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Planar‐chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of centrally or axially chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar‐chiral [2,2]‐paracyclophanes and metallocenes. This Minireview describes recent advancements in asymmetric catalytic synthesis of planar‐chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar‐chiral skeletons. [ABSTRACT FROM AUTHOR]

Catalytic enantioselective preparation of alkene atropisomers with multiple stereogenic elements and discovery of their applications have become significant but challenging issues in the scientific community due to the unique structures of this class of atropisomers. We herein report the first catalytic atroposelective preparation of cyclopentenyl[b]indoles, a new kind of alkene atropisomers, with stereogenic point and axial chirality via an unusual rearrangement reaction of 3‐indolylmethanols under asymmetric organocatalysis. Notably, this novel type of alkene atropisomers have promising applications in developing chiral ligands or organocatalysts, discovering antitumor drug candidates and fluorescence imaging materials. Moreover, the theoretical calculations have elucidated the possible reaction mechanism and the non‐covalent interactions to control the enantioselectivity. This approach offers a new synthetic strategy for alkene atropisomers with multiple stereogenic elements, and represents the first catalytic enantioselective rearrangement reaction of 3‐indolylmethanols, which will advance the chemistry of atropisomers and chiral indole chemistry. [ABSTRACT FROM AUTHOR]

The intensity and handedness of circularly polarized luminescence (CPL) were successfully controlled by dynamic molecular motion in solutions. Bis(boron difluoride) complexes with chiral salen ligands were synthesized and their photophysical properties were investigated. Although these complexes showed rapid molecular rotation about the C−N bond axis in solution at room temperature, two conformers assigned as atropisomers were observed in the NMR spectra at low temperature. Furthermore, the equilibrium of these atropisomers was found to change depending on the external environment, such as the solvent and temperature, allowing precise control of the intensity and handedness of CPL without luminescence color shifts. Theoretical calculations based on density functional theory (DFT) revealed that intramolecular chiral exciton coupling is the key to changes in CPL properties. [ABSTRACT FROM AUTHOR]

Due to their molecular topology, atropisomers serve as highly valuable chiral frameworks for diverse applications across academic research and industry. Despite the availability of numerous established catalytic methods for their synthesis, there is still a high demand for the development of novel and resourceful strategies. In this concept article, we will detail our studies on the use of transient Lewis acid‐base interactions (LABI) as a dynamization strategy for the synthesis of (hetero)biaryl atropisomers by Dynamic Kinetic Resolution (DKR). The formation of cyclic transition states, resulting from the interaction between an acidic functionality and a basic counterpart, plays a key role in facilitating racemization by substantially reducing the barrier to atropisomerization. In this scenario, we have employed transformations aimed at neutralizing the acidic nature of the Lewis acid, ultimately leading to the formation of configurationally stable enantioenriched compounds. The design of substrates and the employment of stereoselective strategies based on transition metal and biocatalysis for their resolution is detailed. Specific emphasis on the preparation of axially chiral motifs commonly found in catalysis or medicinal chemistry will also be given. [ABSTRACT FROM AUTHOR]

A symmetric anion mediated dynamic kinetic asymmetric Knoevenagel reaction was established as a general and efficient method for accessing both N−C and N−N atropisomers. The resulting highly enantio‐pure pyridine‐2,6(1H,3H)‐diones exhibit diverse structures and functional groups. The key to excellent regio‐ and remote enantiocontrol could be owed to the hydrogen bond between the enolate anion and triflamide block of the organocatalyst. This connected the enolate anion and iminium cation by a chiral backbone. The mechanism investigation via control experiments, correlation analysis, and density functional theory calculations further revealed how the stereochemical information was transferred from the catalyst into the axially chiral pyridine‐2,6(1H,3H)‐diones. The synthetic applications also demonstrated the reaction's potential. [ABSTRACT FROM AUTHOR]

Axially chiral diaryl ethers represent a distinct class of atropisomers, characterized by a unique dual C─O axes system, which have been found in a variety of natural products, pharmaceuticals, and ligands. However, the catalytic enantioselective synthesis of these atropoisomers poses significant challenges, due to the difficulty in controlling both chiral C─O axes, and their more flexible conformations. Herein, an efficient protocol for catalytic enantioselective synthesis of axially chiral diaryl ethers is presented using organocatalyzed asymmetric Povarov reaction‐enabled desymmetrization, followed by aromatizations. This method yields a wide range of novel quinoline‐based diaryl ether atropoisomers in good yields and high enantioselectivities. Notably, various aromatization protocols are developed, resulting in a diverse set of polysubstituted quinoline‐containing diaryl ether atropisomers. Thermal racemization studies suggested excellent configurational stabilities for these novel diaryl ether atropisomers (with racemization barriers up to 38.1 kcal mol−1). Moreover, this research demonstrates for the first time that diaryl ether atropisomers lacking the bulky t‐Bu group can still maintain a stable configuration, challenging the prior knowledge in the field. The fruitful derivatizations of the functional group‐rich chiral products further underscore the value of this method. [ABSTRACT FROM AUTHOR]

