Atroposelective Synthesis of 3,3’‐Bisindoles Bearing Axial and Central Chirality: Using Isatin‐Derived Imines as Electrophiles

An atroposelective synthesis of a new class of 3,3’‐bisindoles bearing axial and central chirality has been established via catalytic asymmetric addition reactions using isatin‐derived imines as electrophiles (23 examples, up to 80% yield, > 95 : 5 dr, 98 : 2 er). This approach takes advantage of chiral phosphoric acid‐catalyzed dynamic kinetic resolution of 2‐substituted 3,3’‐bisindoles via nucleophilic addition of such substrates with isatin‐derived imines. In this approach, isatin‐derived imines acted as a class of competent electrophiles due to their high reactivity and bulky size, which provided an easy access to axially chiral 3,3'‐bisindoles incorporated with a biologically important chiral 3‐aminooxindole unit. This approach has greatly expanded the generality and applicability of the strategy of dynamic kinetic resolution for the synthesis of enantioenriched 3,3’‐bisindole derivatives bearing both axial and central chirality.     

Design and Enantioselective Construction of Axially Chiral Naphthyl‐Indole Skeletons

The first enantioselective construction of a new class of axially chiral naphthyl‐indole skeletons has been established by organocatalytic asymmetric coupling reactions of 2‐naphthols with 2‐indolylmethanols (up to 99 % yield, 97:3 e.r.). This approach not only affords a new type of axially chiral heterobiaryl backbone, but also provides a new catalytic enantioselective strategy for constructing axially chiral biaryl scaffolds by making use of the C3‐electrophilicity of 2‐indolylmethanols.     

Enantioselective Palladium‐Catalyzed C?H Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

A palladium‐catalyzed enantioselective C H functionalization of indoles was achieved with an axially chiral 2,2′‐bipyridine ligand, thus providing the desired indol‐3‐acetate derivatives with up to 98 % ee. Moreover, the reaction protocol was also effective for asymmetric O H insertion reaction of phenols using α‐aryl‐α‐diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium‐catalyzed carbene migratory insertion reactions.     

Axially Chiral Aryl‐Alkene‐Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

A new class of axially chiral aryl‐alkene‐indole frameworks have been designed, and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)‐selective and enantioselective (4+3) cyclization of 3‐alkynyl‐2‐indolylmethanols with 2‐naphthols or phenols (all >95 : 5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic asymmetric construction of axially chiral alkene‐heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not only confronted the great challenges in constructing axially chiral alkene‐heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl‐alkene‐indole frameworks.     

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.     

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.     

A Strategy for Synthesizing Axially Chiral Naphthyl‐Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates

A new strategy for enantioselective synthesis of axially chiral naphthyl‐indoles has been established through catalytic asymmetric addition reactions of racemic naphthyl‐indoles with bulky electrophiles. Under chiral phosphoric acid catalysis, azodicarboxylates and o‐hydroxybenzyl alcohols served as bulky but reactive electrophiles that were attacked by C2‐unsubstituted naphthyl‐indoles, which underwent a dynamic kinetic resolution to afford two series of axially chiral naphthyl‐indoles in good yields (up to 98 %) and high enantioselectivities (up to 98:2 er).     

Enantioselective Palladium‐Catalyzed C?H Functionalization of Indoles Using an Axially Chiral 2,2′‐Bipyridine Ligand

A palladium‐catalyzed enantioselective C H functionalization of indoles was achieved with an axially chiral 2,2′‐bipyridine ligand, thus providing the desired indol‐3‐acetate derivatives with up to 98 % ee. Moreover, the reaction protocol was also effective for asymmetric O H insertion reaction of phenols using α‐aryl‐α‐diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium‐catalyzed carbene migratory insertion reactions.     

Enantioselective Synthesis of 3,3′‐Diaryl‐SPINOLs: Rhodium‐Catalyzed Asymmetric Arylation/BF3‐Promoted Spirocyclization Sequence

The enantioselective synthesis of a series of C₂‐symmetric 3,3′‐diarylated 1,1′‐spirobiindane‐7,7′‐diols (3,3′‐diaryl‐SPINOLs) was developed by sequential Rh‐catalyzed twofold asymmetric conjugate arylation/BF₃‐promoted diastereoselective spirocyclization (>20:1 d.r. and >99 % ee for all examples). Some phosphoramidite ligands were prepared from the 3,3′‐Ph‐SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′‐diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands.     

Enantioselective Synthesis of Chiral Oxime Ethers: Desymmetrization and Dynamic Kinetic Resolution of Substituted Cyclohexanones

Axially chiral cyclohexylidene oxime ethers exhibit unique chirality because of the restricted rotation of C=N. The first catalytic enantioselective synthesis of novel axially chiral cyclohexylidene oximes has been developed by catalytic desymmetrization of 4‐substituted cyclohexanones with O‐arylhydroxylamines and is catalyzed by a chiral BINOL‐derived strontium phosphate with excellent yields and good enantioselectivities. In addition, chiral BINOL‐derived phosphoric acid catalyzed dynamic kinetic resolution of α‐substituted cyclohexanones has been performed and yields versatile intermediates in high yields and enantioselectivities.     

