Recent Advances in Palladium-Catalyzed Enantioselective Cyclization for the Construction of Atropisomers

Abstract

Axially chiral structures have become increasingly common in modern materials and pharmaceuticals, especially as chiral ligands and organocatalysts, highlighting their growing significance. In the field of pharmaceutical research, there are several notable examples worth highlighting, such as the antibiotics vancomycin, Knipholone, and Mastigophorene A. Over the past decade, the availability of axially chiral compounds has significantly improved through advancements in existing strategies and the introduction of modern catalytic atroposelective synthesis concepts. These synthetic advancements not only broaden the scope of chemical reactions, but also facilitate the construction of axially chiral frameworks with high application value. Currently, various synthetic methods are available for achieving stereoselective synthesis of axially chiral compounds under catalyst control, including desymmetrization, (dynamic) kinetic resolution, cross-coupling reactions, and de novo ring-forming synthesis. This paper focuses on recent advances in constructing atropisomers through palladium-catalyzed asymmetric cyclization strategies.

1. Introduction

Axial chirality is a stereochemical phenomenon arising from the restricted rotation around a stereogenic axis that has non-planar substituents [1,2,3,4,5,6,7,8,9,10]. In 1922, Christie and Kenner successfully crystallized two enantiomeric salts of 6,6′-dinitro-2,2′-diphenylacetic acid for the first time, confirming the significance of axial chirality [11]. Since then, axial chirality has been widely applied in the study of bioactive natural products and in the design of modern drugs and functional materials [12,13,14,15,16,17]. In 1980, Noyori and his colleagues first employed the optically pure BINAP (2,2′-bis (diphenylphosphino)-1,1′-binaphthyl) as a ligand in asymmetric metal catalysis, revealing the stereocontrol ability of axial chiral frameworks and providing a new perspective on axial chirality [18]. Subsequently, QUINAPs (1-(2-phenylphosphino-1-naphthyl)isoquinoline) and phosphoramidite ligands were introduced, along with many organocatalysts based on axial chirality, such as phase-transfer catalysts and Brønsted acids, which have been extensively studied [19]. The ongoing development of axial chirality has made it an essential component of modern organic synthesis and a key area in asymmetric catalysis. Integrating axial chiral elements into catalytic species has become an effective strategy to induce or enhance enantioselectivity. The design of axially chiral compounds and their applications in catalyzed asymmetric synthesis are at the core of this research, reflecting the high activity in this field. However, the high production costs of certain ligands and catalysts, along with their impractical synthetic routes, remain significant challenges. Additionally, the conformational instability of axially chiral compounds limits their widespread application.

In recent years, tremendous achievements have been made in the catalytic asymmetric construction of atropisomers in molecular synthesis, encompassing multi-axis chiral units that feature biaryl, heterobiaryl, and linked aryl motifs. These significant advances, realized through either transition metal catalysis or organocatalysis, can generally be classified into four strategies: (a) aryl–aryl coupling; (b) cyclization; (c) functional group modification of the biaryl core; and (d) ring-opening [2,3,4,5,20,21,22,23,24,25,26,27,28,29,30,31]. Notably, as one of the important tools for constructing chiral compounds, palladium-catalyzed asymmetric reactions have witnessed rapid development in recent years [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]. Although several reviews on palladium-catalyzed asymmetric cyclization reactions have been published, discussions regarding atropisomeric frameworks remain relatively insufficient. Therefore, this review aims to systematically summarize the latest progress in the enantioselective construction of atropisomers via palladium-catalyzed cyclization reactions. Although there have been reviews on asymmetric cyclization reactions catalyzed by palladium, discussions regarding axial chiral frameworks remain relatively scarce. Therefore, the aim of this review is to summarize recent advances in the enantioselective construction of atropisomers through palladium-catalyzed cyclization. We will focus on various palladium-catalyzed reaction strategies, including the mechanisms of cyclization reactions, catalyst design, and their effects on reaction selectivity. Furthermore, we will analyze current challenges in the research, such as catalyst selectivity and optimization of reaction conditions, and explore potential future research directions, including the development of new ligands, improvements in reaction conditions, and how to enhance the environmental friendliness of synthesis through green chemistry principles. This comprehensive summary not only includes useful synthetic strategies, but also incorporates some recent references, aiming to provide researchers with a holistic perspective to promote further applications and developments of axially chiral compounds in asymmetric catalysis. By gathering current research achievements and trends, this paper hopes to inspire new thoughts on axial chirality and its applications, laying a foundation for future research.