Atropisomers have attracted a great deal of attention lately due to their numerous applications in organic synthesis and to their employment in drug discovery. However, the synthetic arsenal at our disposal with which to access them remains limited. The research described herein is two‐pronged; we both demonstrate the use of MCR chemistry as a synthetic strategy for the de novo synthesis of a class of atropisomers having high barriers to rotation with the simultaneous insertion of multiple chiral elements and we study these unprecedented molecular systems by employing a combination of crystallography, NMR and DFT calculations. By fully exploiting the synthetic capabilities of our chemistry, we have been able to monitor a range of different types of interaction, i. e. π‐π, CH–π, heteroatom‐π and CD–π, in order to conduct structure‐property studies. The results could be applied both to atroposelective synthesis and in drug discovery. [ABSTRACT FROM AUTHOR]

The Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under PIII/PV=O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene‐forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert‐butyloxycarbonylated Morita–Baylis–Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94 : 6 enantioselectivity. [ABSTRACT FROM AUTHOR]

A ruthenium‐catalyzed reductive amination via asymmetric transfer hydrogenation (ATH) has been used to perform an efficient dynamic kinetic resolution (DKR) of N‐aryl 2‐formyl pyrroles decorated with a phosphine moiety positioned at the ortho' position. The strategy relies on the labilization of the stereogenic axis in the substrate facilitated by a transient Lewis acid‐base interaction (LABI) between the carbonyl carbon and the phosphorus center. The reaction features broad substrate scope of aliphatic amines and N‐aryl pyrrole scaffolds, and proceeds under very mild conditions to afford P,N atropisomers in good to high yields and excellent enantioselectivities (up to 99 % ee) for both diphenyl and dicyclohexylphosphino derivatives. [ABSTRACT FROM AUTHOR]

Diarylethenes are an important class of photoswitches that usually exist in interconvertible parallel (photoinert) and antiparallel (photochromic) conformational states. Recent research afforded sterically congested diarylethenes that exist as stable and separable configurational atropisomers. Rational manipulation of stereochemistry is a robust strategy for regulating diarylethene photochemistry. Here, we present a brief account of the conformer/atropisomer-dependent photochromism of diarylethene photoswitches, and we discuss a recent advance at the interface of diarylethene photochemistry and polymer mechanochemistry: our group recently introduced a mechanical approach for converting a parallel diarylbenzothiadiazole into its antiparallel configurational diastereomers, thereby turning on its photochromic reactivity. After mechanical activation, UV light changes the converted diarylethene molecule into a colored ring-closed form by a 6π-electrocyclization reaction that permits the visualization of the mechanical activation event. Besides the fundamentally new mechanism of converting a molecule into its configurational diastereomers through force–stereochemistry coupling, the conversion of atropisomer stereochemistry is a noncovalent process and features high mechanical reactivity in comparison to conventional mechanophores, which require covalent bond scission. This new type of configurational mechanophore holds promise for various applications, such as high-sensitivity stress sensing, lithography, and information storage. 1 Diarylethene Conformers and Atropisomers 2 Polymer Mechanochemistry and Configurational Mechanophores 3 Regulating the Stereochemistry and Reactivity of a Diarylethene Atropisomer with Mechanical Force 4 Summary and Future Outlook [ABSTRACT FROM AUTHOR]

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM. [ABSTRACT FROM AUTHOR]

Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA‐approved drugs and experimental molecules, display markedly different biological activities. The time‐dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future. [ABSTRACT FROM AUTHOR]

