Enantioselective Iodination and Bromination for the Atroposelective Construction of Axially Chiral Compounds

Abstract

Axially chiral compounds play a pivotal role in organic synthesis, materials science, and pharmaceutical development. Among the various strategies for their construction, enantioselective iodination and bromination have emerged as powerful and versatile approaches, enabling the introduction of halogen functionalities that serve as valuable synthetic handles for further transformations. This review highlights recent advances in atroposelective iodination and bromination, with a particular focus on the synthesis of axially chiral biaryl and heterobiaryl frameworks. Key catalytic systems are discussed, including transition metal complexes, small-molecule organocatalysts, and high-valent metal catalysts in combination with chiral ligands or transient directing groups. Representative case studies are presented to elucidate mechanistic pathways, stereochemical induction models, and synthetic applications. Despite notable progress, challenges remain, such as expanding substrate scope, improving atom economy, and achieving high levels of regio- and stereocontrol in complex molecular settings. This review aims to provide a comprehensive overview of these halogenation strategies and offers insights to guide future research in the atroposelective synthesis of axially chiral molecules.

1. Introduction

Axially chiral compounds are widely found in natural products, bioactive molecules, optically pure materials, and privileged chiral ligands. These molecules exhibit unique stereochemical properties arising from restricted rotation around a single bond, which leads to the formation of configurationally stable atropisomers [1,2,3,4,5,6,7,8,9]. The axial chirality often plays a crucial role in determining molecular function. Representative examples, such as BINOL, QUINAP, and the anticancer natural product colchicine, highlight the central importance of axial chirality in molecular activity and asymmetric catalysis [10]. With the expanding applications of axially chiral compounds in drug discovery and materials science, the development of efficient and general strategies for constructing axially chiral frameworks has become a major focus in modern organic synthesis [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25].

Given the significance of axial chirality, researchers have developed a variety of efficient synthetic strategies. Traditional methods such as asymmetric alkylation [26,27,28,29,30,31,32,33], arylation [34,35,36,37,38,39,40], and alkenylation (or alkynylation) [41,42,43,44,45,46,47,48,49,50,51,52,53,54] remain common approaches for atropisomer construction. In recent years, enantioselective halogenation has rapidly emerged as a transformative strategy. This approach offers excellent atom economy and broad functional group tolerance, while also enabling the installation of halogen functional groups that can be further elaborated. Several landmark advances in catalytic enantioselective halogenation have greatly accelerated progress in this area. The emergence of novel catalytic systems—such as chiral organocatalysts, transition metal complexes, and cooperative high-valent metal/chiral transient directing group (cTDG) catalysis—has led to significant methodological breakthroughs. These strategies have enabled efficient and highly selective halogenation of a wide range of biaryl and heteroaryl scaffolds and have been successfully applied to the construction of single, vicinal, and even multiple stereogenic axes [55,56,57,58,59]. The enantioselectivity in these reactions typically arises from the precise spatial control exerted by chiral catalysts or ligands, which differentiate the prochiral faces of the substrate. Key factors influencing the stereochemical outcome include steric hindrance and transition state organization.

This review provides a systematic overview of recent advances in the construction of axially chiral compounds via catalytic enantioselective halogenation. It focuses on two representative types of reactions—iodination and bromination—organized in chronological order, discusses underlying reaction mechanisms and methodological innovations, and offers a perspective on the current challenges and future directions in catalyst design, substrate expansion, and potential applications.

