxic natural precursors is the need of the era, and along this line, we have synthesized a new D‐glucose derived ligand (4,6‐O‐ethylidene‐N‐(2‐hydroxy‐4‐(octyloxy)benzylidene)‐β‐D‐glucopyranosylamine) and its dinuclear copper(II) complex. The molecular structure of the complex has been established by single‐crystal X‐ray diffraction studies and detailed noncovalent intermolecular interactions present in it have been explored by Hirshfeld surface analysis. Further, the complex has been used as a catalyst in the enantioselective (87–99 % ee) synthesis of propargylamines in good to excellent yield (82–95 %) via aldehyde‐amines‐alkynes (A3) coupling reaction under solvent‐free condition. The formation of aminal intermediate during the reaction has been confirmed by 1H‐NMR and single‐crystal X‐ray diffraction studies. The catalytic system is reusable without any appreciable loss in the enantioselectivity or product yield. [ABSTRACT FROM AUTHOR]

Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long‐standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP‐Ligand P‐chiral stereocenter is first designed and synthesized, called MQ‐Phos, and successfully applied it in the Pd‐catalyzed enantioselective higher‐order formal [4+4]‐cycloaddition of α, β‐unsaturated imines with 2‐(hydroxymethyl)‐1‐arylallyl carbonates. The reaction features mild conditions, excellent regio‐ and enantiocontrol and a broad substrate scope (54 examples). Various medium‐sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ‐Phos is critical for synthesis of the medium‐sized ring in excellent catalytic reactivity and enantioselectivity. [ABSTRACT FROM AUTHOR]

Herein we report the first transition metal‐catalyzed approach to the enantioenriched synthesis of cyclic sulfonimidamides relying on commercially available palladium catalysts and ligands. High‐throughput experimentation (HTE) was employed to identify the optimal catalyst system and solvent. The method is applied to a variety of saturated and unsaturated rings and exhibits the highest selectivity for 2‐substituted allyl electrophiles. The products are further elaborated to complex, tricyclic scaffolds. DFT experiments presented herein highlight the key ligand substrate interactions leading to the high levels of enantioselectivity. [ABSTRACT FROM AUTHOR]

In the presence of 1 mol % of a chiral iron porphyrin catalyst, various 3‐arylmethyl‐substituted 2‐quinolones and 2‐pyridones underwent an enantioselective amination reaction (20 examples; 93–99 % ee). The substrates were used as the limiting reagents, and fluorinated aryl azides (1.5 equivalents) served as nitrene precursors. The reaction is triggered by visible light which allows a facile dediazotation at ambient temperature. The selectivity of the reaction is governed by a two‐point hydrogen bond interaction between the ligand of the iron catalyst and the substrate. Hydrogen bonding directs the amination to a specific hydrogen atom within the substrate that is displaced by the nitrogen substituent either in a concerted fashion or by a rebound mechanism. [ABSTRACT FROM AUTHOR]

The chemical space of chiral Brønsted acid catalysts is defined by quantity and complexity, reflecting the diverse synthetic challenges confronted and the innovative molecular designs introduced. Here, we detail how this successful outcome is a powerful demonstration of the benefits of utilizing both local structure searches and a comprehensive understanding of catalyst performance for effective and efficient exploration of Brønsted acid properties. In this concept article we provide an evolutionary overview of this field by summarizing the approaches to catalyst optimization, the resulting structures, and functions. [ABSTRACT FROM AUTHOR]

Developing new enantioselective reactions is an important part of chemical discovery but requires time and resources to test large arrays of potential reaction conditions. New techniques are required to analyse many different reactions quickly and efficiently. Mass spectrometry is a high‐throughput method; when combined with ion‐mobility spectrometry, this technique can monitor diastereomeric reaction intermediates and thus be a handle to study enantioselective reactions. Through this technique and others, it was noted before that in the organocatalytic 1,4‐addition to α,β‐unsaturated aldehydes, the abundance of initial diastereomeric intermediates correlates strongly to that of the final enantiomeric products. This work determines isomeric abundance for various catalysts and aldehydes and uses it to predict the enantiomeric excess of two control reactions. The prediction matches well for one reaction but does not predict the obtained results for the second. This finding confirms that the E/Z ratio of the iminium intermediates can be used as a predictor for some reactions, but the kinetics of the following steps can dramatically change the true enantioselectivity. [ABSTRACT FROM AUTHOR]

A highly diastereo‐ and enantioselective organocatalytic Michael addition of α‐aryl isocyanoacetates to aurone‐derived azadienes under mild conditions has been developed. This efficient methodology enables access to chiral α,α‐disubstituted α‐amino ester derivatives with two adjacent stereocenters, one of them quaternary, bearing a benzofuran scaffold in their structure in high yields and stereocontrol. Furthermore, the reaction product can be readily converted into an α,α‐disubstituted α‐amino acid in high yield via hydrolysis of the isocyano group without compromising enantioselectivity. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: An asymmetric isomerization/intramolecular coupling reaction of allylic alcohols to synthesize chiral dihydrocoumarins was successfully accomplished through ruthenium catalysis. This method demonstrates a wide substrate applicability, excellent tolerance for various functional groups, and good enantioselectivities (up to 90% ee). It provides a convenient pathway to produce a diverse range of structurally distinct chiral dihydrocoumarins in good efficiency. [ABSTRACT FROM AUTHOR]