2. Heteropalladation of Triple Bonds Initiates Cyclization

The de novo synthesis of (hetero)aromatic rings to create diverse axially chiral compounds represents a significant advancement in modern synthetic organic chemistry, establishing itself as a key strategy for preparing these unique structures [25,49]. Recently, palladium-catalyzed enantioselective cyclization reactions have demonstrated promising potential, particularly in transforming ortho-alkynyl anilines into indole-based axially chiral biphenyls. Chiral N-arylindole skeletons featuring C–N axial chirality are commonly found in natural products and serve as crucial chiral ligands in asymmetric catalysis [50,51,52,53]. However, the catalytic asymmetric synthesis methods for these compounds remain relatively limited. In 2010, the Kitagawa group reported the first catalytic atroposelective synthesis of axially chiral N-arylindoles through the de novo construction of the indole ring. Utilizing the chiral ligand SEGPHOS (L1), the palladium-catalyzed intramolecular endo-hydroaminocyclization of ortho-alkynylaniline 1 effectively transformed it into N-arylindoles 2, achieving high yields along with moderate to good enantioselectivities (Scheme 1) [54].

In 2011, Tanaka and his team proposed a palladium-catalyzed axially selective intramolecular hydroxylative aromatization strategy [55]. This method successfully synthesized the corresponding axially chiral 4-aryl-2-quinolone 4 from 3-aryl propargyl amide 3 using an optimized chiral ligand L2 with a palladium catalyst, as shown in Scheme 2. The researchers proposed a reasonable mechanism to explain how the synthesis of product 4 is achieved through asymmetric hydroxylative aromatization. The formation of the key intermediate Ts occurs through the chelation of the alkyne and ether groups with the palladium cation, significantly enhancing the reactivity of the alkyne. Moreover, the avoidance of steric interactions between the benzyl group of 3 and the aryl group of the chiral ligand allows for good control over the axial chirality of product 4.

In 2019, Kato and his team reported the first asymmetric cyclization–dimerization reaction of (ortho-alkynylphenyl) (methoxymethyl) sulfide 5, successfully synthesizing enantiomerically enriched axially chiral dibenzothiophenes 6 (Scheme 3) [56]. The reaction mechanism involves the formation of a key intermediate—bisoxazoline. The reaction starts with the sulfur atom attacking the alkyne from below the palladium complex, followed by coordination with a second alkyne substrate, triggering a secondary cyclization and generating the target product through reductive elimination. Density functional theory (DFT) calculations suggest that the box ligand enhances the affinity of the palladium (II) intermediate for the alkyne, promoting the coordination of the benzothiophene–palladium (II) intermediate with the second alkyne, thereby facilitating the dimerization reaction. This method utilizes a palladium (II) bisoxazoline (box) catalyst to construct dibenzothiophenes in a one-step process, achieving efficient control of axial chirality. The final products exhibit good yields and optical purity.

In 2020, Zhu and colleagues reported the first palladium-catalyzed asymmetric Cacchi reaction, which successfully synthesized highly enantioselective 2,3-disubstituted indoles 8 with chiral C₂-aryl axes by reacting N-aryl(alkyl) sulfonyl-2-alkynyl anilide 7 with aryl boronic acids under ambient oxygen conditions (Scheme 4) [57]. This reaction demonstrated good substrate adaptability; however, when using 2-methylphenylboronic acid, the products formed two non-diastereomers with a low enantiomeric excess. Control experiments by the authors indicated that chiral transfer occurs through a chelation-induced mechanism, from the ligand to the product. The proposed reaction mechanism is as follows: First, the L4-Pd(II) complex undergoes a transmetallation reaction with aryl boronic acid to generate the L4-ArPdX species. Subsequently, this species coordinates with N-sulfonyl-2-alkynylaniline to form the p-alkynyl–palladium complex INT-1. In this complex, the aryl substituent may twist out of the plane, creating a chiral Csp–Csp² axis. Due to minimized steric clashes between the aryl substituent and the QuinoxP* ligand, complex INT-1a is more stable than INT-1b. Next, INT-1a undergoes an anti-aminopalladation reaction to yield indole INT-2a as the major product, which is formed as an enantiomerically enriched final product 8 through reductive elimination, alongside the generation of Pd(0) species. Finally, Pd(0) is oxidized by O₂ to form a Pd(II) peroxide complex, which then reacts with aryl boronic acid, completing the catalytic cycle. Despite employing the anti-aminopalladation mechanism, high enantioselectivity is still achieved, indicating that chirality is transmitted from the chiral ligand to the product during the formation of the Pd complex, rather than in the cyclization step.

