Dynamic Kinetic Resolution Process Research Articles

An E-Z resolution

Organic Chemistry Compounds with carbon-carbon double bonds can adopt two distinct geometries, designated E or Z on the basis of whether the largest substituents on each carbon are across from or adjacent to each other. Majhi et al. report a method to transform a mixture of E and Z reactants into a single E -configured alkylated product. This dynamic kinetic resolution process relies on deprotonating the carbon next to the double bond to facilitate the rotation. Modeling highlights a coordinative role of the base's sodium counter-ion after deprotonation. J. Am. Chem. Soc. 141 , 11770 (2019).

Rhodium(I)-Catalyzed Enantioselective Hydroacylation of Racemic Allenals via Dynamic Kinetic Resolution.

Rhodium(I)-catalyzed enantioselective hydroacylation of 4-allenals was found to proceed smoothly, giving six-membered ketones in good yields (up to 84% yield) with high enantiomeric excess (up to 96% ee) even from racemic allenes as substrates. Mechanistic studies revealed that racemization of the allene moiety in the substrate would occur via a dynamic kinetic resolution (DKR) process during the hydroacylation.

RhIII -Catalyzed Asymmetric Transfer Hydrogenation of α-Methoxy β-Ketoesters through DKR in Water: Toward a Greener Procedure.

The asymmetric reduction of α-methoxy β-ketoesters through transfer hydrogenation with a new rhodium(III) complex was developed. The reaction was efficient in 2-MeTHF with formic acid/triethylamine or in water with sodium formate. The corresponding syn α-methoxy β-hydroxyesters were obtained with high diastereoselectivities and excellent levels of enantioselectivity through a dynamic kinetic resolution process.

Rh-Mediated Asymmetric-Transfer Hydrogenation of 3-Substituted Chromones: A Route to Enantioenriched cis-3-(Hydroxymethyl)chroman-4-ol Derivatives through Dynamic Kinetic Resolution.

Enantioenriched cis-3-(hydroxymethyl)chroman-4-ol derivatives were conveniently prepared by rhodium-catalyzed asymmetric transfer hydrogenation of 3-formylchromones through a dynamic kinetic resolution process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (5:2) as the hydrogen source, delivering the reduced compounds in good yields, high diastereomeric ratio (up to 98:2 dr), and excellent enantioselectivities (up to >99% ee).

Enantioselective Access to Axial Biaryls via Ruthenium‐Catalyzed Hydrogen‐Transfer Reductive Amination

AbstractAxially chiral biaryls are widespread in natural products, and often utilized as chiral ligands or catalysts in asymmetric catalysis. Driven by the demand of efficient assembly of axial biaryls, we describe herein a novel atropoenantioselective synthesis of biaryls via a ruthenium catalyzed hydrogen‐transfer reductive amination and dynamic kinetic resolution process. This protocol enriches the diversity of axial biaryl amine‐alcohols bearing various substituents and functional groups.

Chemoenzymatic Dynamic Kinetic Resolution of Amines in Fully Continuous-Flow Mode.

In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a-g) is presented which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol-gel immobilized lipase B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2-ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.

Dynamic Kinetic Resolution of Phosphinic Acid Derivatives via Nucleophilic­ Substitution at Phosphorus Center

Reaction of racemic phosphinic acid derivatives with chiral alcohols proceeds with predominant formation of one diastereomer. The highest level of enrichment has been obtained for transesterfication of racemic methyl benzylphenylphosphinate (64% de). The outcome of the reaction depends on both the structure of chiral alcohol and the starting organophosphorus compound. The results strongly suggest that the nature of the observed phenomena is not a classical equilibration of intermediates found in dynamic kinetic resolution process but is a result of a different reactivity of both enantiomers of racemic substrate towards the same chiral nucleophile.

An Aminocaprolactam Racemase from Ochrobactrum anthropi with Promiscuous Amino Acid Ester Racemase Activity.

The kinetic resolution of amino acid esters (AAEs) is a useful synthetic strategy for the preparation of single-enantiomer amino acids. The development of an enzymatic dynamic kinetic resolution (DKR) process for AAEs, which would give a theoretical yield of 100 % of the enantiopure product, would require an amino acid ester racemase (AAER); however, no such enzyme has been described. We have identified low AAER activity of 15 U mg-1 in a homologue of a PLP-dependent α-amino ϵ-caprolactam racemase (ACLR) from Ochrobactrum anthropi. We have determined the structure of this enzyme, OaACLR, to a resolution of 1.87 Å and, by using structure-guided saturation mutagenesis, in combination with a colorimetric screen for AAER activity, we have identified a mutant, L293C, in which the promiscuous AAER activity of this enzyme towards l-phenylalanine methyl ester is improved 3.7-fold.

