Enantioselective Synthesis and Application to the Allylic Imidate Rearrangement of Amine‐Coordinated Palladacycle Catalysts of Cobalt Sandwich Complexes

The reaction of (η⁵‐(N,N‐dimethylaminomethyl)cyclopentadien‐yl)(η⁴‐tetraphenylcyclobutadiene)cobalt with sodium tetrachloropalladate and (R)‐N‐acetylphenylalanine gave planar chiral palladacycle di‐μ‐chloridebis[(η⁵‐(S_p)‐2‐(N,N‐dimethylaminomethyl)cyclopentadienyl,1‐C,3′‐N)(η⁴‐tetraphenylcyclobutadiene)cobalt]dipalladium [(S_p)‐Me₂‐CAP‐Cl] in 92 % ee and 64 % yield. Enantiopurity (>98 % ee) was achieved by purification of the monomeric (R)‐proline adducts and conversion back to the chloride dimer. Treatment with AgOAc gave (S_p)‐Me₂‐CAP‐OAc which was applied to asymmetric transcyclopalladation (up to 78 % ee). The (R)‐N‐acetylphenylalanine mediated palladation methodology was applicable also to the corresponding N,N‐diethyl (82 % ee, 39 % yield) and pyrrolidinyl (>98 % ee, 43 % yield) cobalt sandwich complexes. A combination of 5 mol % of the latter [(S_p)‐Pyrr‐CAP‐Cl] and AgNO₃ (3.8 equiv) is a catalyst for the allylic imidate rearrangement of an (E)‐N‐aryltrifluoroacetimidate (up to 83 % ee), and this catalyst system is also applicable to the rearrangement of a range of (E)‐trichloroacetimidates (up to 99 % ee). This asymmetric efficiency combined with the simplicity of catalyst synthesis provides accessible solutions to the generation of non‐racemic allylic amine derivatives.     

Ruthenium and enzyme-catalyzed dynamic kinetic resolution of alcohols

Ruthenium acts as a good catalyst for the racemization reaction of secondary alcohols and amines. Ruthenium-catalyzed racemization is coupled with enzymatic kinetic resolution to prepare chiral compounds in 100% theoretical yield. Ten ruthenium complexes (1–10) act as a good catalyst the for racemization reaction and are also compatible with DKR process. Two other ruthenium complexes [RuCl₂(PPh₃)₃] and [Cp^*RuCl(COD)] are active for racemization reaction but their successful compatibility with DKR has not yet been reported. Ru/γ-Al₂O₃ and Ru–HAP are the heterogeneous catalysts used for the racemization reaction. They have also not been employed for DKR process. Polymer supported ruthenium is employed as a reusable racemization catalyst for aerobic DKR of alcohols.     

Highly efficient dynamic kinetic resolution of secondary aromatic alcohols at low temperature using a low-cost sulfonated sepiolite as racemization catalyst

A highly efficient dynamic kinetic resolution system for secondary aromatic alcohol using low-cost sulfonated sepiolite as a racemization catalyst has been developed. The system operates at 25 °C, achieves good ee_p (>99%) and substrate conversion ratio (>99%), is applicable to a variety of substrates and can be reused more than 10 times.     

Effects of organic solvents and ionic liquids on the aminolysis of (RS)-methyl mandelate catalyzed by lipases

The enzymatic resolution of (RS)-methyl mandelate with n-butylamine using lipases in organic solvents (n-hexane, tert-butanol, and chloroform) and ionic liquids [BMIm][BF₄] and [BMIm][PF₆] is reported. The amide configuration is dependent on the organic solvent. When using mixtures of chloroform or tert-butanol/ionic liquids (10:1 v/v) with CAL-B as the catalyst, the amides were obtained in high enantiomeric excess (ee_p >99% and E >200).     