Meanwhile, Li and Qi focused their research on the asymmetric Cacchi reaction between aryl bromides and ortho-alkynyl anilines, utilizing an N,P-ligand based on ferrocene to provide a straightforward synthetic route for producing C(3)–C(aryl) axially chiral indole 11 (Scheme 5a) [58]. In this transformation, B(OH)₂ as an additive significantly suppressed the formation of 3-unfunctionalized indoles. When phenol was used instead of aniline as the nucleophile, the yield and enantioselectivity of the resulting axially chiral naphthyl-fused furan were lower. Additionally, the experimental results indicated that the active organic palladium species in the catalytic cycle was derived from the Pd-C bond formed during cyclization. The Wang team developed a new method using Pd(0)/(S)-Segphos L6 to catalyze the asymmetric Cacchi reaction of 2-alkynyl anilines with sterically hindered naphthyl halides 12, successfully obtaining multiple axially chiral naphthyl-C₃ indoles 14 containing free NH groups (Scheme 5b) [59]. Notably, the addition of water played a crucial role in this reaction, and the pre-mixing of the palladium complex with naphthyl halides was also necessary for the success of the reaction.

In 2021, Xu and colleagues developed a new method for the convenient synthesis of chiral indole 17, substituted with indanone, by combining cyclobutanone with ortho-alkynyl aniline through a tandem C–C bond activation and Cacchi reaction (Scheme 6) [60]. Additionally, the authors demonstrated the broad applicability of this cascade process, successfully applying it to naphthyl-substituted ortho-alkynyl aniline 16 as a substrate to construct axially chiral indoles 17. Notably, the control experiment’s results indicated that the reaction was unlikely to involve C–H activation of the indole intermediate, suggesting that the reaction mechanism may follow different pathways.

In 2023, the Parr group reported a study exploring the selectivity (atroposelective) in synthesizing bisindoles through palladium-catalyzed intramolecular 5-hydroxyamino cyclization reactions [61]. After comprehensive optimization of the reaction conditions (including transition metals, ligands, solvents, and additives), the best results were achieved at 60 °C, using Pd(CH₃CN)Cl₂ in combination with the (R)-DM-SEGPHOS ligand L8 for a reaction time of 66 h. However, the overall process exhibited moderate yields and enantioselectivity, along with some limitations (Scheme 7). In the study of the amino carbazole framework, three key structural positions were identified as important strategic sites for effectively achieving enantioselective transformations. When the 2-position of the carbazole was occupied by a bulky substituent, an overall enhancement in enantioselectivity was commonly observed. Furthermore, the alkyne portion with ortho-substituted aromatic rings showed the best results in terms of yield and selectivity, remaining unaffected by the electronic nature of the aryl substituents.

Larock indole synthesis is one of the most direct and efficient methods for constructing indoles. However, since its initial report in 1991, there has been no asymmetric version targeting axially chiral N-arylindoles [62]. In 2024, Zhang’s group successfully achieved the first asymmetric Larock indole synthesis by combining a chiral sulfinamide phosphine ligand L9 with a palladium catalyst [63]. This method enabled the rapid construction of a range of axially chiral N-arylindole compounds with excellent yields and ee of up to 96% (Scheme 8). The unique chiral scaffold also showed broad potential for applications in organocatalysis. Among them, the 2,3-dimethyl axially chiral indole can be selectively oxidized to yield axially chiral 2-formyl indole, with both high yields and enantioselectivity (99%). Additionally, the aldehyde group within this compound can undergo multiple transformations. For instance, through a series of reactions, the compound can be converted into a bifunctional thiourea catalyst 24, which retains high enantioselectivity throughout the transformation. Notably, catalyst 24 efficiently promotes an asymmetric Mannich-type reaction between stable phosphorus ylides 25 and N-Boc imines 26, highlighting its vast potential as an organocatalyst.

