Adaptative Biaryl Phosphite–Oxazole and Phosphite–Thiazole Ligands for Asymmetric Ir‐Catalyzed Hydrogenation of Alkenes

A library of readily available phosphite–oxazole/thiazole ligands ( L1 a – g – L7 a – g ) was applied in the Ir‐catalyzed asymmetric hydrogenation of several largely unfunctionalized E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The ability of the catalysts to transfer chiral information to the product could be tuned by choosing suitable ligand components (bridge length, the substituents in the heterocyclic ring and the alkyl backbone chain, the configuration of the ligand backbone, and the substituents/configurations in the biaryl phosphite moiety), so that enantioselectivities could be maximized for each substrate as required. Enantioselectivities were therefore excellent (enantiomeric excess (ee) values up to >99 %) for a wide range of E‐ and Z‐trisubstituted and 1,1‐disubstituted terminal alkenes. The biaryl phosphite moiety was a very advantageous ligand component in terms of substrate versatility.     

Supramolecularly Regulated Ligands for Asymmetric Hydroformylations and Hydrogenations

Herein we report the use of polyether binders as regulation agents (RAs) to enhance the enantioselectivity of rhodium‐catalyzed transformations. For reactions of diverse substrates mediated by rhodium complexes of the α,ω‐bisphosphite‐polyether ligands 1 – 5 , a – d , the enantiomeric excess (ee) of hydroformylations was increased by up to 82 % (substrate: vinyl benzoate, 96 % ee), and the ee value of hydrogenations was increased by up to 5 % (substrate: N‐(1‐(naphthalene‐1‐yl)vinyl)acetamide, 78 % ee). The ligand design enabled the regulation of enantioselectivity by generation of an array of catalysts that simultaneously preserve the advantages of a privileged structure in asymmetric catalysis and offer geometrically close catalytic sites. The highest enantioselectivities in the hydroformylation of vinyl acetate with ligand 4 b were achieved by using the Rb[B(3,5‐(CF₃)₂C₆H₃)₄] (RbBArF) as the RA. The enantioselective hydrogenation of the substrates 10 required the rhodium catalysts derived from bisphosphites 3 a or 4 a , either alone or in combination with different RAs (sodium, cesium, or (R,R)‐bis(1‐phenylethyl)ammonium salts). This design approach was supported by results from computational studies.     

Construction of Optically Active Quaternary Propargyl Amines by Highly Enantioselective Zinc/BINOL‐Catalyzed Alkynylation of Ketoimines

A general and efficient method for the highly enantioselective alkynylation of ketoimines through a zinc/1,1′‐bi‐2‐naphthol (BINOL)‐catalyzed process has been developed. A variety of ketoimines, including α‐fluoroalkyl α‐imine esters, α‐aryl α‐imine esters, and trifluoromethyl aryl ketoimines, are applicable and provide their corresponding quaternary propargyl amines in excellent yields with high ee values (up to 99 % ee). Both the steric and electronic effects of substituents at the 3,3′ positions of BINOL are critical for the reaction efficiency and enantioselectivity. To demonstrate the usefulness of the method, (R)‐α‐CF₃ α‐proline has been prepared in a highly efficient manner. The notable features of this protocol are its broad substrate scope, high reaction efficiency (up to 99 %) and enantioselectivity (up to 99 % ee), low catalyst loading (5 mol % of BINOL derivative), and mild reaction conditions.     

Nickel-Catalyzed Asymmetric Hydrogenation for the Synthesis of a Key Intermediate of Sitagliptin

Nickel-catalyzed enantioselective hydrogenation of enamines leading to the efficient synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric esters, the key intermediate of the blockbuster antidiabetic drug (R)-SITAGLIPTIN, is described. The sitagliptin motifs were isolated in more than 99% yield and with 75–92% ee using the earth-abundant nickel catalyst. Upon chiral resolution with (R)- and (S)-1-phenylethylamines, the partially enantioenriched (R)- and (S)-Boc-3-amino-4-(2,4,5-trifluorophenyl)butanoic acids provided >99.5% ee of the crucial sitagliptin intermediate. The asymmetric hydrogenation protocol was scaled up to 10 g with consistency in yield and ee, and has been reproduced in multiple batches.     