Dynamic kinetic resolution of 2-methyl-2-nitrocyclohexanol: Combining the intramolecular nitroaldol (Henry) reaction & lipase-catalysed resolution

Efforts to combine the intramolecular nitroaldol reaction with lipase-catalysed resolution of the resulting nitroaldol adduct in a one-pot dynamic kinetic resolution (DKR) are described. Significant challenges were encountered in the combination of the two systems. trans-2-Methyl-2-nitrocyclohexyl acetate (±)-3b was isolated in excellent enantiopurity (>98% ee) via a sequential DKR sequence where the lipase-mediated resolution and base-mediated interconversion of 2-methyl-2-nitrocyclohexanol 2 were effected alternately, demonstrating the feasibility of this approach initially. Further work showed, for the first time, evidence that a DKR-type system is possible for 2. Reaction engineering allowed the design of a sequential one-pot reaction system which furnished the products with excellent enantioselectivity, and good diastereoselectivity.     

Catalytic Conversion of Xylose to Furfural by p-Toluenesulfonic Acid (pTSA) and Chlorides: Process Optimization and Kinetic Modeling

Furfural is one of the most promising precursor chemicals with an extended range of downstream derivatives. In this work, conversion of xylose to produce furfural was performed by employing p-toluenesulfonic acid (pTSA) as a catalyst in DMSO medium at moderate temperature and atmospheric pressure. The production process was optimized based on kinetic modeling of xylose conversion to furfural alongwith simultaneous formation of humin from xylose and furfural. The synergetic effects of organic acids and Lewis acids were investigated. Results showed that the catalyst pTSA-CrCl₃·6H₂O was a promising combined catalyst due to the high furfural yield (53.10%) at a moderate temperature of 120 °C. Observed kinetic modeling illustrated that the condensation of furfural in the DMSO solvent medium actually could be neglected. The established model was found to be satisfactory and could be well applied for process simulation and optimization with adequate accuracy. The estimated values of activation energies for xylose dehydration, condensation of xylose, and furfural to humin were 81.80, 66.50, and 93.02 kJ/mol, respectively.     

Efficient dynamic kinetic resolution of secondary alcohols with a novel tetrafluorosuccinato ruthenium complex

Dynamic kinetic resolution (DKR) of a series of secondary alcohols has been conducted with a novel dinuclear ruthenium complex, bearing tetrafluorosuccinate and (rac)-BINAP ligands as the racemization catalyst. Novozym 435 has been used as the enzyme, and isopropyl butyrate as the acyl donor. Five substrates underwent DKR successfully: an aliphatic and an aromatic secondary alcohol, an aromatic alcohol with an electron-withdrawing substituent on the phenyl ring, an aromatic alcohol bearing an electron-donating substituent on the ring and a heteroaromatic secondary alcohol. The catalyst performed optimally at 70 °C. Typically the reaction reached complete conversion within 1 day with 0.1 mol % of racemization catalyst relative to the substrate. The addition of the ketone corresponding to the substrate stabilizes the active Ru complex and, therefore, increases the rate of the reaction.     

Racemization of secondary alcohols catalyzed by ruthenium: application to chemoenzymatic dynamic resolution

In this paper, we have shown that the [RuCl₂(p-cymene)]₂ complex associated with simple hemisalen ligands is able to racemize (S)-1-phenylethanol. The influence on the racemization process of the ligand’s structure as well as the nature of a co-catalyst have been evaluated and optimized. This [RuCl₂(p-cymene)]₂/Ligand/TEMPO racemization system was then associated with the Candida Antarctica B lipase in order to carry out dynamic kinetic resolution experiments on rac-phenylethanol. This led us to identify the best conditions for effective DKR, which was then applied to various secondary benzylic and aliphatic alcohols. It was thus possible to obtain (R)-1-cyclohexylethyl acetate from rac-1-cyclohexylethanol in quantitative conversion and with high enantioselectivity (98%).     