A series of naphthalene‐diimide (NDI) and perylene‐diimide (PDI) connected bis‐N‐heterocyclic carbene complexes of iridium(III) have been prepared and fully characterized. The analysis of their NMR spectroscopic features, together with their molecular structures show that these species display lone‐pair‐π interactions between the chloride ligands of the Ir(III) complex and the heterocycles of the NDI/PDI moieties. The detection of this type of interaction in solution is due to the formation of two atropisomers, which are formed as a result of the restricted rotation about the Ir−Ccarbene bond imposed by the (Cl)lp⋅⋅⋅π interaction. Variable‐temperature 1H NMR analysis allowed the determination of the strength of this non‐covalent interaction, which lies between ΔH=6.6 and 10 kcal/mol. The computational studies performed fully support the experimental findings. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Axially chiral biaryls represent the most important class of atropisomers, and they widely exist in natural products and biologically active molecules. They also constitute a unique scaffold for chiral ligands and catalysts in organic synthesis. The development of synthetic methods to obtain such chiral compounds has received widespread attention, among which catalytically atroposelective ring‐opening of configurationally labile compounds represents one of the most attractive strategies. Various substrates with strained cyclic structures, such as the renowned Bringmann's lactones, can undergo asymmetric transformation into stable atropisomers. Known advancement primarily relies on metal catalyst combined with well‐designed chiral ligands, the approaches utilizing organocatalysis as a critical resolution strategy are notably scarce. In this study, we disclosed a N‐heterocyclic carbene (NHC)‐catalyzed asymmetric ring‐opening reaction of biaryl lactams via direct atroposelective nucleophilic activation. The optimized bulky carbene catalyst ensures that the reaction can proceed under mild conditions, affording the desired product with good to excellent yields and atroposelectivity. [ABSTRACT FROM AUTHOR]

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C–C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations. The three-dimensional conformation of macrocycles determine their chemical and recognition properties and the factors that influence the interconversion between macrocyclic forms are poorly understood. Here the authors describe a macrocycle existing as two stable atropisomers and the mechanism behind the thermally-induced transition between them. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Axially chiral biaryls represent the most important class of atropisomers, and they widely exist in natural products and biologically active molecules. They also constitute a unique scaffold for chiral ligands and catalysts in organic synthesis. The development of synthetic methods to obtain such chiral compounds has received widespread attention, among which catalytically atroposelective ring‐opening of configurationally labile compounds represents one of the most attractive strategies. Various substrates with strained cyclic structures, such as the renowned Bringmann's lactones, can undergo asymmetric transformation into stable atropisomers. Known advancement primarily relies on metal catalyst combined with well‐designed chiral ligands, the approaches utilizing organocatalysis as a critical resolution strategy are notably scarce. In this study, we disclosed a N‐heterocyclic carbene (NHC)‐catalyzed asymmetric ring‐opening reaction of biaryl lactams via direct atroposelective nucleophilic activation. The optimized bulky carbene catalyst ensures that the reaction can proceed under mild conditions, affording the desired product with good to excellent yields and atroposelectivity. [ABSTRACT FROM AUTHOR]

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide‐ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom‐linked non‐biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non‐biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview. [ABSTRACT FROM AUTHOR]

Axially chiral biaryl scaffolds are important in pharmaceuticals, natural products, and asymmetric synthesis. Atroposelective ring‐opening of configurationally labile biaryl reagents via dynamic kinetic asymmetric transformation provides a valuable approach to access axially chiral biaryl atropisomers. This review summarizes seminal contributions and recent advancements on this topic based on the use of different types of configurationally labile biaryl reagents. [ABSTRACT FROM AUTHOR]

Axially chiral biaryl ethers and related compounds hold valuable potential in natural products, medicinal chemistry, and catalysis; however, their asymmetric syntheses have always been overlooked compared to other biaryl/hetero-biaryl atropisomers. Unlike the later class molecules bearing a single chiral axis, the former category possesses a unique type of atropisomerism bearing two potential axes. Due to their great importance in diverse research domains, catalytic atropselective biaryl ether synthesis has recently witnessed an upsurge. This highlight article provides an elaborated view on the developments of catalytic synthetic methods that have been explored to achieve dual axial chirality in biaryl ethers and related scaffolds. [ABSTRACT FROM AUTHOR]

5N‐Benzoyl‐1,5‐benzodiazepin‐2‐ones with various substituents were synthesized and their atropisomeric properties were analyzed. For the rotational isomers (E/Z) based on the amide bond [N−C(=O)], the E‐isomers were preferentially formed regardless of the substituents. Atropisomers (aR/aS) due to the Ar−N(CO) (sp2‐sp2) axis were isolated using chiral HPLC, and the rotational barrier (ΔG≠) in thermal isomerization was measured. The rotation barrier about the Ar−N(CO) axis was affected by both the substituents at the C6‐position and the p‐substituents on the benzoyl group. The substituents at C6 (R1) caused both steric and electronic effects. On the other hand, the p‐substituents (R2) on the benzoyl group caused electronic effects: the electron‐donating group (EDG) lowered the ΔG≠ value, whereas the electron‐withdrawing group (EWG) raised it. The ΔG≠ values were linearly correlated with the magnitude of the electronic effect (Hammett σ constants) of functional groups (R2). The EDG causes an increase in the electron density on the carbonyl moiety in the amide, which may disturb the planarity of the amide bond, resulting in a decrease in the ΔG≠ value. [ABSTRACT FROM AUTHOR]