Stereoconvergent 1,4-Addition Reaction of 5H-Oxazol-4-ones with E,Z Isomeric Mixture of Alkylidene β-Ketoesters Catalyzed by Chiral Guanidines.

A 1,4-addition reaction of 5H-oxazol-4-ones to alkylidene β-ketoesters, which was catalyzed by using chiral guanidines via a dynamic kinetic resolution process that involved geometric isomerization of the alkylidene β-ketoesters, was developed. This method allowed using E,Z isomeric mixture of various acyclic alkylidene β-ketoesters to obtain the products stereoselectively. The relation between the geometry and the stereoselectivity of products was investigated, and the derivatization of the products to the corresponding α-acyl-γ-lactone was performed.

One‐step Synthesis of α‐Keto Acids from Racemic Amino Acids by A Versatile Immobilized Multienzyme Cell‐free System

AbstractThe elevated value of α‐keto acids has pushed scientists to explore more efficient and less expensive alternatives for their synthesis. In this work, an immobilized tri‐enzyme system that produced α‐keto acids in “one‐pot” from l‐ or racemic mixtures of diverse amino acids was presented. The system combined a broad‐spectrum amino acid racemase (BsrV), a d‐amino acid oxidase (DAAO) and catalase (CAT). BsrV racemized l‐amino acids into their d‐enantiomers, DAAO catalyzed the stereospecific oxidative deamination of the d‐amino acids into their corresponding α‐keto acids, ammonium ion, and H2O2. Finally, CAT converted the inactivating H2O2 into H2O and O2, which can be reused by the oxidase reaction. BsrV thermal stability was improved 3,300‐fold by immobilizing the enzyme on glyoxyl‐activated agarose beads. DAAO and CAT were co‐immobilized on agarose beads functionalized with glutaraldehyde groups for enhancing their stabilities and eliminating H2O2 in a much more effective way. To show the versatility of this system, racemic mixtures of amino acids were converted in their corresponding α‐keto acids. The coupling of the three immobilized enzymes permitted conversions of approximately 99 % through a dynamic kinetic resolution process. This system conserved 100 % of its initial effectiveness after 8 reaction cycles. Collectively, our innovative tri‐enzyme system for the synthesis of α‐keto acids opens the door for a cheapening in the production of many pharmaceutical and cosmetics.

Dynamic kinetic resolution of amines by using palladium nanoparticles confined inside the cages of amine-modified MIL-101 and lipase

Dynamic kinetic resolution (DKR) of amines is an important strategy for the synthesis of chiral drugs and their building blocks; however, improving the matchability of metal-catalyzed racemization and enzymatic resolution is still a task. In this paper, Pd nanoparticles (NPs) were encapsulated inside the cages of ethylenediamine-grafted MIL-101 (ED-MIL-101), giving highly efficient catalysts (Pd/ED-MIL-101) for the racemization of primary amines. The racemization can be combined with lipase-catalyzed resolution in a one-pot DKR of rac-1-phenylethylamine leading to optically pure product (>99% ee value) with an excellent conversion and selectivity up to 99% and 93%, respectively, superior to other catalysts, such as Pd/MIL-101, Pd/MCM-41 and commercially available Pd/C. Furthermore, the heterogeneous chemoenzymatic catalyst combination can be recovered and recycled 8 times without significant loss of efficiency. The enhance catalytic performances were found to depend on the amine modification of MIL-101 that not only endows the surface of its cages with basic property, but also enables efficiently confining Pd NPs in the cages. In addition, the matchability of such chemoenzymatic catalyst combination can be further enhanced by conducting the DKR process under microwave irradiation.

Enantioselective and Diastereoselective Construction of Chiral Amino Alcohols by Iridium-f-Amphox-Catalyzed Asymmetric Hydrogenation via Dynamic Kinetic Resolution.

The iridium-f-amphox-catalyzed asymmetric hydrogenation of racemic α-amino β-unfunctionalized ketones proceeds via a DKR (dynamic kinetic resolution) process for the construction of various chiral N,N-disubstituted α-amino β-unfunctionalized alcohols in quantitative yields with excellent enantioselectivities and diastereoselectivities (all products >99% ee and >99:1 dr, TON up to 100 000). Importantly, this catalytic asymmetric hydrogenation with a DKR process provided a highly efficient and powerful synthetic strategy for the preparation of key chiral intermediates of the preclinical antitumor agent (S,S)-R116010.