2. Atroposelective Iodination

In recent years, catalytic asymmetric iodination reactions have attracted considerable attention due to their significant value in the construction of chiral organoiodine compounds, offering an efficient and straightforward strategy for the synthesis of axially or centrally chiral molecules [60]. In 2013, the Yu group reported the first Pd/mono-N-protected amino acid (MPAA) co-catalyzed asymmetric C–H iodination, achieving desymmetrization of a triflyl-protected diarylmethylamine scaffold and affording centrally chiral diarylmethylamines with up to 99% ee [61]. This pioneering work laid a solid foundation for the subsequent development of asymmetric iodination reactions for the construction of axially chiral compounds. In 2014, the You group reported the kinetic resolution of axially chiral compounds via Pd(II)-catalyzed direct C–H iodination (Scheme 1). This strategy represents the first example of asymmetric C–H bond functionalization based on a Pd(II)/Pd(IV) catalytic cycle for the construction of axially chiral biaryl frameworks, although the enantioselectivity achieved was only moderate (22–94% ee). The authors proposed a plausible catalytic mechanism: the enantioselective C–H activation likely proceeds via a concerted metalation–deprotonation (CMD) pathway to afford the Pd(II) intermediate INT 1, while retaining the (Ra)-configuration of compound 2. Subsequently, INT 1 undergoes oxidation by NIS to generate a high-valent Pd(IV) intermediate INT 2, which then undergoes reductive elimination to furnish the desired product 3, along with regeneration of the Pd(II) catalyst to complete the catalytic cycle [62].

Moreover, the resulting iodinated product could be conveniently transformed into aryl-substituted pyridine N-oxides 4 via Suzuki–Miyaura coupling, which exhibited good catalytic activity in the asymmetric allylation of benzaldehyde with allyltrichlorosilane (Scheme 2).

In 2018, the Yan group reported an organocatalytic method with high diastereo- and enantioselectivity for the construction of vicinal diaxial styrenes and multi-axial chiral systems (Scheme 3). This strategy proceeded smoothly under mild reaction conditions and exhibited a broad substrate scope, enabling the efficient synthesis of multi-axial chiral compounds bearing two-to-three stereogenic axes in high yields with excellent selectivity. The authors proposed a plausible reaction mechanism: In the first step, substrate 6 forms a complex INT 1 with the catalyst through hydrogen bonding involving the formamide moiety. Subsequently, under the basic conditions provided by the quinoline ring, the naphthol unit undergoes deprotonation, leading to the generation of a chiral tetrasubstituted intermediate INT 2 in the presence of NIS. Meanwhile, the released succinimide anion abstracts a proton from PhSO₂H, yielding a nucleophilic PhSO₂⁻ species. Finally, a nucleophilic addition occurs to afford the desired product [63].

In 2020, the He group developed an efficient copper-catalyzed asymmetric halogenation reaction (Scheme 4). By using tetrabutylammonium halides to halogenate cyclic diaryliodonium salts 9 in the presence of copper halides and chiral bisoxazoline ligands L2 in hexafluoroisopropanol (HFIP), a wide range of axially chiral 2,2′-dihalobiaryls 10 were successfully synthesized in good-to-excellent yields with outstanding enantioselectivities. This strategy features mild reaction conditions, operational simplicity, and broad substrate scope, making it an effective approach for constructing diverse axially chiral frameworks. Notably, the resulting axially chiral 2,2′-dihalobiaryls 10a can be further transformed into various enantiopure chiral ligands, offering structural diversity and promising potential in asymmetric catalysis. The success of this methodology relies on the synergistic effect of CuI, the chiral bisoxazoline ligand, and the HFIP solvent [64].

In 2022, Denmark and co-workers reported a DSI-catalyzed atroposelective iodination of 2-amino-6-arylpyridines, enabled by a data-driven catalyst design strategy (Scheme 5). A training set of chiral disulfonimides was constructed, and computational models incorporating chemoinformatics and unsupervised learning were used to predict high-performing catalysts. This approach successfully identified optimal 3,3′-alkynyl-substituted DSIs, which afforded excellent enantioselectivity (up to 92% ee) and broad substrate scope. The study also introduced a catalyst structure comparison (CSC) workflow to address cases dominated by catalyst–substrate interactions [65]. More recently, Kwon and co-workers reported a chiral phosphoric acid-catalyzed atroposelective iodination of N-arylindoles, achieving high enantioselectivity (up to 98:2 er) through a halogen migration and deprotonation pathway. This study expands the limited examples of atroposelective halogenation of indole-based scaffolds and provides a new strategy for constructing axially chiral C–N frameworks [66].