Nickel‐catalyzed transannulation reactions triggered by the extrusion of small gaseous molecules have emerged as a powerful strategy for the efficient construction of heterocyclic compounds. However, their use in asymmetric synthesis remains challenging because of the difficulty in controlling stereo‐ and regioselectivity. Herein, we report the first nickel‐catalyzed asymmetric synthesis of N−N atropisomers by the denitrogenative transannulation of benzotriazones with alkynes. A broad range of N−N atropisomers was obtained with excellent regio‐ and enantioselectivity under mild conditions. Moreover, density functional theory (DFT) calculations provided insights into the nickel‐catalyzed reaction mechanism and enantioselectivity control. [ABSTRACT FROM AUTHOR]

The Friedel‐Crafts reaction stands as a powerful synthetic tool for C−H functionalization of aromatic feedstocks, which is conventionally realized through electrophilic alkylation and acylation. The burgeoning interests in axially chiral compounds across diverse fields have spurred extensive exploration of this classic transformation for catalytic atroposelective synthesis. Consequently, the past decade has witnessed the rapid expansion of various non‐canonical Friedel‐Crafts reactions, including electrophilic arylation, alkenylation, halogenation, sulfenylation, and amination of aryl C−H bonds, thereby delving into new chemical spaces. A range of catalytic atroposelective synthetic methods have been devised for these significant arene C−H functionalization. This review provides a comprehensive overview of the cutting‐edge catalytic synthesis of atropoisomers through non‐canonical Friedel‐Crafts reactions, categorized into three parts based on the type of bond formation on the aromatics: C(sp2)−C(sp3) bond formations, C(sp2)−C(sp2) bond formations and C(sp2)−heteroatom bond formations. The richness of electrophiles and the modulation of atroposelectivity by diverse chiral organocatalysts, particularly chiral Brønsted acids, are elucidated. We anticipate that the repertoire of asymmetric Friedel‐Crafts reaction will continue to flourish and to be demonstrated in not only scientific researches but also industrial organic synthesis. [ABSTRACT FROM AUTHOR]

The development of new methods for regio‐ and stereoselective activation of C−O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C−N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel‐catalyzed regio‐ and enantioselective carbon‐oxygen arylation reaction for atroposelective synthesis of N‐arylisoquinoline‐1,3(2H,4H)‐diones. The high regioselectivity of C−O cleavage benefits from the high stability of the in situ formed (amido)ethenolate via oxidative addition. Additionally, the self‐activation of the aryl C−O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post‐functionalizations of the axially chiral isoquinoline‐1,3(2H,4H)‐diones further highlighted the utility of this protocol in preparing valuable C−N atropisomers, including the chiral phosphine ligands. [ABSTRACT FROM AUTHOR]

Atroposelective synthesis of N-N atropisomers is an emerging area but remains underexplored; in particular, the synthesis of N-N benzimidazole atropisomers is still unprecedented. Herein, the first enantioselective synthesis of N-N benzimidazole atropisomers via the palladium-catalyzed de novo construction of benzimidazole skeleton is presented. With readily available palladium catalyst and biphosphine ligand, a broad range of nonbiaryl benzimidazole and indole-benzimidazole atropisomers were conveniently accessed in high yields and with excellent enantioselectivities. Significantly, these N-N benzimidazole atropisomers showed great antitumor activity and selectivity to breast cancer MCF-7 cells. The simple catalytic system, broad substrate scope, high enantioselectivity, and good bioactivity make this approach highly attractive. [ABSTRACT FROM AUTHOR]

Herein, we report an asymmetric two-component alkenyl Catellani reaction for the construction of C--N axial chirality through a palladium/chiral norbornene cooperative catalysis and an axial-to-axial chirality transfer process. Various partially aromatic iodinated 2-pyridones, quinolones, coumarin and uracil substrates react with 2,6-disubstituted aryl bromides with a tethered amide group, to afford a wide variety of polycyclic C--N atropisomers (38 examples, up to 97% e.e.). The obtained C--N axial chirality originates from the preformed transient C--C axial chirality with high fidelity. The synthetic utility of this chemistry is demonstrated by facile preparation of complex quinoline and pyridine based C--N atropisomers through a N-deprotection and aromatization sequence. In addition, a remote axial-to-central diastereoinduction process dictated by C--N axial chirality is observed with excellent diastereocontrol. [ABSTRACT FROM AUTHOR]

