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.

Kinetics of Lipase Catalyzed Enantioselective Esterification of Racemic Ibuprofen in Isooctane

The kinetics of Candida rugosa lipase catalyzed esterification of racemic ibuprofen with n-butanol in isooctane was studied. The kinetic study was carried out with the addition of 0.1% and 2% (by volume) of water for enzyme activation respectively when celite was added into isooctane for enzyme dispersion. The specific initial rate for S-ibuprofen can be fitted with the Ping Pong Bi Bi mechanism with dead-end competitive inhibition by the alcohol. The time courses of the enantioselective esterification of the two ibuprofen enantiomers with different initial substrate concentrations and water contents were simulated with a model in which both effects of enzyme inactivation by long term reaction and reversed hydrolytic reaction under high water content were taken into consideration.

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.

Study on extraction kinetics ofα-cyclopentylmandelic acid enantiomers with hydroxyethyl-β-cyclodextrin as chiral selector

In this work,the kinetic study on reactive extraction ofα-cyclopentylmandelic acid(α-CPMA)enantiomers was performed in a Lewis cell using hydroxyethyl-β-cyclodextrin(HE-β-CD)as chiral selector.The enantioselective complexation equilibrium between HE-β-CD andα-CPMA enantiomers was studied by phase solubility method.The important process parameters affecting the initial extraction rate were separately studied and the reaction rate equations were deduced.The optimal conditions for kinetic study were as follows:stirring speed of 75 r·min^(-1),interfacial area of 12.56 cm^2,pH of 2.5,initial HE-β-CD concentration of 0.05 mol·L^(-1),initialα-CPMA concentration of 5 mmol·L^(-1),and temperature of 278 K.The reaction has been found to be first order inα-CPMA and second order in HE-β-CD with the forward rate constants of 2.056×10^(-3)m^6·mol^(-2)·s^(-1)and 1.459×10^(-3)m^6·mol^(-2)·s^(-1)for(S)-α-CPMA and(R)-α-CPMA,respectively.The complexation equilibrium constants were evaluated as 61 L·mol^(-1) and 117 L·mol^(-1)for(S)-α-CPMA and(R)-α-CPMA,and the intrinsic enantioselectivity is estimated as 1.92.

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.

Enantio-selective preparation of (S)-1-phenylethanol by a novel marine GDSL lipase MT6 with reverse stereo-selectivity

We previously functionally characterized a novel marine microbial GDSL lipase MT6 and identified that the stereo-selectivity of MT6 was opposite to that of other common lipases in trans-esterification reactions.Herein,we have investigated the use of MT6 in stereo-selective biocatalysis through direct hydrolysis reactions.Notably,the stereo-selectivity of MT6 was also demonstrated to be opposite to that of other common lipases in hydrolysis reactions.Parameters,including temperature,organic co-solvents,pH,ionic strength,catalyst loading,substrate concentration,and reaction time,affecting the enzymatic resolution of racemic 1-phenylethyl acetate were further investigated,with the e.e.of the final（S）-l-Phenylethanol product and the conversion being 97%and 28.5%,respectively,after process optimization.The lengths of side chains of 1-phenylethyl esters greatly affected the stereo-selectivity and conversion during kinetic resolutions.MT6 is a novel marine microbial GDSL lipase exhibiting opposite stereo-selectivities than other common lipases in both trans-esterification reactions and hydrolysis reactions.

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.

Characterization of a novel marine microbial esterase and its use to make D-methyl lactate

A novel marine microbial esterase PHE14 was cloned from the genome of Pseudomonas oryzihabit‐ans HUP022 isolated from the deep sea of the western Pacific Ocean. Esterase PHE14 exhibited very good tolerance to most organic solvents, surfactants and metal ions tested, thus making it a good esterase candidate for organic synthesis that requires an organic solvent, surfactants or metal ions. Esterase PHE14 was utilized as a biocatalyst in the asymmetric synthesis of D‐methyl lactate by enzymatic kinetic resolution. D‐methyl lactate is a key chiral chemical. Contrary to some previous reports, the addition of an organic solvent and surfactants in the enzymatic reaction did not have a beneficial effect on the kinetic resolution catalyzed by esterase PHE14. Our study is the first report on the preparation of the enantiomerically enriched product D‐methyl lactate by enzymatic kinetic resolution. The desired enantiomerically enriched product D‐methyl lactate was obtained with a high enantiomeric excess of 99%and yield of 88.7%after process optimization. The deep sea mi‐crobial esterase PHE14 is a green biocatalyst with very good potential in asymmetric synthesis in industry and can replace the traditional organic synthesis that causes pollution to the environment.