Green Strategies for the Preparation of Enantiomeric 5–8-Membered Carbocyclic β-Amino Acid Derivatives through CALB-Catalyzed Hydrolysis

Candida antarctica lipase B-catalyzed hydrolysis of carbocyclic 5–8-membered cis β-amino esters was carried out in green organic media, under solvent-free and ball-milling conditions. In accordance with the high enantioselectivity factor (E > 200) observed in organic media, the preparative-scale resolutions of β-amino esters were performed in tBuOMe at 65 °C. The unreacted β-amino ester enantiomers (1R,2S) and product β-amino acid enantiomers (1S,2R) were obtained with modest to excellent enantiomeric excess (ee) values (ee_s > 62% and ee_p > 96%) and in good chemical yields (>25%) in one or two steps. The enantiomers were easily separated by organic solvent/H₂O extraction.     

Polymerizations of methyl methacrylate and p-fluorostyrene with Ziegler-Natta catalyst system

Methyl methacrylate and p-fluorostyrene were polymerized with Co(acac)₃-A1Et₃ catalyst system in benzene at 60°. Maximum conversion of polymer was obtained when the catalyst was aged for 15 min. Maximum activity of the catalyst was found at Al/Co ratio of 3. The polymerization was first order with respect to monomer. The orders with respect to catalyst and cocatalyst were found to be 0.5 and 1.5 respectively. The overall activation energies for the polymerizations of methyl methacrylate and p-fluorostyrene were found to be 54.5 and 59.6 kJ/mol respectively. A free-radical mechanism is postulated.     

Asymmetric hydrogenation of aromatic ketones catalyzed by achiral monophosphine TPPTS-stabilized Ru in ionic liquids

Achiral monophosphine TPPTS [TPPTS: P(m-C₆H₄SO₃Na)₃]-stabilized Ru was synthesized by reduction of RuCl₃·3H₂O with hydrogen in ethanol using TPPTS as the stabilizer. The catalytic asymmetric hydrogenation of aromatic ketones using TPPTS-stabilized Ru modified by a chiral diamine (1R,2R)-DPENDS [disodium salt of sulfonated (1R,2R)-1,2-diphenyl-1,2-ethylene-diamine] was investigated in hydrophilic ionic liquid [RMIM]Ts (1-alkyl-3-methylimidazolium p-methylphenylsulfonates, R = ethyl, butyl, octyl, dodecyl, hexadecyl). Hundred percent conversion and 85.1% ee were obtained for acetophenone under optimized conditions. The resulting products can be easily separated from the catalyst immobilized in ionic liquid by simple extraction with n-hexane, and the catalyst can be reused several times without a significant loss of ee value or conversion. In particular, the addition of water can improve the catalyst performance.     

Combined Dynamic Kinetic Resolution and C−H Functionalization for Facile Synthesis of Non-Biaryl-Atropisomer-Type Axially Chiral Organosilanes

Although asymmetric C−H functionalization has been available for the synthesis of structurally diverse molecules, catalytic dynamic kinetic resolution (DKR) approaches to change racemic stereogenic axes remain synthetic challenges in this field. Here, a concise palladium-catalyzed DKR was combined with C−H functionalization involving olefination and alkynylation for the highly efficient synthesis of non-biaryl-atropisomer-type (NBA) axially chiral oragnosilanes. The chemistry proceeded through two different and distinct DKR: first, an atroposelective C−H olefination or alkynylation produced axially chiral vinylsilanes or alkynylsilanes as a new family of non-biaryl atropisomers (NBA), and second, the extension of this DKR strategy to twofold o,o′-C−H functionalization led to the multifunctional axially chiral organosilicon compounds with up to >99 % ee.     

