Asymmetric Addition of Triethylaluminium to Aromatic Aldehydes Catalyzed by Titanium‐(5,5’‐Biquinoline‐6,6’‐Diol) Complexes

A novel convenient procedure for the resolution of 5,5’‐biquinoline‐6,6’‐diol (BIQOL) was achieved by separating the corresponding diastereomeric mixture of (S)‐(+)‐camphorsulfonates on a semiprepared XDB‐C8 column followed by hydrolysis. The efficient asymmetric addition of triethylaluminium to aromatic aldehydes catalyzed by Ti‐(+)/(–)BIQOL complexes under mild conditions is described. The reactions led to the formation of 1‐arylpropan‐1‐ol in up to 87.5% ee. Chirality 26:268‐271, 2014. © 2014 Wiley Periodicals, Inc.     

Copper‐Chiral Camphor β‐Amino Alcohol Complex Catalyzed Asymmetric Henry Reaction

Four novel chiral amino alcohols were synthesized from D‐(+)‐camphor and utilized as ligands in a Cu(I)‐catalyzed asymmetric Henry reaction. The reactions were carried out under mild conditions with excellent enantioselectivities and moderate yields without the exclusion of air or moisture. The highest enantioselectivity was observed up to 94% enantiomeric excess (ee) with ligand L1 in toluene at room temperature. Chirality 27:761–765, 2015. © 2015 Wiley Periodicals, Inc.     

Application of a new amidophosphite ligand to Rh‐catalyzed asymmetric hydrogenation of β‐dehydroamino acid derivatives in supercritical carbon dioxide: Activation effect of protic co‐solvents

New chiral amidophosphite ligand was synthesized and tested in the Rh‐catalyzed asymmetric hydrogenation of (Z)‐β‐(acylamino)acrylates in protic solvents and supercritical carbon dioxide (scCO₂) The catalytic performance is affected greatly by the acidity of the solvents. Better enantioselectivity (up to 88% ee) was achieved in scCO₂ containing 1,1,1,3,3,3‐hexafluoro‐2‐propanol, compared to neat protic solvents. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

The Use of Phosphite‐Type Ligands in the Ir‐Catalyzed Asymmetric Hydrogenation of Heterocyclic Compounds

A series of chiral phosphite‐type ligands was tested in asymmetric Ir‐catalyzed hydrogenation of quinolines and 2,4,5,6‐tetrahydro‐1H‐pyrazino(3,2,1‐j,k)carbazole. Hydrogenation of quinaldine hydrochloride provided superior enantioselectivity up to 65% ee compared to quinaldine free base. The ligands were tested for the first time in the asymmetric Ir‐Ircatalyzed hydrogenation of 2,4,5,6‐tetrahydro‐1H‐pyrazino(3,2,1‐j,k)carbazole yielding the antidepressant drug, pirlindole. Chirality 26:56–60, 2013. © 2013 Wiley Periodicals, Inc.     

Dehalogenation Activity of Selected Fungi Toward δ‐Iodo‐γ‐Lactone Derived from trans,trans‐Farnesol

Time‐course of biotransformation of racemic trans‐4‐((E)‐4′,8′‐dimethylnona‐3′,7′‐dien‐1‐yl)‐5‐iodomethyl‐4‐methyldihydrofuran‐2‐one ( 1 ) in fungal and yeast cultures was investigated. In these conditions, the substrate 1 was enantioselectively dehalogenated yielding 4‐((E)‐4′,8′‐dimethylnona‐3′,7′‐dien‐1‐yl)‐4‐methyl‐5‐methylenedihydrofuran‐2‐one ( 2 ) and its structure was established based on the spectroscopic data. The most effective biocatalyst used was Didymosphaeria igniaria, which catalyzed the process with highest rate and enantioselectivity (ee of product = 76%). The antiproliferative activity of δ‐iodo‐γ‐lactone 1 , product of its biotransformation 2 , and starting substrate (farnesol) were evaluated toward two cancer cell lines: A549 (human lung adenocarcinoma) and HL‐60 (human promyelocytic leukemia).     