Characterization ofanovel deep-seamicrobial esterase EstC 10 and its use in the generation o f(R)-methyl 2-chloropropionate

A novel esterase EstC10 from Bacillus sp. CX01 isolated from the deep sea of the Western Pacific Ocean and the functionalities of EstC 10 was characterized. At present, the reports about the kinetic resolution ofracemic methyl 2-chloropropionate were quite rare. So we developed deep-sea microbial esterase EstC10 as a novel biocatalyst in the kinetic resolution of racemic methyl 2-chloropropionate and generate （R）-methyl 2-chloropropionate with high enantiomeric excess （〉99%） after the optimization of process parameters such as pH, temperature, organic co-solvents, surfactants, substrate concentration and reaction time. Notably, the optimal substrate concentration （80 mmol/L） of esterase EstC10 was higher than the kinetic resolution of another esterase, Estl2-7 （50 mmoFL）. The novel microbial esterase EstC10 identified from the deep sea was a promising green biocatalyst in the generation of （R）-methyl 2-chloropropionate as well of many other valuable chiral chemicals in industry.

A Facile Synthetic Method for (3Z,6Z,9S,10R)-9,10-Epoxy-3,6-heneicosadiene,Sex Pheromone Component of Hyphantria Cunea (Drug)

Total synthesis of (3Z, 6Z, 9S, 10R)-9, 10-epoxy-3, 6-heneicosadiene, sex pheromone component of Hyphantria cunea (Drug), was achieved using Sharpless AE kinetic resolution and alkylative epoxide rearrangement as key steps.

Recent advance of chemoenzymatic catalysis for the synthesis of chemicals: Scope and challenge

Chemoenzymatic catalysis can give full play to the advantages of versatile reactivity of chemocatalysis and excellent chemo-,regio-,and stereoselectivities of biocatalysis.These chemoenzymatic methods can not only save resource,cost,and operating time but also reduce the number of reaction steps,and avoid separating unstable intermediates,leading to the generation of more products under greener circumstances and thereby playing an indispensable role in the fields of medicine,materials and fine chemicals.Although incompatible challenges between chemocatalyst and biocatalyst remain,strategies such as biphasic system,artificial metalloenzymes,immobilization or supramolecular host,and protein engineering have been designed to overcome these issues.In this review,chemoenzymatic catalysis according to different chemocatalysis types was classifiably described,and in particular,the classic dynamic kinetic resolutions(DKR)and cofactor regeneration were summarized.Finally,the bottlenecks and development of chemoenzymatic catalysis were summarized,and future development was prospected.

Enantioselective esterification of(R,S)-2-(4-methylphenyl)propionic acid via Novozym 435:Optimization and application

This paper reports on the resolution of(R,S)-2-(4-methylphenyl)propionic acid(MPPA)enantiomers by enzymatic esterification in organic solvent.Novozym 435(CALB)has the best catalytic performance compared with other lipases.Of the alcohols screened,n-hexanol is the best acyl acceptor and gives the highest enzyme activity and enantioselectivity in n-hexane.Response surface methodology(RSM)was used to evaluate the influence of the factors,such as temperature,enzyme amount,substrate concentration and reaction time on the substrate conversion(c)and enantiomeric excess(ee).The correlation coefficient R2 for enantiomeric excess and the conversion are 0.9827 and 0.9910,respectively,indicating that can accurately predict the experimental results.By simulation and optimization,the optimal conditions were obtained,involving 600 mmol·L^-1 MPPA concentration(0.60 mmol),850 mmol·L^-1 hexanol concentration(0.85 mmol),58 mg enzyme amount,75℃temperature and 4.5 h reaction time,respectively.Under the optimized conditions,the experimental values of conversion and enantiomeric excess were 89.34%and 97.84%,respectively,which are in good agreement with the model predictions.

