Kinetic Resolution Research Articles

Switching the Stereopreference of TeSADH: Enabling Anti‐Prelog Asymmetric Reduction of Aryl‐Ring‐Containing Ketones

AbstractThe biocatalytic asymmetric reduction of prochiral ketones offers a promising approach for producing optically active secondary alcohols. Alcohol dehydrogenases (ADHs) are enzymes that facilitate the reversible conversion of prochiral ketones into their corresponding optically active secondary alcohols, and thus are pivotal for this process. Most ADHs adhere to Prelog's rule in determining the stereopreference for the asymmetric reduction of prochiral ketones. This study focuses on the ΔP84/A85G mutation of TeSADH, demonstrating its capability to reduce aryl‐ring‐containing ketones to their corresponding alcohols in anti‐Prelog mode with high stereoselectivities. The study also highlights the crucial role of P84 in switching the stereopreference of TeSADH in the asymmetric reduction of aryl‐ring‐containing ketones. Furthermore, this mutant exhibits a broad substrate scope, including substrates accepted by the previously reported W110 mutants of TeSADH with opposite stereopreference. The ability to create mutants of the same enzyme with opposite stereopreferences presents intriguing opportunities for fascinating transformations, such as bienzymatic racemization, which can be utilized in dynamic kinetic resolution, and stereoinversion using two enantiocomplementary mutants of the same enzyme.

Overcoming the Limitations of Transition-Metal Catalysis in the Chemoenzymatic Dynamic Kinetic Resolution (DKR) of Atropisomeric Bisnaphthols

Overcoming the Limitations of Transition-Metal Catalysis in the Chemoenzymatic Dynamic Kinetic Resolution (DKR) of Atropisomeric Bisnaphthols

Kinetic Resolution of α‐Allyl‐α‐Cinnamyl Carboxylic Acids Bearing an All‐Carbon Quaternary Stereocenter via Bromolactonization Catalyzed by a Chiral Bifunctional Sulfide

AbstractCatalytic kinetic resolutions of racemic carboxylic acids are important methods for preparing chiral carboxylic acids in their optically active forms. While several effective methods for the catalytic kinetic resolution of chiral α‐tertiary carboxylic acids have been reported, the efficient kinetic resolution of α‐quaternary carboxylic acids remains a significant challenge. In this context, we aimed to develop methods for the kinetic resolution of α‐quaternary carboxylic acids. Our approach involves a BINOL‐derived chiral bifunctional sulfide‐catalyzed bromolactonization technique, which was developed by our research group. In this work, we report the kinetic resolution of α‐allyl‐α‐cinnamyl carboxylic acids bearing an α‐quaternary stereocenter via chemo‐ and stereoselective bromolactonizations. The use of a BINOL‐derived chiral bifunctional sulfide catalyst with a hydroxy group was key for the efficient kinetic resolution of racemic α‐allyl‐α‐cinnamyl carboxylic acids.

Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

AbstractThe 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.

Varying the Electronics on Isothiourea Catalysts: Basicity, Rate, and Selectivity

AbstractChiral and achiral substituted isothiourea catalysts were synthesized and employed in model silylation reactions to understand how changing the electronics on the catalyst core affected intermolecular interactions between catalyst intermediates and substrates, ultimately affecting selectivity and rate. Five different chiral catalysts were utilized in a silylation‐based kinetic resolution of 2‐(para substituted)phenylcyclohexanols and the rate of silylation of these same alcohols was investigated with three different achiral catalysts. Linear free energy relationships were examined, highlighting that rate and selectivity were highly dependent on the electronics of the catalyst and the substrate, and that both affected the intermolecular interactions that resulted.

Synthesis of Novel Pseudo-Enantiomeric Phase-Transfer Catalysts from Cinchona Alkaloids and Application to the Hydrolytic Dynamic Kinetic Resolution of Racemic 3-Phenyl-2-oxetanone.

Naturally occurring Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs. Utilizing these pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions. During the screening of Cinchona alkaloid phase-transfer catalysts (PTCs) in the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (1) to tropic acid (2), we found that the introduction of a 4-trifluoromethylphenyl group at the vinyl terminus of BnQN significantly reduced the enantioselectivity to 41% enantiomeric excess (ee). The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH-) of hydrolysis obtained by density functional theory (DFT) calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, allowing good π-π interaction with the benzene ring of 1.

Topology of Gemini-shaped Hexagonal Heterojunction for Efficient Stereoconvergent Transformation via Dynamic Kinetic Resolution.

