Lipase-catalyzed Kinetic Resolution of Racemic 1-Trimethylsilylethanol in Organic Solvent

The enantioselective esterification of racemic 1-trimethylsilylethanol with acids catalyzed by lipase in organic solvent was successfully performed. The influence of some factors on the reaction was investigated. Among the four lipases explored, Candida rugosa lipase (CRL) showed the highest activity and enantioselectivity. Octanoic acid was the best acyl donor among the eleven acids studied and n-hexane was the most suitable medium for the reaction. The optimum shaking rate and temperature were found to be 150r·min-1 and 20℃ to 30℃, respectively. The enantiomeric excess of the remaining (5)-(-)-1-trimethylsilylethanol was 93% when substrate conversion was 53% upon incubation of the reaction mixture at 30℃, 150r·min-1 for 12 h.

ENZYME REACTION IN AQUEGUB-ORGANIC BYSTEM —KINETIC RESOLUTION OP RACEMIC OXIRANECARBOXYLIC ESTERS WITH LIPASE

The chiral oxiranecarboxylic acids or esters 2a-e were obtained with lipase (CCL) in aqueous-organic system.The ee and the absolute configurations of the products were determined.

Kinetic Resolution of DL-Phenylalanine Methyl Ester by α -Chymotrypsin ImmobiIized on Porous Silica Beads

Kinetic resolution of DL-phenylalanine methyl ester was carried out using drimobilized α -chymotrypsin (IC) as catalyst. The effects of temperatUre, pH, concentration of substrate and reactionvessels on the resolution were investigated. High quality L-phenylalanine was obtained in good yieldby an IC column.

N-Heterocyclic carbene-catalyzed enantioselective(dynamic) kinetic resolutions and desymmetrizations

N-heterocyclic carbene-catalyzed enantioselective kinetic resolutions,dynamic kinetic resolutions,and desymmetrization reactions are systematically reviewed.The content is organized according to the activation modes involved in these transformations.Future advances within this highly active research field are discussed from our perspectives on the topic.

(Parallel) kinetic resolution of 3,3-disubstituted indolines via organocatalyzed reactions with azodicarboxylates

A novel kinetic resolution(KR) method has been developed for 3,3-disubstituted indolines, whose catalytic asymmetric synthesis remains a significant challenge in organic synthesis. The key to the success of this KR protocol lies in the utilization of chiral phosphoric acid-catalyzed triazane formation reaction with azodicarboxylates, which enables the enantioselective synthesis of various substituted indolines bearing C3-quaternary stereocenters with good to high enantioselectivities(with sfactors up to 70). Moreover, an intriguing parallel kinetic resolution(PKR) has been developed by combining triazane formation and dehydrogenation reactions using different azodicarboxylates. Experimental studies have provided insight into the mechanism of this PKR reaction, demonstrating stereoselectivity in both triazane formation and dehydrogenation steps, favoring the opposite enantiomers. The large-scale synthesis and diverse derivatizations of the products, particularly the imine groupcontaining 3H-indoles, demonstrate the value of these(P)KR methods.

A kinetic resolution accompanied chirality transformation process for asymmetric synthesis of chiral phenol,oxaziridine,andα-hydroxyl cyclic ketone

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

Chiral Isothiourea-Catalyzed Acylative Dynamic Kinetic Resolution of 3-Hydroxyphthalides for Enantioselective Synthesis of Phthalidyl Esters

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

Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation

Esters are abundant in natural and synthetic products and their conversion into primary alcohols holds great importance in fine chemical synthesis.However,achieving asymmetric hydrogenation(AH)of racemic esters with remote stereocenters via kinetic resolution(KR)remains a formidable challenge due to the difficulties associated with discerning spatially distant stereocenters.To address this issue,we have designed a hydroxy-assisted strategy that introduces a hydroxy group into racemicβ-aryl esters to facilitate hydrogenation and enhance chiral discrimination through a lactone form.By employing chiral Ir-SpiroPAP catalysts,we achieved exceptional AH of racemic 4-substituted chroman-2-ones,lactone form of ortho-hydroxylatedβ-aryl esters,via KR,resulting in impressive selectivity factor(s)values of up to 600.This approach exhibited significant efficacy for racemic chroman-2-ones containingβ-aryl,alkenyl,alkynyl,and alkyl groups,enabling the synthesis of chiralγ-aryl primary alcohols and the recovery of chiralβ-aryl esters or chroman-2-ones,typically difficult to access using existing methods.The scalability and broad synthetic applications of this method were exemplified by successfully synthesizing chiral drugs(R)-fesoterodine and enrasentan,alongside various chiral intermediates essential for producing chiral drugs and natural products.These promising results highlight the potential of this approach as a powerful tool for synthesizing valuable chiral compounds.

