Recent advances in the catalytic asymmetric construction of axially chiral azole-based frameworks

Abstract

Atropisomers featuring restricted rotation around a single bond have emerged as important structural motifs due to their prevalence in drug discovery, materials science and catalyst design. In recent years, the catalytic asymmetric synthesis of atropisomers has garnered significant fascination from chemists. While traditional six-membered axially chiral skeletons are commonly studied, methodologies directed towards less abundant five-membered heterobiaryls are relatively rare. In particular, axially chiral azole-based skeletons are essential components of five-membered heterocyclic frameworks and have received considerable interest. This review focuses on recent achievements in the atroposelective preparation of azole derivatives, by emphasizing mechanistic insights and synthetic applications. We hope that this review will encourage chemists worldwide to promote the continued development of this field in the future.

---

Weiwei Luo

Weiwei Luo received his bachelor's degree (2012) and PhD (2017) from Sichuan University under the supervision of Prof. Xiaoming Feng. From 2017 to 2020, he conducted postdoctoral research at the University of North Texas with Prof. Hong Wang. In 2020, he began his independent career at Changsha University of Science and Technology. His current research interests focus on asymmetric catalysis and synthetic methodology.

Yu Zhang

Yu Zhang was born in Chongqing, China. He received his bachelor's degree in chemistry from Chongqing University of Science and Technology in 2023. He is now doing his MSc research at Changsha University of Science and Technology, under the guidance of Prof. Weiwei Luo. His current research interests focus on catalytic asymmetric construction of axially chiral azole-based frameworks.

Meijun Ming

Meijun Ming was born in Chongqing, China. She received her bachelor's degree in 2012 and her PhD in 2018 from Sichuan University, under the supervision of Prof. Xiangyuan Li. In 2018, she began her independent academic career at Sichuan Police College. Her current research interests focus on catalytic asymmetric synthesis of chiral heterocycles.

Lin Zhang

Lin Zhang received her Master's Degree in 2015 and her PhD in 2019 from Xi'an Jiaotong University under the supervision of Prof. Zhongfeng Xu. She then joined Sichuan Police College as a research associate. Her current research interests include catalytic asymmetric synthesis of axially chiral five-membered heterobiaryls.

---

1. Introduction

Axial chirality is a form of stereoisomerism that arises from the nonplanar arrangement of four substituents in pairs around a stereogenic axis.¹ Key examples include atropisomers, spiranes, allenes and spiro chiral structures. Among all the subclasses, atropisomers are of great interest because of their numerous applications in medicinal chemistry,^2–6 chiral materials,^7–10 ligands^11–13 and organocatalysts (Fig. 1).^14–17 To define a molecule as atropisomeric according to Oki's guideline, the rotational barrier to enantiomerization must exceed 23.3 kcal mol⁻¹.¹⁸ LePlante proposed that if the rotational barriers are higher than 28.0 kcal mol⁻¹, the atropisomeric molecules can be considered to be configurationally robust.¹⁹ Interestingly, while the first optically active atropisomers were isolated and determined by Christie and Kenner in early 1922,²⁰ the utility of atropisomers in asymmetric synthesis was initially reported late in 1980 by Noyori and Takaya.²¹ Since then, the catalytic atroposelective construction of axially chiral molecules and the utility of atropisomers in asymmetric synthesis have been intensively developed. Over the past decades, numerous catalytic enantioselective methodologies have been established for the synthesis of axially chiral biaryls and heterobiaryls, especially for hexatomic rings. Efficient enantioselective methodologies have been developed for the construction of axially chiral biaryls, including de novo arene formation,^22–24 functionalization of prochiral/racemic biaryls,^25–27 central-to-axial chirality conversion,^28,29 cross-coupling^30,31 and Michael-type arylation reactions,^32,33 as well as ring-opening reactions.^34,35 However, only recently has dramatic progress been made toward the rational design and atroposelective synthesis of axially chiral compounds containing five-membered heteroaryls.^36–38

Fig. 1 Atropisomers in medicinal chemistry, materials science, and catalyst design.

The inclusion of a pentatomic heterocycle leads to an increased distance between the ortho-substituents around the chiral axis, which is responsible for a lower barrier to rotation and labile conformation (Fig. 2). Despite the inherent structural challenge, significant progress has been made with both axially chiral arylindoles and arylpyrroles due to the rapid development of asymmetric catalysis. As a result, several reviews and monographs have been published, discussing the advances of axially chiral indole and pyrrole-based frameworks.^39–42 In contrast, methodologies for the construction of arylazoles have been far less explored because it is more challenging to simultaneously control the formation of heterocycles and the atroposelective installation of a chiral axis (Fig. 2).

Fig. 2 Situation of six- versus five-membered atropisomeric systems.

The azole moiety is one of the fundamental building blocks in organic synthesis, mainly including imidazoles, pyrazoles, isoxazoles, triazoles and other five-membered heterocycles with at least one nitrogen atom.^43–47 Among these, axially chiral arylazoles are unique structural frameworks with important applications in drug discovery and catalyst/ligand design (Fig. 3). For instance, alpelisib is an oral medication used to treat certain types of breast cancer, showing good efficacy in inhibiting the growth of tumours driven by the phosphoinositide 3-kinase (PI3K) enzyme.⁴⁸ As is known, an irrelevant enantiomer may contribute little to potency and even cause undesired side effects. Therefore, it is essential to separate and analyze atropisomers to ensure the safety and efficacy of potential pharmaceuticals. Moreover, StackPhos, an imidazole-based P,N-ligand with unique ligation properties and catalytic activity, has been designed and utilized as a privileged chiral ligand in the field of asymmetric metal catalysis.⁴⁹ Consequently, developing effective strategies for the catalytic enantioselective synthesis of axially chiral azole derivatives has become an urgent task and has attracted increasing attention from chemists.

Fig. 3 Representative arylazole scaffolds in drug molecules, catalysts, and chiral ligands.

Unlike the construction of axially chiral biaryls, the preparation of axially chiral azoles requires not only robust synthetic and isolation techniques but also careful consideration of configurational stability, which is affected by the increased distance between the flanking substituents around the axis. This indicates that introducing axial chirality into a substituted azole ring reduces steric interactions between the ortho-substituents around the chiral axis. As a result, due to their labile conformation, axially chiral azoles are more challenging to prepare compared to axially chiral biaryls. To maintain a stable configuration, two relatively bulky ortho-substituents on the azole ring are typically required to preserve axial chirality. Alternatively, a relatively short chiral axis, connected via a C–N or N–N bond, can provide sufficient steric interactions to achieve the same effect, even when only a single ortho-substituent is present on the azole ring.

In recent years, advancements in asymmetric catalysis have paved the way for pioneering and significant work on the atroposelective synthesis of arylazoles. Four primary strategies have emerged for the direct synthesis of optically pure azole-containing atropisomers (Fig. 4). The most widely used approach involves the atroposelective functionalization of prochiral or racemic precursors through desymmetrization, kinetic resolution, or dynamic kinetic resolution, with most examples featuring a preformed azole ring. Alternatively, a less common but more challenging approach involves the simultaneous construction of the azole ring and the chiral axis from simple acyclic and achiral precursors. This strategy, known as de novo azole synthesis, includes intramolecular cyclization and intermolecular annulation. Additionally, atroposelective C–H arylation catalyzed by either a transition metal or an organocatalyst has emerged as a powerful alternative for constructing axially chiral azole-containing scaffolds. There are exceptions to these structural limitations, where the azole ring itself functions as an ortho-substituent around the chiral axis, thus simplifying the challenges and enabling the formation of more commonly occurring axially chiral biaryls.

Fig. 4 Schematic presentation of synthetic strategies.

We thus aim to provide an overview of the latest developments and trends in the synthesis of axially chiral arylazoles through either transition metal catalysis or organocatalysis. Unlike the well-summarized reviews that are typically organized based on various reaction categories, this review is structured according to the different types of axially chiral azole-based scaffolds, to provide readers with a clearer and more efficient understanding of the development of various azole rings. We hope that this review will offer readers a quick entry into this rapidly expanding domain and will promote further developments in the synthesis of axially chiral azole-based frameworks.

2. Pyrazole-based frameworks

Pyrazole, a five-membered heterocycle with two adjacent nitrogen atoms, is recognized as a privileged structure frequently found in pharmaceutical lead compounds, therapeutic agents, and agricultural chemicals.⁵⁰ Interestingly, although the first natural pyrazole, 1-pyrazolyl-alanine, was isolated from the seeds of watermelons in 1959, the enantioselective synthesis of a pyrazole derivative was not reported until as late as 2009.⁵¹ The asymmetric synthesis of axially chiral pyrazoles emerged even later, despite the fact that atroposelective arylpyrazoles hold significant promise for the discovery of new compounds with unique properties and potential applications across a wide range of fields.

Organocatalytic C–H arylation typically exploits the nucleophilicity of aromatic nucleophiles for electrophilic addition with different highly reactive electrophiles (e.g., quinones and azonaphthalenes).^32,33 These electrophiles often possess functional groups that serve as both directing and activating groups, thereby facilitating organocatalytic C–H arylation. These transformations proceed through stereoselective Michael-type addition, generating stereochemically enriched intermediates with point chirality. Then aromatization occurs, accompanied by central-to-axial chirality conversion, resulting in a stereochemically defined biaryl linkage. Due to the presence of multiple functional groups in the electrophiles capable of forming hydrogen bonds, chiral phosphoric acids (CPAs) are commonly employed as organocatalysts.⁵²

The multiple reactive sites of pyrazolone synthons enable the development of versatile strategies for synthesizing various chiral pyrazole derivatives under enantioselective catalytic systems.⁵³ Among them, electrophilic substitution at the C-4 position of pyrazolones is one of the most common and efficient methods for constructing pyrazoles linked to chiral groups. In 2019, Li and co-workers reported the first catalytic asymmetric synthesis of axially chiral N-arylpyrazoles, utilizing pyrazolones 1 as C-nucleophilic precursors.⁵⁴ In the presence of a SPINOL (1,1′-spirobiindane-7,7′-diol)-derived CPA, the enantioselective C–H arylation reaction of pyrazolones 1 with azonaphthalenes 2 afforded a variety of axially chiral 4-arylpyrazoles 3 in good yields and excellent enantioselectivities (Scheme 1). The enantiomerization barrier of a model atropisomeric pyrazole framework 3a was determined to be 27.3 kcal mol⁻¹, which was in good agreement with the calculated value of 26.7 kcal mol⁻¹. Theoretical calculations in this work suggested that the CPA acts as a proton-transfer shuttle to facilitate proton transfer from the enolate of pyrazolone to the azo moiety of azonaphthalene through dual hydrogen bonding interactions. Moreover, the enantiocontrol was largely attributed to the extra aromatic C–H–O hydrogen bonding interaction and π–π stacking interaction between the substrates and the catalyst. The chiral information from the CPA could be transferred to the intermediate Micheal product, which is then translated into axial chirality during the subsequent aromatization process.

Scheme 1 Organocatalytic C–H arylation of pyrazolones with azonaphthalenes.

5-Aminopyrazoles are recognized as an important class of aromatic nucleophiles for the construction of chiral pyrazole scaffolds. Very recently, Zhao's team successfully achieved the direct arylation reaction of 5-aminopyrazoles 4 with azonaphthalenes 2 under CPA catalysis, furnishing pyrazole-based heterobiaryl diamines 5 with high efficiency while demonstrating broad substrate compatibility (Scheme 2).⁵⁵ The reaction proceeded with high yields and enantioselectivities, though at the expense of longer reaction times in the tested substrates. Notably, this method could also be applied on a larger scale without any loss of enantioselectivity.

Scheme 2 Organocatalytic C–H arylation of 5-aminopyrazoles with azonaphthalenes.

As is common in CPA catalysis, the simultaneous activation of both azonaphthalene 2a and 5-aminopyrazole 4a through a dual hydrogen-bonding mechanism leads to the formation of intermediate Int-I. Subsequently, 5-aminopyrazole 4a preferentially undergoes nucleophilic attack at the α-position of azonaphthalene, with (R)-CPA2 serving as a proton-transfer mediator, facilitating the transfer of a proton from the N–H of 5-aminopyrazole to the N=N double bond of azonaphthalene. This process is followed by the rearomatization of intermediate Int-II, resulting in the formation of pentatomic heterobiaryl diamine 5a featuring a pyrazole ring.

In addition to azonaphthalenes, quinones have also been employed as efficient electrophiles in organocatalytic C–H arylation reactions with pyrazoles, enabling the synthesis of axially chiral arylpyrazoles. In 2023, Li, Chen and co-workers reported a highly enantioselective arylation reaction for the construction of arylpyrazole atropisomers by using a CPA catalyst (Scheme 3).⁵⁶ Starting from 3-aryl-5-aminopyrazoles 4 and quinone derivatives 6, a wide range of axially chiral arylpyrazoles 7 could be obtained in generally high yields and very good enantioselectivities. In addition, the racemization experiment to study the thermal stability of axially chiral pyrazole product 7a presented a good result in isopropyl alcohol at 70 °C. The rotation barrier was calculated to be 27.393 kcal mol⁻¹, with a half-life of 3.83 hours, indicating good synthetic potential for further biological studies.

Scheme 3 Organocatalytic C–H arylation of 5-aminopyrazoles with quinones.

The proposed mechanism shows that chiral phosphoric acid CPA3 simultaneously activates 5-aminopyrazole 4a and 1,4-quinone 6a by forming multiple hydrogen bonds, accordingly allowing further enantiocontrol. 5-Aminopyrazole 4a undergoes Michael-type addition to 1,4-quinone 6a through the more favorable intermediate A1, producing transition intermediate Int-I with two adjacent stereogenic centers. Finally, aromatization of Int-I proceeds through center-to-axial chirality transfer, resulting in the formation of axially chiral arylpyrazole 7a.

The following year, after switching quinone to naphthoquinone, Zheng's group⁵⁷ and Wang's group⁵⁸ independently reported an asymmetric arylation reaction of 5-aminopyrazoles 4 for the assembly of axially chiral naphthylpyrazoles 9. As depicted in Scheme 4, the reaction of 5-aminopyrazoles 4 with naphthoquinone derivatives 8 in the presence of CPA catalysts delivered chiral 4-arylpyrazoles 9 in moderate to good yields with generally excellent enantioselectivities. However, replacing the tert-butyl group with a methyl group resulted in racemic product 9d, indicating that the sterically demanding group on the pyrazole ring is essential for atropostability. It should be noted that the reaction was also extended to other electrophilic partners, including naphthoquinones without the electron-deficient ester group and quinone methyl ester, as demonstrated in Zheng's work. Moreover, the thermal racemization experiment conducted by Wang et al. revealed that compound 9a exhibits a high enantiomerization barrier of 31.1 kcal mol⁻¹ at 90 °C, with a half-life time of racemization at room temperature of approximately 107 years. Given the similarity of this methodology to Li's work,⁵⁶ the authors herein proposed that CPA-catalyzed enantioselective conjugate addition occurred first, generating centrally chiral intermediates. In the following central-to-axial chirality conversion step, the aromatization of the intermediate produced axially chiral naphthylpyrazoles.

Scheme 4 Organocatalytic C–H arylation of 5-aminopyrazoles with naphthoquinones.