Despite recent advances in the combination of kinetic resolution and racemization for efficient stereoconvergent transformation, the poor stability and limited reaction activities of the products restrict their wide application in industrial production. To overcome these problems, Gemini-shaped hexagons with para-heterojunctions for one-dimensional and two-dimensional supramolecular polymers were designed via hydrogen-bonding adhesion by racemization catalyst 1and kinetic resolution 2in this work. The polymers from the assembly of Gemini-shaped hexagons exhibit rapid catalytic behaviour with efficient selectivity for the desired configuration in the synthesis of tertiary alcohols with contiguous stereocenters through dynamic kinetic resolution for the nanoscale heterojunctions of dissimilar catalysts. Among them, the developed 2D polymers gave outstanding enantioselectivities and diastereoselectivities (>99% ee, 20:1 dr) through the cooperation of adjacent dissimilar catalysts. The heterojunctions varying dimensions and distances of dissimilar catalysts provide new insight for increasing the enantioselectivity of chiral organocatalysts.

Topology of Gemini‐shaped Hexagonal Heterojunction for Efficient Stereoconvergent Transformation via Dynamic Kinetic Resolution

Despite recent advances in the combination of kinetic resolution and racemization for efficient stereoconvergent transformation, the poor stability and limited reaction activities of the products restrict their wide application in industrial production. To overcome these problems, Gemini‐shaped hexagons with para‐heterojunctions for one‐dimensional and two‐dimensional supramolecular polymers were designed via hydrogen‐bonding adhesion by racemization catalyst 1 and kinetic resolution 2 in this work. The polymers from the assembly of Gemini‐shaped hexagons exhibit rapid catalytic behaviour with efficient selectivity for the desired configuration in the synthesis of tertiary alcohols with contiguous stereocenters through dynamic kinetic resolution for the nanoscale heterojunctions of dissimilar catalysts. Among them, the developed 2D polymers gave outstanding enantioselectivities and diastereoselectivities (>99% ee, 20:1 dr) through the cooperation of adjacent dissimilar catalysts. The heterojunctions varying dimensions and distances of dissimilar catalysts provide new insight for increasing the enantioselectivity of chiral organocatalysts.

Kinetic Resolution of BINOLs and Biphenols by Atroposelective, Cu-H-Catalyzed Si-O Coupling with Hydrosilanes.

A nonenzymatic kinetic resolution of monoprotected BINOL and biphenol derivatives by atroposelective Si-O coupling with hydrosilanes is described. The reaction relies on a previously unprecedented Cu-H-catalyzed silylation of phenols. The catalyst system consisting of CuCl, (R,R)-Ph-BPE, and NaOtBu enables the enantioselective coupling of the phenolic hydroxy group with a hydrosilane with moderate to good selectivity factors.

Silyl Ethers as Latent Pronucleophiles in Enantioselective Lewis Base Catalyzed Synthesis of Allylic Ethers from Allylic Fluorides

Allylic ethers are a common occurrence in natural products and are often used as intermediates in target-oriented synthesis. Their synthesis often relies on the use of transition metal catalysts. Here we report an organocatalytic method for allylation of O-centered nucleophiles: Lewis base catalyzed allylation of silyl ethers with allylic fluorides. The method relies on the concept of latent pronucleophiles in Lewis base catalysis to overcome common limitations in substrate scope even allowing for allylation of sterically congested O-pronucleophiles. When chiral Lewis base catalysts are used, the allyl ethers are produced in enantioenriched form via a kinetic resolution of fluorides where streoselectivity is determined by the chiral catalyst.

Enhanced stereodivergent evolution of carboxylesterase for efficient kinetic resolution of near-symmetric esters through machine learning