Enantioselective Synthesis of 3-Substituted 3-Amino-2-oxindoles by Amination with Anilines

A chiral N,N′-dioxide-nickel(II) complex-catalyzed asymmetric amination of 3-bromo-3-substituted oxindoles with anilines has been developed. A series of alkyl or aryl 3-amino-indolinones with quaternary stereocenters were obtained in high yields with excellent ee values in one step (up to 99 % yield, up to 96 % ee). The method provided a ready route to optically active intermediates of 3-amino-2-oxindole-based bioactive compounds. Moreover, a possible transition-state model is proposed so as to elucidate the origin of the chirality based on the X-ray crystal structure of the catalyst and the adduct.     

Design,Synthesis, and Application of Chiral C2‐Symmetric Spiroketal‐Containing Ligands in Transition‐Metal Catalysis

We present an expedient and economical route to a new spiroketal‐based C₂‐symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium‐catalyzed hydroarylations (up to 95 % ee), palladium‐catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium‐catalyzed Heck couplings (up to 94 % ee), and rhodium‐catalyzed dehydroalanine hydrogenation (up to 93 % ee).     

Design,Synthesis, and Application of Chiral C2‐Symmetric Spiroketal‐Containing Ligands in Transition‐Metal Catalysis

We present an expedient and economical route to a new spiroketal‐based C₂‐symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium‐catalyzed hydroarylations (up to 95 % ee), palladium‐catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium‐catalyzed Heck couplings (up to 94 % ee), and rhodium‐catalyzed dehydroalanine hydrogenation (up to 93 % ee).     

Synthesis of New Chiral and Racemic 1,3‐Dioxolanes

A series of chiral 1,3‐dioxolanes, 3 – 12 , with >99% ee values, have been synthesized. This is the first study of chiral ketalization reaction starting from ketones with aryl, monosubstituted aryl, and long alkyl chains (C₁₁—AC₁₃). Their ee values were determined by chiral high‐performance liquid chromatography (HPLC) on Chiralcel OD column, using their racemic 1,3‐dioxolanes rac‐ 3 – 12 , which were also synthesized for the first time. These chiral and racemic 1,3‐dioxolanes were characterizated by infrared, NMR (¹H, ¹³C), mass spectrometry, elemental analysis, optical rotation, and chiral HPLC.     

Synthesis and Application of Modular Phosphine–Phosphoramidite Ligands in Asymmetric Hydroformylation: Structure–Selectivity Relationship

A series of hybrid phosphine–phosphoramidite ligands has been designed and synthesized in moderate yields from chiral BINOL (1,1′‐bi‐2‐naphthol) or NOBIN (2‐amino‐2′‐hydroxy‐1,1′‐binaphthyl). They have achieved highly regio‐ and enantioselectivities in Rh‐catalyzed asymmetric hydroformylations of styrene derivatives (branched/linear ratio up to 56.6, ee up to 99 %), vinyl acetate derivatives (up to 98 % ee), and allyl cyanide (up to 96 % ee). Systematic variation of ligand structure showed that the steric factor on the phsophoramidite moiety determined the performance of the ligand. With the increased hindrance, the branched/linear ratio rose, while the ee value dropped in the hydroformylation of styrene. However, the N‐substituents did not influence the selectivities much.     

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.     

A Highly anti‐Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)‐Spisulosine and a Pyrroloisoquinoline Derivative

A highly anti‐selective asymmetric Henry reaction has been developed, affording synthetically versatile β‐nitroalcohols in a predominately anti‐selective manner (mostly above 15:1) and excellent ee values (mostly above 95 %). Moreover, the anti‐selective Henry reaction was carried out in the presence of water for the first time with up to 99 % ee. The catalytic mechanism was proposed based on the detection of the intermediates by extractive electrospray ionization mass spectrometry (EESI‐MS). Furthermore, the anti adducts have been successfully transformed into the biochemically important (+)‐spisulosine and a pyrroloisoquinoline derivative.     

Self‐Supported Chiral Titanium Cluster (SCTC) as a Robust Catalyst for the Asymmetric Cyanation of Imines under Batch and Continuous Flow at Room Temperature

A robust heterogeneous self‐supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine‐cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self‐supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium‐alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed‐bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h^?1 were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three‐component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging α‐branched aliphatic aldehyde by using the three‐component continuous Strecker reaction.     