Axially chiral architectures exist widely in natural products, biologically relevant molecules, chiral ligands and catalysts as well as functional materials. Therefore, catalytic asymmetric synthesis of atropisomers has become one of the most fast‐growing fields in the community of chemistry and rapid advances have occurred. Among different methods reported, the organocatalytic atroposelective dynamic kinetic resolution (DKR) involving ring manipulations stands out as a cutting‐edge technology to construct axial chirality from the point of atom/step economy. In this DKR strategy, the configurational lability of starting materials originates from chirally‐labile ring structure of cyclic substrates/intermediates or transient ring formation through noncovalent interactions from acyclic substrates. The two atropisomers of starting material are in equilibrium in the reaction medium, ensuring the constant transformation of the less reactive atropisomer into the more reactive one, and then to a single enantiopure product in the presence of an appropriate organocatalyst. This review summarizes recent advancements on this topic, including their scopes, limitations, mechanisms, applications and provides some insights into further developments. [ABSTRACT FROM AUTHOR]

The efficient cross-dehydrogenative coupling of electronically rich and sterically congested benzofulvene with bi-(hetero)aryl moieties to construct an axially chiral benzofulvene core remains a formidable task. In this study, we describe a highly efficient and practical palladium-catalyzed approach for atroposelective bi-(hetero)aryl benzofulvene synthesis, achieving excellent enantioselectivity with moderate yields. This protocol offers a remarkable opportunity for the direct regio- and enantioselective conversion of C–H bonds of benzofulvene to C–C bonds. Furthermore, the protocol permits the incorporation of benzofulvene with a 4-phenyl coumarin core, enabling access to a novel class of axially chiral coumarins. [ABSTRACT FROM AUTHOR]

Azomethine imines, as a prominent class of 1,3‐dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper‐ or chiral phosphoric acid catalyzed ring‐closure reactions of N′‐(2‐alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy‐induced peripheral neuropathy (CIPN). Remarkably, the (S)‐ and (R)‐atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry. [ABSTRACT FROM AUTHOR]

Axially chiral diaryl ethers are present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N‐heterocyclic carbene‐catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2‐aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late‐stage functionalization, gram‐scale synthesis, and diverse enantioretentive transformations. Control experiments and DFT calculations support the association of NHC‐catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity. [ABSTRACT FROM AUTHOR]

The first atroposelective Chan–Lam coupling for the synthesis of C–N axial enantiomers is reported with good yields and ee. MnO2 additive is crucial for the success of the coupling. The longstanding problem of the lack of enantioselective synthesis to make chiral C–N linked atropisomers is solved. [ABSTRACT FROM AUTHOR]

The construction of N–N axially chiral motifs is an important research topic, owing to their wide occurrence in natural products, pharmaceuticals and chiral ligands. One efficient method is the atroposelective dihydropyrimidin-4-one formation. We present herein a direct catalytic synthesis of N–N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC (N-heterocyclic carbenes) catalyzed (3 + 3) cycloaddition. Using our method, we are able to synthesize structurally diverse N–N axially chiral pyrroles and indoles with vicinal central chirality or bearing a 2,3-dihydropyrimidin-4-one moiety in moderate to good yields and excellent enantioselectivities. Further synthetic transformations of the obtained axially chiral pyrroles and indoles derivative products are demonstrated. The reaction mechanism and the origin of enantioselectivity are understood through DFT calculations. N–N axially chiral motifs are of synthetic interest due to their presence in natural products, pharmaceuticals, and chiral ligands. Here, the authors develop a direct catalytic synthesis of N–N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC catalyzed (3 + 3) cycloaddition. [ABSTRACT FROM AUTHOR]

With the rapid development of asymmetric catalysis, the demand for the enantioselective synthesis of complex and diverse molecules with different chiral elements is increasing. Owing to the unique features of atropisomerism, the catalytic asymmetric synthesis of atropisomers has attracted a considerable interest from the chemical science community. In particular, introducing additional chiral elements, such as carbon centered chirality, heteroatomic chirality, planar chirality, and helical chirality, into atropisomers provides an opportunity to incorporate new properties into axially chiral compounds, thus expanding the potential applications of atropisomers. Thus, it is important to perform catalytic asymmetric transformations to synthesize atropisomers bearing multiple chiral elements. In spite of challenges in such transformations, in recent years, chemists have devised powerful strategies under asymmetric organocatalysis or metal catalysis, synthesizing a wide range of enantioenriched atropisomers bearing multiple chiral elements. Therefore, the catalytic asymmetric synthesis of atropisomers bearing multiple chiral elements has become an emerging field. This review summarizes the rapid progress in this field and indicates challenges, thereby promoting this field to a new horizon. [ABSTRACT FROM AUTHOR]