Catalytic enantioselective synthesis of atropisomeric biaryls by a cation-directed O-alkylation.

Axially chiral biaryls, as exemplified by 1,1'-bi-2-naphthol (BINOL), are key components of catalysts, natural products and medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls by a cation-directed O-alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O-alkylation with e.r. up to 98:2. Oxidation with DDQ gives access to C2-symmetric and non-symmetric BINOL derivatives without compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating atropisomeric enolates, leading to highly atropselective O-alkylation. This dynamic kinetic resolution process offers a general approach to the synthesis of enantioenriched atropisomeric materials.

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights.

2-Hydroxydihydropyran-5-ones behave as excellent polyfunctional reagents able to react with enals through oxa-Michael/Michael process cascade under the combination of iminium and enamine catalysis. These racemic hemiacetalic compounds are used as unconventional O-pronucleophiles in the initial oxa-Michael reaction, also leading to the formation of a single stereoisomer under a dynamic kinetic resolution (DKR) process. Importantly, by using β-aryl or β-alkyl substituted α,β-unsaturated substrates as initial Michael acceptors either kinetically or thermodynamically controlled diastereoisomers were formed with high stereoselection through the careful selection of the reaction conditions. Finally, a complete experimental and computational study confirmed the initially proposed DKR process during the catalytic oxa-Michael/Michael cascade reaction and also explained the kinetic/thermodynamic pathway operating in each case.

Catalytic Kinetic Resolution of Saturated N-Heterocycles by Enantioselective Amidation with Chiral Hydroxamic Acids.

The preparation of enantioenriched chiral compounds by kinetic resolution dates back to the laboratories of Louis Pasteur in the middle of the 19th century. Unlike asymmetric synthesis, this process can always deliver enantiopure material (ee > 99%) if the reactions are allowed to proceed to sufficient conversion and the selectivity of the process is not unity (s > 1). One of the most appealing and practical variants is acylative kinetic resolution, which affords easily separable reaction products, and several highly efficient enzymatic and small molecule catalysts are available. Unfortunately, this method is applicable to limited substrate classes such as alcohols and primary benzylamines. This Account focuses on our work in catalytic acylative kinetic resolution of saturated N-heterocycles, a class of molecules that has been notoriously difficult to access via asymmetric synthesis. We document the development of hydroxamic acids as suitable catalysts for enantioselective acylation of amines through relay catalysis. Alongside catalyst optimization and reaction development, we present mechanistic studies and theoretical calculation accounting for the origins of selectivity and revealing the concerted nature of many amide-bond forming reactions. Immobilization of the hydroxamic acid to form a polymer supported reagent allows simplification of the experimental setup, improvement in product purification, and extension of the substrate scope. The kinetic resolutions are operationally straight forward: reactions proceed at room temperature and open to air conditions, without generation of difficult-to-remove side products. This was utilized to achieve decagram scale resolution of antimalarial drug mefloquine to prepare more than 50 g of (+)-erythro-meflqouine (er > 99:1) from the racemate. The immobilized quasienantiomeric acyl hydroxamic acid reagents were also exploited for a rare practical implementation of parallel kinetic resolution that affords both enantiomers of the amine products in high enantiopurity. The success of this process relied on identification of two cleavable acyl groups alongside implementation of flow-chemistry techniques to ensure reusability of the resolving agents. The work discussed in this Account has laid foundations for new catalyst design as well as development of desymmetrization and dynamic kinetic resolution processes. In the meantime, as all the requisite reagents are commercially available, we hope that hydroxamic acid promoted acylative kinetic resolution will become a method of choice for preparation of saturated N-heterocycles in enantiopure form.

Recent Advances in Dynamic Kinetic Resolution by Chiral Bifunctional (Thio)urea- and Squaramide-Based Organocatalysts.

The organocatalysis-based dynamic kinetic resolution (DKR) process has proved to be a powerful strategy for the construction of chiral compounds. In this feature review, we summarized recent progress on the DKR process, which was promoted by chiral bifunctional (thio)urea and squaramide catalysis via hydrogen-bonding interactions between substrates and catalysts. A wide range of asymmetric reactions involving DKR, such as asymmetric alcoholysis of azlactones, asymmetric Michael–Michael cascade reaction, and enantioselective selenocyclization, are reviewed and demonstrate the efficiency of this strategy. The (thio)urea and squaramide catalysts with dual activation would be efficient for more unmet challenges in dynamic kinetic resolution.