Convenient enzymatic resolution of (R,S)‐2‐methylbutyric acid catalyzed by immobilized lipases

The application of several immobilized lipases has been explored in the enantioselective esterification of (R,S)‐2‐methylbutyric acid, an insect pheromone precursor. With the use of Candida antarctica B, using hexane as solvent, (R)‐pentyl 2‐methylbutyrate was prepared in 2 h with c 40%, ee_p 90%, and E = 35, while Thermomyces lanuginosus leads to c 18%, ee_p 91%, and E = 26. The (S)‐enantiomer was obtained by the use of Candida rugosa or Rhizopus oryzae (2‐h reaction, c 34% and 35%, ee_p 75 and 49%, and E = 10 and 4, respectively). Under optimal conditions, the effect of the solvent, the molar ratio, and the nucleophile were evaluated.     

β‐Hydroxyamide‐Based Ligands and Their Use in the Enantioselective Borane Reduction of Prochiral Ketones

Hydroxyamide‐based ligands have occupied a considerable place in asymmetric synthesis. Here we report the synthesis of seven β‐hydroxyamide‐based ligands from the reaction of 2‐hydroxynicotinic acid with chiral amino alcohols and test their effect on the enantioselective reduction of aromatic prochiral ketones with borane in tetrahydofuran (THF). They produce the corresponding secondary alcohols with up to 76% enantiomeric excess (ee) and good to excellent yields (86‐99%). Chirality 26:21–26, 2013. © 2013 Wiley Periodicals, Inc.     

Modular amino acids‐based chiral ligands for copper‐catalyzed enantioselective conjugation addition of diethylzinc to cyclic enones

New amino acid‐based modular chiral ligands were readily synthesized and used to catalyze the asymmetric conjugate addition of Et₂Zn to various cyclic enones in the presence of a variety of copper sources. Moderately high ee of up to 72% were obtained using ligand (S)‐ 1e under mild conditions. Chirality 2011. © 2010 Wiley‐Liss, Inc.     

Stereoselective Synthesis of (3R)‐3‐Alkyl‐4,1‐Benzoxazepine‐2,5‐Diones

Novel 3‐alkyl‐4,1‐benzoxazepine‐2,5‐diones were synthesized in good ee exploiting the chiral pool methodology, an economical way of asymmetric synthesis. Various anthranilic acids are coupled with different α‐haloacids to afford N‐acylated anthranilic acid intermediates which undergo cyclization to (3R)‐3‐alkyl‐4,1‐benzoxazepines‐2,5‐diones. Chirality 25:865–870, 2013. © 2013 Wiley Periodicals, Inc.     

Lipase‐Catalyzed Kinetic Resolution of (±)‐1‐(2‐Furyl) Ethanol in Nonaqueous Media

S‐1‐(2‐Furyl) ethanol serves as an important chiral building block for the preparation of various natural products, fine chemicals, and is widely used in the chemical and pharmaceutical industries. In this work, lipase‐catalyzed kinetic resolution of (R/S)‐1‐(2‐furyl) ethanol using different acyl donors was investigated. Vinyl esters are good acyl donors vis‐à‐vis alkyl esters for kinetic resolution. Among them, vinyl acetate was found to be the best acyl donor. Different immobilized lipases such as Rhizomucor miehei lipase, Thermomyces lanuginosus lipase, and Candida antarctica lipase B were evaluated for this reaction, among which C. antarctica lipase B, immobilized on acrylic resin (Novozym 435), was found to be the best catalyst in n‐heptane as solvent. The effect of various parameters was studied in a systematic manner. Maximum conversion of 47% and enantiomeric excess of the substrate (ee_s) of 89% were obtained in 2 h using 5 mg of enzyme loading with an equimolar ratio of alcohol to vinyl acetate at 60°C at a speed of 300 rpm in a batch reactor. From the analysis of progress curve and initial rate data, it was concluded that the reaction followed the ordered bi–bi mechanism with dead‐end ester inhibition. Kinetic parameters were obtained by using nonlinear regression. This process is more economical, green, and easily scalable than the chemical processes. Chirality 26:286–292, 2014. © 2014 Wiley Periodicals, Inc.     