In addition to the aforementioned organocatalytic C–H arylation, transition-metal catalyzed C–H functionalization has also been developed as an efficient strategy for synthesizing axially chiral arylpyrazoles. Although direct atroposelective C–H arylation circumvents the need to preform densely substituted and sterically hindered aryl halides or organometallic reagents, as required in cross-coupling reactions, the harsh conditions necessary to form such congested bonds can compromise configurational stability, thereby limiting broader applicability.

In 2023, Tang and co-workers developed a Pd-AntPhos-catalyzed enantioselective C–H arylation of ortho-functionalized five-membered heterocycles (pyrazoles, 1,2,3-triazoles, and imidazoles), allowing access to a large number of axially chiral heterobiaryls in good yields with excellent enantioselectivities under mild reaction conditions (Scheme 5).⁵⁹ Among the various AntPhos-type ligands screened, the sterically smaller CD₃-AntPhos outperformed CH₃-AntPhos in terms of both yield and enantioselectivity in the typical model reaction. This case is particularly notable because it is rare for a deuterated ligand to provide superior enantioselectivity compared to the corresponding non-deuterated ligand. An edge-to-face C–H⋯π interaction between Np–H of compound 11 and the anthracene face of L1, along with a strong noncovalent C–D⋯O interaction between the CD₃ group of L1 and the methoxy group on the naphthalene ring of compound 11, plays a significant role in influencing enantioselectivity. Benefiting from the unique properties of axially chiral heterobiaryl skeletons, axially chiral arylazole 12c could be easily transformed into monophosphine ligand 14, which holds significant potential for application in the development of chiral ligands.

Scheme 5 Pd-catalyzed C–H arylation of functionalized azoles.

Kinetic resolution (KR) is a widely used method for differentiating between two enantiomers in a racemic mixture, based on their differing reaction rates with a chiral catalyst or reagent. In this process, enantiomerization occurs more slowly than selective transformation of one enantiomer, thereby limiting the maximum yield of one pure enantiomer to 50%. To overcome this limitation, in situ racemization of the starting material can be combined with KR, a process known as dynamic kinetic resolution (DKR), where the two enantiomers are in equilibrium. In the context of DKR, quantitative enantioenrichment of one enantiomer is afforded in the transformed product, as the inversion of configurationally labile substrates (to generate a more reactive enantiomer) occurs more rapidly than the transformation of the less reactive enantiomer.

Recently, configurationally labile atropochiral scaffolds have been identified as ideal candidates for the synthesis of axially chiral atropisomers through the DKR strategy. In this process, a small group (e.g., a hydrogen atom) adjacent to the axis is replaced by a larger group via asymmetric induction, thereby restricting free rotation and allowing the formation of the stereogenic axis through the DKR pathway. The Shi group has successfully constructed various indole-based scaffolds bearing both axial and central chirality via DKR of 3-arylindoles.^60–64 Inspired by this research, Zhan and Huang designed a new type of pyrazole-indole scaffold through a CPA-catalyzed aza-Friedel–Crafts reaction of 3-indolyl pyrazoles 15 with pyrazolone-derived imines 16 in 2022 (Scheme 6).⁶⁵ This reaction can produce 4′-indole-pyrazolylacetate derivatives 17 featuring both a chiral axis and a quaternary stereocenter in good to high yields with exceptional diastereoselectivities and enantioselectivities. Interestingly, the OAc group on compound 15 was found to increase the HOMO energy compared to a methyl group, which played an important role in promoting the conversion. Remarkably, the stereodetermining step involved chiral acid CPA6-catalyzed stereoselective C–C bond formation via a Mannich reaction, which allowed for the simultaneous establishment of both axial chirality and central chirality with high selectivity.

Scheme 6 Aza-Friedel–Crafts reaction of 3-indolyl pyrazoles with imines via the DKR strategy.

The de novo synthesis of azoles represents a straightforward pathway for the enantioselective preparation of axially chiral arylazoles due to its high bond-forming efficiency and atom economy. A retrosynthetically unique atroposelective synthetic approach diverges from the conventional view of considering the arene as a preformed moiety; instead, it involves the asymmetric generation of the stereogenic biaryl linkage concurrently with the de novo construction of an aromatic ring. Diverse catalytic systems, particularly organocatalytic approaches, have been developed to construct arylazole frameworks from simple starting materials through asymmetric cyclization reactions.

In particular, Yan's work in the field of ring formation to construct axially chiral heterocycles using vinylidene ortho-quinone methides (VQMs) as key intermediates is both highly representative and influential.^66,67 In 2022, the Yan group designed a strategy to construct chiral naphthyl-pyrazoles through a ring formation method that utilized modified VQM intermediates. Prior to this, no catalytic synthetic approach has been developed to simultaneously construct the stereogenic axis and the pyrazole ring, a process also known as de novo pyrazole synthesis. This innovative approach was catalyzed by cinchona alkaloid derivative C1 or C2, leading to the synthesis of atropoisomeric naphthyl pyrazoles with excellent yields and enantioselectivities (Scheme 7).⁶⁸ It is important to note that for sulfonyl hydrazone substrates, no brominating reagent is required for the formation of the VQM intermediate. In contrast, diphenylphosphine oxide hydrazone substrates require NBS as a brominating reagent, and pleasingly, satisfactory results were achieved in a short reaction time. Moreover, thermal racemization experiments on axially chiral pyrazole 19b, which bears a single ortho-benzenesulfonyl group on the pyrazole ring, revealed modest axial stability with a half-life of 169 minutes at 55 °C and 14 minutes at 90 °C, respectively.

Scheme 7 De novo pyrazole synthesis via intramolecular cyclization of VQMs.

The plausible reaction mechanism involves a VQM intermediate, which plays a crucial role in determining the stereoselectivity of the process. Subsequently, the sp³-N of the hydrazone acts as a nucleophile, attacking the central sp-C of the VQM intermediate from the less sterically hindered side, thereby facilitating intramolecular cyclization and leading to the formation of intermediate Int-III. The protonation of Int-III leads to the release of axially chiral naphthyl-pyrazole 19a and simultaneously regenerates the catalyst.

Simultaneously, Wang, Song and colleagues developed an asymmetric synthesis of axially chiral arylpyrazole atropisomers containing a phosphorus unit, which was achieved through dipeptide phosphonium salt catalysis via a de novo pyrazole synthesis approach.⁶⁹ The synthetic route combines a Huisgen-type cycloaddition/aromatization cascade reaction with a central-to-axial chirality conversion strategy. As shown in Scheme 8, the reaction of naphthyl substituted nitroolefins 21 and α-diazo phosphonate 22 led to a range of 4-arylpyrazoles 23 bearing a chiral C–C axis. Furthermore, the reaction demonstrated high enantioselectivity and good scalability. Importantly, the synthesized axially chiral arylpyrazoles could be transformed into atropisomeric mono- and bisphosphine compounds without any loss of enantiomeric purity. These phosphorus molecules were successfully employed as chiral ligands in Pd-catalyzed asymmetric allylic alkylation/amination and Rh-catalyzed asymmetric 1,4-addition.

Scheme 8 De novo pyrazole synthesis via Huisgen-cycloaddition/aromatization cascade reaction.

In the proposed reaction mechanism, the base-triggered deprotonation of diazophosphonate 22a generates anionic intermediate Int-I, which is likely stabilized by a phosphonium cation. Simultaneously, the dipeptide-phosphonium catalyst activates nitroolefin substrates 21 through a hydrogen-bonding mode. A subsequent 1,3-dipolar (3 + 2) cycloaddition occurs to yield enantioenriched intermediate Int-II. Subsequently, stereospecific intramolecular 1,3-H shift takes place on the pyrazole ring to produce intermediate Int-III, which rapidly underwent elimination and aromatization under basic conditions, leading to the formation of axially chiral arylpyrazoles with central-to-axial chirality conversion.

3. Triazole-based frameworks

Among nitrogen-containing aromatic heterocyclic scaffolds, triazoles are considered as privileged structural motifs and have received increasing attention from chemists in academics and industry. Although not common in nature, triazoles have found numerous applications in modern synthetic chemistry, drug discovery, polymer chemistry, bioconjugation, supramolecular chemistry and materials science.⁷⁰ Additionally, 1,2,3-triazoles are commonly employed as connecting linkers in click chemistry, particularly in azide–alkyne cycloaddition (AAC) reactions.⁷¹ In 2022, Sharpless, Meldal, and Bertozzi were awarded the Nobel Prize in Chemistry for their pioneering work in the development of the click reaction.⁷² Consequently, the de novo construction of triazoles via enantioselective azide–alkyne cycloaddition (E-AAC) is anticipated to be an undoubtably efficient click technology for synthesizing structurally diverse chiral triazoles. However, the synthesis and application of atropisomeric triazoles have long been overlooked, likely due to the lack of rational substrate design and the low configurational stability of these compounds.

Enantioselective copper-catalyzed azide–alkyne cycloaddition (E-CuAAC) is one of the most straightforward and atom-economical approaches for the synthesis of structurally diverse chiral 1,2,3-triazoles. The challenges of achieving asymmetry in the E-CuAAC reaction have perplexed organic chemists for a long time, primarily due to the linear structures of the azide and alkyne, which complicate the control of enantioselectivity. More importantly, the CuAAC reaction produces a triazole, which lacks a stereocenter within the ring. Early efforts of Fokin,⁷³ Zhou⁷⁴ and Stephenson⁷⁵ have reported important enantioselective examples featuring central chirality, achieved through either a KR process or a desymmetrization strategy. As one approach for the atroposelective functionalization of prochiral or racemic precursors, desymmetrization can lead to the exclusive formation of a single chiral product if the difference in reaction rates between the two enantiotopic groups is sufficiently large, with the assistance of a chiral catalyst.

In 2014, Uozumi reported the enantioposition-selective CuAAC reaction of dialkynes 24 with azides 25, leading to the formation of axially chiral biaryls containing a 1,2,3-triazole ring (Scheme 9).⁷⁶ The reaction was limited to the use of benzyl azide to achieve good enantioselectivities; however, modifications to the aryl ring of the dialkynes were well tolerated, as were the use of both naphthalene and ortho-substituted benzene rings as the sole aryl moiety. The resulting axially chiral monotriazoles 26 can be used as synthetic intermediates for subsequent catalytic hydrogenation and the Sonogashira reaction. Although the substrate scope of this methodology is limited, it represents the first example of a prochiral biaryl being desymmetrized by a chiral copper complex via an E-CuAAC reaction, yielding a triazole-based axially chiral biaryl product in high efficiency.

Scheme 9 De novo triazole synthesis via a desymmetrizing E-CuAAC reaction of achiral biaryls.

Building on the elegant work by the Uozumi group, chemists have been exploring the possibility of constructing axially chiral diaryl ethers through a transition-metal-catalyzed desymmetric AAC reaction. Further challenges remain with this reaction, particularly related to the dual-axial C–O chirality, which must be addressed. Inspired by the biocatalytic and organocatalytic approaches for constructing various axially chiral diaryl ethers developed by the group of Clayden and Turner,⁷⁷ the group of Zeng and Zhong,⁷⁸ Yang group,⁷⁹ Biju group⁸⁰ and others,⁸¹ Yao et al.⁸² and Lu et al.⁸³ successively reported methods starting from dialkynes 29 using the CuAAC strategy with simple azides in the presence of oxazoline ligands (Scheme 10). A wide range of C–O atropisomers possessing 1,2,3-triazole rings were obtained in good yields and with excellent enantioselectivities. Notably, the residual alkyne motifs in these products provide a versatile platform for further diversification and product enrichment. Thermal racemization experiments determined the rotational barrier and half-life period of the C–O axis in 30a to be 35.9 kcal mol⁻¹ and 38.5 hours at 150 °C, respectively, providing a foundation for its isolation and potential further applications.

Scheme 10 De novo synthesis of triazole via a desymmetrizing E-CuAAC reaction of achiral diaryl ethers.

The Yao group observed a negative nonlinear effect between the ee values of ligand L3 and product 30a, suggesting that the heterochiral dimeric species is more reactive than the corresponding homodimer. In contrast, the Lu group observed a positive nonlinear effect, indicating that the mononuclear copper catalyst may not be the active catalytic species in this E-CuAAC reaction. Control experiments indicate that the desymmetrization step plays a major role in enantioselectivity control for this E-CuAAC reaction. Although a subsequent kinetic resolution process is involved, it has a negligible effect on improving the enantioselectivity of product 30a. In the proposed reaction mechanism by Lu, the diaryl ether undergoes desymmetrization with the assistance of a chiral copper(I) complex, forming Cu(I) acetylide at one of the alkynyl sites. The subsequent cycloaddition reaction yields triazole ent-30a as a major enantiomer, followed by a kinetic resolution process that consumes the minor enantiomer, resulting in the formation of a symmetric bistriazole. As a result, the enantiomeric excess of the major enantiomer of ent-30a increases as the reaction progresses, reaching the highest when the minor enantiomer of 30a is fully converted into the bistriazole byproduct.

Although seminal reports have clearly demonstrated the efficiency of direct catalytic E-CuAAC in producing axially chiral compounds containing a triazole ring, applying this strategy to construct atropisomeric 1,2,3-triazoles remained challenging, presumably due to the potential conformational instability of such compounds. It is worth noting that Dehaen et al.⁸⁴ and Fossey et al.⁸⁵ have independently reported the construction of atropisomeric aryltriazoles; however, both of them relied on non-asymmetric click reactions. In 2022, Xu's team stereoselectively synthesized axially chiral aryltriazoles 33via an E-AAC reaction of naphthol-containing alkynes 32 with both aromatic and aliphatic azides 25, promoted with high efficiency through Ir(I)/quinidine squaramide cooperative catalysis (Scheme 11).⁸⁶ The reaction system was tolerant of a wide range of functional groups at various positions on both alkynes and azides. More importantly, configuration-reversed products were readily obtained in high yields and excellent enantioselectivities when a quinine-derived squaramide was applied together with an Ir(I) catalyst.

Scheme 11 De novo triazole synthesis by an Ir-catalyzed E-AAC reaction.

As proposed in Scheme 11, tridentate chelation of squaramide C4 with the Ir(I) center results in the in situ formation of active artificial metal/organo-catalyst Int-I. This catalyst subsequently reacts with (phenylethynyl)naphthalen-2-ol 32a to generate a VQM intermediate through 1,5-hydrogen migration. The Ir(I)/squaramide complex bifunctionally activates the VQM intermediate and azide 25a by the acidic NH group and Ir(I) center through hydrogen-bonding interaction and coordination interaction. The rigid transition state Int-II facilitates the enantioselective cycloaddition to form intermediate Int-III, which then undergoes stereospecific 1,5-hydrogen migration to afford the final product 33a.

Shortly after, Li's group⁸⁷ and Cui's group⁸⁸ independently devised analogous E-AAC reactions employing a catalyst system comprising a Rh(I) complex and a phosphoramidite ligand (Scheme 12). In lieu of 1-(azidomethyl)naphthalene type azides used in Li's protocol, the scope of the azide fragment was used extensively in Cui's study. Both catalytic systems exhibited mild reaction conditions, excellent functional group tolerance, remarkable efficiency, enantioselectivity, and scalability. Moreover, the obtained atropisomers could be easily converted to chiral heteroaryl monophosphine ligands, which show promising potential in asymmetric catalysis. The axial stability of tetra-ortho-substituted aryltriazoles was substantial in toluene at 120 °C (33f and 33a, 30.1 kcal mol⁻¹ and 34.6 kcal mol⁻¹, respectively), demonstrating that five-membered C–C axially chiral 1,2,3-triazoles are sufficiently stable to serve as brand-new scaffolds for the development of chiral ligands and catalysts.

