Enzymatic kinetic resolution of racemic 4-tetrahydropyranols by Candida rugosa lipase

Enzymatic kinetic resolution of (±)-hydroxytetrahydropyrans has been achieved for the first time by means of lipase-mediated transesterification to afford optically active (2S,4R)-tetrahydropyranyl acetates and (2R,4S)-tetrahydropyranols in excellent yields with high enantioselectivity. Absolute configurations of the tetrahydropyranyl acetates were assigned as (S) by chemical correlation.     

Oxidative kinetic resolution of racemic alcohols catalyzed by chiral ferrocenyloxazolinylphosphine-ruthenium complexes

Oxidative kinetic resolution of racemic secondary alcohols by using acetone as a hydrogen acceptor in the presence of a catalytic amount of [RuCl(2)(PPh(3))(ferrocenyloxazolinylphosphine)] (2) proceeds effectively to recover the corresponding alcohols in high yields with an excellent enantioselectivity. When 1-indanol is employed as a racemic alcohol, the oxidation proceeds quite smoothly even in the presence of 0.0025 mol % of the catalyst 2 to give an optically active 1-indanol in good yield with high enantioselectivity (up to 94% ee), where turnover frequency (TOF) exceeds 80,000 h(-1). From a practical viewpoint, the kinetic resolution is investigated in a large scale, optically pure (S)-1-indanol (75 g, 56% yield, >99% ee) being obtained from racemic 1-indanol (134 g) by employing this kinetic resolution method twice.     

Kinetic resolution of racemic epoxides using a chiral diamine catalyst

The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand. Using 5 mol % of catalyst very high selectivity could be achieved; both epoxide and the corresponding allylic alcohol could be obtained in up to 99% ee.     

Amplification of the enantiomeric excess of a compound in kinetic resolution by a racemic reagent

The possibility of amplifying the small ee of a enantioimpure substance using a racemic reagent in kinetic resolution is discussed. A kinetic treatment of this problem along with some experimental proofs of the concept is presented. Simulation on kinetic resolution of small ee substrate by a racemic reagent showed an important enantioenrichment in the substrate ee, sometimes reaching close to absolute ee. Experiments of kinetic resolution of an amine of a small ee by a racemic acylating reagent gave a substantial amplification in ee of the amine. The possible transformation of an undetectable low ee in substrate to a detectable higher ee by using a suitable racemic reagent is also briefly discussed with help of calculations. The usefulness of asymmetric amplification by a racemic reagent is considered in the context of the biomolecular homochirality on earth.     

Mechanoenzymatic resolution of racemic chiral amines,a green technique for the synthesis of pharmaceutical building blocks

Very recently, several successful biocatalytic processes using mechanical activation to carry out enantioselective reactions have been reported. The present work describes the use of Candida antarctica Lipase B (CALB) in the kinetic resolution of racemic chiral amines by means of High-Speed Ball Milling (HSBM), minimizing the use of solvent and reducing reaction times. This approach provides an efficient and easily scalable strategy that was used for the green synthesis of enantiopure Rasagiline, as an illustrative example.     

A practical concept for the kinetic resolution of a chiral secondary alcohol based on a polymeric silane

The paper describes our preliminary studies on the use of PMHS as a functionalizable polymer and hydride source for the kinetic resolution of secondary alcohols via chiral Cu(I)-catalyzed dehydrogenative silylating process. The chiral phosphine that chelates the Cu metal center has little influence on the selectivity factor of the kinetic resolution. The use of a stereogenic silane appears to be a key requirement to reach enantiodifferentiation in such a process.     