Chiral Amine Enantiomeric Excess Determination Using Self‐Assembled Octahedral Fe(II)‐Imine Complexes

A receptor assembly composed of iron(II) triflate and pyridine‐2,6‐dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha‐chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha‐chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay. Chirality 27:294–298, 2015. 2015 Wiley Periodicals, Inc.     

Fractional Reactive Extraction for Symmetrical Separation of 4‐Nitro‐D,L‐Phenylalanine in Centrifugal Contactor Separators: Experiments and Modeling

The enantioselective liquid–liquid extraction of 4‐nitro‐D,L‐phenylalanine (D,L‐Nphy) using PdCl₂{(s)‐BINAP} as extractant in dichloroethane was studied experimentally in a countercurrent cascade of 10 centrifugal contactor separators (CCSs) at 5°C, involving flow ratio, extractant concentration, and Cl^? concentration. The steady‐state enantiomeric excess (ee) in both stream exits was 90.86% at a 93.29% yield. The predicted value was modeled using an equilibrium stage approach. The correlation between model and experiment was satisfactory. The model was applied to optimize the production of both enantiomers in >97% ee and >99% ee. 14 stages and 16 stages are required for 97% ee and 99% ee for both enantiomers, respectively. Chirality 27:75–81, 2015. © 2014 Wiley Periodicals, Inc.     

Propioin synthesis using thiamine diphosphate‐dependent enzymes

Benzaldehyde lyase (BAL, EC 4.1.2.38) from Pseudomonas fluorescens and benzoylformate decarboxylase (BFD, EC 4.1.1.7) from Pseudomonas putida are thiamine diphosphate‐dependent enzymes. These enzymes share a common tetrameric structure and catalyze various C? C‐bond forming and breaking reactions. Here we describe a detailed study of the asymmetric synthesis of propioin from propanal catalyzed by BAL or BFD in aqueous solution in a batch reactor. Both enzymes are deactivated in the presence of high concentration of propanal. Compared to BAL, BFD is more stable under reaction conditions as well as during storage. The kinetic studies showed a typical Michaelis‐Menten kinetic for BAL with a maximal specific reaction rate of 26.2 U/mg and an unusually high K_M of 415 mM, whereas the v/[S]‐plot for BFD is almost linear in the concentration range (100–1500 mM) investigated. Both enzymes produce propioin with opposite enantiomeric excess: BAL produced the (S)‐propioin (ee of 35%), whereas BFD yielded the (R)‐enantiomer (ee of 67%). © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

Engineering of recombinant E. coli cells co‐expressing P450pyrTM monooxygenase and glucose dehydrogenase for highly regio‐ and stereoselective hydroxylation of alicycles with cofactor recycling