Iridium-Catalyzed Site-and Enantioselective C(sp^(2))-H Borylation of Benzhydryl Ethers:Enantioselectivity Amplification by Kinetic Resolution Relay

Comprehensive Summary,We herein report a simple ether-directed iridium-catalyzed site-and enantioselective C(sp^(2))-H borylation of benzhydryl ethers for the first time.Various chiral benzhydryl ethers were obtained with high enantioselectivities in the presence of a tailor-made chiral bidentate boryl ligand.We found that the kinetic resolution relay significantly amplified the enantioselectivity.The synthetic utility of the current method was demonstrated by gram-scale C—H borylation and C—B bond transformations.

Asymmetric synthesis of syn-aryl-(2S,3R)-2-chloro-3-hydroxy esters via an engineered ketoreductase-catalyzed dynamic reductive kinetic resolution

We report here a generic,green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1)in 73%-99%isolated yields along with 6.1:1–83:1 dr and 31%~>99%ee,through dynamic reductive kinetic resolution of racemic arylα–chloroβ-keto esters(2)catalyzed by an engineered ketoreductase which was obtained via ep PCR-based directed evolution.The hectogram scale synthesis of syn-(2S,3R)-1b at a substrate concentration of 120 g/L showcased the application potential of the biocatalytic method developed presently.

Nickel-catalyzed kinetic resolution to achieve P-chiral phosphine oxides and sec-phosphine oxides

P-Chiral phosphines and sec-phosphine oxides(SPO) are found in a diverse range of compounds that play crucial roles in various fields, including asymmetric catalysis, materials, agrochemistry, and pharmaceutical chemistry. Herein, we describe an enantioselective Ni-catalyzed kinetic resolution of racemic sec-phosphine oxides to obtain the corresponding optically pure Pchiral phosphine oxides and sec-phosphine oxides, respectively. These products are versatile chiral phosphine building blocks that can be used to construct an extensive range of P-chiral phosphines.

Highly selective kinetic resolution of D/L-syn-p-sulfone phenylserine catalyzed by D-threonine aldolase in two-phase ionic solvent

In the chemical synthesis of L-syn-p-methylsulfoxide phenylserine ethyl ester(D-ethyl ester),L-tartaric acid or enzymatic resolution is employed to resolve the racemate,and thus obtain the target compound,and the remaining isomer can be recycled to obtain the raw material.In this study,high-purity L-syn-p-methylsulfoxide phenylserine(L-syn-MPS)was obtained.The kinetics of the D-threonine aldolase enzymatic hydrolysis reaction reveals that D-syn-p-sulfoxylphenylserine resolves well in[BMIM][BF 4]ionic solvents.The D/L-syn-MPS racemate was resolved using a two-phase ionic solvent[BMIM][NTf 2]to afford L-syn-MPS(ee(enantiomeric excess)>99%)and a white solid in 41.7%yield.Therefore,this system is suitable for the separation of insoluble aldehydes and successfully avoids the condensation of hydroxyl aldehydes to form D-anti-MPS.

Chiral Betaine-Mediated Asymmetric Peroxidation-Kinetic Resolution Cascade for the Synthesis of Optically Pure Peroxides

An array of natural products bearing chiral peroxide motifs display antitumor,anticancer,and antiparasitic activities.However,there are very few catalytic asymmetric syntheses of chiral peroxides.Moreover,effective catalysts for asymmetric catalytic peroxidations are limited to chiral amines.To further expand synthetic access to chiral peroxides,the development of new catalysts realizing catalytic asymmetric peroxidation is highly desirable yet challenging.We report here a catalytic asymmetric peroxidation of anα,β-unsaturated triflone-kinetic resolution cascade reaction,which furnishes chiral peroxides in greater than 99.9%ee.The realization of this cascade reaction resulted from the development of two betaines as novel catalysts for chiral peroxide synthesis;one betaine promoted enantioselective peroxidation ofα,β-unsaturated triflones via conjugate addition affording peroxides in 80-92%ee,while the other betaine catalyzed kinetic resolution of the newly generated chiral peroxides to further increase the ee to greater than 99.9%.

Asymmetric Aminations and Kinetic Resolution of Acyclic α-Branched Ynones

An efficient method for asymmetric synthesis of acyclic α-tertiary amine derivatives has been achieved through enantioselective aminations of α-branched ynones with azodicarboxylates enabled by chiral phosphoric acid catalysis.Moreover,kinetic resolution of racemic starting material was realized under these conditions,which gave access to valuable enantioenriched α-substituted ketones.

Kinetic Resolution of 1,2-Diamines via Organocatalyzed Asymmetric Electrophilic Aminations of Anilines

An efficient kinetic resolution(KR)protocol for 1,2-diamines has been developed through asymmetric electrophilic aminations of anilines enabled by chiral phosphoric acid catalysis.A wide array of substituted 1,2-diamines were compatible with this method,generating both the recovered staring materials and the amination products with high enantioselectivities(with s-factor up to 218).Notably,this method is amenable to the kinetic resolution of 1,2-diamines bearingα-tertiary amine moieties,which represents the first KR of this type of 1,2-diamines.Facile removal of the introduced hydrazine group and oxidative cleavage of the N-aryl group to release the free primary amine demonstrate the value of this method.