Scheme 12 De novo triazole synthesis by an Rh-catalyzed E-AAC reaction.

In Li's report, control experiments using O-methyl-protected alkyne revealed that the hydroxy group plays an important role in achieving excellent regioselective [3 + 2] cycloaddition. Density functional theory (DFT) calculations further revealed that the O–H⋯Cl hydrogen-bonding interaction between the Rh(I) complex and the phenolic hydroxyl of substrate 32a was crucial for controlling the regioselectivity. In the proposed mechanism, the initial step involves the coordination of (phenylethynyl)naphthalen-2-ol 32a with [Rh(COD)Cl], leading to the formation of Rh-complex Int-I. This intermediate is then trapped by naphthylazide 25, affording intermediate Int-II. Subsequently, intermediate Int-II undergoes a [3 + 2] cycloaddition, followed by reductive elimination, yielding the final product 33f and regenerating the catalyst.

Apart from electrophilic naphthol-containing alkynes, naphthylamine-containing alkynes have also been explored for the preparation of triazolyl atropisomers. In 2023, Cui and co-workers further developed a rhodium-catalyzed atroposelective synthesis of 1-triazolyl-2-naphthylamines 35 through an asymmetric click AAC reaction of 1-alkynyl-2-naphthylamines 34 with azides 25 (Scheme 13).⁸⁹ Along similar lines, utilizing [Rh(COD)OH]₂ in combination with phosphoramidite ligand L6, the Cui group constructed quite a few 1-triazolyl-2-naphthylamine scaffolds with high efficiency and atroposelectivity. The atropostability of these skeletons was verified with 1-triazolyl-2-naphthylamine product 35c, where the ee remained unchanged at 90 °C after 96 hours. Notably, this method was applicable on a gram-scale, affording product 35f with 91% yield and 87% ee through crystallization rather than chromatography. Importantly, the amino group of the synthesized axially chiral aryltriazole could be transformed into different functionalities (e.g., chlorine, bromo, and azido) via the Sandmeyer reaction. It can also be transformed into atropisomeric urea 39, which could be a potential organocatalyst in asymmetric transformations.

Scheme 13 De novo triazole synthesis by an Rh-catalyzed E-AAC reaction of 1-alkynyl-2-naphthylamines.

Undoubtedly, the enantioselective IrAAC and RhAAC reactions mentioned above represent significant breakthroughs in the atropisomeric synthesis of aryltriazoles. These reactions not only paved the way for accessing axially chiral multi-substituted 1,2,3-triazoles, which are otherwise difficult to obtain through traditional E-CuAAC reactions, but also remarkably advanced the understanding of asymmetric AAC chemistry.

Despite the significant progress made in the design and synthesis of axially chiral aryltriazoles featuring [5.6] aryl-heteroaryls, the preparation of axially chiral [5.5] heterobiaryls remains more challenging due to their more labile conformations compared to [5.6]-aryl-heteroaryls. Xu et al. produced axially chiral N-triazolyl indoles 41 by rhodium-catalyzed click cycloaddition of N-alkynylindoles with azides in the presence of Tol-BINAP ligand L7 in 2023.⁹⁰ A wide range of C–N axially chiral triazolyl indoles could be obtained in high yields with excellent regio- and enantioselectivity (Scheme 14). The stereochemical stability of this novel framework was exemplified by 41b, for which the rotational barrier and half-life period were determined to be 32.9 kcal mol⁻¹ and 23 h at 120 °C, respectively. The utility of the current protocol was demonstrated through a gram-scale experiment and further transformations of the indole ring and ester group.

Scheme 14 De novo triazole synthesis by an Rh-catalyzed E-AAC reaction of N-alkynylindoles.

Control reactions highlighted the crucial role of sp² oxygen in the tosyl or carbonyl group as an important directing group for coordination with the Rh(I) catalyst. Based on the control experiments, a mechanism was proposed involving a direct [3 + 2] cycloaddition of azide with the triple bond of an internal alkyne. The chiral Rh(I) catalyst coordinates with both the alkyne and oxygen moieties of N-alkynyl indole 40c, thereby fixing the conformation to form intermediate Int-II. This intermediate was then trapped by azide 25a, leading to the formation of intermediate Int-III. Subsequently, the final product 41c is obtained through an asymmetric click cycloaddition. This study represents the first example of an E-AAC reaction in producing [5.5] heterobiaryls with C–N axial chirality, which could offer new insights for the application and development of other click reactions.

In 2023, Miller's team stereoselectively synthesized axially chiral N-aryl 1,2,4-triazoles by de novo formation of the triazole ring via an organocatalytic cyclodehydration reaction (Scheme 15).⁹¹ Using a C₂-symmetric CPA as the catalyst, the condensation of imidothioate 42 and hydrazide 43 proceeded efficiently to deliver N-aryl triazole atropisomers 44 with up to 78% ee. Further enantioenrichment of these atropisomeric triazoles to near-enantiopurity could be achieved via simple recrystallization. Moreover, the enantiopure sample of 44c maintained adequately high stereochemical stability without ee erosion, even when heated in toluene overnight, suggesting that the moderate ee of the product was not due to its modest axial stability.

Scheme 15 De novo triazole synthesis via an organocatalytic cyclodehydration reaction.

In their proposed mechanism, imidothioate 42 first condenses with hydrazide 43 to generate hydrazonamide intermediate Int-I and release a H₂O molecule, with the CPA acting as a bifunctional catalyst. Int-I then binds to CPA, leading to cyclization and forming intermediate Int-II under the dual activation of (R)-CPA7. The final dehydration of the thus-formed intermediate yields the desired axially chiral aryltriazole product. The CPA catalyst could provide dual activation and act as a proton-transfer shuttle, facilitating proton transfer from the nucleophile to electrophilic species in each mechanistic step. Although the enantioselectivities achieved by CPA catalysis were suboptimal, this seminal work represents the first organocatalyzed method for accessing atropisomeric N-aryl 1,2,4-triazoles.

Although de novo triazole synthesis is the primary strategy for constructing triazole-based axially chiral frameworks, transition metal-catalyzed direct C–H arylation offers an alternative approach for accessing these structures. In 2020, Cramer et al. reported a highly enantioselective C–H arylation of various 1,2,3-triazoles 45 with α-bromonaphthalenes 46 promoted by a chiral Pd(0) complex, enabling efficient access to axially chiral aryltriazoles 47 with excellent yields and selectivities (Scheme 16).⁹² Although an aromatic substituent at the C4 position of the triazole was not essential, its increased steric demand lowered the enantioselectivity of products. It is worth pointing out that pyrazoles with electron-withdrawing groups at the 3-position also underwent a smooth and highly enantioselective C–H arylation. Moreover, a double atroposelective C–H arylation of dibromo substrate 46f smoothly constructed two stereogenic axes in 47f with >99% ee.

Scheme 16 Pd-catalyzed C–H arylation of 1,2,3-triazoles.

In the subsequent mechanistic studies, they proposed that the C–H activation step, proceeding via a concerted metalation–deprotonation (CMD) mechanism, is rate-limiting, while the reductive elimination step is enantio-determining, as the enantioinduction level varied with the biaryl dihedral angle of the ligand. This strategy thus represents the first successful assembly of configurationally stabilized naphthyltriazoles through atropo-enantioselective C–H functionalization.

4. Imidazole-based frameworks

Imidazoles are important nitrogen-containing heterocycles with two nitrogen atoms in meta-positions, exhibiting unique functions in synthetic chemistry, biological processes and materials science.⁹³ Many elegant ligands and organocatalysts featuring imidazole motifs with point chirality have been developed and widely applied in asymmetric catalysis.^94–96 However, axially chiral imidazoles have been relatively less studied due to their decreased rotational barriers and low configurational stability.^97,98 Due to the presence of two nitrogen atoms in meta-positions on the imidazole ring, establishing a C–C axis with sufficient steric hindrance from the ortho-substituent is challenging. As a result, a relatively short chiral axis (e.g., C–N bond and N–N bond) can provide sufficient steric interactions, making N–C axial chirality in axially chiral imidazoles the most extensively studied. Moreover, de novo imidazole synthesis through intramolecular cyclodehydration or Buchwald–Hartwig amination represents the primary strategy for constructing imidazole-based axially chiral frameworks.

As a workaround for the challenging atroposelective construction of the imidazole ring, Miller et al. reported a successful case of axially chiral N-aryl benzimidazole in 2018 (Scheme 17). A peptidyl copper complex-catalyzed enantioselective C–N cross-coupling through a remote desymmetrization process, followed by a CPA promoted atroposelective intramolecular cyclodehydration, enabled the efficient and highly stereoselective synthesis of a series of N-aryl benzimidazoles bearing a N–C stereogenic axis and a remote stereocenter.⁹⁹ In addition to the 1,1′-binaphthyl-2,2′-diol (BINOL)-derived CPA catalyst, phosphothreonine (pThr)-derived CPA also demonstrated comparable efficiency in the intramolecular cyclodehydration of 48. Thus, the suitable combination of a chiral Cu complex and a chiral CPA catalyst was assembled, enabling stereodivergent access to four possible stereoisomers of a point and axially chiral benzimidazole scaffold.

Scheme 17 De novo imidazole synthesis through a cross-coupling/cyclodehydration cascade reaction.

Building on their previous work on catalyst-controlled atroposelective cyclodehydration in the enantioselective construction of axially chiral N-aryl benzimidazoles, Miller and colleagues further investigated the catalytic performance of two disparate CPAs (i.e., BINOL-type and pThr-type) in a wide array of trifluoroacetyl-protected ortho-diaminobenzenes 52 (Scheme 18).¹⁰⁰ While pThr3 and CPA2 are generally indistinguishable with most of these substrates, the peptidic catalyst pThr3 appears to offer more generality, as seen in the case of substitution at the 7-position (53b and 53c).

Scheme 18 De novo imidazole synthesis through intramolecular cyclodehydration.

Mechanistic studies revealed distinct determinants associated with the two catalysts. Enantioselectivity in the C₂-type CPA catalyst (CPA2) is attributed to steric mismatch with the substrate, while the key controlling element in the pThr-type CPA (pThr3) is the conformational adjustment that limits repulsive interactions. The authors described that the CPA catalyst bifunctionally activates the carbonyl and amino groups of 52 through dual H-bonding interactions. An acid-promoted cyclization then takes place to produce hemiacetal Int-II, followed by central-to-axial chirality conversion via dehydration–aromatization to form axially chiral N-aryl benzimidazole 53.

In 2020, the Fu group reported another heteroannulation of N-(aryl)benzene-1,2-diamines with multicarbonyl compounds for the assembly of axially chiral N-aryl benzimidazoles (Scheme 19).¹⁰¹ In contrast to the strategy developed by Miller, they utilized a CPA to selectively cleave the carbon–carbon bond of 1,3-dicarbonyls 55. Acetylacetone (55a), ethyl acetoacetate (55b) and 1-phenylbutane-1,3-dione (55c) were found to be generally suitable for installing a methyl group into the target N-aryl benzimidazoles 56. Moreover, other open-chain and cyclic 1,3-dicarbonyls were also applicable for this transformation. The configurational stability of this class of axially chiral N-aryl benzimidazoles was characterized with 56a, 56c and 56e, which demonstrated racemization barriers of >32.0 kcal mol⁻¹ at 120 °C.

Scheme 19 De novo imidazole synthesis through carbon–carbon bond cleavage.

In this reaction, both imine Int-III and enamine Int-VI are potential intermediates that play a vital role in determining stereoselectivity. First, the CPA catalyst simultaneously activates both substrates by dual hydrogen-bonding interactions, followed by nucleophilic attack on intermediate Int-II. The subsequent dehydration of Int-II leads to the formation of imine Int-III. A CPA-guided intramolecular addition of the amino group to the imine proceeds and yields atropisomeric N-aryl benzimidazole skeleton 56 after a retro-Mannich reaction. Alternatively, N-tautomerization of imine Int-III furnishes enamine Int-VI. A CPA-directed intramolecular Michael addition of Int-VI followed by an O-tautomerization sequence facilitates the formation of intermediate Int-V, which enables further C–C bond cleavage for the final axially chiral N-aryl benzimidazoles 56.

The asymmetric ring-closing Buchwald–Hartwig reaction of amidines presents a significant challenge due to the potential coordination of amidines to transition metals, which can cause catalyst deactivation, as well as the issues arising from tautomerization and E/Z isomerization of amidines. In 2021, Lu, Liu, and co-workers described a palladium/(S)-BINAP-catalyzed intramolecular Buchwald–Hartwig amination for the asymmetric synthesis of C–N axially chiral N-aryl benzimidazoles (Scheme 20).¹⁰² A broad spectrum of benzimidazoles 58 containing N–C axial chirality can be efficiently constructed with yields of up to 98% and ee of 93%. Moreover, this strategy was further extended to the construction of dibenzimidazoles featuring two chiral C–N axes from the corresponding diamidines.

Scheme 20 De novo imidazole synthesis through Buchwald–Hartwig amination of amidine.

The plausible mechanism likely proceeds through an initial oxidative addition of amidine 57a with the active Pd(0) complex to form Pd(II) intermediate Int-I, followed by deprotonation to generate amidine-Pd complex Int-II or Int-II′. Ligand exchange between bromide and diazaallyl anions generates either Int-III or Int-III′. Steric bias favors reductive elimination in Int-III, leading to the production of axially chiral N-aryl benzimidazole 58a. In contrast, Int-III′ experiences strong steric repulsion between the equatorial phenyl group on the phosphorus ligand and the ortho-substituent on the diazaallyl palladacycle intermediate, making this transition state model less favorable.

In a synthetic approach primarily aimed at generating N–N atropisomers, Liu's group in 2024 further reported a palladium-catalyzed de novo construction of a benzimidazole ring.¹⁰³ Using Pd(OAc)₂ with a bisphosphine ligand, a wide range of axially chiral benzimidazole-containing skeletons were efficiently accessed with high yields and excellent enantioselectivities (Scheme 21). Apart from nonbiaryl benzimidazole frameworks (60a–e), indole-benzimidazole was also applicable for this intramolecular Buchwald–Hartwig amination reaction (60f–j). On a 4.0 mmol scale, product 60f was prepared in 60% yield with 92% ee, comparable to the results achieved in a small-scale reaction. Moreover, the stability of three types of N–N benzimidazole atropisomers was investigated. Although the N–N bond length in the nonbiaryl-benzimidazole atropisomer is longer than that in the indole-benzimidazole and indole-indole atropisomers, the indole atropisomer possesses the highest racemization barrier. Notably, these N–N benzimidazole atropisomers demonstrated significant antitumor activity and selectivity against MCF-7 breast cancer cells. Therefore, this approach not only established the first enantioselective synthesis of N–N benzimidazole atropisomers, but also advanced the asymmetric Buchwald–Hartwig amination reaction of imidohydrazides to a new level.

Scheme 21 De novo imidazole synthesis through intramolecular Buchwald–Hartwig amination of imidohydrazide.