ChemInform Abstract: Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines Through Dynamic Kinetic Resolution

AbstractReview: [75 refs.

ChemInform Abstract: Azlactone Reaction Developments

AbstractReview: 100 refs.

Single-Electron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp(3)-sp(2) Cross-Coupling.

ConspectusThe important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chemical territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex molecule construction, contemporary protocols are not without their Achilles’ heel: Csp3–Csp2/sp3 coupling. The underlying challenge in sp3 cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability. Despite the ubiquity of this problem, the nature of the transmetalation step has remained unchanged from the seminal reports of Negishi, Suzuki, Kumada, and Stille, thus suggesting that the challenges in Csp3–Csp2/sp3 coupling result from inherent mechanistic constraints in the traditional cross-coupling paradigm. Rather than submitting to the limitations of this conventional approach, we envisioned that a process rooted in single-electron reactivity could furnish the same key metalated intermediate posited in two-electron transmetalation, while demonstrating entirely complementary reactivity patterns.Inspired by literature reports on the susceptibility of organoboron reagents toward photochemical, single-electron oxidative fragmentation, realization of a conceptually novel open shell transmetalation framework was achieved in the facile coupling of benzylic trifluoroborates with aryl halides via cooperative visible-light activated photoredox and Ni cross-coupling catalysis. Following this seminal study, we disclosed a suite of protocols for the cross-coupling of secondary alkyl, α-alkoxy, α-amino, and α-trifluoromethylbenzyltrifluoroborates. Furthermore, the selective cross-coupling of Csp3 organoboron moieties in the presence of Csp2 organoboron motifs was also demonstrated, highlighting the nuances of this approach to transmetalation. Computational modeling of the reaction mechanism uncovered useful details about the intermediates and transition-state structures involved in the nickel catalytic cycle. Most notably, a unique dynamic kinetic resolution process, characterized by radical homolysis/recombination equilibrium of a NiIII intermediate, was discovered. This process was ultimately found to be responsible for stereoselectivity in an enantioselective variant of these cross-couplings.Prompted by the intrinsic limitations of organotrifluoroborates, we sought other radical feedstocks and quickly identified alkylbis(catecholato)silicates as viable radical precursors for Ni/photoredox dual catalysis. These hypervalent silicate species have several notable benefits, including more favorable redox potentials that allow extension to primary alkyl systems incorporating unprotected amines as well as compatibility with less expensive Ru-based photocatalysts. Additionally, these reagents exhibit an amenability to alkenyl halide cross-coupling while simultaneously expanding the aryl halide scope. In the process of exploring these reagents, we serendipitously discovered a method to effect thioetherification of aryl halides via a H atom transfer mechanism. This latter discovery emphasizes that this robust cross-coupling paradigm is “blind” to the origins of the radical, opening opportunities for a wealth of new discoveries. Taken together, our studies in the area of photoredox/nickel dual catalysis have validated single-electron transmetalation as a powerful platform for enabling conventionally challenging Csp3–Csp2 cross-couplings. More broadly, these findings represent the power of rational design in catalysis and the strategic use of mechanistic knowledge and manipulation for the development of new synthetic methods.

Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

The transition-metal-catalyzed asymmetric transfer hydrogenation (ATH) and asymmetric hydrogenation (AH) of α- and β-substituted ketone or imine derivatives are efficient methods for accessing chiral alcohols or amines bearing up to three stereogenic centers through a dynamic kinetic resolution (DKR) process. This review provides a summary of recent work in this field, focusing on the development of new catalytic systems and on the extension of these asymmetric reductions to new classes of substrates. 1 Introduction 2 Asymmetric Hydrogenation via Dynamic Kinetic Resolution 2.1 α-Substituted Ketones 2.2. α-Substituted β-Keto Esters and Amides 2.3 α-Substituted β-Keto Phosphonates and Sulfones 2.4 α,α′-Disubstituted Cyclic Ketones 2.5 α,β-Disubstituted Cyclic Ketones 2.6 Imine Derivatives 3 Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution 3.1 α-Substituted β-Diketones and Ketones 3.2 α-Substituted β-Keto Esters, Amides and Phosphonates 3.3 β-Substituted α-Keto Esters and Phosphonates 3.4 β-Substituted γ-Keto Esters 3.5 β-Alkoxy Ketones 3.6 Imine Derivatives 4 Conclusion