Efficient transesterification 4-hydroxytetrahydropyran immobilized lipase resolution of 2-（4-chlorophenyl）- with magnetically separable

We report an efficient kinetic resolution of racemic 2-（4-chlorophenyl）-4-hydroxytetrahydro-pyran （CLP-4-HTHP） via Pseudomonas cepacia lipase （PSL）-catalyzed transesterification, where PSL is immobilized on a core-shell MnFe204@SiO2-（CH2）3-NH2 carrier and used as a magnetically separable catalyst. The as-synthesized PSL/MnFe204@SiO2-（CH2）3-NH2 catalyst exhibits enhanced catalytic activity for resolving racemic CLP-4-HTHP to the corresponding optically pure （2R,4S）-CLP-4-HTHP compared to the free PSL. The ees for the former is 2.3 times larger than that for the latter under optimized conditions （99.4% and 44.1%, respectively）, although the eep for them are same （99.2%）. Meanwhile, the PSL/MnFe204@SiO2-（CH2）3-NH2 catalyst possesses a high saturate magnetization of 59.7 emu/g and could be easily recovered by magnetic separation and reused. The catalytic activity in six recycling tests did not significantly decrease, suggesting its great potential for industrial applications.     

A parametric study on biphasic medium conditions for the enantioselective production of naproxen by <Emphasis Type="Italic">Candida rugosa</Emphasis> lipase

A parametric study to increase the enantioselectivity of Candida rugosa lipase (CRL) toward S-Naproxen production by the hydrolysis of racemic Naproxen methyl ester in an aqueous-organic biphasic batch system was carried out. Effects of organic solvent type, aqueous phase/organic solvent volume ratio, agitation rate, concentrations of the substrate and the enzyme, pH of the aqueous phase, and temperature on the en antiomeric excess for the product (ee_p), on the enantiomeric ratio (E) and on the conversion (x) were evaluated. Employing isooctane as the solvent resulted in higher ee_p, E, and x than those obtained in hexane, cyclohexane, and toluene. The higher the volume ratio of aqueous phase/organic solvent employed, the higher the conversion and enantioselectivity achieved. The increase in agitation rate increased the hydrolysis rate. Higher concentration of racemic Naproxen methyl ester than 10 mg/mL decreased both the conversion and enantioselectivity. The increase in crude CRL concentration resulted in enhancement of x, but the decrease of fee_p and E. Acidic pH led to higher conversion and enantioselectivity than the medium and alkaline pH values. A further increase in temperature to over 45°C decreased the conversion and enantioselectivity. The highest enantiomeric ratio achieved in the S-Naproxen production was E=171.1, with x=49.8% and ee_p=95.7%.     

Asymmetric Cyanation of Aldehydes,Ketones, Aldimines,and Ketimines Catalyzed by a Versatile Catalyst Generated from Cinchona Alkaloid,Achiral Substituted 2,2′‐Biphenol and Tetraisopropyl Titanate

Full investigation of cyanation of aldehydes, ketones, aldimines and ketimines with trimethylsilyl cyanide (TMSCN) or ethyl cyanoformate (CNCOOEt) as the cyanide source has been accomplished by employing an in situ generated catalyst from cinchona alkaloid, tetraisopropyl titanate [Ti(OiPr)₄] and an achiral modified biphenol. With TMSCN as the cyanide source, good to excellent results have been achieved for the Strecker reaction of N‐Ts (Ts=p‐toluenesulfonyl) aldimines and ketimines (up to >99 % yield and >99 % ee) as well as for the cyanation of ketones (up to 99 % yield and 98 % ee). By using CNCOOEt as the alternative cyanide source, cyanation of aldehyde was accomplished and various enantioenriched cyanohydrin carbonates were prepared in up to 99 % yield and 96 % ee. Noteworthy, CNCOOEt was successfully employed for the first time in the asymmetric Strecker reaction of aldimines and ketimines, affording various α‐amino nitriles with excellent yields and ee values (up to >99 % yield and >99 % ee). The merits of current protocol involved facile availability of ligand components, operational simplicity and mild reaction conditions, which made it convenient to prepare synthetically important chiral cyanohydrins and α‐amino nitriles. Furthermore, control experiments and NMR analyses were performed to shed light on the catalyst structure. It is indicated that all the hydroxyl groups in cinchona alkaloid and biphenol complex with Ti^IV, forming the catalyst with the structure of (biphenoxide)Ti(OR*)(OiPr). The absolute configuration adopted by biphenol 4 m in the catalyst was identified as S configuration according to the evidence from control experiments and NMR analyses. Moreover, the roles of the protonic additive (iPrOH) and the tertiary amine in the cinchona alkaloid were studied in detail, and the real cyanide reagent in the catalytic cycle was found to be hydrogen cyanide (HCN). Finally, two plausible catalytic cycles were proposed to elucidate the reaction mechanisms.     