In addition to intramolecular cyclodehydration and Buchwald–Hartwig amination, Tan's group reported on the successful de novo synthesis of N-aryl benzimidazoles through CPA catalyzed annulation of 2-naphthylamines and nitrosobenzenes (Scheme 22).¹⁰⁴ In this domino reaction involving N-naphthylglycine derivatives, nitrosobenzenes could function as both electrophilic and nucleophilic sites at different stages of the reaction, while also serving as an oxidant during the final oxidative aromatization process. When N-naphthylbenzylamine derivatives were reacted with ortho-substituted nitrosobenzenes in the presence of SPINOL-type CPA9, the use of an exogenous oxidant, bis((cyclopentanecarbonyl) oxy)-copper, proved beneficial for this enantioselective domino reaction, resulting in products 63e–h with the opposite configuration. This phenomenon could be attributed to the different non-covalent interactions between the catalyst and N-protecting groups of 2-naphthylamines (i.e., H-bond interaction and π–π stacking interaction). Furthermore, the configurational integrity of a representative product (63d) was retained after 24 hours of heating in the solution of toluene at 120 °C, demonstrating high rotational barriers and good configurational stability.

Scheme 22 De novo imidazole synthesis through intermolecular annulation.

The mechanism proceeds through an initial CPA-catalyzed nucleophilic addition of a 2-naphthylamine derivative to nitrosobenzene, forming intermediate Int-I. The subsequent dehydration of thus-formed Int-I leads to the formation of vicinal diimine Int-II, which could then undergo a direct [1,5]-hydrogen shift to yield benzyl imine Int-IV. An alternative pathway involving successive reduction and oxidation through Int-III cannot be excluded, potentially also giving rise to intermediate Int-IV. With the assistance of a CPA catalyst, an intramolecular stereoselective addition of the amino group to the imine moiety takes place to form annulated intermediate Int-V, which was postulated to be the stereoselectivity determination step (S.D.S.) for this domino reaction. Finally, the desired axially chiral N-aryl benzimidazole 63 is formed through oxidative aromatization of Int-V.

In 2023, Zhang, Terada, Bao and colleagues pioneered the asymmetric synthesis of axially chiral heterobiaryls featuring benzimidazole and quinoline rings through the heteroannulation reaction of 2-alkynylbenzimidazoles with ortho-aminophenylketone (Scheme 23).¹⁰⁵ Under the catalysis of the classical organocatalyst CPA10, a range of axially chiral 2-aryl benzimidazoles 66 were synthesized with good yields and enantioselectivities (up to 97% yield and 91% ee). The ee of a model compound (66a) decreased only slightly after 48 hours in EtOH at 80 °C, demonstrating that this class of axially chiral heterobiaryls has a relatively high atropostability. It is worth noting that the benzimidazole ring with a single ortho-Boc group around the axis represents one of the few examples that transcend current structural limitations, where two ortho-substituents on the benzimidazole ring are typically required to maintain axial chirality.

Scheme 23 De novo imidazole synthesis through a heteroannulation reaction.

The reported heteroannulation reaction initiates with a CPA-facilitated nucleophilic attack of the amino group on the alkyne moiety, activated by dual H-bonding interactions. This is followed by an intramolecular enamine-aldol reaction in an enantiospecific manner, resulting in the formation of intermediate Int-III. The protonation of the hydroxyl group in Int-III produces Int-IV, which then undergoes dehydration to yield an enantioenriched heterobiaryl product, while simultaneously regenerating the catalyst.

In 2024, Hong and Ackermann evaluated enantioselective C–H activation catalyzed by a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni–Al bimetallic catalyst, achieving the formation of C–N axially chiral N-arylbenzimidazole 69a in 82% yield and 93% ee from benzimidazole derivative 67a and styrene 68a.¹⁰⁶ Aside from ortho-substituents on the N-aromatic that help restrict axial rotation, a broad range of alkenes, including aryl alkenes, alkyl alkenes, internal alkenes, and 1,3-dienes, were employed and overall commendable enantioselectivities were achieved (Scheme 24). The successful compatibility with these alkenes highlights the exceptional versatility of this HASPO-enabled nickel-catalyzed atroposelective C–H alkylation methodology.

Scheme 24 Atroposelective synthesis of N-arylbenzimidazoles through functionalization of prochiral pre-existing biaryls.

Deuterium labeling experiments were conducted to investigate the reaction mechanism, suggesting that the formation of the alkyl-nickel species involves a reversible process. Chiral HASPO-ligated Ni–Al bimetallic catalyst A initially coordinates with benzimidazole substrate 67a and styrene 68a, forming intermediate Int-I. Direct ligand-to-ligand hydrogen transfer then occurs, bypassing the competing oxidative addition/olefin insertion pathway, leading to the formation of intermediate Int-II. Finally, Int-II undergoes irreversible reductive elimination, releasing the desired product 69a and regenerating catalytically active PO–Ni–Al intermediate A, thereby completing the catalytic cycle.

Despite the elegance and diversity of these approaches for synthesizing benzo-fused imidazoles, the direct catalytic asymmetric synthesis of axially chiral imidazoles remains in its infancy. A salient milestone was achieved in 2023 when Aponick introduced phase-transfer catalysis to assemble axially chiral imidazoles via a desymmetrization strategy (Scheme 25).¹⁰⁷ A wide range of StackPhos oxides, including variations in imidazole substituents, different ortho-substituents on the naphthalene ring and various benzylating reagents, could be synthesized in high yields with excellent enantioselectivities. The reduction of the StackPhos oxide with tetramethyldisiloxane (TMDS) and Ti(OⁱPr)₄ at 60 °C yielded StackPhos smoothly with some erosion of enantiopurity. Interestingly, both the racemates of StackPhos oxides and StackPhos could selectively crystallize, affording a variety of phosphine oxides and phosphines with excellent ee.

Scheme 25 Desymmetrization in N-benzylation of 2-aryl imidazoles.

Moreover, the practical application of this method was demonstrated in the facile synthesis of enantiopure StackPhos. As shown in Scheme 25, 2-aryl imidazole B could be acquired in a >10 g scale reaction through condensation and triflation, with an overall yield of 80%. P–C coupling of triflate B and diphenylphosphine oxide, followed by enantioselective desymmetrization on a gram scale, produced (S)-StackPhos oxide 72a in 85% overall yield with 92% ee. StackPhos oxide 72a was selectively reduced with only 2% ee loss. After selective racemate crystallization, optically pure (S)-StackPhos 73a was obtained in high yield on a >1 g scale. The barrier to rotation around the C–C stereogenic axis in StackPhos oxide 72a was determined to be 29.7 kcal mol⁻¹ at 75 °C in 1,2-dichloroethane (DCE), ensuring stereochemical integrity at room temperature with a half-life of 10.3 years. However, the rotational barrier of 72d was determined to be 26.4 kcal mol⁻¹ at 75 °C in DCE, corresponding to a half-life of 14 days at room temperature. The observed difference in the configurational stability demonstrated a pentafluorobenzene π-stacking stabilization effect of 3.3 kcal mol⁻¹. A similar difference in the rotational barrier due to the π-stacking effect of the pentafluorobenzene moiety was observed between 73a and 73d, with a decrease of 3.0 kcal mol⁻¹. This work addressed the challenging issue of the lower rotational barrier in atropisomeric 2-aryl imidazoles without pentafluorobenzene π-stacking stabilization and successfully accomplished enantioselective phase-transfer desymmetrization with mild conditions and high effectiveness.

5. Urazole-based frameworks

Urazoles, also known as 1,2,4-triazolidine-3,5-diones, are highly important five-membered heterocycles with potential pharmaceutical applications and valuable utilities in medicinal chemistry. For example, the urazole moiety serves as a scaffold for generating libraries of thrombin inhibitors. Since the first synthesis of phenyl urazole in 1887, urazoles have been widely used as versatile building blocks in organic synthesis. However, urazoles have been recognized as not adopting an optically active form due to the easy inversion of the two pyramidal nitrogen atoms. Upon oxidation, urazoles produce 1,2,4-triazoline-3,5-diones (TADs), which are among the most electron deficient species and are highly prone to undergoing versatile transformations (e.g., Diels–Alder and Alder–ene reactions).

Before 2016, there were no reports on the direct construction of chiral urazoles in a catalytic enantioselective manner. Tan and co-workers then explored 4-aryl-1,2,4-triazole-3,5-diones (ATADs) 74 in an organocatalytic tyrosine click reaction, leading to the direct construction of atropisomerically enriched N-aryl urazoles.¹⁰⁸ By using a desymmetrization strategy, bifunctional organocatalysts, such as thiourea-tertiary amine C6 and chiral phosphorous acid (S)-CPA11, were employed to catalyze rapid Friedel–Crafts amination with phenol derivatives or 2-substituted indoles as nucleophiles, respectively (Scheme 26). A class of urazoles with axial chirality by restricted rotation around a C–N bond was synthesized in high yields with excellent enantioselectivities under mild reaction conditions. The bifunctional organocatalysts simultaneously activate both the nucleophile (phenol or indole) and the electrophile (ATAD) through hydrogen-bonding interactions in a suitable spatial configuration, differentiating the two nonequivalent nitrogen centers in the ATAD (a and b) for further nucleophilic addition. This activation may transfer stereochemical information from the catalyst to the distal C–N chiral axis, thereby enabling efficient remote control of the axial chirality of arylurazoles.

Scheme 26 Desymmetrization in Friedel–Crafts amination of ATADs.

Apart from their prominent role as electrophiles, Xiang, Guo, Tan and co-workers further used ATADs as enophiles in ene reactions through desymmetrization with remote stereocontrol.¹⁰⁹ In 2018, a tandem asymmetric Diels–Alder (D–A) reaction and an ene reaction were developed for the construction of spirooxindole–urazoles with multiple central or axial chiralities. Bisthiourea catalysis was employed in the designed multicomponent reaction (MCR) of 3-vinylindoles, methyleneindolinones and ATADs, resulting in the formation of optically pure spirooxindole–urazoles with good yields and satisfactory stereoselectivities (Scheme 27). To verify the origin of stereocontrol in the ene reaction, intermediate Int-I was then synthesized from 79a and 80a through a reported asymmetric D–A reaction.¹¹⁰ Similar results were observed with or without the C7 catalyst, suggesting that the spatial configuration of Int-I plays a more decisive role than catalyst C7 in the subsequent stereoselective formation of the C–N bond. The proposed mechanism revealed that the reaction occurs via a central-to-axis chirality relay mechanism: an initial bisthiourea-catalyzed stereoselective D–A reaction between 3-vinylindole 79a and methyleneindolinone 80a proceeds to afford spirooxindole derivative Int-I. Subsequently, an aromaticity-driven ene reaction occurred with substrate-controlled stereoselectivity, where ATAD approaches the alkene from the face opposite to the bulky ester group and the bicyclic moiety. This process ultimately yielded spirooxindole–urazole 81a with configurationally defined carbon centers and a remote C–N axis.

Scheme 27 Desymmetrization in successive Diels–Alder and ene reactions of ATADs.

In 2021, a distinctive desymmetrization strategy differing from the generation of a distal C–N chiral axis was exemplified by Tan et al. in CPA-catalyzed electrophilic aromatic substitution reactions of 3,5-disubsituted phenols with ATADs, leading to the catalytic enantioselective construction of axially chiral B-aryl-1,2-azaborines with a remote C–B stereogenic axis (Scheme 28).¹¹¹ The substrate generality of ATAD with a sterically tert-butyl moiety at the ortho position of the phenyl ring was particularly noteworthy, as it enabled remote enantiocontrol over two distal stereogenic axes, leading to the efficient formation of 1,6-diaxial azaborine 83d bearing both C–B and C–N axial chirality (95% yield, >20 : 1 dr, and 95% ee). Mechanistic control experiments using N-methylated or O-methylated azaborine revealed that both the NH group and the phenolic OH moiety are essential for this catalytic reaction. Accordingly, a stereocontrol model with the involvement of multiple H-bonding interactions among the CPA species, azaborine and ATAD was proposed for this enantioselective transformation.

Scheme 28 Desymmetrization in electrophilic amination of ATADs.

In the approach proposed by Pan and co-workers in 2023, ATADs 74 and various β-naphthols 84 reacted together in the presence of CPA catalyst (S)-CPA13 to form axially chiral urazoles 85 bearing both axial and central chirality (Scheme 29).¹¹² The asymmetric dearomatization reaction demonstrates functional-group tolerance, and its substrate scope could be extended to include other challenging 1-naphthol and 5-hydroxy indole derivatives. Axially chiral urazole 85a possesses a particularly high rotational barrier of 31.54 kcal mol⁻¹ at 120 °C, corresponding to a half-life of 9.5 hours. The hydroxyl group of naphthol is crucial for the reaction, as no product was formed when an O-methylated substrate was subjected to dearomatization conditions. In the more favored transition state, the CPA catalyst activates naphthol and ATAD through H-bonding interactions, allowing a nucleophilic attack to occur from the Re face at the α-position of 2-naphthol. In contrast, nucleophilic attack from the Si face is disfavored due to steric repulsion.

Scheme 29 Desymmetrization in the dearomatization reaction of ATADs.

Nowadays, the catalytic asymmetric synthesis of chiral molecules bearing both axial and central chirality has emerged as a rapidly expanding field because the incorporation of central chirality into atropisomers presents an opportunity to introduce new properties into axially chiral molecules. However, atropisomers bearing helical chirality present significant challenges, which may be attributed to their limited structural variability in constructing helical chirality and the difficulty in achieving enantiocontrol. In 2024, Wang et al. reported a direct terminal peri-functionalization strategy that enables the efficient assembly of [4]-, [5]- and [6]-helicenes via an organocatalyzed enantioselective Friedel–Crafts amination reaction (Scheme 30).¹¹³ In the presence of Takemoto thiourea catalyst C8, 2-hydroxybenzo[c]phenanthrene derivatives reacted smoothly with ATADs, providing a gateway to [4]carbohelicenes with good yields and excellent enantioselectivities. Importantly, this approach could be used to construct stereochemically complex molecules, particularly those with both helical and axial chirality.

Scheme 30 Desymmetrization of ATADs by Friedel–Crafts amination.

The mechanism investigation suggests that excellent enantiocontrol stems from configurationally unstable polycyclic phenols at low temperature. The relatively lower calculated barrier to enantiomerization for [4]helicene 86a (21.5 kcal mol⁻¹) enabled a catalytic kinetic resolution process, effectively increasing the barrier of racemization for 1,12-disubstituted [4]helicene 87a by 40 kcal mol⁻¹. In their proposed nucleophilic addition transition states based on DFT calculations, steric repulsion between the tert-butyl group on ATAD and the polycyclic phenolate is the key for enantiocontrol. The transition state TS-MS is 3.3 kcal mol⁻¹ lower in free energies than TS-MR, leading to the formation of the major (M,S)-configured product, which is consistent with the experimental observation. This work provided efficient access to enantioenriched helicenes featuring a urazole scaffold with excellent functional group tolerance, structural diversity and stereochemical complexity.

In the year 2024, Mei's group reported the first catalytic asymmetric dearomative azo-Diels–Alder reaction between 2-vinylindoles and ATADs, allowing for the efficient construction of tetracyclic indole derivatives with good to excellent yields and excellent stereoselectivities.¹¹⁴ This approach also successfully created a remote rotationally stable C–N axis when prochiral ATAD 74a was used as the azo-dienophile (Scheme 31). Furthermore, DFT calculations support that C3-N bond formation occurs first, with the stepwise and endo pathway being the most favorable.

Scheme 31 Desymmetrization in the dearomative azo-Diels–Alder reaction of ATADs.