E. coli (P450pyrTM‐GDH) with dual plasmids, pETDuet containing P450pyr triple mutant I83H/M305Q/A77S (P450pyrTM) and ferredoxin reductase (FdR) genes and pRSFDuet containing glucose dehydrogenase (GDH) and ferredoxin (Fdx) genes, was engineered to show a high activity (12.7 U g^?1 cdw) for the biohydroxylation of N‐benzylpyrrolidine 1 and a GDH activity of 106 U g^?1 protein. The E. coli cells were used as efficient biocatalysts for highly regio‐ and stereoselective hydroxylation of alicyclic substrates at non‐activated carbon atom with enhanced productivity via intracellular recycling of NAD(P)H. Hydroxylation of N‐benzylpyrrolidine 1 with resting cells in the presence of glucose showed excellent regio‐ and stereoselectivity, giving (S)‐N‐benzyl‐3‐hydroxypyrrolidine 2 in 98% ee as the sole product in 9.8 mM. The productivity is much higher than that of the same biohydroxylation using E. coli (P450pyrTM)b without expressing GDH. E. coli (P450pyrTM‐GDH) was found to be highly regio‐ and stereoselective for the hydroxylation of N‐benzylpyrrolidin‐2‐one 3 , improving the regioselectivity from 90% of the wild‐type P450pyr to 100% and giving (S)‐N‐benzyl‐4‐hydroxylpyrrolidin‐2‐one 4 in 99% ee as the sole product. A high activity of 15.5 U g^?1 cdw was achieved and (S)‐ 4 was obtained in 19.4 mM. E. coli (P450pyrTM‐GDH) was also found to be highly regio‐ and stereoselective for the hydroxylation of N‐benzylpiperidin‐2‐one 5 , increasing the ee of the product (S)‐N‐benzyl‐4‐hydroxy‐piperidin‐2‐one 6 to 94% from 33% of the wild‐type P450pyr. A high activity of 15.8 U g^?1 cdw was obtained and (S)‐ 6 was produced in 3.3 mM as the sole product. E. coli (P450pyrTM‐GDH) represents the most productive system known thus far for P450‐catalyzed hydroxylations with cofactor recycling, and the hydroxylations with E. coli (P450pyrTM‐GDH) provide with simple and useful syntheses of (S)‐ 2 , (S)‐ 4 , and (S)‐ 6 that are valuable pharmaceutical intermediates and difficult to prepare. Biotechnol. Bioeng. 2013; 110: 363–373. © 2012 Wiley Periodicals, Inc.     

Synthesis and application of 3‐substituted (S)‐BINOL as chiral ligands for the asymmetric ethylation of aldehydes

A series of (S)‐BINOL ligands substituted at the 3 position with some five‐membered nitrogen‐containing aromatic heterocycles were effectively prepared and their catalytic abilities were evaluated in the asymmetric addition of diethylzinc to benzaldehyde in the presence of titanium tetraisopropoxide. Under the optimized reaction conditions, titanium complex of (S)‐3‐(1H‐benzimidazol‐1‐yl)‐1,1′‐bi‐2‐naphthol was found to be the most efficient catalyst for asymmetric ethylation of various aldehydes to generate the corresponding secondary alcohols in up to 99% yield and 91% ee. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Resolution of (R,S)‐ibuprofen catalyzed by immobilized Novozym40086 in organic phase

The enantioselective esterification of ibuprofen catalyzed by Novozym40086 was successfully conducted in organic solvent. Removing‐water reagent was added into the reaction mixture to remove water produced in the esterification. The effects of temperature, n‐hexanol concentration, ibuprofen concentration, and loading of enzymes were investigated. Under the condition of equilibrium, the thermodynamic equilibrium constant (K) of 7.697 and enantioselectivity (E) of 8.512 were obtained. The esterification reaction achieved its equilibrium in approximately 30 hours with conversion of 56% and ee_S of 93.78%. The predicted values of X and ee_S were 67.90% and 95.60%, respectively. The experimental value is approximately equal to the theoretical value, which indicates the feasibility of ideal models.     