Development of practically valuable enantioselective desymmetrization reactions for the efficient synthesis of enantioenriched axially chiral biaryl compounds remains a significant challenge in the field of asymmetric catalysis. In 2023, the Lin group reported a highly enantioselective desymmetrization reaction. Utilizing Pd(II) coordinated by N-benzoyl-L-phenylalanine (L3) as the chiral catalyst, they achieved atroposelective C-H iodination of 1-phenylisoquinoline N-oxide (13) at room temperature, synthesizing the axially chiral biaryl N-oxide 14 (Scheme 6). This method exhibits broad substrate scope and delivers target products in high yields (up to 99%) with excellent enantioselectivity (up to 98% ee). Mechanistic studies of this reaction revealed that in the presence of the Pd(II)/monoprotected amino acid complex, ortho C-H bond cleavage of INT 1 occurs via concerted metalation–deprotonation (CMD), generating the Pd(II) intermediate INT 2. This step constitutes the rate-determining step and is also the enantioselectivity-determining step. Following the C-H activation step, INT 2 undergoes oxidative addition by NIS to form the highly reactive Pd(IV) intermediate INT 3. Reductive elimination of INT 3 then furnishes the desired product 14, concurrently regenerating the Pd(II) species to complete the catalytic cycle [67].

In 2023, the You group reported a rhodium-catalyzed enantioselective C–H halogenation reaction under mild conditions (Scheme 7). This method employs a chiral CpRh(III) complex to catalyze the direct C–H iodination of 1-aryl isoquinolines 15 with N-iodosuccinimide, efficiently constructing a series of axially chiral biaryl iodides 16 with yields up to 99% and enantioselectivities reaching 97% ee. In addition to iodination, this catalytic system is also applicable to C–H bromination and chlorination, demonstrating excellent regioselectivity and enantioselectivity. Based on the above-mentioned results, the authors proposed a plausible catalytic cycle: substrate 15 coordinates with the chiral CpRh(III) complex and undergoes enantioselective C–H activation via a carboxylate-assisted concerted metalation–deprotonation (CMD) process, forming a five-membered rhodacycle intermediate INT 1. The carboxylate anion plays a critical role in abstracting the proton from the C–H bond and stabilizing the transition state during metal insertion, thereby ensuring both the efficiency and stereocontrol of the C–H activation step. In pathway a, INT 1 undergoes oxidative addition with N-iodosuccinimide to afford a high-valent CpRh(V) intermediate INT 2, which then undergoes reductive elimination to deliver the iodinated product 16, accompanied by regeneration of the Rh(III) catalyst with the assistance of acetic acid. Alternatively, pathway b, involving a direct nucleophilic substitution of INT 1 with NIS to form product 16, cannot be ruled out [68].

The resulting axially chiral biaryl iodides can be transformed into QUINAP-type and N,N-type chiral ligands, demonstrating their potential as a versatile platform for chiral ligand synthesis through C–C, C–N, and C–P bond-forming transformations. This method is compatible with nitrogen-containing aromatic heterocycles such as pyridines, isoquinolines, and benzoisoquinolines, and the halogenated products exhibit both high yields and excellent enantioselectivities (Scheme 8). For example, iodinated compound 16 with 94% ee underwent Suzuki coupling with phenylboronic acid to afford compound 17 (91% yield, 94% ee); Sonogashira coupling furnished alkynylated product 18 in 97% yield without loss of enantiopurity; reaction with diphenylphosphine yielded the QUINAP ligand 19 (77% yield); and Buchwald–Hartwig amination with methylamine or benzylamine provided N,N-biaryl ligands 20 (51% yield) and 21 (91% yield), respectively.