In 2024, Li’s group reported an asymmetric Larock indole synthesis method, successfully constructing N–N axially symmetric indoles using chiral phosphoramidite ligands L10. Through a palladium-catalyzed cyclization reaction, the enantiomeric indole ring was generated between the readily available N-pyrrolyl-o-iodoaniline 28 and an internal alkyne 21, demonstrating high efficiency and good enantioselectivity (Scheme 9) [64]. This method exhibits broad substrate adaptability and functional group compatibility, and the synthesized N–N axially symmetric indole-based biaryls provide various functionalized derivatives, expanding the compound library of N–N enantiomers. Representative products could serve as potential chiral additives in asymmetric C–H activation reactions. Therefore, this research not only showcases an efficient Larock indole formation system, but also opens new pathways for the synthesis of N–N axially symmetric indole rings, enriching this important family of N–N enantiomers.

3. Cyclization via C–N Coupling

Asymmetric cyclization C–N coupling reactions are a crucial tool in organic synthesis, widely used in drug development and natural product synthesis [65,66,67]. With the continuous advancement of catalysts, the efficiency and selectivity of asymmetric C–N coupling reactions have significantly improved, evolving from early copper and nickel catalysts to palladium, rhodium, iridium, and even organocatalysts. The introduction of chiral ligands has further enhanced the stereoselectivity of these reactions, allowing for the synthesis of specific isomers. In-depth studies of the reaction mechanisms, which often involve steps like oxidative addition, insertion, and reductive elimination, have also driven the development of new catalytic systems. In recent years, the principles of green chemistry have increasingly been incorporated into this field, with more sustainable reaction conditions and eco-friendly catalysts being employed to lower costs and make the processes more economically viable. Asymmetric C–N coupling reactions are expanding their applications in fields such as pharmaceuticals, agrochemicals, and material science. They show great potential, particularly in synthesizing biologically active nitrogen-containing heterocyclic structures. In 2012, Kitagawa reported a method for constructing asymmetric products through a Buchwald–Hartwig amination–cyclization reaction. Using a palladium catalyst and the chiral ligand MOP L11, the reaction employed aniline 31 and ynone 30 as substrates (Scheme 10) [68]. The process begins with the 1,4-addition of 31 to 30, followed by an asymmetric C–N coupling reaction, ultimately yielding an axially chiral product 32. The method demonstrated good enantioselectivity, achieving an enantiomeric excess (ee) of up to 72%, showcasing its potential for asymmetric synthesis applications. This approach highlights a practical strategy for constructing axial chirality in organic molecules, particularly relevant for the synthesis of complex compounds with potential applications in pharmaceuticals and material sciences.

In 2016, Kitagawa’s group successfully synthesized C–N axial phenylfuran-6-ketone derivatives through an intramolecular C–N coupling reaction (Scheme 11) [69]. The catalytic system employed Pd(OAc)₂ along with the chiral ligand (R)-DTBM-SEGPHOS, achieving an enantiomeric excess (ee) of up to 77% in the synthesis of C–N atropisomers 34. Their study revealed that the enantioselectivity of the reaction was significantly influenced by factors such as the choice of base, solvent, reaction temperature, and the presence of substituents at the ortho position of the substrate.

In 2021, Zhu’s group successfully synthesized 2-aryl quinazolinones 37 using a method that involved palladium-catalyzed imination–cyclization reactions (Scheme 12) [70]. This process entailed the reaction of N-substituted 2-isocyanobenzamide 35 with 2,6-disubstituted aryl iodides 36. The approach involved a sequence of biaryl coupling and heterocycle formation, offering an efficient and novel coupling–cyclization strategy for synthesizing axially chiral aryl-heteroaryl compounds. Notably, when the functionalized isocyanide coupling partner contained ortho-substituted aryl groups, the method enabled the construction of 4,2,3-diaryl quinazolinones with both diastereoselectivity and enantioselectivity, incorporating two stereocenters. This methodology provides the first general synthetic route for axially chiral 2-aryl quinazolinones, holding significant implications for biological applications and asymmetric synthesis.