Supramolecular Architecture of an Amphiphilic Amino Alcohol as a Versatile Chiral Environment for Stereocontrolled Photoreaction of Various Anthracenes

The photocyclodimerization of 2-anthracenecarboxylic acid has been extensively studied as a model reaction of asymmetric photochemistry. So far, numerous chiral environments have been employed to control this photoreaction, while the scope of photoreactants has been limited only to 2-anthracenecarboxylic acid and its simple esters and amides. Here, we developed a systematic series of photoreactants ( 2 a – d ) by introducing various substituents to 2-anthracenecarboxylic acid, which showed different reactivities and selectivities depending on the substituents. By using the photoreactants 2 a – d , we evaluated the performance of a chiral environment composed of an amphiphilic amino alcohol ( 1 ), where the photocyclodimerization of 2 a – d generally proceeded in excellent regio- and enantioselectivities (71–98 % regio ratio, 76–86 % ee). Furthermore, by reacting 2 a and 2 b together in the chiral environment of 1 , we succeeded in the first stereocontrolled cross-photocyclodimerization between two prochiral anthracenes (58 % chemo ratio, 83 % regio ratio, 90 % ee).     

Kinetic Resolution of Racemic Mandelic Acid Esters by N,N′‐Dioxide–Scandium‐Complex‐Catalyzed Enantiomer‐Selective Acylation

A simple and efficient acylative kinetic resolution of racemic mandelic acid esters was accomplished with a chiral N,N’‐dioxide–scandium(III) complex under mild and base‐free reaction conditions. A variety of mandelic acid esters performed well in the reaction, obtaining both acylated products (up to 49% yield, 97% ee) and recovered substrates (up to 49% yield, 95% ee) in high enantioselectivities with perfect selectivity factors (up to 247). The enantioselective recognition and catalytic models were also proposed for the catalytic KR reaction.     

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.     

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%).     

Palladium-catalyzed allylic substitution assisted by 1,3,2-diazaphospholidine derivatives of (<Emphasis Type="Italic">R,R</Emphasis>)-<Emphasis Type="Italic">N</Emphasis>-naphthyltartarimide

P,P-Bidentate diamidophosphite ligands containing the (3R,4R)-3,4-dioxy-1-(1-naphthyl)pyrrolidine-2,5-dione framework and 1,3,2-diazaphospholidine rings with the stereogenic P atoms were obtained. The use of these ligands provides up to 85% ee in Pd-catalyzed asymmetric amination of (E)-1,3-diphenylallyl acetate and up to 95% ee in its asymmetric alkylation with dimethyl malonate.     

Efficient Synthesis of Chiral Trisubstituted 1,2‐Allenyl Ketones by Catalytic Asymmetric Conjugate Addition of Malonic Esters to Enynes

An N,N′‐dioxide/scandium(III) complex catalyzed, highly efficient conjugate addition of malonic esters to enynes is described. A range of trisubstituted 1,2‐allenyl ketones were obtained in high yields (up to 99 %) with good d.r. (up to 95/5) and excellent ee values (97 %–99 %). Moreover, the products could be easily transformed into chiral furan and 5‐hydroxypyrazoline derivatives, both of which are important skeletons of many biologically active compounds and pharmacologicals.     

Stereo‐ and Chemodivergent NHC‐Promoted Functionalisation of Arylalkylketenes with Chloral

Stereo‐ and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N‐heterocyclic carbenes, giving selectively either β‐lactones (up to 88:12 dr, up to 94 % ee) or α‐chloroesters (up to 94 % ee). Either 2‐arylsubstitution or an α‐branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.     

On‐line two‐dimensional LC: A rapid and efficient method for the determination of enantiomeric excess in reaction mixtures

A novel LC‐based method for the determination of enantiomeric excess (ee) in a sample mixture has been developed by employing on‐line 2D LC. The orthogonal separation system is composed of an NH₂ column as the first dimension to elute the target chiral compound from the crude mixture and a chiral column as the second dimension to determine the ee of the target chiral product. A series of crude mixtures from asymmetric reactions have been directly analyzed without prepurification. Good reproducibility (intra‐ and interday precisions were all under 1.33%) and good accuracy (deviations from ee values determined by 1D HPLC were all <1.03%) have been obtained. Compared with the traditional method for the determination of ee, on‐line 2D HPLC can be used in real time and holds great potential in the time‐saving determination of ee in asymmetric synthesis.