Optimization of 2-alkoxyacetates as acylating agent for enzymatic kinetic resolution of chiral amines

In this study, the activity of acetic acid esters modified with electron withdrawing 2-alkoxy-groups was investigated as acylating agent in kinetic resolution (KR) of racemic amines. A homologous series of the isopropyl esters of four 2-alkoxyacetic acids (2-methoxy-, 2-ethoxy-, 2-propoxy- and 2-butoxyacetic acids) were prepared and investigated for enantiomer selective N-acylation, catalyzed by lipase B from Candida antarctica, under batch and continuous-flow conditions. In the first set of experiments, isopropyl 2-propoxyacetate showed the highest effectivity with all of the four racemic amines [(±)-1-phenylethylamine, (±)-4-phenylbutan-2-amine, (±)-heptan-2-amine and (±)-1-methoxypropane-2-amine] in the set enabling excellent conversions (≥46%) and enantiomeric excess values (ee?≥?99%) with each amines in continuous-flow mode KRs under the optimized reaction conditions. In a second set of experiments, KRs of five additional amines – being substituted derivatives of (±)-1-phenylethylamine – further demonstrated the usefulness of isopropyl 2-propoxyacetate – being the best acylating agent in the first set of KRs – in KRs leading to (R)-N-propoxyacetamides with high ee values (≥99.8%).     

Lipase-mediated enantioselective kinetic resolution of racemic acidic drugs in non-standard organic solvents: Direct chiral liquid chromatography monitoring and accurate determination of the enantiomeric excesses

The enantioselective resolution of a set of racemic acidic compounds such as non-steroidal anti-inflammatory drugs (NSAIDs) of the group arylpropionic acid derivatives is demonstrated. Thus, a set of lipases were screened and manipulated in either the esterification or hydrolysis mode for the enantioselective kinetic resolution of these racemates in non-standard organic solvents. The accurate determination of the enantiomeric excesses of both substrate and product during such reaction is demonstrated. This was based on the development of a direct and reliable enantioselective high performance liquid chromatography (HPLC) procedure for the simultaneous baseline separation of both substrate and product in one run without derivatization. This was achieved using the immobilized chiral stationary phase namely Chiralpak IB, a 3,5-dimethylphenylcarbamate derivative of cellulose (the immobilized version of Chiralcel OD) which proved to be versatile for the monitoring of the lipase-catalyzed kinetic resolution of racemates in non-standard organic solvents.     

Studies on the radical addition reaction of perfluoroalkyl iodides with 2,3-allenols and the Pd-catalyzed kinetic resolution via Sonogashira coupling reaction

A radical addition reaction promoted by Na₂S₂O₄ of perfluoroalkyl iodides with 2,3-allenols affording E/Z mixtures of 3-iodo-4-perfluoroalkyl-substituted allylic alcohols has been studied. Kinetic resolution with Sonogashira coupling reaction was applied to afford the Z isomer of 3-iodo-4-perfluoroalkyl-substituted allylic alcohol (Z-3) and the E isomer of conjugated enynic diols (E-5) in 39-52% and 22-40% yields, respectively.     

The deoxygenation of sulfoxide mediated by the Ph3P/Lewis acid combination and the application to the kinetic resolution of racemic phosphines using optically active sulfoxide

It was found that the combination of Ph₃P/TiCl₄ was an effective promoter for the deoxygenation of sulfoxides and gave the corresponding sulfides in good yield (up to 97%) under mild conditions. This method was applied to the reaction between racemic phosphines and (R)-methyl p-tolyl sulfoxide, and it was found that the kinetic resolution was achieved in moderate selectivities.     

原子转移自由基聚合技术制备L-苯丙氨酸手性配体交换色谱固定相及其对手性化合物的拆分

在室温条件下,以甲基丙烯酸环氧丙酯(GMA)为单体,溴异丁酰溴为引发剂,CuCl/2,2′-联吡啶(Bpy)为催化剂,通过原子转移自由基聚合(ATRP)反应,将甲基丙烯酸环氧丙酯聚合在硅胶表面。然后再将L-苯丙氨酸共价键合在硅胶表面的聚合物上,制备了新型手性配体交换色谱固定相,并用该固定相对DL-氨基酸进行分离。用元素分析对其进行了表征;详细考察了固定相的合成过程以及流动相pH值、流动相铜离子浓度、柱温等色谱条件对DL-氨基酸对映体拆分的影响。元素分析得出该固定相表面L-苯丙氨酸接枝密度达到4.32 mg/m2;在手性配体交换分离模式下,流动相为0.05 mol/L KH2PO4-0.1 mmol/L Cu(Ac)2水溶液、流速为1.0 mL/min、柱温为50 ℃和检测波长为223 nm条件下,该色谱固定相可以分离DL-天冬氨酸、DL-天冬酰胺等。同时,流动相pH值、铜离子浓度以及柱温对手性对映体的拆分有较大影响。与传统的在硅胶表面直接键合L-苯丙氨酸制得的固定相相比,所合成的固定相接枝密度高,分离效果好,对DL-天冬氨酸及DL-天冬酰胺实现了基线分离。结果表明,在手性配体交换分离模式下,固定相具有良好的拆分性能。     