In 2021, Chi's group reported an intriguing desymmetrization strategy for the NHC-catalyzed oxidative [3 + 2] annulation of ynals 90 with N-arylurazoles 91 (Scheme 32).¹¹⁵ Axially chiral N-arylurazole derivatives bearing various functional substituents are obtained as the final products in good to excellent yields (up to 98%) and atroposelectivities (up to 96%). Product 92a exhibits a high rotational barrier of 29.8 kcal mol⁻¹ at 125 °C in mesitylene, suggesting that this scaffold possesses suitable axial stability.

Scheme 32 Desymmetrization in [3 + 2] annulation of urazoles.

Similar to previous work, the reaction proceeds through a tandem Michael addition/lactonization annulation sequence. Initially, the chiral NHC catalyst reacts with ynal substrate 90a under oxidative conditions, yielding acetylenic acylazolium intermediate Int-I. Urazole substrate 91a is then desymmetrized by chiral Int-I through a reversible atroposelective 1,4-addition reaction, yielding diastereomeric adducts Int-III and Int-IV. Therefore, the Michael addition step can be involved in the overall enantioselectivity determination for this domino reaction. Notably, adduct Int-III is thermodynamically unstable and can revert to intermediate Int-II due to steric repulsion. As a result, a DKR process occurs between adducts Int-III and Int-IV, affording Int-V as the major isomerization intermediate. Finally, the lactam formation reaction of Int-V produces the desired axial chiral product 92a, which bears a urazole moiety, and releases the chiral NHC catalyst for the subsequent catalytic cycles.

6. Isothiazole-based frameworks

Isothiazole (1,2-thiazole), a privileged five-membered heteroaromatic scaffold, has been extensively explored in drug discovery and agricultural chemistry due to its diverse biological activities, including antimicrobial, fungicidal, anti-TMV, anti-inflammatory and insecticidal properties. However, enantioenriched synthesis of isothiazole derivatives has been rarely reported, and the synthesis of axially chiral isothiazole derivatives is even less explored.

In the same report by Yan's group,⁶⁸ high-value naphthyl-isothiazole S-oxides 94, featuring a stereogenic sulfur center and a chiral C–C axis, were obtained from racemic N-naphthyl propargylsulfinamides 93via a KR process with high S factors (Scheme 33). It is worth noting that substrates 93 are limited to those with a gem-dimethyl moiety attached to the propargylic carbon. Other gem-disubstituted groups (e.g., dihydro, diethyl and cyclohexyl) result in the target isothiazole derivatives being produced with extremely low yields and poor enantioselectivities. Atroposelectivity was induced during the ring formation step from a more stable VQM transition state, which has reduced repulsion between the substituent on the sulfinamide moiety and the iso-propyl group of catalyst C10. Intramolecular S–C bond formation then takes place, leading to the formation of axially chiral naphthyl-isothiazole S-oxide through kinetic resolution, with the other enantiomer of sulfinamides 93 as a stereogenic sulfur center derivative.

Scheme 33 De novo isothiazole synthesis via intramolecular cyclization of VQMs.

In 2022, Zhang and co-workers also exemplified CPA-catalyzed atroposelective arylation of 5-amino-isothiazoles to derive isothiazole-containing axially chiral biaryls in moderate to good yields with moderate and enantioselectivities (Scheme 34).¹¹⁶ The absolute configurations of the product could not be determined due to the stereochemical lability of the [5.6] aryl-heteroaryl axis. The barrier to rotation around the stereogenic axis in 96a was determined to be 29.6 kcal mol⁻¹ at 100 °C, a magnitude insufficient to prevent the racemization of product 96a during the crystallization. However, it is important to emphasize that most products exhibit conformational lability, underscoring the outstanding enantioinduction capability of this catalytic system. The bifunctional phosphoric acid positions 5-amino-isthiazole 95a and methyl p-quinone carboxylate 6a in a suitable chiral cavity through dual hydrogen bonding interactions. Nucleophilic addition of 95a to the p-quinone then leads to intermediate Int-II, which possesses central chirality. Aromatization then occurs, followed by central-to-axial chirality conversion, thereby defining the stereochemistry of axially chiral product 96a.

Scheme 34 Organocatalytic C–H arylation of 5-amino-isothiazoles.

7. Isoxazole-based frameworks

Isoxazole, an important member of the five-membered heterocycle family, is commonly found in many natural products and pharmaceuticals, demonstrating prominent potential as an analgesic, anti-inflammatory, anticancer, antimicrobial, antiviral, anticonvulsant, antidepressant and immunosuppressant agent.¹¹⁷ Due to its biological activities and therapeutic potential, significant advances have been made in the construction and derivatization of the isoxazole scaffold. However, the construction of isoxazole-based atropisomers has been relatively underexplored, which may be due to challenges in controlling the axial stability and the lack of efficient synthetic methods.

In 2024, our group employed a CPA catalyst to develop an asymmetric arylation of 5-aminoisoxazoles 97 with azonaphthalenes 2 and yielded enantioenriched axially chiral 4-aryl isoxazoles 98 with high efficiency (Scheme 35).¹¹⁸ Wide-ranging aliphatic and aromatic substituents on the isoxazole ring proved to be suitable nucleophiles. Additionally, the reaction exhibited broad tolerance for a range of azonaphthalenes, including those with various substituents on the naphthalene ring and different types of ester groups. Moreover, the enantiomerization barrier of compound 98d was determined to be 32.4 kcal mol⁻¹ at 90 °C, with a half-life time for racemization of 20.5 hours.

Scheme 35 Organocatalytic C–H arylation of 5-aminoisoxazoles.

In this reaction, the bifunctional chiral phosphoric acid simultaneously activates both azonaphthalenes 2 and 5-aminoisoxazoles 97 through a dual hydrogen-bonding mode, thereby facilitating the subsequent stereoselective nucleophilic attack. Central-to-axial chirality conversion from intermediate Int-II determines the configuration of the stereogenic axis in axially chiral product 98 during the aromatization process. It is noteworthy that this transformation represents the first atroposelective construction of axially chiral aryl-isoxazole scaffolds.

Shortly after, also with a CPA catalysis method, the group of Wang successfully prepared axially chiral 4-arylisoxazoles with excellent ee values (Scheme 36).¹¹⁹ The synthetic utility of this methodology was demonstrated by a gram-scale experiment and further modifications. Hydrogenolysis with RANEY®-Ni catalysis resulted in reductive N–N bond cleavage, while Pd/C catalysis led to the removal of the N-Cbz group. Upon oxidation of naphthalene hydrazine 98i by using NBS, azonaphthalene 100 is readily generated with minimal erosion of its enantioselectivity. Similar to our work, this reaction also offers an efficient methodology for the synthesis of relatively unexplored axially chiral 4-arylisoxazoles.

Scheme 36 Enantioselective synthesis of axially chiral 4-aryl isoxazoles.

8. Oxazole-based frameworks

Oxazole, a five-membered heterocyclic ring containing one nitrogen and one oxygen atom separated by a single carbon atom, serves as the parent compound for a broad class of heterocyclic aromatic organic compounds. Many naturally occurring oxazole compounds represent an important class of biologically active natural metabolites, exhibiting a wide range of biological activities and serving as key leads in drug discovery.¹²⁰ Although several elegant enantioselective transformations have been reported for the synthesis of enantioenriched oxazole derivatives,^121–125 challenges and limitations remain in this area. In particular, the asymmetry of axially chiral oxazoles has yet to be fully explored, which we attribute to the absence of the typical four ortho-substituents around the chiral axis. Significant progress has only recently been made toward the design and synthesis of axially chiral oxazole-substituted biaryls. Although the axial stereoisomerism does not originate from the oxazole ring itself, the oxazole acts as a sterically encumbered motif, contributing to the overall configurational stability.

Bringmann's lactones, which contain a configurationally labile axis, are often employed in atroposelective ring-opening with various nucleophiles via a DKR process.¹²⁶ This protocol has been efficiently applied to the synthesis of several challenging atropisomeric biaryls using either reducing reagents¹²⁷ or O-nucleophiles.¹²⁸ In contrast, the catalytic asymmetric DKR of Bringmann's lactones with C-nucleophiles in a highly enantioselective manner remains a long-standing challenge due to the configurational instability of the ring-opening product, caused by stereochemical leakage through lactol formation. Liao et al. tackled this challenge by utilizing activated isocyanides to achieve highly atroposelective ring opening, followed by rapid cyclization to minimize the undesired lactol formation.¹²⁹ In 2021, Liao's group implemented an Ag-catalyzed atroposelective DKR of Bringmann's lactone using a cinchonine-derived phosphine as the privileged chiral ligand, successfully accessing a wide range of novel axially chiral oxazole-substituted biaryl phenols in high yields with excellent enantioselectivities (Scheme 37). With respect to the scope of this catalytic system for binaphthyl-type Bringmann's lactone, the desired product 104e was obtained with an 88% yield but with very low enantioselectivity (6% ee). However, upon increasing the reaction temperature to 40 °C, the enantioselectivity improved to 80% ee. DFT calculations were conducted to explain this temperature effect, showing that the racemization rate of binaphthyl-type lactone 102e is much slower than that of mononaphthyl-type lactone 102a, thus requiring a higher temperature for an efficient DKR.

Scheme 37 DKR in ring-opening of Bringmann's lactones.

While significant efforts have been made toward the DKR of configurationally labile Bringmann's lactones via C–O bond cleavage, considerably less progress has been achieved in the atroposelective amide C–N bond cleavage of biaryl lactams. The challenges arise not only from the low electrophilicity of amides but also from the weak nucleophilicity of activated isocyanides, resulting in generally poor reactivity. Qian, Liao and co-workers addressed these aforementioned challenges by employing a cooperative catalytic system that combines organocatalysis and metal catalysis to simultaneously activate both biaryl lactams and activated isocyanides. In 2022, they reported the atroposelective synthesis of a new class of oxazole-containing axially chiral biaryl anilines 106 through DKR of configurationally labile bridged biaryl lactams 105, proceeding via a C–N bond cleavage/cyclization cascade process (Scheme 38).¹³⁰ By employing a cooperative catalytic system combining a quinidine-derived squaramide catalyst with Ag₂CO₃, a series of structurally novel oxazole-containing products were obtained in high yields with excellent enantioselectivities.

Scheme 38 DKR in ring-opening of bridged biaryl lactam.

A plausible mechanism was proposed based on control experiments, which involved varying the reaction conditions and modifying the biaryl lactam. The squaramide moiety of C11 serves as a hydrogen-bond donor, activating the amide carbonyl and increasing its electrophilicity. Simultaneously, silver coordination to the isocyanide facilitates the deprotonation of its α-C–H by the quinuclidine nitrogen of C11, generating a nucleophilic enolate. The additional coordination of silver to the amide carbonyl, along with the hydrogen-bonding interaction between C11 and the sulfonamide moiety, plays a crucial role in further defining the stereochemical environment of intermediate Int-I. The subsequent cyclization of Int-I releases the final axially chiral biaryl aniline containing an oxazole ring.

The same group next developed a stepwise cut-and-sew strategy to achieve the atroposelective synthesis of oxazole-containing eight-membered lactam-bridged N-arylindoles 108 in 2023 (Scheme 39).¹³¹ The highly constrained lactam-bridged N-arylindoles featuring an oxazole ring could be obtained in good yields with high enantioselectivities through an operationally simple one-pot procedure utilizing silver catalysis to achieve these transformations. Key to the success of this approach lies in the development of a silver-catalyzed atroposelective ring-opening/cyclization cascade reaction of N-arylindole lactams 107 with isocyanoacetates 103, enabling the establishment of C–N axial chirality. The configurational stability regarding the stereogenic C–N axis in lactam-bridged N-arylindoles was evaluated in toluene at 100 °C for 24 hours, during which the enantiopurity remained unchanged. This result suggests that lactam products possess high rotation barriers, making them well-suited for further transformations and applications.

Scheme 39 DKR in ring-opening of N-arylindole lactams.

The silver-catalyzed atroposelective ring-opening step was proposed to be stereodetermining, where the Ag/L15 complex synergistically activates both the isocyanide and the lactam, resulting in the formation of optically active intermediate Int-I. Meanwhile, the rate of interconversion between the two atropisomers of N-arylindole lactams is expected to be faster than the rate of ring-opening of N-arylindole lactams with isocyanoacetates. Furthermore, the prominent kinetic resolution during the ring-opening step occurs through a preferred transition-state model. The phosphorus and amide nitrogen atoms of L15 coordinate to silver in a bidentate manner, which then coordinates with the isocyanide, facilitating the deprotonation of its α-proton by the Brønsted basic nitrogen and generating the nucleophilic enolate. The lactam could be activated by coordinating to the silver atom in a bidentate fashion. Nucleophilic addition of the enolate to the lactam results in ring-opening intermediate Int-I, which then undergoes a facile intramolecular cyclization, forming the oxazole ring driven by aromatization.

Beyond the aforementioned asymmetric ring-opening/cyclization of six-membered lactones and lactams, five-membered bridged biaryl reagents with bended biaryl structures exhibit much lower configurational stability. Among them, cyclic diaryliodonium salts represent an appealing class of configurationally labile biaryl reagents and are expected to be promising reactants for the synthesis of oxazole-containing axially chiral biaryls. Readily available cyclic diaryliodoniums have recently been used as effective arylating reagents in the synthesis of biaryl atropisomers with diverse nucleophiles via a ring-opening/cross coupling strategy, as demonstrated in the work of Gu,^132–134 Zhang¹³⁵ and He.¹³⁶ However, it was not until 2022 that Zhu and co-workers reported the synthesis of axially chiral oxazole 2-iodobiaryls through an enantioselective intramolecular oxidation of cyclic diaryliodoniums (Scheme 40).¹³⁷ Using CuI and chiral bisoxazoline (BOX) ligand L16 as the catalyst, cyclic diaryliodoniums underwent smooth asymmetric ring-opening/cyclization to generate a range of functionalized chiral oxazoles with high yields and excellent enantioselectivities.

Scheme 40 DKR in ring-opening of cyclic diaryliodoniums.

The catalytic cycle closely resembles those reported in other studies on the atroposelective ring opening of cyclic diaryliodonium salts,^132,134 although the authors did not provide a detailed discussion of the mechanism. The CuI and BOX ligands form a chiral copper complex, which might coordinate with iodonium salt 109a. Oxidative addition results in the formation of axially chiral Cu(III) intermediate Int-I. Subsequent O-tautomerization and ligand exchange lead to the formation of complex Int-III, with reductive elimination of Int-III generating axially chiral oxazole biaryl product 110a.

Cyclic diarylphosphine salts represent another attractive class of configurationally labile biaryl reagents capable of undergoing ring-opening reactions with various nucleophiles, leading to atropisomers containing useful phosphine moieties that can be further used as chiral ligands or organocatalysts.^138,139 In 2023, Li, Yu, and co-workers reported an atroposelective ring-opening of diarylphosphonium salts via palladium-catalyzed asymmetric cleavage of the C–P bond and intermolecular C(sp²)–H bond functionalization. This approach offers a general method for constructing P-stereogenic and axially chiral phosphinooxazoles with high atroposelectivities and diastereoselectivities (Scheme 41).¹⁴⁰ Furthermore, benzothiazoles bearing either electron-rich or electron-deficient substituents were also suitable for this protocol, delivering the corresponding products in good to high yields with excellent enantioselectivities. These privileged P,N-skeletons have the potential to be developed as effective chiral organocatalysts or ligands for use in asymmetric catalysis.

Scheme 41 DKR in ring-opening of diarylphosphonium salts.