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C–N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation. Developing efficient methods for the formation and cleavage of amide species is a primary research goal, but the amide C–N bond cleavage is exceptionally challenging. Here, the authors report the development of an organocatalyst that can effectively catalyze the atroposelective ring-opening of biaryl lactams via amide C–N bond cleavage. [ABSTRACT FROM AUTHOR]

Atropisomers have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N−N biaryl atropisomers have drawn increasing interest due to their unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well‐developed C−C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N−N biaryl atropisomers including N−N pyrrole−pyrrole, N−N pyrrole−indole, N−N indole−indole, and N−N indole−carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N−N biaryl atropisomers synthesis is offered. [ABSTRACT FROM AUTHOR]

Herein we report the first synthesis of tetrahydrocarbazole embedded styrene atropisomers via the reaction between 1‐(aryl‐ethynyl)‐naphthalen‐2‐ol and 2,3,4,9‐tetrahydro‐1H‐carbazole. The reaction proceeds through in situ vinylidene ortho‐quinone methide (VQM) intermediate formation. The styrene derivatives were obtained in good to high yields with high diastereoselectivities with a catalytic amount of PTSA. A catalytic asymmetric version is also reported. [ABSTRACT FROM AUTHOR]

Axially chiral open‐chained olefins are an underexplored class of atropisomers, whose enantioselective synthesis represents a daunting challenge due to their relatively low racemization barrier. We herein report rhodium(I)‐catalyzed hydroarylative cyclization of 1,6‐diynes with three distinct classes of arenes, enabling highly enantioselective synthesis of a broad range of axially chiral 1,3‐dienes that are conformationally labile (ΔG≠(rac)=26.6–28.0 kcal/mol). The coupling reactions in each category proceeded with excellent enantioselectivity, regioselectivity, and Z/E selectivity under mild reaction conditions. Computational studies of the coupling of quinoline N‐oxide system reveal that the reaction proceeds via initial oxidative cyclization of the 1,6‐diyne to give a rhodacyclic intermediate, followed by σ‐bond metathesis between the arene C−H bond and the Rh−C(vinyl) bond, with subsequent C−C reductive elimination being enantio‐determining and turnover‐limiting. The DFT‐established mechanism is consistent with the experimental studies. The coupled products of quinoline N‐oxides undergo facile visible light‐induced intramolecular oxygen‐atom transfer, affording chiral epoxides with complete axial‐to‐central chirality transfer. [ABSTRACT FROM AUTHOR]

Boron-doped organic compounds display unique properties as a result of the presence of an empty p orbital on boron and the ability to switch between a trigonal planar and a tetrahedral geometry. In recent years, they have found several applications not only as synthetic reagents, e.g., in the Suzuki–Miyaura reaction, but also as pharmaceuticals and as specialized materials due to their optical and electronic properties. Some boron compounds may exist as atropisomers, and these rotamers may have different properties according to their sense of rotation. Synthetic strategies to separate them and, more recently, to obtain them in an asymmetric manner are becoming popular. In this review, we survey the literature on this emerging field of research. [ABSTRACT FROM AUTHOR]

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N‐heterocyclic carbene (NHC)‐catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde‐containing diaryl ethers. Mechanistically, the reaction proceeds via NHC‐catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented. [ABSTRACT FROM AUTHOR]

An uracil-azo derivative of quinoline, 1,3-dimethyl-5-(8′-quinolinyl-azo)-6-aminouracil (H2L, 1), was synthesized and then converted into its atropisomers, 1,3-dimethyl-8-(8′-quinolinyl)azaxanthine (α-atropisomer (2) and β-atropisomer (3)). It is indeed a notable accomplishment that the atropisomers were synthesized selectively under dissimilar reaction conditions. Additionally, an axially elongated 5-coordinated distorted square pyramidal copper(II)-complex, [CuII(HL)(H2O)2]NO3 (4), was synthesized from H2L, where it acts as a tridentate ligand. Single crystals of compounds 2–4 were analyzed for their stereochemical characterization. The compounds (2 and 3) belong to the same space group P21 with Z = 2. Based on a torsional angle about N3–N2–C1–C9, which is 48.7(2)° for the α-atropisomer (2) and −48.7(2)° for the β-atropisomer (3), respectively, they are revealed to be atropisomers. According to TD-DFT analysis, the α-atropisomer (2) is 0.05 kcal mol−1 more energetically stable than the β-atropisomer (3). The 5-coordinated Cu1 centre adopts a distorted square pyramidal geometry (space group P21/n, Z = 4), wherein the coordination sites were occupied by three-N and two O-donor atoms from the HL− moiety and the two H2O molecules, respectively. The polycrystalline sample of 4 was subjected to direct current (dc) variable-temperature magnetic susceptibility studies over the temperature range of 1.8–300 K. The magnetic study suggests that copper(II) ions in the crystal lattice have a weak antiferromagnetic interaction, demonstrating the complex to be a mononuclear species. According to the EPR study, the distorted square-pyramidal copper(II) complex may have a dx2−y2 orbital as a ground state. All the compounds have shown significant efficacy against the bacterial plant pathogen, Ralstonia solanacearum Smith. and the fungal plant pathogen, Rhizoctonia solani Kuhn., which cause bacterial wilting of solanaceous crops and sheath blight of rice, respectively. Besides, the atropisomers have demonstrated effectiveness against another bacterial plant pathogen, Xanthomonas oryzaepv. oryzae. that causes bacterial blight of rice. The atropisomers thus differ with respect to biological efficacy towards both bacterial and fungal diseases. [ABSTRACT FROM AUTHOR]

