Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands

The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]₂, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.     

Enantioselective Synthesis of Chiral Isotopomers of 1‐Alkanols by a ZACA–Cu‐Catalyzed Cross‐Coupling Protocol

Chiral compounds arising from the replacement of hydrogen atoms by deuterium are very important in organic chemistry and biochemistry. Some of these chiral compounds have a non‐measurable specific rotation, owing to very small differences between the isotopomeric groups, and exhibit cryptochirality. This particular class of compounds is difficult to synthesize and characterize. Herein, we present a catalytic and highly enantioselective conversion of terminal alkenes to various β and more remote chiral isotopomers of 1‐alkanols, with ≥99 % enantiomeric excess (ee), by the Zr‐catalyzed asymmetric carboalumination of alkenes (ZACA) and Cu‐catalyzed cross‐coupling reactions. ZACA‐in situ iodinolysis of allyl alcohol and ZACA‐in situ oxidation of TBS‐protected ω‐alkene‐1‐ols protocols were applied to the synthesis of both (R)‐ and (S)‐difunctional intermediates with 80–90 % ee. These intermediates were readily purified to provide enantiomerically pure (≥99 % ee) compounds by lipase‐catalyzed acetylation. These functionally rich intermediates serve as very useful synthons for the construction of various chiral isotopomers of 1‐alkanols in excellent enantiomeric purity (≥99 % ee) by introducing deuterium‐labeled groups by Cu‐catalyzed cross‐coupling reactions without epimerization.     

Catalytic Asymmetric Addition of Diorganozinc Reagents to Pyrazole-4,5-Diones and Indoline-2,3-Diones

The catalytic enantioselective diorganozinc additions to cyclic diketones including pyrazolin-4,5-diones and isatins have been developed. In the presence of morpholine-containing chiral amino alcohol ligand, the corresponding chiral cyclic tertiary alcohols were produced in good to excellent yields (up to 97 %) and enantioselectivities (up to 95 % ee). The notable feature of this protocol includes its mild reaction conditions, Lewis acid additives free and broad functional group tolerance.     

Kinetic Resolution of 1,1′‐Biaryl‐2,2′‐Diols and Amino Alcohols through NHC‐Catalyzed Atroposelective Acylation

We present here a highly efficient NHC‐catalyzed kinetic resolution of a wide range of 1,1′‐biaryl‐2,2′‐diols and amino alcohols to provide them in uniformly ≥99 % ee. This represents the first highly enantioselective catalytic acylation of axially chiral alcohols. The aldehyde backbone that is incorporated into the chiral acyl azolium intermediate was found to have a significant effect on the enantioselectivity of the process.     

Highly enantioselective conjugate addition of dialkylzinc reagents to acyclic nitroalkenes: a catalytic route to beta2-amino acids,aldehydes, and alcohols

Using chiral phosphoramidite ligand (S,R,R)-L1 in the conjugate addition to acyclic nitroalkenes for the first time, we obtained enantioselectivities up to 98%. The use of acyclic substrates with different dialkylzinc reagents provides a catalytic enantioselective route to (functionalized) beta2-amino aldehydes, acids, and alcohols.     

Organoiodine‐Catalyzed Enantioselective Alkoxylation/Oxidative Rearrangement of Allylic Alcohols

An enantioselective catalytic alkoxylation/oxidative rearrangement of allylic alcohols has been established by using a Brønsted acid and chiral organoiodine. The presence of 20 mol % of an (S)‐proline‐derived C₂‐symmetric chiral iodine led to enantioenriched α‐arylated β‐alkoxylated ketones in good yields and with high levels of enantioselectivity (84–94 % ee).     

Room-Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

We report herein an unprecedented highly efficient Guerbet-type reaction at room temperature (catalytic TON up to >6000). This β-alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher-order secondary alcohols in an economical, redox-neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.     