Iron(III) p-toluenesulfonate catalyzed synthesis of homoallyl ethers from acetals and aldehydes

Iron(III) p-toluenesulfonate, Fe(OTs)₃·6H₂O, is an inexpensive, versatile and commercially available catalyst for the allylation of acetals using allyltrimethylsilane to yield homoallyl ethers in moderate to good yields. The one-pot conversion of aldehydes to homoallyl ethers using alkoxysilanes has also been accomplished using Fe(OTs)₃·6H₂O as a catalyst. The use of mild reaction conditions and a relatively non-corrosive catalyst make this method an attractive option for the synthesis of a range of homoallyl ethers.     

Synthesis of (R)-propane-1,2-diol from lactides by dynamic kinetic resolution

The dynamic kinetic resolution (DKR) of rac-1-tert-butoxypropan-2-ol with isopropenyl acetate in the presence of Novozyme 435 and a ruthenium catalyst produces enantiomerically pure (R)-1-tert-butoxy-2-acetoxy-propane (>99.5 %ee) in a good yield. The product can be easily transformed into (R)-propane-1,2-diol without loss of stereoselectivity. Together with recently published procedures, the herein described DKR offers the possibility to use any lactide source as starting material for the production of (R)-propane-1,2-diol. The chiral diol may serve as the chiral building block for the synthesis of important enantiopure esters, like propylene carbonate, chiral polymers, etc.     

Catalytic asymmetric brominative dearomatization reaction of benzofurans

A catalytic asymmetric brominative dearomatization reaction of benzofuran derivatives was achieved by using hydroquinidine 1,4-phthalazinediyl diether [(DHQ)₂PHAL] as the catalyst and N-bromoacetamide (NBAc) as the brominating reagent. A series of brominated spiro[benzofuran-2,5'-oxazoles] bearing two contiguous stereogenic centers were obtained in high yields (up to 99%) with excellent enantioselectivity (up to 97% ee).     

手性二胺修饰的负载型钌催化剂催化芳香酮不对称加氢

研究了用手性修饰剂(1S,2S)-(－)-1,2-二苯基乙二胺修饰的负载型钌催化剂(Ru/γ-Al₂O₃)催化芳香酮的不对称加氢反应, 在KOH的异丙醇溶液中, 10～20 ℃, p_H2＝5 MPa条件下, 芳香酮及其衍生物加氢产物的ee值达79.5%～85.0%, 2-乙酰基噻吩加氢产物的ee值可达86.2%. 此催化剂制备简单, 容易与产物分离, 重复使用4次, 对映选择性基本保持不变.     

Enantioselective Synthesis of α-Thiocarboxylic Acids by Nitrilase Biocatalysed Dynamic Kinetic Resolution of α-Thionitriles

The enantioselective synthesis of α-thiocarboxylic acids by biocatalytic dynamic kinetic resolution (DKR) of nitrile precursors exploiting nitrilase enzymes is described. A panel of 35 nitrilase biocatalysts were screened and enzymes Nit27 and Nit34 were found to catalyse the DKR of racemic α-thionitriles under mild conditions, affording the corresponding carboxylic acids with high conversions and good-to-excellent ee. The ammonia produced in situ during the biocatalytic transformation favours the racemization of the nitrile enantiomers and, in turn, the DKR without the need of any external additive base.