In 2021, the Zhou group proposed a modular and convergent approach to the synthesis of C–N axially chiral benzo [4]quinolizin-8-ones 40 via a palladium/chiral norbornene (NBE) synergistic catalysis strategy (Scheme 13) [71]. This method successfully achieved axial-to-axial chirality transfer, demonstrating high efficiency both in constructing adjacent axes through bisaxial-selective C–H arylation and in the diastereoselective synthesis of remote stereogenic axes via axial-to-axial induction. Mechanistic experiments and DFT calculations revealed that the bulky substituents at the ortho position of the aniline group played a critical role in stabilizing the C–N axial configuration. The reaction mechanism begins with the oxidative addition of the aryl iodide, followed by the insertion of chiral norbornene (NBE). Under the influence of a base, the aryl C–H bond is activated, forming intermediate INT-1. This is followed by a second oxidative addition, reductive elimination, and β-carbon elimination to generate the C–C axially chiral intermediate INT-2. Subsequently, an intramolecular amidation occurs, forming an aminopalladium(II) intermediate INT-3, which undergoes C–N reductive elimination to yield the target product.

In 2021, Liu’s group developed a palladium-catalyzed selective amination method for benzamide 41, aimed at synthesizing N-C dual aryl twisted isomers (Scheme 14) [72]. This method enabled the convenient construction of various benzimidazole compounds 42 with excellent enantioselectivity, demonstrating N-C axial chirality. Their research also indicated that this method can be utilized to synthesize highly enantiomerically enriched 1,4- and 1,5-dibenzimidazole compounds 44, which contain two chiral N-C axes. Given that this method supports gram-scale synthesis and the diversified transformation of products, it shows great promise for application in the valuable synthesis of drugs featuring the N-C dual-aryl twisted isomer framework.

In 2023, Liu successfully achieved the dynamic kinetic resolution of aryl amidines through an intramolecular C–N coupling reaction, synthesizing C–N axially chiral isomers (Scheme 15) [73]. During the reaction, the racemization of aryl amidine 45 occurred, facilitating the formation of axial chirality. This method efficiently produced various functionalized C–N axially chiral aryl benzimidazole isomers with excellent yields and enantioselectivity. Notably, the approach also enabled the synthesis of 1,4-dibenzimidazole 48 compounds with two C–N axes of chirality, demonstrating its broad potential for applications.

Liu’s group subsequently developed a palladium-catalyzed asymmetric N-arylation reaction that enabled the rapid synthesis of structurally diverse five–six fused and six–six non-fused N-C axially chiral isomers (Scheme 16) [74]. In this reaction, various indole, pyrrole, and 4-quinoline derivatives can be quickly prepared with high yields and excellent enantioselectivity, making them suitable for library construction. These structurally diverse and highly enantiomerically enriched indoles demonstrate potential as hole transport materials, especially for applications involving two or three axial chirality axes. Furthermore, quinoline N-C axially chiral isomers can be synthesized from intermolecular alkynones and primary aryl amines through simple filtration followed by subsequent cross-coupling reactions. Gram-scale experiments and their conversion to useful five–six and six–six axially chiral isomers render this strategy highly attractive.

4. Cyclization via C–H Activation

Enantioselective C–H activation has become a powerful strategy for constructing atropisomeric compounds [21,75,76,77,78,79]. In 2017, the Gu group demonstrated the superior efficiency of the TADDOL-derived phosphoramidite ligand in palladium-catalyzed dynamic kinetic intramolecular C–H cyclization for the construction of indole-based atropisomers 54 (Scheme 17) [80]. Through dynamic kinetic resolution (DKR), they successfully achieved enantioselective C–H arylation of indole-based atropisomers using a modified TADDOL-derived phosphoramidite ligand L18.