C(sp3) centers adjacent to (hetero) aryl groups are widely present in physiologically active molecules. Metal‐hydride‐catalyzed hydroalkylation of alkenes represents an efficient means of forging C(sp3)−C(sp3) bonds, boasting advantages as a wide source of substrates, mild reaction conditions, and facile selectivity manipulation. Nevertheless, the hydroalkylation of vinylarenes encounters constraints in terms of substrate scope, necessitating the employment of activated alkyl halides or alkenes containing chelating groups, remains a challenge. In this context, we report a general nickel‐hydride‐catalyzed hydroalkylation protocol for vinylarenes. Remarkably, this system enables α‐selective hydroalkylation of both aryl and heteroaryl alkenes under an extra ligand‐free condition, demonstrating excellent coupling efficiency and selectivity. Furthermore, through the incorporation of chiral bisoxazoline ligands, we have achieved regio‐ and enantioselective hydroalkylation of vinylpyrroles, thereby facilitating the synthesis of α‐branched alkylated pyrrole derivatives. [ABSTRACT FROM AUTHOR]

Herein, we disclose a simple copper‐catalyzed method for enantioselective allylic C(sp3)−H oxidation of unsymmetrical acyclic alkenes, specifically 1‐aryl‐2‐alkyl alkenes. The C−H substrates are used in limiting amounts, and the products are obtained with high enantioselectivity, E/Z‐selectivity, and regioselectivity. The method exhibits broad functional group tolerance, and E/Z‐alkene mixtures are suitable C−H substrates. The transformation is enabled by light irradiation, which sustains the enantioselective copper catalysis by photoinduced oxidant homolysis. [ABSTRACT FROM AUTHOR]

A positive correlation was observed between the enantiomeric excess (ee) of L-isovaline (L-iVal) and the degree of aqueous alteration (AqA) of carbonaceous meteorites. The origin of this remarkable phenomenon has remained enigmatic from two points of view: First, the correlation is between seemingly unrelated observables-nothing about AqA is of chiral characteristics; and second, following the accepted assumption that circularly polarized light (CPL) was the origin of the observed meteoritic ee of L-amino acids (AAs), it remined unclear why some of the observed levels of the ee of L-iVal in that correlation are significantly higher than those observed in laboratory simulations or those obtained from circular dichroism (CD) g-factor calculations. The current proposition accounting for this picture attributes late AqA conditions of the meteoritic parent bodies as providing the grounds for amplification of early initially CPL-generated low levels of L-ee. For reasons summarized below, this interpretation, which treats the CPL event and the AqA process as occurring in wide-time separated eras, is re-visited. An alternative interpretation of the observed correlation and of the high ee-values, is provided. It focuses on hydrophilic dust-aggregates clouds in wet star-forming regions in early presolar times, where both the CPL event and the grounds leading to the later AqA processes of the parent bodies, occurred. This mechanism removes the time separation between the initial ee formation and the AqA of the parent body, and replaces it with parallel processes, providing a scenario to the observation of high ee's without total destruction, and to the apparent AqA/L-ee correlation. Although iVal is at the focus of this report, the steps of the development of the alternative mechanism and the conclusions that arise from it, are relevant and applicable to the general observations of L-ee's of meteoritic AA's. [ABSTRACT FROM AUTHOR]

The first enantioselective Friedel‐Crafts (FC) allenylation reaction for the creation of central chirality is developed under cooperative Ir(I)/(phosphoramidite,olefin) and Lewis acid catalysis. This enantioconvergent reaction utilizes racemic allenylic alcohol as the electrophile and shows compatibility with a variety of electron‐rich arenes and heteroarenes. The resulting highly enantioenriched (up to >99.5 : 0.5 e.r.) 1,1‐disubstituted allenylic methanes, bearing a benzylic carbon stereocenter, are obtained with complete regiocontrol – both on (hetero)arenes as well as on the allenylic fragment. This protocol allows for the enantioselective formal introduction of a 4‐carbon alkyl chain into (hetero)arenes, along with the creation of a benzylic stereocenter. Judicious synthetic elaborations not only lead to formal enantioselective FC alkylation products of less electron‐rich arenes but also of substituted arenes in ortho‐ and even meta‐selective fashion. An intramolecular version of this FC allenylation is shown to proceed with promising enantioselectivity under the same catalytic conditions. Mechanistic studies revealed the involvement of dynamic kinetic asymmetric transformation (DyKAT) of racemic allenylic alcohols in this reaction. [ABSTRACT FROM AUTHOR]