3. Atroposelective Bromination

Aromatic and heteroaromatic bromides are pivotal synthetic building blocks in organic chemistry, with their significance increasingly underscored by the widespread application of cross-coupling reactions. These brominated compounds are ubiquitous in natural products and bioactive molecules, particularly the mono- and polybrominated phenols, pyrroles, indoles, and carbazoles isolated from marine natural sources over the past three decades, many of which exhibit notable biological activities. In addition, bromoarenes find broad utility across pharmaceuticals, dyes, agrochemicals, and flame retardants [69,70,71]. Traditional strategies for asymmetric arene bromination primarily fall into two categories. One approach leverages the intrinsic symmetry or electronic bias of the substrate to induce enantioselectivity using chiral reagents or catalysts. The other employs ortho-directing activation strategies to control both regio- and stereoselectivity through prefunctionalization. However, these methods often suffer from limitations in substrate scope, functional group compatibility, and operational practicality. Against this backdrop, in 2010, the Miller group developed a class of tripeptide-based small-molecule catalysts capable of effecting dynamic kinetic resolution (DKR) of racemic biaryl substrates via atroposelective electrophilic aromatic bromination with simple brominating reagents (Scheme 9). This strategy enables efficient construction of axially chiral biaryl scaffolds under mild conditions, affording products with excellent enantiomeric purity (typically er > 95:5) and high isolated yields (65–87%). A plausible mechanistic model was proposed to rationalize the observed high selectivity, offering a novel and generalizable platform for the asymmetric synthesis of axially chiral biaryl compounds [72].

In 2013, the Miller group developed a novel asymmetric synthesis strategy for atropisomeric benzamides based on catalytic electrophilic aromatic bromination (Scheme 10). This reaction employs a tetrapeptide organocatalyst containing a tertiary amine and efficiently constructs enantioselective di- and tribrominated products 25 from various substituted aromatic substrates 24. Tertiary benzamides, which exhibit configurational stability after ortho-functionalization, serve as ideal substrates for atropisomer construction. Mechanistic studies revealed that kinetic experiments at low conversion confirmed the initial bromination step to be both regioselective and stereochemistry-determining. NMR analysis detected a specific catalyst–substrate complex, indicating that non-covalent interactions play a key role in the stereochemical induction process. The resulting chiral brominated products can be efficiently derivatized via regioselective metal–halogen exchange and subsequent iodination, providing a versatile platform for multifunctional molecule synthesis [73].

In 2013, the Akiyama group developed a novel chiral phosphoric acid-catalyzed asymmetric bromination strategy (Scheme 11). This approach achieves the atroposelective construction of multi-substituted biaryl compounds by coupling desymmetrization with kinetic resolution. Using N-bromosuccinimide as the brominating agent, the reaction delivers products with high enantioselectivity (up to 99% ee). Experimental and computational studies confirmed that a hydrogen-bonding network among the substrate, catalyst, and NBP is crucial for the observed selectivity. The system demonstrates broad substrate scope, being compatible with biphenyls bearing electron-donating/withdrawing groups and aryl-naphthalene substrates, enabling efficient synthesis of axially chiral monobromides [74].

In 2015, the Matsubara group developed a novel highly enantioselective synthesis method using an amino-urea bifunctional organocatalyst, enabling the efficient construction of axially chiral isoquinoline N-oxides (Scheme 12). These N-oxides serve as both chiral ligands and organocatalysts, making them valuable in asymmetric synthesis. Notably, this represents the first report of achieving highly enantioselective synthesis of axially chiral biaryl compounds using a structurally simple bifunctional organocatalyst. The method exhibits excellent substrate scope, generally affording good to excellent enantioselectivities [75].

In 2015, Miller group developed a β-turn peptide catalyst containing a tertiary amine moiety that enables the atroposelective bromination of pharmaceutically relevant 3-arylquinazolin-4(3H)-one 33 scaffolds (Scheme 13). This catalytic system exhibits excellent enantioselectivity and broad substrate scope. The structures of both the free catalyst and its complex with the substrate were elucidated by X-ray crystallography and 2D-NOESY NMR spectroscopy. Additionally, DFT calculations indicated that substrates with higher rotational barriers tend to exhibit improved enantioselectivity, suggesting that the configurational stability of the chiral axis plays a critical role in achieving high stereocontrol in this catalytic system. Mechanistic investigations indicate that the initial bromination step is stereodetermining, leading primarily to the selective ortho-bromination of the aryl ring, affording a configurationally stable atropisomer. These axially chiral intermediates are not only stable but also amenable to further regioselective transformations while preserving their stereochemical integrity. For instance, the tribrominated products can undergo dehalogenative Suzuki–Miyaura cross-coupling to generate ortho-arylated derivatives, or Buchwald–Hartwig amination to introduce para-amino functionalities [76].

