Kinetic Resolution Research Articles

Design of a Chiral Molecular Pocket in a Ni(II) Complex to Improve Stereoselectivity in the Kinetic Resolution of Racemic Epoxides with CO2

The kinetic resolution of racemic epoxides using the carbon dioxide (CO2) molecule is of significant practical interest because the reaction yields the valuable products – enantiomerically enriched cyclic carbonates (1,3-dioxolan-2-ones), along with the remaining opposite enantiomer of the epoxide. However, one is the main challenges in this direction is the absence of the universal and efficient chiral catalytic systems for the resolution of different epoxides by CO2 with a high selectivity factor (s). In this context, we herein present a perspective proof-of-concept approach for the improvement of stereoselectivity in the resolution of terminal epoxides by a rational design of an appropriate chiral molecular pocket in a Ni(II) complex based on commercially available (S)-(2-aminomethyl)pyrrolidine and 3,5-di-tert-butylsalicylaldehyde. The obtained chiral Ni(II) complex with iodide-anion catalyzes the kinetic resolution of epoxides by CO2 with s-factor up to 7.8, while the addition of a suitable chiral ligand to this system, particularly, (S)-(2-anilinomethyl)pyrrolidine led to the increasing of s-factor up to 11.5 in the case of challenging styrene oxide (ee of styrene cyclic carbonate was 82%) which is being one of the best results for this substrate to date. It is gratifying to note that even achiral co-ligands can be used, greatly simplifying the catalytic system. The experimental and spectral data and DFT calculations revealed the mechanism of catalysis and enantioselection.

Engineering enzyme conformation within liquid-solid hybrid microreactors for enhanced continuous-flow biocatalysis

The artificial engineering of an enzyme’s structural conformation and dynamic properties to promote its catalytic activity and stability outside cellular environments is highly pursued in industrial biotechnology. Here, we describe an elegant strategy of combining the rationally designed liquid-solid hybrid microreactor with a tailor-made polyethylene glycol functional ionic liquid (PEG-IL) microenvironment to exercise a high level of control over the configuration of enzymes for practical continuous-flow biocatalysis. As exemplified by a lipase driven kinetic resolution reaction, the obtained system exhibits a 2.70 to 30.35-fold activity enhancement compared to their batch or traditional IL-based counterparts. Also, our results demonstrate that the thermal stability of encapsulated lipase can be significantly strengthened in the presence of PEG groups, showcasing a long-term continuous-flow stability even up to 1000 h at evaluated temperature of 60 oC. Through systematic experiment and molecular dynamics simulation studies, the conformational changes of the active site cavity in the modified lipases are correlated with enzymatic properties alteration, and the pronounced effects of PEG-groups in stabilizing enzyme’s secondary structures by delaying unfolding at elevated temperatures are identified. We believe that this study will guide the design of high-performance enzymatic systems, promoting their utilization in real-world biocatalysis applications.

A Chemically Powered Rotary Molecular Motor Based on Reversible Oxazepine Formation.

While biological machines are powered mainly by chemical transformations, chemically driven artificial rotary motor systems are very limited. Here, we report an aniline-phenol-based rotary molecular motor that operates via an information ratchet mechanism. The 360° directional rotation about a single covalent bond can be chemically driven by reversible oxazepine formation. Both the oxazepine formation and hydrolysis steps are kinetically gated via dynamic kinetic resolution, arising from the kinetic bias of chiral catalysts for enantiomers. Given the 95 % ee (97.5 : 2.5) and 88 % ee (94 : 6) of the individual gating steps of motor analogues, the overall directionality ratio could be calculated to be 91.7 : 8.3 (97.5 %×94 %≈91.7 %), which means that the motor will make one mistake (backward rotation) approximately every 11 to 12 turns.

Highly Efficient and Enantioselective Iridium-Catalyzed Asymmetric Reductive Cycloetherification.

