Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C−H Olefination Enabled by an Amino Amide Transient Directing Group

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through Pd^II-catalyzed atroposelective C−H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in Co^III-catalyzed enantioselective C(sp³)−H amidation of thioamide. Mechanistic studies suggest that C−H cleavage is the enantioselectivity-determining step.     

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II‐catalyzed atroposelective C?H olefination. A broad range of axially chiral biaryl‐2‐amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram‐scale synthesis. The resulting axially chiral biaryl‐2‐amines also provide a platform for the synthesis of a set of chiral ligands.     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C?H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Scalable,Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium‐catalyzed atroposelective C−H alkynylation and its application in gram‐scale, stereocontrolled formal syntheses of (+)‐isoschizandrin and (+)‐steganone. tert‐Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99 %) with excellent enantioselectivity (up to >99 % ee).     

Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu‐Catalyzed Atroposelective Aryl Amination

N?C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal‐catalyzed atroposelective N‐arylations have been described. Herein, we disclose an unprecedented Cu‐catalyzed atroposelective N?C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N?C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post‐modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.     

Organocatalytic Asymmetric Annulation of ortho‐Alkynylanilines: Synthesis of Axially Chiral Naphthyl‐C2‐indoles

A chiral Brønsted base catalyzed asymmetric annulation of ortho‐alkynylanilines has been developed to access axially chiral naphthyl‐C2‐indoles via vinylidene ortho‐quinone methide (VQM) intermediates. This strategy provides a unique organocatalytic atroposelective route to axially chiral aryl‐C2‐indole skeletons with excellent enantioselectivity and functional‐group tolerance. This transformation was applicable to decagram‐scale preparation (50.0 g) with perfect enantioselectivity through simple recrystallization. Moreover, the utility of this reaction was demonstrated by a variety of transformations towards chiral naphthyl‐C2‐indoles for a series of carbon–heteroatom bond formations. Furthermore, the prepared axially chiral naphthyl‐C2‐indoles were applied as a chiral skeleton for organocatalytic aza‐Baylis–Hillman reaction and asymmetric formal [4+2] tandem cyclization to give the corresponding adducts in high yields with improved enantioselectivity and diastereoselectivity.     

Enantioselective Synthesis of Biaryl Atropisomers by Pd‐Catalyzed C−H Olefination using Chiral Spiro Phosphoric Acid Ligands

The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C?H activation. Herein, we reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C?H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.     

Construction of Axial Chirality by Rhodium‐Catalyzed Asymmetric Dehydrogenative Heck Coupling of Biaryl Compounds with Alkenes

Enantioselective construction of axially chiral biaryls by direct C? H bond functionalization reactions has been realized. Novel axially chiral biaryls were synthesized by the direct C? H bond olefination of biaryl compounds, using a chiral [Cp*Rh^III] catalyst, in good to excellent yields and enantioselectivities. The obtained axially chiral biaryls were found as suitable ligands for rhodium‐catalyzed asymmetric conjugate additions.     

Synthesis of Chiral Aldehyde Catalysts by Pd‐Catalyzed Atroposelective C−H Naphthylation

Chiral aldehyde catalysis opens new avenues for the activation of simple amines. However, the lack of easy access to structurally diverse chiral aldehyde catalysts has hampered the development of this cutting‐edge field. Herein, we report a Pd‐catalyzed atroposelective C?H naphthylation with 7‐oxabenzonorbornadienes for the preparation of axially chiral biaryls with excellent enantioselectivities (up to >99 % ee). This reaction is scalable and robust, which serves as a key step to provide a rapid access to axially chiral aldehyde catalysts through a three‐step C?H functionalization sequence. These chiral aldehydes exhibit better activities and enantioselectivities than the previously reported organocatalysts in the asymmetric activation of glycine derived amides and dipeptides. Moreover, preliminary investigation also discloses that the aldehyde catalyst can effectively override the intrinsic facial selectivity of chiral dipeptide substrates, showcasing the strong chiral induction ability of this type of novel aldehyde catalysts.     

Synthesis of Axially Chiral Biaryl-2-amines by PdII-Catalyzed Free-Amine-Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II-catalyzed atroposelective C−H olefination. A broad range of axially chiral biaryl-2-amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram-scale synthesis. The resulting axially chiral biaryl-2-amines also provide a platform for the synthesis of a set of chiral ligands.     

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by Rh^III‐catalyzed C?H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.     