Carboxylesterases serve as potent biocatalysts in the enantioselective synthesis of chiral carboxylic acids and esters. However, naturally occurring carboxylesterases exhibit limited enantioselectivity, particularly toward ethyl 3-cyclohexene-1-carboxylate (CHCE, S1), due to its nearly symmetric structure. While machine learning effectively expedites directed evolution, the lack of models for predicting the enantioselectivity for carboxylesterases has hindered progress, primarily due to challenges in obtaining high-quality training datasets. In this study, we devise a high-throughput method by coupling alcohol dehydrogenase to determine the apparent enantioselectivity of the carboxylesterase AcEst1 from Acinetobacter sp. JNU9335, generating a high-quality dataset. Leveraging seven features derived from biochemical considerations, we quantitively describe the steric, hydrophobic, hydrophilic, electrostatic, hydrogen bonding, and π-π interaction effects of residues within AcEst1. A robust gradient boosting regression tree model is trained to facilitate stereodivergent evolution, resulting in the enhanced enantioselectivity of AcEst1 toward S1. Through this approach, we successfully obtain two stereocomplementary variants, DR3 and DS6, demonstrating significantly increased and reversed enantioselectivity. Notably, DR3 and DS6 exhibit utility in the enantioselective hydrolysis of various symmetric esters. Comprehensive kinetic parameter analysis, molecular dynamics simulations, and QM/MM calculations offer insights into the kinetic and thermodynamic features underlying the manipulated enantioselectivity of DR3 and DS6.

Construction of P-stereogenic Centres via Palladium/Chiral Norbornene Cooperative Catalysis-Enabled Desymmetrization and Kinetic Resolution

Construction of P-stereogenic Centres via Palladium/Chiral Norbornene Cooperative Catalysis-Enabled Desymmetrization and Kinetic Resolution

Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-β-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-β-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions. The reaction proceeds in a sequential fashion involving synergistic Cu/Ir-catalyzed stereodivergent allylation and the Brønsted acid-promoted stereospecific Pictet-Spengler reaction, affording a wide range of chiral tetrahydro-β-carbolines bearing up to four stereogenic centers in good yields with excellent stereoselectivity control. When N-aryl-substituted tryptophan-derived aldimine esters were utilized, notably, a unique C-N heterobiaryl axis could be simultaneously constructed with the formation of the third point stereogenic center in the last cyclization step through dynamic kinetic resolution (DKR). Computational mechanistic studies established a plausible synergistic mechanism for dual Cu/Ir-catalyzed asymmetric allylation and the succeeding protonation-assisted Pictet-Spengler cyclization to complete the annulation. Structure-activity relationship analyses unveil the origins of stereochemistry for the building of one axis and three point stereogenic centers.

Halogen-Bond-Assisted NHC-Catalyzed (Dynamic) Kinetic Resolution for the Atroposelective Synthesis of Heterobiaryls.

We report a novel halogen-bond-assisted NHC-catalyzed (dynamic) kinetic resolution strategy for the synthesis of axially chiral heterobiaryls. A class of axially chiral quinolines are prepared efficiently in excellent enantioselectivities (≤98% ee) employing 3-5 mol % NHC catalyst. Mechanistic studies reveal the indispensability of 5-bromo-2-iodobenzaldehyde in this reaction, in which a pivotal halogen bonding interaction plays a crucial role in the process.

Si-Linked Glycomimetics through a Stereoselective Silicon Transfer and Anion Addition.

We report a synthesis of silicon-linked glycomimetics, demonstrating unique structural properties and metabolic stability due to the inertness of the C-Si bond. Our method focuses on the stereoselective transfer of silicon and anion addition, revealing that chirality at the silicon atom can be controlled through kinetic resolution. This approach allows for the selective generation of 1,2-cis and 1,2-trans isomers via the manipulation of C2-protected silicon ethers and nucleophilic opening of glycal epoxides. We achieved high selectivity at the anomeric carbon and expanded the scope to include various saccharides and substituted silanes. Our findings indicate that silicon transfer occurs intramolecularly and is influenced by the nature of the counterion and reaction conditions. Additionally, chiral silanes produced through our method hold promise for medicinal chemistry applications, addressing significant gaps in the synthesis and utility of glycomimetics. This work opens new avenues for the development of bioactive silicon-based molecules.

Enantiocomplementary Synthesis of Tetrahydrofurans by Engineered Halohydrin Dehalogenases

AbstractChiral tetrahydrofurans are prevalent structural motifs in biologically active compounds, approved drugs and natural products, but relevant enantiocomplementary synthesis remains underdeveloped. In this study, wild type halohydrin dehalogenase HheC from Agrobacterium radiobacter AD1, was first discovered to enable the intramolecular substitution of δ‐halohydrins for the formation of tetrahydrofurans but with unsatisfied activity and stereoselectivity. Through structure‐guided protein engineering, two completely enantiocomplementary variants T134M and P84L/W139A of HheC were obtained for the synthesis of tetrahydrofurans by the kinetic resolution of δ‐halohydrins (both giving products with up to 99% e.e., E>200). This research unveiled the halohydrin dehalogenases’ catalytic ability to form chiral cyclic ethers larger ring size than three‐membered epoxides, which has hitherto been unexplored, and provided an enzymatic synthesis access to valuably enantiocomplementary tetrahydrofurans.