A catalytic protocol for the iridium-catalyzed asymmetric hydrogenation (AH) of γ- or δ-hydroxy ketones to rapidly assemble various aliphatic enantioenriched tetrahydrofurans (THFs) or tetrahydropyrans (THPs) is disclosed. A wide range of enantioenriched THFs or THPs were obtained in high yields and excellent enantioselectivities (up to 99% and up to 96.5:3.5 er). The dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) process was also achieved, simultaneously constructing enantioenriched THP scaffolds with two contiguous stereogenic centers with high yields and stereoselectivities (up to 92% yield, up to 98.5:1.5 er and >20:1 dr). Mechanistic investigation indicates that the key step of the reaction involves the AH of the challenging cyclic, aliphatic oxocarbenium ions. Furthermore, this catalytic enantioselective approach could be carried out on a gram scale, and various enantioenriched cyclic ethers were further transformed into an array of useful building blocks for enantioenriched natural products and bioactive molecules.

Bienzymatic Dynamic Kinetic Resolution of Secondary Alcohols by Esterification/Racemization in Water.

Dynamic kinetic resolution (DKR) is a key method used to prepare optically pure compounds in 100% theoretical yield starting from racemic substrates by combining the interconversion of substrate enantiomers with an enantioselective transformation. Various chemoenzymatic DKR approaches have been developed to deracemize secondary alcohols, typically requiring an organic solvent to facilitate enantioselective acylation, primarily catalyzed by lipases, alongside racemization mediated by an achiral, non-enzymatic catalyst. Achieving both steps in an aqueous solution remained elusive. Here, we report a DKR of racemic sec-alcohols in an aqueous solution requiring only two biocatalysts. The first key to success was to achieve fast racemization in a buffer employing a non-stereoselective variant of alcohol dehydrogenase (Lk-ADH-Prince) via a hydrogen-borrowing oxidation-reduction sequence. Engineered variants of the acyltransferase from Mycobacterium smegmatis (MsAcT) enabled enantioselective acyl transfer in water. Besides the appropriate choice of the enzymes, identifying a suitable acyl donor was a second key to the success. The DKR was successfully demonstrated using (R)-selective MsAcT variants for a broad range of racemic (hetero)benzylic alcohols using 2,2,2-trifluoroethyl acetate as the acyl donor, yielding (R)-acetates with up to >99% conv. and high-to-excellent optical purity (83-99.9% ee). The (S)-acetates were accessible using a stereocomplementary (S)-selective MsAcT variant.

Catalytic kinetic resolution of helical polycyclic phenols via an organocatalyzed enantioselective dearomative amination reaction.

Despite the considerable potential applications for helically chiral molecules across various sectors, their catalytic asymmetric synthesis remains nascent and has seen very limited advancement compared to that of central and axial chiral compounds, primarily owing to the scarcity of available starting materials and the immense challenges associated with achieving stereochemical control. Herein, we report an innovative approach to the facile synthesis and catalytic kinetic resolution of uniquely structured and stereochemically complex helical polycyclic phenols by using a steric hindrance-regulated enantioselective dearomative amination reaction. The distinguished aspects of this method include the exceptional stability of the dearomatized products and impressive versatility of the recovered substrates in the construction of enantioenriched helical frameworks. This work showcases that the strategic incorporation of appropriate steric groups near the reaction site of an electron-rich aromatic compound can indeed enable an interrupted Friedel-Crafts reaction, thus opening an alternate avenue for the study of dearomatization in nonfunctionalized arenes.

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Lost in post-translation. Cordycicadins A-D are four C20polyketides, all containing ag-lactonefused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion,viaan efficient ketene trapping-intramolecular Michael addition sequence that delivered the requisite 3,4-trans-fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve asin situketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent-convergent syntheticstrategy, based on the use of two products from an early-stage enzymatic resolution. The synthetic routes afforded (-)-cordycicadin D in 14 steps and 3,4-trans-cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (-)-cordycicadin D and the observed instability of the anticipated natural product 3,4-trans-cordycicadin B during purification may explain why it is yet to be isolated.

Catalytic Construction of Stereogenic Boron Center on BODIPY via Enantioselective Suzuki–Miyaura Coupling

Abstract Catalytic and enantioselective construction of the boron-stereogenic center is challenging due to the instability of the tetracoordinate boron center. We herein report the enantioselective intermolecular Suzuki–Miyaura coupling of dichloro BODIPY through desymmetrization. The mechanistic study reveals that kinetic resolution plays an important role in the improvement of enantioselectivity.