Functional characterization of a novel microbial esterase identified from the Indian Ocean and its use in the stereoselective preparation of(R)-methyl mandelate

Genomic mining has identifi ed a novel microbial alkaline esterase from the Indian Ocean. This esterase was overexpressed in E. coli BL21（DE3） and further functionally characterized. Under optimal conditions（10 mmol/L substrate, p H 6.0, 2 h at 40 ℃）, this esterase can hydrolyze racemic methyl mandelate to（ R）-methyl mandelate with very high optical purity（e. e. 〉99%） and yield（nearly 90%）. Interestingly, the stereoselectivity of this esterase is opposite to that of two previously reported lipases that can generate（ S）-methyl mandelate through the hydrolysis of racemic methyl mandelate. No organic solvents or other additives were required to optimize the optical purity and production of the fi nal chiral product（R）-methyl mandelate, which can potentially simplify the production procedure of（ R）-methyl mandelate catalyzed by esterase.

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.

Characterization of four diol dehydrogenases for enantioselective synthesis of chiral vicinal diols

Enantiopure vicinal diols are important building blocks used in the synthesis of fine chemicals and pharmaceutical compounds. Diol dehydrogenase(DDH) mediated stereoselective oxidation of racemic vicinal is an efficient way to prepare enantiopure vicinal diols. In this study, four new bacterial DDHs(AnDDH from Anoxybacillus sp. P3 H1 B, HcDDH from Hazenella coriacea, GzDDH from Geobacillus zalihae and LwDDH from Leptotrichia wadei) were mined from the GenBank database and expressed in E. coli T7.The four DDHs were purified and biochemically characterized for oxidation activity toward(R)-1-phenyl-1,2-ethanediol, with the optimal reaction condition of pH9.0(AnDDH), 10.0(HcDDH) and 11.0(GzDDH and LwDDH) and the temperatures at 40 ℃(AnDDH), 50 ℃(HcDDH) and 60 ℃(GzDDH and LwDDH), respectively. The four enzymes were stable at the pH from 7.0 to 9.0 and below 40 ℃.Kinetic parameters of four DDHs showed that the HcDDH from Hazenella coriacea had high activity toward a broad range of vicinal diols. A series of racemic vicinal diols were successfully resolved by recombinant E. coli(HcDDH-NOX) resting cells co-expression of an NADH oxidase(NOX), affording(S)-diols and(1 S, 2 S)-trans-diols in ≥99% ee. The synthetic potential of HcDDH was proved by E. coli(HcDDH-NOX) via kinetic resolution of racemic trans-1,2-indandiol on a 100 ml scale reaction,(S, S)-trans-1,2-indandiol was prepared in 46.7% yield and >99% ee. In addition, asymmetric reduction of four α-Hydroxy ketones(10–300 mmol·L^(-1)) by E. coli(HcDDH-GDH) resting cells resulted in >99% ee and69–98% yields of(R)-vicinal diols. The current research expands the toolbox of DDHs to synthesize chiral vicinal diols and demonstrated that the mined Hc DDH is a potential enzyme in the synthesis of a broad range of chiral vicinal diols.

Approach to the Synthesis of Dimeric Salen-Co(Ⅲ):A Recoverable Catalyst for Rac-Eprichlorohydrin HKR

The synthesis of chiral dimeric Salen ligand 5, 5＇-methylene-di-[（R, R ）-｜ N-（3-tert-butylsalicylidine）-N＇- （ 3＇, 5＇-di- tert-butylsalicylidene） ｜ - 1, 2-cyclohexanediamine ] which using 2-tert-butylphenol as starting material is reported. This compound reacts with cobalt （Ⅱ） acetate and then oxidized by air to give dimeric Salen catalyst 5 in this paper, which catalyzes the hydrolytic kinetic resolution （HKR） of racemic epichlorohydrin to afford biologically important chiral epoxides and diols. Ee values of diol up to 97 % were obtained, and the catalyst was recovered with no apparent loss.