According to previous studies on the catalytic asymmetric ring opening of cationic cyclic compounds, the authors proposed a Pd(0)/Pd(II) cycle for this atroposelective C–P bond cleavage/intermolecular C–H bond functionalization. Similar to other five-membered bridged substrates, diarylphosphonium salt (R_a)-111a and (S_a)-111a rapidly interconvert through the rotation of the C_aryl–C_aryl single bond. Steric bias favors aryl C–P bond cleavage at position a, facilitating the oxidative addition of Pd(0) with a C–P bond and yielding optically active Pd(II) intermediate Int-I with high diastereoselectivity. Subsequent transmetalation with the preformed 2-benzoxazole−copper species generates another Pd(II) species Int-II, which undergoes reductive elimination and then reacts with S₈ to produce P-stereogenic and axially chiral products 113a, along with the concurrent regeneration of the Pd(0) catalyst.

9. Thiazole-based frameworks

Thiazole is a 5-membered heterocyclic compound that contains both sulfur and nitrogen, characterized by significant π-electron delocalization and a higher degree of aromaticity compared to the corresponding oxazoles. The thiazole ring is commonly found in biomolecules and thus has attracted much synthetic interest.¹⁴¹ The catalytic asymmetric synthesis of axially chiral thiazoles suffers from an inherent challenge due to the absence of two ortho-substituents on the five-membered thiazole ring, which significantly reduces the rotational barriers and lowers the configurational stability. However, there are occasional examples of enantioselective synthesis of thiazole-containing axially chiral biaryls, where the thiazole serves as a sterically encumbered motif.^140,142

Compared to the extensive studies on the ring-opening of Bringmann's lactones, whose reactivity is largely influenced by torsional strain, there are relatively few reports on the ring-opening reactions of thionolactones. In 2022, Liao and co-workers reported a torsional strain-independent reaction between biaryl thionolactones 114 and activated isocyanides 103.¹⁴² Utilizing auto-tandem silver catalysis, a broad range of thiazole-containing axially chiral biaryls 115 and bridged biaryls 116 bearing an eight-membered lactone were obtained in high yields with good to excellent enantioselectivities (Scheme 42). Of particular note, torsional strain in cyclic biaryl thionolactones is not essential for atroposelective ring-opening reactions, which can furnish tri-ortho-substituted thiazole-containing biaryls. Moreover, axially chiral biaryls containing both ester and phenol moieties were efficiently transformed into eight-membered lactone-bridged biaryls via a simple one-pot procedure, further demonstrating the synthetic utility of this method.

Scheme 42 DKR in ring-opening of biaryl thionolactones.

Mechanistic studies suggested that the reaction starts with the deprotonation of isocyanoacetate, forming nucleophilic enolate Int-I or its tautomer Int-I′. This species undergoes nucleophilic addition to (S)-114a selectively to generate the key S,O-ketal Int-II, which establishes both axial and central chirality simultaneously. The subsequent cyclization of Int-II, followed by protonation, produces spiro-S,O-ketal intermediate Int-IV and regenerates the catalyst to complete the first [3 + 2] cycloaddition process. The C–O bond in Int-IV is then cleaved, promoted by the same silver catalyst, leading to the formation of the final product 115a. The authors proposed that the ring strain of the spirocyclic structure, along with the aromatization in thiazole formation, serves as the driving force for the cleavage process.

10. Conclusions

Axially chiral azole derivatives represent an important class of chiral molecules with a significant role across many research domains, including natural product synthesis, drug design, and asymmetric catalysis. Therefore, the atroposelective synthesis of azole-based frameworks has drawn considerable attention from researchers in the field of chemistry. However, the synthesis and isolation of stable atropisomers with axially bonded azoles are far less developed compared to the more classical six-membered axially chiral biaryl compounds, which are also more prevalent in nature. The primary reason for this is the increased distances between the crucial ortho-substituents adjacent to the chiral axis, resulting in lower rotational barriers and greater configurational lability. Additionally, the limited structural diversity of axially chiral azole derivatives also contributes to these challenges. Notably, due to significant advancements in catalytic activation models, various elegant enantioselective methodologies have been developed, enabling access to several new families of atropisomers featuring axially nitrogen-containing five-membered heterocyclic rings. Also, chiral ligands and catalysts based on axially chiral azole scaffolds have been preliminarily applied in asymmetric synthesis.

In light of the significant advancements made over the past decade, the atroposelective functionalization of preformed (prochiral or racemic) biaryl scaffolds, using organo- or metal catalysis, has proven to be a versatile and efficient strategy for the construction of axially chiral biaryl frameworks. Resultantly, racemic axially chiral compounds with a lower rotation barrier have emerged as ideal candidates for the synthesis of axially chiral azole-containing atropisomers through the DKR approach. Many catalytic atroposelective ring-opening reactions of configurationally labile bridged biaryls containing five-membered or six-membered rings have been developed and have become an important tool for the synthesis of axially chiral oxazole- or thiazole-substituted biaryls. In contrast, there is only one report on the construction of axially chiral pyrazoles using a DKR strategy, in which the hydrogen atom near the axis is replaced by a bulky group through an electrophilic substitution reaction. This challenge is likely attributed to the difficulty in constructing preformed azole-containing biaryl skeletons and the limited availability of methods to selectively modify the hydrogen atom. On the other hand, as urazole and its oxidized precursor ATAD are important prochiral substrates with highly symmetrical structures, desymmetrization strategies are predominantly employed for the construction of axially chiral urazole-based skeletons.

Many complex azoles can be synthesized de novo via intramolecular cyclization or intermolecular annulation, which is considered to be the most straightforward pathway to access axially chiral azole-based systems through organocatalysis or transition metal catalysis. Among them, the transition-metal-catalyzed E-AAC reaction, a key approach for de novo azole synthesis, has been proved to be highly effective in achieving triazole-based axially chiral biaryls. Intramolecular cyclodehydration and Buchwald–Hartwig amination are two important methods for de novo synthesis of imidazole.

Currently, organocatalytic C–H arylation reactions are strongly influenced by the nucleophilicity of aromatic nucleophiles, many of which have structures similar to 2-naphthol and 2-naphthylamine containing enol or enamine motifs. Consequently, the application of organocatalytic C–H arylation for the synthesis of axially chiral azole scaffolds is largely constrained by structural limitations (e.g., 5-aminopyrazole, 5-aminoisothiazole and 5-aminoisoxazole). Transition metal-catalyzed direct C–H arylation including asymmetric C–H functionalization of heterobiaryls, ring-forming C–H functionalization and intermolecular C–H arylation holds great promise as a versatile and synthetically useful and atom-efficient strategy for constructing axially chiral arylazoles. Few examples of enantioselective intermolecular C–H arylation have utilized ortho-functionalized azoles (e.g., pyrazoles, 1,2,3-triazoles, and imidazoles), offering valuable insights for developing practical enantioselective C–H arylation strategies for the construction of axially chiral arylazoles.

Despite some progress, challenges remain in the catalytic enantioselective synthesis of axially chiral azole derivatives, and continued efforts are necessary to address the great challenges in both synthesis and application. For example, the atroposelective synthesis of other non-aryl scaffolds (e.g., alkenes, amides and imides) linked to azoles is anticipated to be further exploited. Exploring the introduction of additional chiral elements beyond carbon centered chirality, such as heteroatomic chirality, planar chirality and helical chirality, warrants further investigation. Moreover, the introduction of additional non-covalent interactions (e.g., intramolecular H-bonding and π–π stacking) can ensure configurational stability, thereby minimizing the necessity for increased steric congestion. Overall, with the advancement of novel strategies and methodologies for enantioselective construction of atropisomers, we can efficiently synthesize a diverse array of chiral ligands/catalysts, bioactive molecules and organic functional materials, providing more opportunities to address existing challenges in this field. We hope that this review will help provide potential inspiration for chemists working on azole-containing atropisomers and anticipate more reports in the near future.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (22201022), the Natural Science Foundation of Hunan Province (2024JJ5011), and the Scientific Research Fund of Hunan Provincial Education Department (21B0312).