PVP-assisted in situ immobilizing lipase on covalent organic framework for enhanced catalytic activity and stability in bioconversions

Covalent organic frameworks (COFs) are crystalline, porous organic materials that have significant potential as supports for enzyme immobilization. Nevertheless, the in situ preparation of biocatalysts during the COF formation process remains a considerable challenge. Herein, we developed a one-pot in situ preparation strategy. The immobilized lipase PS@TPB-TFPB COF-I was fabricated by mixing the polyvinylpyrrolidone (PVP)-lipase PS complex with precursors 1,3,5-tris(4-aminophenyl)benzene (TPB) and 1,3,5-tris(4-formylphenyl)benzene (TFPB) in acetonitrile catalyzed by acetic acid at room temperature for 48 h. The formation mechanism was systematically investigated using time-dependent microscopy techniques. PVP acts as a guiding reagent, controlling the morphological changes that occur during this process. Furthermore, the biocatalyst was employed in the kinetic resolution of racemic 1-phenylethanol, resulting in a significant enhancement in the conversion rate, with a range of 2.1 to 10.6 times higher compared to free PS at the same reaction time. The robust biocatalyst maintained high catalytic activity and enantioselectivity even after 10 cycles. The strategy described here is promising for lipase immobilization and expands the range of applications for COFs in biomanufacturing.

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.

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

AbstractDespite 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.

Manganese-Catalyzed Asymmetric Hydrogenation for Atroposelective Dynamic Kinetic Resolution of Heterobiaryl Ketone N-Oxides

Manganese-Catalyzed Asymmetric Hydrogenation for Atroposelective Dynamic Kinetic Resolution of Heterobiaryl Ketone <i>N</i>-Oxides

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

Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, while compatibility of dual catalysis is the key issue. Conventional solutions have utilized presynthesized metal complexes with a fixed and bulky ligand to protect the metal from the enzyme system; however, this has been generally limited to anionic ligands. Herein, we report our strategy to solve the compatibility issue by employing a reliable ligand that firmly coordinates in situ to the metal. Such a reliable ligand offers π* orbitals, allowing additional metal-to-ligand d-π* back-donation, which can significantly enhance coordination effects between the ligand and metal. Therefore, we developed an efficient DKR method to access chiral BINOLs from racemic derivatives under dual copper and enzyme catalysis. In cooperation with lipase LPL-311-Celite, the DKR of BINOLs was successfully realized with a copper catalyst via in situ coordination of BCP (L8) to CuCl. A series of functionalized C 2- and C 1-symmetric chiral biaryls could be synthesized in high yields with good enantioselectivity. The racemization mechanism was proposed to involve a radical-anion intermediate, which allows the axial rotation with a dramatic decrease of the rotation barrier.

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.

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

AbstractAllylic 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 the allylation of O-centered nucleophiles, the 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 permitting the allylation of sterically congested O-pronucleophiles. When chiral Lewis base catalysts are used, the allyl ethers are produced in an enantioenriched form through kinetic resolution of fluorides, where the stereoselectivity is determined by the chiral catalyst.

Dynamic Asymmetric Diamination of Allylic Alcohols through Borrowing Hydrogen Catalysis: Diastereo‐Divergent Synthesis of Tetrahydrobenzodiazepines

AbstractWe present herein a catalytic enantioconvergent diamination of racemic allylic alcohols with the construction of two C−N bonds and 1,3‐nonadjacent stereocenters. This iridium/chiral phosphoric acid cooperative catalytic system operates through an atom‐economical borrowing hydrogen amination/aza‐Michael cascade, and converts readily available phenylenediamines and racemic allylic alcohols to 1,5‐tetrahydrobenzodiazepines in high enantioselectivity. An intriguing solvent‐dependent switch of diastereoselectivity was also observed. Mechanistic studies suggested a dynamic kinetic resolution process involving racemization through a reversible Michael addition, making the last step of asymmetric imine reduction the enantiodetermining step of this cascade process.

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 &gt;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 &gt;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.

Isothiourea-Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols.

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 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, 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 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.

Stereoselective Synthesis of Oxetanes Catalyzed by an Engineered Halohydrin Dehalogenase.

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.