Gold‐Catalyzed Atroposelective Synthesis of 1,1′‐Binaphthalene‐2,3′‐diols

A highly atroposelective (up to 97 % ee) Au‐catalyzed synthesis of 1,1′‐binaphthalene‐2,3′‐diols is reported starting from a range of substituted benzyl alkynones. Essential for the achievement of high enantioselectivity during the key assembly of the naphto‐3‐ol unit is the use of TADDOL‐derived α‐cationic phosphonites as ancillary ligands. Preliminary results demonstrate that the transformation of the obtained binaphthyls into axially chiral monodentate phosphines is possible without degradation of enantiopurity.     

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.     

Rhodium(III)‐Catalyzed Asymmetric Access to Spirocycles through C−H Activation and Axial‐to‐Central Chirality Transfer

Axial‐to‐central chirality transfer is an important strategy to construct chiral centers, where the axially chiral reagents are mostly limited to atropomerically stable ones. Reported herein is a Rh^III‐catalyzed enantioselective spiroannulative synthesis of nitrones. The coupling proceeds via C?H arylation to give an atropomerically metastable biaryl, followed by intramolecular dearomative trapping under oxidative conditions with high degree of chirality transfer.     

Organocatalytic Atroposelective Arylation of 2‐Naphthylamines as a Practical Approach to Axially Chiral Biaryl Amino Alcohols

The first phosphoric acid catalyzed direct arylation of 2‐naphthylamines with iminoquinones for the atroposelective synthesis of axially chiral biaryl amino alcohols has been developed. This reaction constitutes a highly functional‐group‐tolerant route for the rapid construction of enantioenriched axially chiral biaryl amino alcohols, and is a rare example of 2‐naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation. Furthermore, the products, which feature various halogen atoms, provide access to structurally diverse axially chiral amino alcohols through further transformations.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Asymmetric Synthesis of Axially Chiral Isoquinolones: Nickel‐Catalyzed Denitrogenative Transannulation

The first Ni⁰/bis(oxazoline)‐catalyzed asymmetric denitrogenative transannulation of 1,2,3‐benzotriazin‐4(3H)‐ones with bulky internal alkynes to form novel axially chiral isoquinolones in an atroposelective manner has been developed. This method provides direct asymmetric access to axially chiral isoquinolones with excellent functional‐group tolerance in excellent yields and stereoselectivities from readily available starting materials under mild reaction conditions. These axially chiral isoquinolones exhibit high cytotoxicity against a number of human cancer cell lines. DFT calculations reveal the nature of the transition state in the key annulation step.     

Lipase‐Catalyzed Dynamic Kinetic Resolution of C1‐ and C2‐Symmetric Racemic Axially Chiral 2,2′‐Dihydroxy‐1,1′‐biaryls

We have discovered that the racemization of configurationally stable, axially chiral 2,2′‐dihydroxy‐1,1′‐biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35–50 °C. Combining this racemization procedure with lipase‐catalyzed kinetic resolution led to the first lipase/metal‐integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio‐enriched C₁‐ and C₂‐symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis.     

Enantioselective Synthesis of C−N Axially Chiral N‐Aryloxindoles by Asymmetric Rhodium‐Catalyzed Dual C−H Activation

The first enantioselective Satoh–Miura‐type reaction is reported. A variety of C?N axially chiral N‐aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium‐catalyzed dual C?H activation reaction of N‐aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.     

PdII‐Catalyzed Enantioselective C(sp3)–H Arylation of Cyclobutyl Ketones Using a Chiral Transient Directing Group

The use of chiral transient directing groups (TDGs) is a promising approach for developing Pd^II‐catalyzed enantioselective C(sp³)?H activation reactions. However, this strategy is challenging because the stereogenic center on the TDG is often far from the C?H bond, and both TDG covalently attached to the substrate and free TDG are capable of coordinating to Pd^II centers, which can result in a mixture of reactive complexes. We report a Pd^II‐catalyzed enantioselective β‐C(sp³)?H arylation reaction of aliphatic ketones using a chiral TDG. A chiral trisubstituted cyclobutane was efficiently synthesized from a mono‐substituted cyclobutane through sequential C?H arylation reactions, thus demonstrating the utility of this method for accessing structurally complex products from simple starting materials. The use of an electron‐deficient pyridone ligand is crucial for the observed enantioselectivity. Interestingly, employing different silver salts can reverse the enantioselectivity.