References

1. Axially Chiral Compounds: Asymmetric Synthesis and Applications, ed. B. Tan, Wiley-VCH, Weinheim, Germany, 2021.
2. J. Clayden, W. J. Moran, P. J. Edwards and S. R. Laplante, The Challenge of Atropisomerism in Drug Discovery, Angew. Chem., Int. Ed., 2009, 48, 6398–6401.
3. G. Bringmann, T. Gulder, T. A. M. Gulder and M. Breuning, Atroposelective Total Synthesis of Axially Chiral Biaryl Natural Products, Chem. Rev., 2011, 111, 563–639.
4. J. E. Smyth, N. M. Butler and P. A. Keller, A twist of nature – the significance of atropisomers in biological systems, Nat. Prod. Rep., 2015, 32, 1562–1583.
5. J. K. Cheng, S.-H. Xiang, S. Li, L. Ye and B. Tan, Recent Advances in Catalytic Asymmetric Construction of Atropisomers, Chem. Rev., 2021, 121, 4805–4902.
6. M. Basilaia, M. H. Chen, J. Secka and J. L. Gustafson, Atropisomerism in the Pharmaceutically Relevant Realm, Acc. Chem. Res., 2022, 55, 2904–2919.
7. L. Pu, Enantioselective Fluorescent Sensors: A Tale of BINOL, Acc. Chem. Res., 2012, 45, 150–163.
8. B. S. L. Collins, J. C. M. Kistemaker, E. Otten and B. L. Feringa, A chemically powered unidirectional rotary molecular motor based on a palladium redox cycle, Nat. Chem., 2016, 8, 860–866.
9. K. Takaishi, M. Yasui and T. Ema, Binaphthyl–Bipyridyl Cyclic Dyads as a Chiroptical Switch, J. Am. Chem. Soc., 2018, 140, 5334–5338.
10. M. Sapotta, P. Spenst, C. R. Saha-Möller and F. Würthner, Guest-mediated chirality transfer in the host–guest complexes of an atropisomeric perylene bisimide cyclophane host, Org. Chem. Front., 2019, 6, 892–899.
11. W. Tang and X. Zhang, New Chiral Phosphorus Ligands for Enantioselective Hydrogenation, Chem. Rev., 2003, 103, 3029–3070.
12. Y. Chen, S. Yekta and A. K. Yudin, Modified BINOL Ligands in Asymmetric Catalysis, Chem. Rev., 2003, 103, 3155–3212.
13. M. Berthod, G. Mignani, G. Woodward and M. Lemaire, Modified BINAP: The How and the Why, Chem. Rev., 2005, 105, 1801–1836.
14. T. Akiyama, Stronger Brønsted Acids, Chem. Rev., 2007, 107, 5744–5758.
15. J. Yu, F. Shi and L.-Z. Gong, Brønsted-Acid-Catalyzed Asymmetric Multicomponent Reactions for the Facile Synthesis of Highly Enantioenriched Structurally Diverse Nitrogenous Heterocycles, Acc. Chem. Res., 2011, 44, 1156–1171.
16. D. Parmar, E. Sugiono, S. Raja and M. Rueping, Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates, Chem. Rev., 2014, 114, 9047–9153.
17. T. Akiyama and K. Mori, Stronger Brønsted Acids: Recent Progress, Chem. Rev., 2015, 115, 9277–9306.
18. M. Oki, Topics in Stereochemistry, in Atropisomerism, Wiley Interscience, 1983, vol. 1.
19. S. R. LaPlante, P. J. Edwards, L. D. Fader, A. Jakalian and O. Hucke, Revealing Atropisomer Axial Chirality in Drug Discovery, ChemMedChem, 2011, 6, 505–513.
20. G. H. Christie and J. Kenner, LXXI.—The molecular configurations of polynuclear aromatic compounds. Part I. The resolution of γ-6:6′-dinitro- and 4:6:4′:6′-tetranitro-diphenic acids into optically active components, J. Chem. Soc., Trans., 1922, 121, 614–620.
21. A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi and R. Noyori, Synthesis of 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), an Atropisomeric Chiral Bis(triaryl)phosphine, and Its Use in the Rhodium(I)-Catalyzed Asymmetric Hydrogenation of .alpha.-(Acylamino)acrylic Acids, J. Am. Chem. Soc., 1980, 102, 7932–7934.
22. D. Lotter, M. Neuburger, M. Rickhaus, D. Häussingera and C. Sparr, Stereoselective Arene-Forming Aldol Condensation: Synthesis of Configurationally Stable Oligo-1,2-naphthylenes, Angew. Chem., Int. Ed., 2016, 55, 2920–2923.
23. D. Xu, S. Huang, F. Hu, L. Peng, S. Jia, H. Mao, X. Gong, F. Li, W. Qin and H. Yan, Diversity-Oriented Enantioselective Construction of Atropisomeric Heterobiaryls and N-Aryl Indoles via Vinylidene Ortho-Quinone Methides, CCS Chem., 2022, 4, 2686–2697.
24. Z.-X. Zhang, L.-G. Liu, Y.-X. Liu, J. Lin, X. Lu, L.-W. Ye and B. Zhou, Organocatalytic intramolecular (4+2) annulation of enals with ynamides: atroposelective synthesis of axially chiral 7-aryl indolines, Chem. Sci., 2023, 14, 5918–5924.
25. B.-B. Zhan, L. Wang, J. Luo, X.-F. Lin and B.-F. Shi, Synthesis of Axially Chiral Biaryl-2-amines by PdII-Catalyzed Free-Amine-Directed Atroposelective C−H Olefination, Angew. Chem., Int. Ed., 2020, 59, 3568–3572.
26. Y. Xu, T.-Y. Zhai, Z. Xu and L.-W. Ye, Recent advances towards organocatalytic enantioselective desymmetrizing reactions, Trends Chem., 2022, 4, 191–205.
27. H.-Y. Luo, Z.-H. Li, D. Zhu, Q. Yang, R.-F. Cao, T.-M. Ding and Z.-M. Chen, Chiral Selenide/Achiral Sulfonic Acid Cocatalyzed Atroposelective Sulfenylation of Biaryl Phenols via a Desymmetrization/Kinetic Resolution Sequence, J. Am. Chem. Soc., 2022, 144, 2943–2952.
28. V. S. Raut, M. Jean, N. Vanthuyne, C. Roussel, T. Constantieux, C. Bressy, X. Bugaut, D. Bonne and J. Rodriguez, Enantioselective Syntheses of Furan Atropisomers by an Oxidative Central-to-Axial Chirality Conversion Strategy, J. Am. Chem. Soc., 2017, 139, 2140–2143.
29. X.-L. Min, X.-L. Zhang, R. Shen, Q. Zhang and Y. He, Recent advances in the catalytic asymmetric construction of atropisomers by central-to-axial chirality transfer, Org. Chem. Front., 2022, 9, 2280–2292.
30. G. Xu, W. Fu, G. Liu, C. H. Senanayake and W. Tang, Efficient Syntheses of Korupensamines A, B and Michellamine B by Asymmetric Suzuki-Miyaura Coupling Reactions, J. Am. Chem. Soc., 2014, 136, 570–573.
31. Z.-S. Liu, Y. Hua, Q. Gao, Y. Ma, H. Tang, Y. Shang, H.-G. Cheng and Q. Zhou, Construction of Axial Chirality via Palladium/Chiral Norbornene Cooperative Catalysis, Nat. Catal., 2020, 3, 727–733.
32. Y.-H. Chen, D.-J. Cheng, J. Zhang, Y. Wang, X.-Y. Liu and B. Tan, Atroposelective Synthesis of Axially Chiral Biaryldiols via Organocatalytic Arylation of 2-Naphthols, J. Am. Chem. Soc., 2015, 137, 15062–15065.
33. S. Yan, W. Xia, S. Li, Q. Song, S.-H. Xiang and B. Tan, Michael Reaction Inspired Atroposelective Construction of Axially Chiral Biaryls, J. Am. Chem. Soc., 2020, 142, 7322–7327.
34. C. Wu, Y. Jin, X. Zhang, R. Gao and X. Dou, Development of Configurationally Labile Biaryl Reagents for Atropisomer Synthesis, Eur. J. Org. Chem., 2024, e202400402.
35. Q. Shi, F. Fang and D.-J. Cheng, Organocatalytic Atroposelective Dynamic Kinetic Resolution Involving Ring Manipulations, Adv. Synth. Catal., 2024, 366, 1269–1284.
36. D. Bonne and J. Rodriguez, Enantioselective syntheses of atropisomers featuring a five-membered ring, Chem. Commun., 2017, 53, 12385–12393.
37. D. Bonne and J. Rodriguez, A Bird's Eye View of Atropisomers Featuring a Five-Membered Ring, Eur. J. Org. Chem., 2018, 2417–2431.
38. X.-L. He, C. Wang, Y.-W. Wen, Z. Wang and S. Qian, Recent Advances in Catalytic Atroposelective Construction of Pentatomic Heterobiaryl Scaffolds, ChemCatChem, 2021, 13, 3547–3564.
39. T.-Z. Li, S.-J. Liu, W. Tan and F. Shi, Catalytic Asymmetric Construction of Axially Chiral Indole-Based Frameworks: An Emerging Area, Chem. – Eur. J., 2020, 26, 15779–15792.
40. H.-H. Zhang and F. Shi, Organocatalytic Atroposelective Synthesis of Indole Derivatives Bearing Axial Chirality: Strategies and Applications, Acc. Chem. Res., 2022, 55, 2562–2580.
41. Y.-B. Chen, Y.-N. Yang, X.-Z. Huo, L.-W. Ye and B. Zhou, Recent advances in the construction of axially chiral arylpyrroles, Sci. China: Chem., 2023, 66, 2480–2491.
42. J. Feng and R.-R. Liu, Catalytic Asymmetric Synthesis of N–N Biaryl Atropisomers, Chem. – Eur. J., 2024, 30, e202303165.
43. Y. Zhang, Y. Huang, K. Yu, X. Zhang, W. Yu, J. Tang, Y. Tian, W. Wei, Z. Zhang and T. Liang, Iron–iodine co-catalysis towards tandem C–N/C–C bond formation: one-pot regioselective synthesis of 2-amino-3-alkylindoles, Org. Chem. Front., 2022, 9, 6165–6171.
44. Y. Zhao, F. Meloni, L. Male, C. S. L. Duff, W. D. G. Brittain, B. R. Buckley and J. S. Fossey, Synthesis of atropisomeric phosphino-triazoles and their corresponding gold(I) complexes, Org. Chem. Front., 2023, 10, 3460–3466.
45. H. Zhang, Y. Xiong, M.-J. Luo, R. Yang, J. Bai, X.-R. Song and Q. Xiao, Metal-free electrochemical oxidative intramolecular cyclization of N-propargylbenzamides: facile access to oxazole ketals, Org. Chem. Front., 2023, 10, 3786–3791.
46. X. Huang, Y. Li, J. He, S. Peng, J. Wang and M. Lang, N-heterocyclic carbene-catalyzed direct enantioselective synthesis of dihydroisoxazolo[5,4-b]pyridin-6-ones, Org. Chem. Front., 2023, 10, 963–969.
47. G. Jan, D. Rajput, A. Gupta, D. Tsering, M. Karuppasamy, K. K. Kapoorb and V. Sridharan, FeCl₃-catalyzed AB₂ three-component [3 + 3] annulation: an efficient access to functionalized indolo[3,2-b]carbazoles, Org. Chem. Front., 2023, 10, 5978–5985.
48. P. Furet, V. Guagnano, R. A. Fairhurst, P. Imbach-Weese, I. Bruce, M. Knapp, C. Fritsch, F. Blasco, J. Blanz, R. Aichholz, J. Hamon, D. Fabbro and G. Caravatti, Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation, Bioorg. Med. Chem. Lett., 2013, 23, 3741–3748.
49. F. S. P. Cardoso, K. A. Abboud and A. Aponick, Design, Preparation, and Implementation of an Imidazole-Based Chiral Biaryl P,N-Ligand for Asymmetric Catalysis, J. Am. Chem. Soc., 2013, 135, 14548–14551.
50. S. Fustero, M. Sánchez-Roselló, P. Barrio and A. Simón-Fuentes, From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of Pyrazoles, Chem. Rev., 2011, 111, 6984–7034.
51. S. Gogoi, C.-G. Zhao and D. Ding, Enantioselective Synthesis of β-(3-Hydroxypyrazol-1-yl) Ketones Using an Organocatalyzed Michael Addition Reaction, Org. Lett., 2009, 11, 2249–2252.
52. X. del Corte, E. Martínez de Marigorta, F. Palacios, J. Vicario and A. Maestro, An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to C=O and C=N bonds, Org. Chem. Front., 2022, 9, 6331–6399.
53. X. Bao, X. Wang, J.-M. Tian, X. Ye, B. Wang and H. Wang, Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis, Org. Biomol. Chem., 2022, 20, 2370–2386.
54. H. Yuan, Y. Li, H. Zhao, Z. Yang, X. Li and W. Li, Asymmetric synthesis of atropisomeric pyrazole via an enantioselective reaction of azonaphthalene with pyrazolone, Chem. Commun., 2019, 55, 12715–12718.
55. S.-N. Zhao, Q. Li, X.-X. Qiao, Y. He, G. Li and X.-J. Zhao, Asymmetric Synthesis of Axially Chiral N, N-1,2-Pentatomic Heterobiaryl Diamines by an Organocatalytic Arylation Reaction, Chem. – Eur. J., 2024, 30, e202402843.
56. X. Gao, C. Li, L. Chen and X. Li, Asymmetric Synthesis of Axially Chiral Arylpyrazole via an Organocatalytic Arylation Reaction, Org. Lett., 2023, 25, 7628–7632.
57. X. Luo, S. Li, Y. Tian, Y. Tian, L. Gao, Q. Wang and Y. Zheng, Atroposelective Construction of Naphthylpyrazoles by Chiral Phosphoric Acid Catalyzed Enantioselective Cross-Coupling of Pyrazoles with Naphthoquinone Esters, Eur. J. Org. Chem., 2024, e202400254.
58. J. Liu, X. Wei, Y. Wang, J. Qu and B. Wang, Asymmetric synthesis of atropisomeric arylpyrazoles via direct arylation of 5-aminopyrazoles with naphthoquinones, Org. Biomol. Chem., 2024, 22, 4254–4263.
59. Z. Liu, B. Gao, K. Chernichenko, H. Yang, S. Lemaire and W. Tang, Enantioselective C−H Arylation for Axially Chiral Heterobiaryls, Org. Lett., 2023, 25, 7004–7008.
60. C. Ma, F. Jiang, F.-T. Sheng, Y. Jiao, G.-J. Mei and F. Shi, Design and Catalytic Asymmetric Construction of Axially Chiral 3,3′-Bisindole Skeletons, Angew. Chem., Int. Ed., 2019, 58, 3014–3020.
61. F. Jiang, K.-W. Chen, P. Wu, Y.-C. Zhang, Y. Jiao and F. Shi, A Strategy for Synthesizing Axially Chiral Naphthyl-Indoles: Catalytic Asymmetric Addition Reactions of Racemic Substrates, Angew. Chem., Int. Ed., 2019, 58, 15104–15110.
62. F.-T. Sheng, Z.-M. Li, Y.-Z. Zhang, L.-X. Sun, Y.-C. Zhang, W. Tan and F. Shi, Atroposelective Synthesis of 3,3′-Bisindoles Bearing Axial and Central Chirality: Using Isatin-Derived Imines as Electrophiles, Chin. J. Chem., 2020, 38, 583–589.
63. P. Wu, L. Yu, C.-H. Gao, Q. Cheng, S. Deng, Y. Jiao, W. Tan and F. Shi, Design and Synthesis of Axially Chiral Aryl-Pyrroloindoles via the Strategy of Organocatalytic Asymmetric (2+3) Cyclization, Fundam. Res., 2023, 3, 237–248.
64. J.-Y. Wang, C.-H. Gao, C. Ma, X.-Y. Wu, S.-F. Ni, W. Tan and F. Shi, Design and Catalytic Asymmetric Synthesis of Furan-Indole Compounds Bearing both Axial and Central Chirality, Angew. Chem., Int. Ed., 2024, 63, e202316454.
65. C. Li, W.-F. Zuo, J. Zhou, W.-J. Zhou, M. Wang, X. Li, G. Zhan and W. Huang, Catalytic asymmetric synthesis of 3,4′-indole–pyrazole derivatives featuring axially chiral bis-pentatomic heteroaryls, Org. Chem. Front., 2022, 9, 1808–1813.
66. W. Qin, Y. Liu and H. Yan, Enantioselective Synthesis of Atropisomers via Vinylidene ortho-Quinone Methides (VQMs), Acc. Chem. Res., 2022, 55, 2780–2795.
67. Z.-X. Zhang, T.-Y. Zhai and L.-W. Ye, Synthesis of axially chiral compounds through catalytic asymmetric reactions of alkynes, Chem. Catal., 2021, 1, 1378–1412.
68. Y. Chang, C. Xie, H. Liu, S. Huang, P. Wang, W. Qin and H. Yan, Organocatalytic atroposelective construction of axially chiral N,N- and N,S-1,2-azoles through novel ring formation approach, Nat. Commun., 2022, 13, 1933.
69. J.-H. Wu, J.-P. Tan, J.-Y. Zheng, J. He, Z. Song, Z. Su and T. Wang, Towards Axially Chiral Pyrazole-Based Phosphorus Scaffolds by Dipeptide-Phosphonium Salt Catalysis, Angew. Chem., Int. Ed., 2023, 62, e202215720.
70. D. P. Vala, R. M. Vala and H. M. Patel, Versatile Synthetic Platform for 1,2,3-Triazole Chemistry, ACS Omega, 2022, 7, 36945–36987.
71. C.-Q. Qin, C. Zhao, G.-S. Chen and Y.-L. Liu, Catalytic Enantioselective Azide−Alkyne Cycloaddition Chemistry Opens Up New Prospects for Chiral Triazole Syntheses, ACS Catal., 2023, 13, 6301–6311.
72. C. Bertozzi, A Special Virtual Issue Celebrating the 2022 Nobel Prize in Chemistry for the Development of Click Chemistry and Bioorthogonal Chemistry, ACS Cent. Sci., 2023, 9, 558–559.
73. J. C. Meng, V. V. Fokin and M. G. Finn, Kinetic Resolution by Copper-Catalyzed Azide-Alkyne Cycloaddition, Tetrahedron Lett., 2005, 46, 4543–4546.
74. F. Zhou, C. Tan, J. Tang, Y. Y. Zhang, W. M. Gao, H. H. Wu, Y. H. Yu and J. Zhou, Asymmetric Copper(I)-Catalyzed Azide Alkyne Cycloaddition to Quaternary Oxindoles, J. Am. Chem. Soc., 2013, 135, 10994–10997.