Synthesis and HHDH‐Catalyzed Kinetic Resolution of Propargylic Epoxides

AbstractThe versatile reactivity of propargylic epoxides and alcohols, due to the presence of a triple bond, is used in the synthesis of various organic compounds and building blocks. However, there are not many known methods for the preparation of optically pure propargylic epoxides and alcohols, and the existing ones often require specific reagents. Halohydrin dehalogenases (HHDHs) can be used to obtain enantiomerically pure compounds from racemic epoxides. These important biocatalysts facilitate epoxide ring‐opening reactions with unnatural nucleophiles such as azides. Here we report the biocatalytic transformation of propargylic epoxides using HHDHs. Six propargylic epoxides with different substituents were synthesized. Kinetic resolution reactions catalyzed by HHDHs in the presence of azide were performed. Two enzymes with opposite stereoselectivities, HheC and HheA2‐N178A were used and yielded azido alcohols (98–>99% ee, E‐value >200) and epoxides (29–88% ee). The best performing p‐tolyl propargylic epoxide derivative was used in a sequence of two enzymatic reactions to obtain both enantiomers of the β‐azido alcohol and the (R)‐enantiomer of the α‐azido alcohol, each in >99% ee, through complete conversion of the starting epoxide. The obtained azido alcohols were used in further transformations. The click reactions with terminal acetylenes gave triazolyl propargylic alcohols (>99% ee, 90–98% yield). In the case of the α‐azido alcohol, the click reaction was followed by intramolecular cyclization to form the dihydrofuranyl triazole motif that is found in biologically active compounds.

Practical Synthesis of Macrobicyclic Thiolincosamines.

Scalable syntheses of the northern macrobicyclic thiolincosamine fragments of two structurally complex antibiotic candidates, BT-33 and cresomycin, are presented. A key transformation in each route is the highly diastereoselective addition of a putative allenylzinc nucleophile to a common Ellman sulfinimine intermediate using a zinc-promoted Barbier-type propargylation protocol that is detailed herein. These transformations proceed with dynamic kinetic resolution and use just 1.2 equiv of each respective propargyl bromide precursor.

New Synthetic Approaches for the Construction of Enantioenriched Molecules Bearing Quaternary Stereocenters

AbstractOptically active molecule architectures stand as an important class of organic compounds and occupy a key role in academic and industrial communities. Particularly, the molecules bearing quaternary carbon are of vital importance because of its favorable conformation and valuable three‐dimensional molecules, which frequently play a key role in a broad spectrum of functional materials, pharmaceutical relevant natural molecules, and agrochemicals. Over the past few decades, a large number of synthetic strategies for the enantioselective construction of compounds with chiral quaternary carbon centers have been the focus of a number of research initiatives. In this review, the state‐of‐the‐art toward the synthesis of enantioenriched molecules bearing quaternary stereocenters are summarized, which could be segmented into four categories: 1) Construction of optically active quaternary carbon centers by addition to prochiral sp2 carbon; 2) Construction of optically active all‐carbon quaternary stereocenters via substitution at non‐chiral tetra‐substituted carbon; 3) Construction of optically active all‐carbon quaternary stereocenters via kinetic resolution; 4) Construction of optically active all‐carbon quaternary stereocenters via desymmetrization reactions.

Copper‐Catalyzed Enantioselective Hydrophosphorylation of Unactivated Alkynes

P‐stereogenic phosphorus compounds are essential across various fields, yet their synthesis via enantioselective P‐C bond formation remains both challenging and underdeveloped. We report the first copper‐catalyzed enantioselective hydrophosphorylation of alkynes, facilitated by a newly designed chiral 1,2‐diamine ligand. Unlike previous methods that rely on kinetic resolution with less than 50% conversion, our approach employs a distinct dynamic kinetic asymmetric transformation mechanism, achieving complete conversion of racemic starting materials. This reaction is compatible with a broad range of aromatic and aliphatic terminal alkynes, producing products with high yields (up to 95%), exclusive cis selectivity, and exceptional regio‐ and enantioselectivity (> 20:1 r.r. and up to 96% ee). The resulting products were further transformed into a diverse array of enantioenriched P‐stereogenic scaffolds. Preliminary mechanistic studies were conducted to elucidate the reaction details.