In 2019, the Matsubara group reported an enantioselective bromination of axially chiral cyanoarenes 37 via a dynamic kinetic resolution strategy (Scheme 14). This transformation employed a bifunctional organocatalyst as the chiral source and was specifically designed for substrates with high intrinsic rotational barriers. By implementing a stepwise, portionwise addition of the brominating reagent at an optimized temperature, a significant improvement in enantioselectivity was achieved. Although the current catalytic system affords only moderate enantioselectivity, this study provides valuable design principles for the asymmetric synthesis of axially chiral cyanoarenes and lays a solid foundation for the construction of more densely substituted axially chiral biaryl frameworks [77].

In 2023, the Rezayee group reported an innovative strategy that combines high-valent palladium catalysis with chiral transient directing groups (cTDGs) to efficiently construct multifunctional atropisomeric biaryl scaffolds (Scheme 15). This method features operational simplicity, good scalability, and excellent tolerance to air and moisture. Under certain conditions, the palladium catalyst loading could be reduced to as low as 1 mol%. Using this approach, the researchers achieved high yields and excellent stereoselectivity in the synthesis of chiral mono-brominated, di-brominated, and bromine-chlorine co-substituted biaryl compounds. These products are not only structurally robust but also possess diverse functionalization sites, making them ideal synthetic platforms for a wide range of stereoretentive transformations. In addition, a rare case of oxidant-dependent regioselectivity mediated by palladium was identified. Unlike NBS, NCS selectively functionalized the H_a position. Specifically, in the presence of NCS, the palladium catalyst and cTDGs cooperatively directed the formation of a single ortho-chlorinated product at the H_a site, even with a large excess of NCS. Subsequent addition of NBS enabled bromination at the H_b position, affording a chiral, mixed-halogenated biaryl scaffold with complete stereo- and regiocontrol. Notably, the reaction did not proceed in the absence of palladium and cTDGs, highlighting a synergistic interaction between the oxidant and the metal catalyst [78].

4. Conclusions

In summary, enantioselective iodination and bromination have emerged as powerful and versatile tools for the atroposelective construction of axially chiral compounds. Significant progress in recent years has been driven by the development of innovative catalytic systems, including chiral small-molecule organocatalysts, transition metal complexes, and high-valent metal catalysts combined with chiral transient directing groups (cTDGs). These methodologies enable the efficient and stereoselective introduction of halogen atoms into a broad array of biaryl and heterobiaryl scaffolds. The resulting halogenated products not only possess intrinsic biological and structural value but also serve as versatile intermediates for downstream transformations such as cross-coupling reactions.

These strategies are characterized by mild reaction conditions, broad functional group compatibility, and the capacity to construct single, vicinal diaxial, or even multiple stereogenic axes. Recent breakthroughs—including data-driven catalyst optimization, cTDG-mediated regio- and stereocontrol, and the broad utility of Rh(III) catalysis—have significantly expanded substrate scope and improved reaction practicality. Nonetheless, challenges remain. Current methods show limited generality for non-biaryl-type chiral frameworks, and the frequent use of stoichiometric or excess halogenating agents compromises atom economy. In addition, a deeper mechanistic understanding is still needed to address regio- and stereocontrol in complex settings, such as multi-step halogenations, high-valent metal cycles, and systems dominated by non-covalent interactions. Developing more effective strategies to activate challenging substrates with high rotational barriers or unique electronic features also remains a pressing need.

Future research should prioritize mechanistic elucidation to guide rational catalyst design and broaden the synthetic applicability of these methods. Simultaneously, the development of greener halogen sources and sustainable reaction conditions, along with the exploration of applications in pharmaceuticals, materials science, and asymmetric catalysis, will be essential. Enantioselective iodination and bromination are poised to remain central strategies in the synthesis of structurally diverse and functionally rich axially chiral molecules.