75. G. R. Stephenson, J. P. Buttress, D. Deschamps, M. Lancelot, J. P. Martin, A. I. G. Sheldon, C. Alayrac, A.-C. Gaumont and P. C. B. Page, An Investigation of the Asymmetric Huisgen ‘Click’ Reaction, Synlett, 2013, 2723–2729.
76. T. Osako and Y. Uozumi, Enantioposition-Selective Copper-Catalyzed Azide−Alkyne Cycloaddition for Construction of Chiral Biaryl Derivatives, Org. Lett., 2014, 16, 5866–5869.
77. B. Yuan, A. Page, C. P. Worrall, F. Escalettes, S. C. Willies, J. J. W. McDouall, N. J. Turner and J. Clayden, Biocatalytic desymmetrization of an atropisomer with both an enantioselective oxidase and ketoreductases, Angew. Chem., Int. Ed., 2010, 49, 7010–7013.
78. L. Dai, Y. Liu, Q. Xu, M. Wang, Q. Zhu, P. Yu, G. Zhong and X. Zeng, A dynamic kinetic resolution approach to axially chiral diaryl ethers by catalytic atroposelective transfer hydrogenation, Angew. Chem., Int. Ed., 2023, 62, e202216534.
79. H. Bao, Y. Chen and X. Yang, Catalytic asymmetric synthesis of axially chiral diaryl ethers through enantioselective desymmetrization, Angew. Chem., Int. Ed., 2023, 62, e202300481.
80. S. Shee, S. S. Ranganathappa, M. S. Gadhave, R. Gogoi and A. T. Biju, Enantioselective synthesis of C−O axially chiral diaryl ethers by NHC-catalyzed atroposelective desymmetrization, Angew. Chem., Int. Ed., 2023, 62, e202311709.
81. B.-A. Zhou, X.-N. Li, C.-L. Zhang, Z.-X. Wang and S. Ye, Enantioselective synthesis of axially chiral diaryl ethers via NHC catalyzed desymmetrization and following resolution, Angew. Chem., Int. Ed., 2024, 63, e202314228.
82. X. Han, L. Chen, Y. Yan, Y. Zhao, A. Lin, S. Gao and H. Yao, Atroposelective Synthesis of Axially Chiral Diaryl Ethers by CopperCatalyzed Enantioselective Alkyne−Azide Cycloaddition, ACS Catal., 2024, 14, 3475–3481.
83. L. Dai, X. Zhou, J. Guo, Q. Huang and Y. Lu, Copper-catalyzed atroposelective synthesis of C–O axially chiral compounds enabled by chiral 1,8-naphthyridine based ligands, Chem. Sci., 2024, 15, 5993–6001.
84. R. Vroemans, S. R. Ribone, J. Thomas, L. V. Meervelt, T. Ollevier and W. Dehaen, Synthesis of Homochiral Sulfanyl- and Sulfoxide-Substituted Naphthyltriazoles and Study of the Conformational Stability, Org. Biomol. Chem., 2021, 19, 6521–6526.
85. F. Meloni, W. D. G. Brittain, L. Male, C. S. L. Duff, B. R. Buckley, A. G. Leach and J. S. Fossey, Enantiomer Stability of Atropisomeric 1,5-Disubstituted 1,2,3-Triazoles, Tetrahedron Chem, 2022, 1, 100004.
86. X. Zhang, S. Li, W. Yu, Y. Xie, C.-H. Tung and Z. Xu, Asymmetric Azide−Alkyne Cycloaddition with Ir(I)/Squaramide Cooperative Catalysis: Atroposelective Synthesis of Axially Chiral Aryltriazoles, J. Am. Chem. Soc., 2022, 144, 6200–6207.
87. W.-T. Guo, B.-H. Zhu, Y. Chen, J. Yang, P.-C. Qian, C. Deng, L.-W. Ye and L. Li, Enantioselective Rh-Catalyzed Azide-Internal-Alkyne Cycloaddition for the Construction of Axially Chiral 1,2,3-Triazoles, J. Am. Chem. Soc., 2022, 144, 6981–6991.
88. L. Zeng, J. Li and S. Cui, Rhodium-Catalyzed Atroposelective Click Cycloaddition of Azides and Alkynes, Angew. Chem., Int. Ed., 2022, 61, e202205037.
89. L. Zeng, F. Zhang and S. Cui, Construction of Axial Chirality via Click Chemistry: Rh-Catalyzed Enantioselective Synthesis of 1-Triazolyl-2-Naphthylamines, Org. Lett., 2023, 25, 443–448.
90. L. Zhou, Y. Li, S. Li, Z. Shi, X. Zhang, C.-H. Tung and Z. Xu, Asymmetric rhodium-catalyzed click cycloaddition to access C–N axially chiral N-triazolyl indoles, Chem. Sci., 2023, 14, 5182–5187.
91. S. Choi, M. C. Guo, G. M. Coombs and S. J. Miller, Catalytic Asymmetric Synthesis of Atropisomeric N-Aryl 1,2,4-Triazoles, J. Org. Chem., 2023, 88, 7815–7820.
92. Q.-H. Nguyen, S.-M. Guo, T. Royal, O. Baudoin and N. Cramer, Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C−H Arylation of Heteroarenes, J. Am. Chem. Soc., 2020, 142, 2161–2167.
93. H. V. Tolomeu and C. A. M. Fraga, Imidazole: Synthesis, Functionalization and Physicochemical Properties of a Privileged Structure in Medicinal Chemistry, Molecules, 2023, 28, 838.
94. Z. Zhang, F. Xie, J. Jia and W. Zhang, Chiral Bicycle Imidazole Nucleophilic Catalysts: Rational Design, Facile Synthesis, and Successful Application in Asymmetric Steglich Rearrangement, J. Am. Chem. Soc., 2010, 132, 15939–15941.
95. K. Miyata, H. Kutsuna, S. Kawakami and M. Kitamura, A Chiral Bidentate sp²-N Ligand, NaphdiPIM: Application to CpRu-Catalyzed Asymmetric Dehydrative C-, N-, and O-Allylation, Angew. Chem., Int. Ed., 2011, 50, 4649–4653.
96. D. A. DiRocco, Y. Ji, E. C. Sherer, A. Klapars, M. Reibarkh, J. Dropinski, R. Mathew, P. Maligres, A. M. Hyde, J. Limanto, A. Brunskill, R. T. Ruck, L.-C. Campeau and I. W. Davies, A multifunctional catalyst that stereoselectively assembles prodrugs, Science, 2017, 356, 426–430.
97. S. Mishra, J. Liu and A. Aponick, Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P,N-Ligands, J. Am. Chem. Soc., 2017, 139, 3352–3355.
98. H.-Q. Shen, B. Wu, H.-P. Xie and Y.-G. Zhou, Preparation of Axially Chiral 2,2′-Biimidazole Ligands through Remote Chirality Delivery and Their Application in Asymmetric Carbene Insertion into N−H of Carbazoles, Org. Lett., 2019, 21, 2712–2717.
99. Y. Kwon, A. J. Chinn, B. Kim and S. J. Miller, Divergent Control of Point and Axial Stereogenicity: Catalytic Enantioselective C−N Bond-Forming Cross-Coupling and Catalyst-Controlled Atroposelective Cyclodehydration, Angew. Chem., Int. Ed., 2018, 57, 6251–6255.
100. Y. Kwon, J. Li, J. P. Reid, J. M. Crawford, R. Jacob, M. S. Sigman, F. D. Toste and S. J. Miller, Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration, J. Am. Chem. Soc., 2019, 141, 6698–6705.
101. N. Man, Z. Lou, Y. Li, H. Yang, Y. Zhao and H. Fu, Organocatalytic Atroposelective Construction of Axially Chiral N-Aryl Benzimidazoles Involving Carbon–Carbon Bond Cleavage, Org. Lett., 2020, 22, 6382–6387.
102. P. Zhang, X.-M. Wang, Q. Xu, C.-Q. Guo, P. Wang, C.-J. Lu and R.-R. Liu, Enantioselective Synthesis of Atropisomeric Biaryls by Pd-Catalyzed Asymmetric Buchwald–Hartwig Amination, Angew. Chem., Int. Ed., 2021, 60, 21718–21722.
103. F.-B. Ge, Q.-K. Yin, C.-J. Lu, X. Xuan, J. Feng and R.-R. Liu, Enantioselective Synthesis of Benzimidazole Atropisomers Featuring a N–N Axis, Chin. J. Chem., 2024, 42, 711–718.
104. Q.-J. An, W. Xia, W.-Y. Ding, H.-H. Liu, S.-H. Xiang, Y.-B. Wang, G. Zhong and B. Tan, Nitrosobenzene-Enabled Chiral Phosphoric Acid Catalyzed Enantioselective Construction of Atropisomeric N-Arylbenzimidazoles, Angew. Chem., Int. Ed., 2021, 60, 24888–24893.
105. L. Hou, S. Zhang, J. Ma, H. Wang, T. Jin, M. Terada and M. Bao, Organocatalytic Atroposelective Construction of Axially Chiral Compounds Containing Benzimidazole and Quinoline Rings, Org. Lett., 2023, 25, 5481–5485.
106. Z.-J. Zhang, M. M. Simon, S. Yu, S.-W. Li, X. Chen, S. Cattani, X. Hong and L. Ackermann, Nickel-Catalyzed Atroposelective C−H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands, J. Am. Chem. Soc., 2024, 146, 9172–9180.
107. S. Yin, J. Liu, K. N. Weeks and A. Aponick, Catalytic Enantioselective Synthesis of Axially Chiral Imidazoles by Cation-Directed Desymmetrization, J. Am. Chem. Soc., 2023, 145, 28176–28183.
108. J.-W. Zhang, J.-H. Xu, D.-J. Cheng, C. Shi, X.-Y. Liu and B. Tan, Discovery and enantiocontrol of axially chiral urazoles via organocatalytic tyrosine click reaction, Nat. Commun., 2016, 7, 10677.
109. L.-L. Zhang, J.-W. Zhang, S.-H. Xiang, Z. Guo and B. Tan, Remote Control of Axial Chirality: Synthesis of Spirooxindole–Urazoles via Desymmetrization of ATAD, Org. Lett., 2018, 20, 6022–6026.
110. B. Tan, G. Hernández-Torres and C. F. Barbas III, J. Am. Chem. Soc., 2011, 133, 12354–12357.
111. J. Yang, J.-W. Zhang, W. Bao, S.-Q. Qiu, S. Li, S.-H. Xiang, J. Song, J. Zhang and B. Tan, Chiral Phosphoric Acid-Catalyzed Remote Control of Axial Chirality at Boron−Carbon Bond, J. Am. Chem. Soc., 2021, 143, 12924–12929.
112. C. Parida, S. K. Dave, K. Das and S. C. Pan, Organocatalytic Asymmetric Dearomatization Reaction for the Construction of Axially Chiral Urazole Embedded Naphthalenones, Adv. Synth. Catal., 2023, 365, 1185–1190.
113. X. Liu, B. Zhu, X. Zhang, H. Zhu, J. Zhang, A. Chu, F. Wang and R. Wang, Enantioselective synthesis of [4]helicenes by organocatalyzed intermolecular C-H amination, Nat. Commun., 2024, 15, 732.
114. Y.-H. Miao, Z.-X. Zhang, X.-Y. Huang, Y.-Z. Hua, S.-K. Jia, X. Xiao, M.-C. Wang, L.-P. Xu and G.-J. Mei, Catalytic asymmetric dearomative azo-Diels–Alder reaction of 2-vinlyindoles, Chin. Chem. Lett., 2024, 35, 108830.
115. J. Jin, X. Huang, J. Xu, T. Li, X. Peng, X. Zhu, J. Zhang, Z. Jin and Y. R. Chi, Carbene-Catalyzed Atroposelective Annulation and Desymmetrization of Urazoles, Org. Lett., 2021, 23, 3991–3996.
116. Y. Yan, M. Li, Q. Shi, M. Huang, W. Li, L. Cao and X. Zhang, Atropoenantioselective Arylation of 5-Amino-Isothiazoles with Methyl p-Quinone Carboxylate, Asian J. Org. Chem., 2023, 12, e202200578.
117. N. Agrawal and P. Mishra, The synthetic and therapeutic expedition of isoxazole and its analogs, Med. Chem. Res., 2018, 27, 1309–1344.
118. W. Luo, H. Guo, X. Qiu, M. Ming, L. Zhang, H. Zhu and J. Zhou, Organocatalytic Atroposelective Construction of Pentatomic Heterobiaryl Diamines through Arylation of 5-Aminoisoxazoles with Azonaphthalenes, Org. Lett., 2024, 26, 2564–2568.
119. Q. Li, Y.-Y. Xu, T. Wang and Y.-Q. Wang, Enantioselective Synthesis of Axially Chiral Heterobiaryl N-Cbz-Protected Diamines via Organocatalytic Arylation of 5-Aminoisoxazoles, Eur. J. Org. Chem., 2024, e202400592.
120. Z. Jin, Muscarine, imidazole, oxazole and thiazole alkaloids, Nat. Prod. Rep., 2016, 33, 1268–1317.
121. T. Yue, M.-X. Wang, D.-X. Wang, G. Masson and J. Zhu, Angew. Chem., Int. Ed., 2009, 48, 6717–6721.
122. W. Luo, J. Zhao, C. Yin, X. Liu, L. Lin and X. Feng, Catalytic hetero-ene reactions of 5-methyleneoxazolines: highly enantioselective synthesis of 2,5-disubstituted oxazole derivatives, Chem. Commun., 2014, 50, 7524–7526.
123. P.-L. Shao, J.-Y. Liao, Y. A. Ho and Y. Zhao, Highly Diastereo- and Enantioselective Silver-Catalyzed Double [3+2] Cyclization of α-Imino Esters with Isocyanoacetate, Angew. Chem., Int. Ed., 2014, 53, 5435–5439.
124. W. Luo, X. Yuan, L. Lin, P. Zhou, X. Liu and X. Feng, A N,N′-dioxide/Mg(OTf)₂ complex catalyzed enantioselective α-addition of isocyanides to alkylidene malonates, Chem. Sci., 2016, 7, 4736–4740.
125. X.-J. Liu, C. Zheng, Y.-H. Yang, S. Jin and S.-L. You, Iridium-Catalyzed Asymmetric Allylic Aromatization Reaction, Angew. Chem., Int. Ed., 2019, 58, 10493–10499.
126. G. Bringmann and D. Menche, Stereoselective Total Synthesis of Axially Chiral Natural Products via Biaryl Lactones, Acc. Chem. Res., 2001, 34, 615–624.
127. G.-Q. Chen, B.-J. Lin, J.-M. Huang, L.-Y. Zhao, Q.-S. Chen, S.-P. Jia, Q. Yin and X. Zhang, Design and Synthesis of Chiral oxa-Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric Reduction of Bringmann's Lactones with Molecular H₂, J. Am. Chem. Soc., 2018, 140, 8064–8068.
128. C. Yu, H. Huang, X. Li, Y. Zhang and W. Wang, Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification, J. Am. Chem. Soc., 2016, 138, 6956–6959.
129. L. Qian, L.-F. Tao, W.-T. Wang, E. Jameel, Z.-H. Luo, T. Zhang, Y. Zhao and J.-Y. Liao, Catalytic Atroposelective Dynamic Kinetic Resolution of Biaryl Lactones with Activated Isocyanides, Org. Lett., 2021, 23, 5086–5091.
130. W.-T. Wang, S. Zhang, L.-F. Tao, Z.-Q. Pan, L. Qian and J.-Y. Liao, Cooperative catalysis-enabled C–N bond cleavage of biaryl lactams with activated isocyanides, Chem. Commun., 2022, 58, 6292–6295.
131. L.-F. Tao, F. Huang, X. Zhao, L. Qian and J.-Y. Liao, Atroposelective synthesis of eight-membered lactam-bridged N-arylindoles via stepwise cut-and-sew strategy, Cell Rep. Phys. Sci., 2023, 4, 101697.
132. W. Guo, J. Gu and Z. Gu, Catalytic Asymmetric Synthesis of Atropisomeric Nitrones: Versatile Intermediate for Axially Chiral Biaryls, Org. Lett., 2020, 22, 7622–7628.
133. Z. Chao, M. Ma and Z. Gu, Cu-Catalyzed Site-Selective and Enantioselective Ring Opening of Cyclic Diaryliodoniums with 1,2,3-Triazoles, Org. Lett., 2020, 22, 6441–6446.
134. S. Yang, T. Zheng, L. Duan, X. Xue and Z. Gu, Atroposelective Three-Component Coupling of Cyclic Diaryliodoniums and Sodium Cyanate Enabled by the Dual-Role of Phenol, Angew. Chem., Int. Ed., 2023, 62, e202302749.
135. K. Zhu, K. Xu, Q. Fang, Y. Wang, B. Tang and F. Zhang, Enantioselective Synthesis of Axially Chiral Biaryls via Cu-Catalyzed Acyloxylation of Cyclic Diaryliodonium Salts, ACS Catal., 2019, 9, 4951–4957.
136. J. Ke, B. Zu, Y. Guo, Y. Li and C. He, Hexafluoroisopropanol-Enabled Copper-Catalyzed Asymmetric Halogenation of Cyclic Diaryliodoniums for the Synthesis of Axially Chiral 2,2′-Dihalobiaryls, Org. Lett., 2021, 23, 329–333.
137. D. Zhu, Y. Sun, H. Peng, H. Li, Y. Yan and H. Kuang, Enantioselective Synthesis of Axially Chiral Oxazole Biaryls by Copper-Catalyzed Oxidation of Cyclic Diaryliodoniums, Eur. J. Org. Chem., 2022, e202101449.
138. L. Pang, Q. Sun, Z. Huang, G. Li, J. Liu, J. Guo, C. Yao, J. Yu and Q. Li, Palladium-Catalyzed Stereoselective Cleavage of C−P Bond: Enantioselective Construction of Atropisomers Containing a P-Stereogenic Center, Angew. Chem., Int. Ed., 2022, 61, e202211710.
139. L. Pang, Z. Huang, Q. Sun, G. Li, J. Liu, B. Li, C. Ma, J. Guo, C. Yao, J. Yu and Q. Li, Diversity-oriented synthesis of P-stereogenicband axially chiral monodentate biaryl phosphines enabled by C-P bond cleavage, Nat. Commun., 2023, 14, 4437.
140. L. Pang, C. Wang, C. Ma, J. Liu, M. C. Yao, J. Yu and Q. Li, Palladium-Catalyzed Modular Assembly of P-Stereogenic and Axially Chiral Phosphinooxazoles (PHOX) Ligands by C−P Bond Cleavage/Intermolecular C(sp²)−H Bond Functionalization, Org. Lett., 2023, 25, 7705–7710.
141. N. Bhanwala, V. Gupta, L. Chandrakar and G. L. Khatik, Thiazole Heterocycle: An Incredible and Potential Scaffold in Drug Discovery and Development of Antitubercular Agents, ChemistrySelect, 2023, 8, e202302803.
142. Z.-H. Luo, W.-T. Wang, T.-Y. Tang, S. Zhang, F. Huang, D. Hu, L.-F. Tao, L. Qian and J.-Y. Liao, Torsional Strain-Independent Catalytic Enantioselective Synthesis of Biaryl Atropisomers, Angew. Chem., Int. Ed., 2022, 61, e202211303.

---