Molecular folding regulation with environmental stimuli is critical in living and artificial molecular machine systems. Herein, we described a macrocycle, cyclo[4] (1,3-(4,6-dimethyl)benzene)[4](1,3-(4,6-dimethyl)benzene)(4-pyridine). Under 298 K, it has three stable stiff atropisomers with names as 1 (Cs symmetry), 2 (Cs symmetry), and 3 (C4v symmetry). At 393 K, 1 can reversibly transform into 2, but at 473 K, it can irrevocably transform into 3. At 338 K, 3 and (PhCN)2PdCl2 complex to produce the metal-organic cage 4. Only at 338 K does the combination of 1 or 2 and (PhCN)2PdCl2 create a gel-like structure. Heating both gels to 473 K transforms them into 4. In addition to offering a thermally accelerated method for modifying self-assembled systems using macrocyclic building blocks, this study also has the potential to develop the nanoscale transformation material with a thermal response. While heat modification is ubiquitous in biologic systems, it remains a significant challenge in artificial systems. Here the authors demonstrate thermal regulation of conversion between different rigid macrocycle atropisomers and related self-assemblies. [ABSTRACT FROM AUTHOR]

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms. [ABSTRACT FROM AUTHOR]

Chiral organosulfur compounds are not only widely distributed in bioactive natural products and pharmaceuticals, but also play a significant role in chiral ligands/catalysts. Throughout the history of synthetic organic chemistry, chemists have been absorbed in the construction of centrally chiral organosulfur compounds. Nevertheless, there are relatively few reports on installing sulfur functional groups into axially chiral compounds. Atropisomerism is one of the fundamental phenomena in nature, which ubiquitously exists in natural products. After more than a century of development, atropisomers have been designed and extensively applied to pharmaceuticals, functional materials and chiral ligands/catalysts. Due to the importance of chiral sulfur-containing atropisomers, there is an increasing demand for enantioselective synthesis of them. Recently, a diversity of approaches by C-S bond formations have been established for the construction of enantioenriched sulfur-containing atropisomers, however, there is no comprehensive review to summarize this great progress. In this mini-review, we summarize recent progress in catalytic asymmetric synthesis of sulfur-containing atropisomers by C-S bond formations, which includes sulfur nucleophilic reactions, sulfur electrophilic reactions and sulfur radical reactions. Furthermore, the reaction mechanisms are also discussed. We hope that this mini-review will enable more researchers to further explore this field. [ABSTRACT FROM AUTHOR]

Herein, we reported the synthesis of enantioenriched N-aryl peptoid atropisomers via Pd(II)-catalyzed atroposelective C–H olefination using the easily accessible L -pyroglutamic acid (L -pGlu-OH) as the chiral ligand. A series of optically active N-aryl peptoid atropisomers were obtained in synthetically useful yields with high enantioselectivities. [ABSTRACT FROM AUTHOR]

Transition‐metal‐catalyzed hydroarylation of unsymmetrical internal alkynes remains challenging because of the difficulty in controlling regioselectivity and stereoselectivity. Moreover, the enantioselective hydroarylation of alkynes using organoboron reagents has not been reported. Herein, we report for the first time that palladium compounds can catalyze the hydroarylation of 1‐alkynylindoles with organoborons for the synthesis of chiral C−N atropisomers. A series of rarely reported vinylindole atropisomers was synthesized with excellent regio‐, stereo‐ (Z‐selectivity), and enantioselectivity under mild reaction conditions. The ready availability of organoborons and alkynes and the simplicity, high stereoselectivity, and good functional group tolerance of this catalytic system make it highly attractive. [ABSTRACT FROM AUTHOR]