Whole‐cell biocatalytic of Bacillus cereus WZZ006 strain to synthesis of indoxacarb intermediate: (S)‐5‐Chloro‐1‐oxo‐2,3‐dihydro‐2‐hydroxy‐1H‐indene‐2‐carboxylic acid methyl ester

In this study, a newly isolated strain screened from the indoxacarb‐rich agricultural soils, Bacillus cereus WZZ006, has a high stereoselectivity to racemic substrate 5‐chloro‐1‐oxo‐2,3‐dihydro‐2‐hydroxy‐1H‐indene‐2‐carboxylic acid methyl ester. (S)‐5‐chloro‐1‐oxo‐2,3‐dihydro‐2‐hydroxy‐1H‐indene‐2‐carboxylic acid methyl ester was obtained by bio‐enzymatic resolution. After the 36‐hour hydrolysis in 50‐mM racemic substrate under the optimized reaction conditions, the e.e._s was up to 93.0% and the conversion was nearly 53.0% with the E being 35.0. Therefore, B cereus WZZ006 performed high‐level ability to produce (S)‐5‐chloro‐1‐oxo‐2,3‐dihydro‐2‐hydroxy‐1H‐indene‐2‐carboxylic acid methyl ester. This study demonstrates a new biocatalytic process route for preparing the indoxacarb chiral intermediates and provides a theoretical basis for the application of new insecticides in agricultural production.     

Chiral amino amides for the ruthenium(II)‐catalyzed asymmetric transfer hydrogenation reaction of ketones in water

The chiral amino amide 3 was derived from L ‐proline and used for the [RuCl₂(p‐cymene)]₂‐catalyzed asymmetric transfer hydrogenation of prochiral ketones performed in water. Moderate to good chemical selectivities (up to 95% yield) and enantioselectivities (up to 90% ee) were obtained in the presence of 2 mol % of TBAB (n‐Bu₄NBr) as the phase transfer catalyst. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Bio‐preparation of (R)‐DMPM using whole cells of Pseudochrobactrum asaccharolyticum WZZ003 and its application on kilogram‐scale synthesis of fungicide (R)‐metalaxyl

Methyl (R)‐N‐(2,6‐dimethylphenyl)alaninate ((R)‐DMPM) is a key chiral intermediate for the production of (R)‐metalaxyl, which is one of the best‐selling fungicides. A new strain, Pseudochrobactrum asaccharolyticum WZZ003, was identified as a biocatalyst for the enantioselective hydrolysis of (R,S)‐DMPM. The key parameters including pH, temperature, rotation speed and substrate concentrations were optimized in the enantioselective hydrolysis of (R,S)‐DMPM. After the 48 h hydrolysis of 256 mM (R,S)‐DMPM under the optimized reaction conditions, the enantiomeric excess of product (e.e._p) was up to 99% and the conversion was nearly 50%. Subsequently, the unhydrolyzed (S)‐DMPM was converted to (R,S)‐DMPM through the n‐butanal‐catalyzed racemization. Furthermore, stereoselective hydrolysis of (R,S)‐DMPM catalyzed by whole cells of P. asaccharolyticum WZZ003 was scaled up to kilogram‐scale, offering (R)‐MAP‐acid with 98.6% e.e._p and 48.0% yield. Moreover, (R)‐metalaxyl was prepared at kilogram scale after subsequent esterification and coupling reactions. Therefore, a practical production process of (R)‐DMPM and (R)‐metalaxyl with the prospect of industrialization was developed in this study. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:921–928, 2018     

Solid‐phase extraction with metal–organic frameworks for the analysis of chiral compounds

Metal–organic frameworks (MOFs) are excellent porous materials with nanoscale cavities and high surface areas, which make them promising as novel adsorbents in solid‐phase extraction (SPE). In this article we report a new application of the chiral MOF [Zn₂(D‐Cam)₂(4,4′‐bpy)]_n in SPE used for the measurement of the enantiomeric excess (ee) of (±)‐1,1′‐bi‐2‐naphthol. Several important experimental parameters that may influence the extraction efficiency were investigated and optimized. Under the optimum conditions, a good linearity (R² > 0.999) was found between the ee value and the reciprocal of the peak areas. When compared with the actual ee measured using chiral HPLC, the SPE‐based assay also showed good accuracy and precision. The results showed that SPE based on chiral MOFs as adsorbents is a simple and effective method for the determination of the ee values of chiral compounds.