The first asymmetric esterification of free carboxylic acids with racemic alcohols using benzoic anhydrides and tetramisole derivatives: an application to the kinetic resolution of secondary benzylic alcohols

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alcohols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the best reagent to use in producing the corresponding esters in high ee when the reaction is catalyzed by (+)-benzotetramisole (BTM); by contrast, when non-substituted benzoic anhydride is used as a coupling reagent, the resulting optically active alcohols are obtained with high selectivities. This protocol directly produces chiral carboxylic esters from free carboxylic acids and racemic secondary alcohols by utilizing the trans-acylation process to generate mixed anhydrides from acid components and benzoic anhydride derivatives under the influence of chiral catalysts.     

Kinetic resolution of racemic alcohols catalyzed by minimal artificial acylases derived from l-histidine

The artificial acylases, tert-butyldiphenylsilyl ether and tris(trimethylsilyl)silyl ether of N(π)-methyl-N(α)-(2,4,6-triisopropylbenzenesulfonyl)-l-histidinol, are simple and small molecules, which contain only one chiral carbon center that originates from natural l-histidine. Asymmetric acylation of racemic secondary alcohols with isobutyric anhydride induced by these artificial acylases gave optically active isobutyrates and optically active alcohols with an S(k_{fast-reacting enantiomer}/k_{slow-reacting enantiomer}) value of up to 132. One hydrogen bonding interaction between a sulfonamidyl group of the catalysts and a substrate should be essential for inducing the high level of kinetic resolution through catalytic asymmetric acylation. Furthermore, a reusable polystyrene-bound artificial acylase was developed to examine its practicality.     

Direct resolution of racemic compounds on chiral microbore columns by sub- and supercritical fluid chromatography

Fast resolutions of racemic compounds (sulfoxides, amino alcohols, and α-methylarylacetic acids derivatives) were achieved on a chiral microbore column using carbon dioxide and a polar methanol/dioxane modifier. The stationary phase used in this study contains the 3,5-dinitrobenzoyl derivative of R,R(?)-1,2-diaminocyclohexane (DACH-DNB) as the chiral moiety, anchored to a silica gel surface by covalent bonds. Both thermodynamic and kinetic separation performances were improved by using a super- or subcritical carbon dioxide mobile phase (SFC, SubFC).     

Oxidative kinetic resolution of heterocyclic sulfoxides with a porphyrin-inspired manganese complex by hydrogen peroxide

We have successfully reported here the low loading porphyrin-inspired high-valent manganese (IV)-oxo complex was applied in oxidative kinetic resolution (OKR) of racemic heterocyclic sulfoxides using the environmentally benign hydrogen peroxide for the first time. This approach allows for rapid OKR (0.5?h) of a variety of racemic sulfoxides (including pyridine, pyrimidine, pyrazine, thiazole, benzothiazole, thiophene) in excellent enantioselectivity (up to?>?99%?ee), simultaneously generating the corresponding sulfones in high yield (up to 80%). The catalytic system also showed an unexceptionable chemoselectivity for the sulfoxide substrates with hydroxyl groups in which only the sulfoxide group was oxidized. The practical utility of the method has been demonstrated in the OKR of gram-scale sulfoxides.     

Highly reactive and enantioselective kinetic resolution of terminal epoxides with H2O and HCl catalyzed by new chiral (salen)Co complex linked with Al

The asymmetric hydrolytic kinetic resolution (HKR) of racemic terminal epoxides by new easily synthesized dimeric chiral (salen)Co bearing Al, provides a practical and straightforward method for the synthesis of enantiomerically enriched terminal epoxides (>99% ee) and diols. An inorganic acid, HCl is applied first time for the asymmetric ring opening reaction of terminal epoxides. Reactions are conveniently carried out at room temperature under an air atmosphere.