Axially chiral compounds are attracting more attention recently. Although hydrogen bonds are reported as a vital weak force that influences the properties of compounds, the effect of intramolecular hydrogen bonds on the atropisomerization of the Caryl−Caryl single bonds has not yet been well quantitatively investigated. Here, a series of axially chiral biaryl compounds were synthesized to study the effect of hydrogen bonds on the rotational barriers of the biaryl C−C axis. Experimental studies demonstrated that the rotational barrier of hydrogen bonding biaryl 9 was significantly lower (46.7 kJ mol−1) than biaryl 10 without hydrogen bonds. Furthermore, theoretical studies revealed that the intramolecular hydrogen bond stabilized the transition state (TS) of tri‐ortho‐substituted biaryl 9, relieving the steric repulsion in the TS. We believe that this study will provide chemists with a deeper understanding of the atropisomerization process of axially chiral biaryl compounds. [ABSTRACT FROM AUTHOR]

Axially chiral N‐substituted quinazolinones are important bioactive molecules, which are presented in many synthetic drugs. However, most strategies toward their atroposelective synthesis are mainly limited to the axially chiral arylquinazolinone frameworks. The development of modular synthetic methods to access diverse quinazolinone‐based atropisomers remains scarce and challenging. Herein, we report the regio‐ and atroposelective synthesis of axially chiral N‐vinylquinazolinones via the strategy of asymmetric allylic substitution‐isomerization. The catalysis system utilized both asymmetric transition‐metal catalysis and organocatalysis to efficiently afford trisubstituted and tetrasubstituted N‐vinylquinazolinone atropisomers, respectively. With the meticulous design of β‐substituted allylic substrates, both Z‐ and E‐tetrasubstituted axially chiral N‐vinylquinazolinones were obtained in good yields and high enantioselectivities. [ABSTRACT FROM AUTHOR]

Herein, we describe the feasibility of atroposelective PIII/PV=O redox organocatalysis by the Staudinger–aza‐Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co‐catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N‐oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration. [ABSTRACT FROM AUTHOR]

Enantioselective synthesis of N−N biaryl atropisomers is an emerging area but remains underexplored. The development of efficient synthesis of N−N biaryl atropisomers is in great demand. Herein, the construction of N−N biaryl atropisomers through iridium‐catalyzed asymmetric C−H alkylation is reported for the first time. In the presence of readily available Ir precursor and Xyl‐BINAP, a variety of axially chiral molecules based on indole‐pyrrole skeleton were obtained in good yields (up to 98 %) with excellent enantioselectivity (up to 99 % ee). In addition, N−N bispyrrole atropisomers could also be synthesized in excellent yields and enantioselectivity. This method features perfect atom economy, wide substrate scope, and multifunctionalized products allowing diverse transformations. [ABSTRACT FROM AUTHOR]

An experimental and theoretical study was carried out to analyze the configurational lability possessed by some of the most common drugs endowed with a central non‐planar seven‐membered cycloheptadiene ring, which confers chirality to these compounds. In fact, the absence of planarity allows the existence of two enantiomeric species that can interconvert thanks to a ring overturning mechanism. The energy barrier that opposes the inversion of the chiral tricyclic scaffold characterizing such species, which is strongly dependent on the presence of appropriate substituents on the two external cycles, has been investigated through Dynamic‐HPLC and off‐column racemization techniques, as well as through assessments based on molecular modelling approaches. Interesting indications were obtained by making targeted structural changes to allow accurate control of the stereolability characterizing the tricyclic framework. [ABSTRACT FROM AUTHOR]

Methyl pyropheophorbides‐a possessing an o/m‐(methoxycarbonyl)phenyl group at the 3‐position were prepared by Diels–Alder reaction of 3‐(trans‐1,3‐butadienyl)chlorin with methyl propiolate and successive didehydrogenation of the resulting 1,4‐cyclohexadienes. The 3‐arylated chlorin bearing the sterically demanding o‐COOMe group as the major product was a 1:1 mixture of high‐performance liquid chromatography‐separable rotational isomers around the C3–C31 bond, while the minor product with the m‐COOMe was less sterically hindered to exhibit rapid atropisomerization at room temperature. The 3‐aryl group of the major product was nearly perpendicular to the chlorin π‐system and less conjugated with the chlorin moiety than that of the minor product wherein more π‐conjugation occurred to give slightly red‐shifted Qy bands. Although both the atropisomers of the o‐substitute in dichloromethane showed similar visible absorption bands and fluorescence emission data, their circular dichroism bands in the ultraviolet‐C light region were dependent on the stereochemistry. [ABSTRACT FROM AUTHOR]