Turning on Asymmetric Catalysis of Achiral Metal-Organic Frameworks by Imparting Chiral Microenvironment

The development of heterogeneous asymmetric catalysts has attracted increasing interest in synthetic chemistry but mostly relies on the immobilization of homogeneous chiral catalysts. Herein, a series of chiral metal–organic frameworks (MOFs) have been fabricated by anchoring similar chiral hydroxylated molecules (catalytically inactive) with different lengths onto Zr-oxo clusters in achiral PCN-222(Cu). The resulting chiral MOFs exhibit regulated enantioselectivity up to 83 % ee in the asymmetric ring-opening of cyclohexene oxide. The chiral molecules furnished onto the catalytic Lewis sites in the MOF create multilevel microenvironment, including the hydrogen interaction between the substrate and the chiral −OH group, the steric hindrance endowed by the benzene ring on the chiral molecules, and the proximity between the catalytic sites and chiral molecules confined in the MOF pores, which play crucial roles and synergistically promote chiral catalysis. This work nicely achieves heterogeneous enantioselective catalysis by chiral microenvironment modulation around Lewis acid sites.     

Room‐Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

We report herein an unprecedented highly efficient Guerbet‐type reaction at room temperature (catalytic TON up to >6000). This β‐alkylation of secondary methyl carbinols with primary alcohols has significant advantage of delivering higher‐order secondary alcohols in an economical, redox‐neutral fashion. In addition, the first enantioselective Guerbet reaction has also been achieved using a commercially available chiral ruthenium complex to deliver secondary alcohols with moderate yield and up to 92 % ee. In both reactions, the use of a traceless ketone promoter proved to be beneficial for the catalytic efficiency.     

Tungsten‐Catalyzed Regio‐ and Enantioselective Aminolysis of trans‐2,3‐Epoxy Alcohols: An Entry to Virtually Enantiopure Amino Alcohols

The first catalytic enantioselective aminolysis of trans‐2,3‐epoxy alcohols has been accomplished. This stereospecific ring‐opening process was efficiently promoted by a tungsten/bis(hydroxamic acid) catalytic system, furnishing various anti‐3‐amino‐1,2‐diols with excellent regiocontrol and high enantioselectivities (up to 95 % ee). Moreover, virtually enantiopure 3‐amino‐1,2‐diols could be obtained by the sequential combination of two reactions that both involve the use of a chiral catalyst.     

Rhodium(I)‐Catalyzed Enantioselective Activation of Cyclobutanols: Formation of Cyclohexane Derivatives with Quaternary Stereogenic Centers

The activation of carbon–carbon σ bonds is a complementary method to access uncommon and difficult‐to‐prepare organometallic species. Herein, we describe the activation of tert‐cyclobutanols through an enantioselective insertion of a chiral rhodium(I) complex into the C? C σ bond of the cyclobutane, forming a quaternary stereogenic center and an alkyl‐rhodium functionality that initiates ring‐closure reactions. This technology provides access to a variety of substituted cyclohexane derivatives with quaternary stereogenic centers. The formation of different product families can be controlled by the employed set of reaction conditions and additives. In general, high yields and excellent enantioselectivities of up to 99 % ee are obtained.     

Copper(I)‐Catalyzed Enantioselective Substitution of Allyl Chlorides with Diorganozinc Compounds

Ferrocenylamines are excellent catalysts for the enantioselective substitution of unsymmetrical allyl chlorides with dialkylzinc compounds in the presence of a copper(I ) salt. For example, in the reaction shown in Equation (1), the product is formed with 87 % ee and a S_N2′:S_N2 ratio of 97:3.     

A Simple Biosystem for the High-Yielding Cascade Conversion of Racemic Alcohols to Enantiopure Amines

The amination of racemic alcohols to produce enantiopure amines is an important green chemistry reaction for pharmaceutical manufacturing, requiring simple and efficient solutions. Herein, we report the development of a cascade biotransformation to aminate racemic alcohols. This cascade utilizes an ambidextrous alcohol dehydrogenase (ADH) to oxidize a racemic alcohol, an enantioselective transaminase (TA) to convert the ketone intermediate to chiral amine, and isopropylamine to recycle PMP and NAD⁺ cofactors via the reversed cascade reactions. The concept was proven by using an ambidextrous CpSADH-W286A engineered from (S)-enantioselective CpSADH as the first example of evolving ambidextrous ADHs, an enantioselective BmTA, and isopropylamine. A biosystem containing isopropylamine and E. coli (CpSADH-W286A/BmTA) expressing the two enzymes was developed for the amination of racemic alcohols to produce eight useful and high-value (S)-amines in 72–99 % yield and 98–99 % ee, providing with a simple and practical solution to this type of reaction.     