Kinetic Resolution of 2-Substituted 1,2-Dihydroquinolines by Rhodium-Catalyzed Asymmetric Hydroarylation

A highly efficient kinetic resolution of racemic 2-substituted 1,2-dihydroquinolines via Rh-catalyzed asymmetric hydroarylation has been described for the first time.A variety of arylboronic acids coupled with 2-substituted 1,2-dihydroquinolines under mild reaction condition.The transformations into the enantio-enriched 2,3-diaryl-tetrahydroquinolines as well as the recovered chiral 2-aryl-dihydroquinolines were obtained with high yields and excellent enantioselectivities(86%-99% ee,s factor up to 1057).

Atroposelective sp3 C—H Coupling for Kinetic Resolution of Thioanilide Atropisomers

A highly efficient kinetic resolution of racemic thioanilide atropisomers via C(sp^(3))-H arylation has been achieved by a hybrid palladium catalyst bearing an anionic chiral Co^(Ⅲ)-complex and a phosphoramidite ligand,leading to both enantioenriched atropisomeric arylation thioanilides(up to 99%ee)and N-Me atropisomeric thioanilides(up to 99%ee),simultaneously.The remained enantioenriched substrates can be arylated again by using an achiral anionic ligand to give the enantiomer with the opposite configuration.

Rh-Catalyzed Kinetic Resolution-Based Enantioselective[4+2]-Cydoaddition-lsomerization of Allene-1,3-dienes

Main observation and conclusion The first example of Rh-catalyzed kinetic resolution of 1,3-disubstituted allene-1,3-dienes involving intramolecular[4+2]-cycloaddition has been developed.Followed by C=C isomerization,the reaction finally afforded aza-[4.3.0]bicyclic compounds with a very high en-antio-and E-selectivity.The mechanism has been unveiled by careful control experiments.The synthetic potentials of highly enanti-oenriched bicyclic products have also been demonstrated.

Organocatalytic dynamic kinetic resolution of N-arylindole lactams:atroposelective construction of axially chiral amino acids bearing a C–N chiral axis

Organocatalytic dynamic kinetic resolution of configurationally labile cyclic molecules represents one of the most efficient methods for the atroposelective construction of axially chiral molecules bearing a tetra-ortho-substituted chiral axis.Notably,this privileged strategy is limited to constructing a C–C chiral axis.Herein,organocatalytic dynamic kinetic resolution of configurationally labile N-arylindole lactams has been successfully achieved at the first time,allowing for access to a structurally diverse set of axially chiral N-arylindole amino esters with a tetra-ortho-substituted C–N chiral axis in excellent yields and atroposelectivities.In addition to the N-arylindole skeleton,N-aryl thieno[3,2-b]pyrrole,furo[3,2-b]pyrrole,and pyrrolo[2,3-b]pyridine skeletons are also compatible with this transformation.This transition-metal-free facile strategy features a broad substrate scope,mild reaction conditions,easy scale-up and excellent atom economy.Several potentially valuable molecules,such as axially chiral peptides,were efficiently generated from the resulting configurationally stable axially-chiral N-arylindole amino esters,demonstrating the power of this strategy.

Constructing Tertiary Alcohols with Vicinal Stereocenters:Highly Diastereo-and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution

We report the first highly diastereo-and enantioselective C-C bond-forming reaction of racemic α-branched ketones to construct tertiary alcohols with adjacent stereocenters.Accordingly,a highly stereoselective cyanosilylation of racemic ketones is developed using our bifunctional cyanating reagent,Me_(2)(CH_(2)Cl)SiCN,giving C^(α)-tetrasubstituted silyl cyanohydrins withtwovicinal stereocenters inupto>20:1 diastereomeric ratio(dr)and 90-98% enantiomeric excess(ee)values,which can undergo various diversification reactions bymanipulating the chloromethyl group.A highly selective kinetic resolution of acyclicα-branched ketones is also developed that allows facile access to acyclic α-alkyl,allyl,and propargyl ketones with good recovery and excellent ee values.The synthetic value of this protocol is further demonstrated by the formal synthesis of the anti-obesity agent,taranabant(MK-0364).The activation of Jacobsen’s privileged catalyst(salen)AlCl by a suitable phosphorane plays a crucial role in the reaction.X-ray crystallographic analysis of single crystals of phosphorane-(salen)AlCl complexes and theoretical calculations help provide a working model.The present transformation opens a new path for the catalytic stereoselective synthesis of stereochemically complex tertiary alcohols featuring two stereocenters(adjacent or not)from racemic ketones.