“Inherently Chiral” Ionic‐Liquid Media: Effective Chiral Electroanalysis on Achiral Electrodes

To achieve enantioselective electroanalysis either chiral electrodes or chiral media are needed. High enantiodiscrimination properties can be granted by the “inherent chirality” strategy of developing molecular materials in which the stereogenic element responsible for chirality coincides with the molecular portion responsible for their specific properties, an approach recently yielding outstanding performances as electrode surfaces. Inherently chiral ionic liquids (ICILs) have now been prepared starting from atropisomeric 3,3′‐bicollidine, synthesized from inexpensive reagents, resolved into antipodes without need of chiral HPLC and converted into long‐chain dialkyl salts with melting points below room temperature. Both the new ICILs and shorter family terms, solid at room temperature, employed as low‐concentration additives in achiral ILs, afford impressive enantioselection for the enantiomers of different probes on achiral electrodes, regularly increasing with additive concentration.     

Carbene‐Catalyzed Desymmetrization and Direct Construction of Arenes with All‐Carbon Quaternary Chiral Center

Multisubstituted arenes such as indanes with attached all‐carbon quaternary centers are unique scaffolds in synthetic functional molecules and sophisticated natural products. A key challenge in preparing such molecules lies in the enantioselective installation of the quaternary carbon centers. Conventional methods in this direction include asymmetric substitution reactions and substrate‐controlled cyclization reactions. These reactions lead to poor stereoselectivities and/or require long and tedious synthetic steps. Disclosed here is a one‐step organic catalytic strategy for enantioselective access to this class of molecules. The reaction involves an N‐heterocyclic carbene catalyzed process for direct benzene construction, indane formation, remote‐carbon desymmetrization, and excellent chirality control. This approach will enable the concise synthesis of arene‐containing molecules, including those with complex structures and challenging chiral centers.     

Highly Stereoselective [3+2] Cycloadditions of Chiral Palladium‐Containing N1‐1,3‐Dipoles: A Divergent Approach to Enantioenriched Spirooxindoles

A catalytic asymmetric [3+2] cycloaddition reaction of chiral palladium‐containing N¹‐1,3‐dipoles with methyleneindolinones has been successfully developed. The reaction allows an efficient construction of 3,3′‐pyrrolinyl spirooxindoles with high yields and excellent stereoselectivities (up to 93 % yield, 19:1 d.r. and >99 % ee). A synthetic application of this methodology is demonstrated and a stereocontrol mechanism is proposed.     

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.     

One‐Pot Organocatalytic Enantioselective Michael/Povarov Domino Strategy for the Construction of Spirooctahydroacridine‐3,3′‐oxindole Scaffolds

An asymmetric organocatalytic one‐pot strategy for the construction of spirooctahydroacridine‐3,3′‐oxindole scaffolds has been successfully developed by means of a domino Michael/Povarov reaction sequence. The one‐pot protocol affords the chiral spirocyclohexaneoxindoles bearing an octahydroacridine motif with five stereocenters in good to high yields (up to 89 % yield) with excellent to perfect diastereoselectivities (up to >20:1 d.r.) and enantioselectivities (up to >99 % ee). This highly efficient one‐pot domino procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.     

An Imidazoline–Aminophenol (IAP) Nickel Catalyst: Structure and Catalytic Activity in the Enantioselective 1,4‐Addition of 3′‐Indolyl‐3‐Oxindoles to Nitroethylene

The structure of a nickel complex of imidazoline–aminophenol (IAP) prepared from IAP with Ni(OAc)₂ was elucidated as cis‐bis(imidazolineaminophenoxide) [Ni(IAP)₂]. The [Ni(IAP)₂] complex smoothly promoted catalytic asymmetric 1,4‐addition of 3′‐indolyl‐3‐oxindole to nitroethylene to provide chiral mixed 3,3′‐bisindoles with high enantioselectivities. Mechanistic studies using ESI‐MS analyses suggest that one IAP ligand dissociated from [Ni(IAP)₂] to generate the Ni–enolate of 3′‐indolyl‐3‐oxindole. From the optically active 3,3′‐mixed indole adduct, biologically important 3′‐indolyl‐3‐pyrrolidinoindoline was successfully synthesized in a three‐step reaction sequence.     

Combining Organocatalysis with Central‐to‐Axial Chirality Conversion: Atroposelective Hantzsch‐Type Synthesis of 4‐Arylpyridines

Suitably substituted enantioenriched 4‐aryl‐1,4‐dihydro‐pyridines prepared by an organocatalytic enantioselective Michael addition were oxidized with MnO₂ into axially chiral 4‐arylpyridines with central‐to‐axial chirality conversion. Moderate to complete percentages (cp) were observed, and a model for the conversion of chirality is discussed.     

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.     

Enantioselective Electrophilic Aromatic Nitration: A Chiral Auxiliary Approach

Enantioselective electrophilic aromatic nitration methodology is needed to advance chirality‐assisted synthesis (CAS). Reported here is an enantioselective aromatic nitration strategy operating with chiral diester auxiliaries, and it provides an enantioselective synthesis of a C_3v‐symmetric tribenzotriquinacene (TBTQ). These axially‐chiral structures are much sought‐after building blocks for CAS, but they were not accessible prior to this work in enantioenriched form without resolution of enantiomers. This nitration strategy controls the stereochemistry of threefold nitration reactions from above the aromatic rings with chiral diester arms. Dicarbonyl‐to‐arenium chelation rigidifies the reaction systems, so that remote stereocenters position the ester‐directing groups selectively over specific atoms of the TBTQ framework. Closely guided by computational design, a more selective through‐space directing arm was first predicted with density functional theory (DFT), and then confirmed in the laboratory, to outperform the initial structural design. This enantio‐ and regioselective TBTQ synthesis opens a new pathway to access building blocks for CAS.     

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N′-Bisindoles

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N′-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N′-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N′-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N′-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.