Rh-Catalyzed Asymmetric Hydrogenation of α,β- and β,β-Disubstituted Unsaturated Boronate Esters

A highly enantioselective hydrogenation of α,β-unsaturated boronate esters catalyzed by Rh-(S)-DTBM-Segphos complex has been developed. Both (Z)-α,β- and β,β-disubstituted substrates can be successfully hydrogenated to afford chiral boronates with excellent enantioselectivities, up to 98 % ee. Furthermore, the obtained chiral boronate esters, as important versatile synthetic intermediates are successfully transformed to the corresponding chiral alcohols, amines and other important derivatives with maintained enantioselectivities.     

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.     

Asymmetric Reduction of α‐Amino Ketones with a KBH4 Solution Catalyzed by Chiral Lewis Acids

An efficient enantioselective reduction of α‐amino ketones with potassium borohydride solution catalyzed by chiral N,N′‐dioxide–metal complex catalysts was accomplished under mild reaction conditions for the first time. It provided a simple, convenient, and practical approaches for obtaining synthetically important chiral β‐amino alcohols in good to excellent yields (up to 98 %) and enantioselectivities (up to 97 % ee).     

The first catalytic asymmetric addition of diethylzinc to aldehyde promoted by chiral thiourea

A series of C₂-symmetric and asymmetric chiral thiourea derivatives were synthesized from commercial L-phenylalanine.All of the new compounds have been fully characterized by IR,¹H NMR,¹³C NMR,MS spectra and elemental analyses.The chiral thioureas were used as chiral ligands in the catalytic enantioselective ethylation of aldehydes with diethylzinc,the corresponding sec-alcohols were gained with excellent enantioselectivities（up to 87.1%ee） and high yields（up to 76.7%） after the conditions were optimized.     

Catalytic Asymmetric [2+3] Cyclizations of Azlactones with Azonaphthalenes

The first catalytic asymmetric [2+3] cyclization of azlactones with azonaphthalenes has been established. This strategy allowed the synthesis of a variety of chiral isatin derivatives in generally good yields and excellent enantioselectivities (up to 99 % yield, 98 % ee). The developed reaction has not only established a catalytic enantioselective [2+3] cyclization using azlactones as two‐carbon building blocks, but also enriches the chemistry of catalytic asymmetric cyclizations of azonaphthalenes. In addition, this protocol will provide a useful method for constructing enantioenriched 3,3′‐disubstituted isatin‐type frameworks.     

A green chemistry approach to a more efficient asymmetric catalyst: solvent-free and highly concentrated alkyl additions to ketones

There is a great demand for development of catalyst systems that are not only efficient and highly enantioselective but are also environmentally benign. Herein we report investigations into the catalytic asymmetric addition of alkyl and functionalized alkyl groups to ketones under highly concentrated and solvent-free conditions. In comparison with standard reaction conditions employing toluene and hexanes, the solvent-free and highly concentrated conditions permit reduction in catalyst loading by a factor of 2- to 40-fold. These new conditions are general and applicable to a variety of ketones and dialkylzinc reagents to provide diverse tertiary alcohols with high enantioselectivities. Using cyclic conjugated enones, we have performed a tandem asymmetric addition/diastereoselective epoxidation using the solvent-free addition conditions followed by introduction of a 5.5 M decane solution of tert-butyl hydroperoxide (TBHP) to generate epoxy alcohols. This one-pot procedure allows access to syn epoxy alcohols with three contiguous stereocenters with excellent enantio- and diastereoselectivities and high yields. Both the solvent-free asymmetric additions and asymmetric addition/diastereoselective epoxidation reactions have been conducted on larger scale (5 g substrate) with 0.5 mol % catalyst loadings. In these procedures, enantioselectivities equal to or better than 92% were obtained with isolated yields of 90%. The solvent-free and highly concentrated conditions are a significant improvement over previous solvent-based protocols. Further, this chemistry represents a rare example of a catalytic asymmetric reaction that is highly enantioselective under more environmentally friendly solvent-free conditions.