Subsequently, the Cramer group employed a similar TADDOL-derived phosphoramidite ligand L19. They proposed a straightforward method for synthesizing axially chiral dibenzazepinone 56 through palladium-catalyzed atroposelective C–H arylation (Scheme 18) [81]. Their study found that the steric bulk near the biaryl linker was crucial for the enantioselectivity of the reaction. Additionally, DFT calculations indicated that C–H functionalization was achieved through a chirality-determining CMD mechanism, forming a configurationally stable eight-membered palladacycle.

The synthesis of ferrocene compounds with both axial and planar chiralities poses a significant challenge. Zhou and his team proposed a novel strategy for constructing both types of chirality in ferrocene systems through palladium/chiral norbornene (Pd/NBE*) cooperative catalysis (Scheme 19) [82]. In this unique multi-step reaction, the initially established axial chirality is determined by the Pd/NBE* cooperative catalysis, while the subsequent planar chirality is controlled by a distinct axial-to-planar diastereoinduction process, influenced by the pre-existing axial chirality. This method utilizes readily available ortho-ferrocene-tethered aryl iodides 57 and 2,6-disubstituted aryl bromides 58 as starting materials. Ultimately, the research team successfully obtained a variety of benzo-fused ferrocenes 59 with five- to seven-membered rings in a single reaction, achieving consistently high levels of enantioselectivity (>99% e.e.) and diastereoselectivity (>19:1 d.r.). This study provided new insights and methods for the preparation of ferrocene compounds exhibiting both axial and planar chiralities.

In 2025, Zhu’s group, based on DFT calculations, designed an efficient asymmetric synthesis method for axially chiral biaryls via C(sp²)-H imidoylative cyclization of isocyanides (Scheme 20) [83]. Building on this, they successfully developed a palladium-catalyzed C–H imidoylation strategy, achieving high yields and enantioselectivity in the synthesis of axially chiral compounds containing indole-fused N-heteroaromatic frameworks. Various efficient cyclization pathways facilitated the construction of indole-fused ring derivatives with either C–C or C–N axial chirality. This approach not only provides an efficient and versatile strategy for the synthesis of axially chiral compounds, but also further demonstrates the reliability and practicality of DFT-assisted design in accurately predicting reaction stereoselectivity, optimizing synthetic routes, and reducing experimental workload.

5. Cyclization via Carbonylation

In 2021, Li’s group reported, for the first time, a palladium-catalyzed asymmetric carbonylation reaction of aryl iodides 60 with carbon monoxide (CO), achieving enantioselective synthesis of 2-arylisoindoline-1,3-diones and N-acetyl-N-phenylbenzamides (Scheme 21) [84]. The reaction demonstrated excellent yields (up to 99%) and high enantioselectivity (up to 96% ee), marking the first example of embedding a carbonyl group into axially chiral amides via a carbonylative reaction. By controlling the position of substituents on the substrates, the group elegantly constructed a pair of enantiomeric 2-arylisoindoline-1,3-diones. Additionally, this method shows potential for application in the synthesis of lead compounds that inhibit NF-κB activation in HeLa cells, as well as for late-stage modifications of known bioactive molecules.

6. Conclusions

In conclusion, significant progress has been achieved in the development of axially chiral compounds in recent years, particularly within the field of palladium-catalyzed asymmetric cyclization. The advent of innovative catalytic strategies has opened new avenues for the efficient synthesis of these valuable molecular architectures. By employing a broad range of synthetic methodologies, researchers have attained remarkable stereoselectivity and excellent functional group compatibility, both of which are essential for constructing complex molecular frameworks. Given the escalating demand for axially chiral compounds, future research should concentrate on optimizing existing methodologies and exploring novel catalysts to further enhance reaction efficiency and selectivity. Nonetheless, several challenges remain unresolved: firstly, the general applicability of heterocyclic axially chiral compounds is still limited, as current catalytic systems are not yet sufficiently versatile to accommodate diverse heterocyclic structures, thereby restricting their application in drug development and functional materials; secondly, the potential of emerging catalytic modalities, such as synergistic photocatalysis and electrocatalysis, has yet to be fully exploited. Although these strategies theoretically offer significant advantages in improving both efficiency and selectivity, their practical application is still in the early stages of exploration, and interdisciplinary approaches are anticipated to drive future breakthroughs.