Recent Advances in Catalytic Atroposelective Synthesis of Axially Chiral Quinazolinones

Abstract

Quinazolinones, a class of nitrogen-containing heterocyclic compounds, occupy a crucial position in medicinal chemistry and materials science due to their significant application potential. In recent years, the catalytic asymmetric synthesis of axially chiral quinazolinones has emerged as a prominent research area, driven by their prospective applications in the development of bioactive molecules, design of chiral ligands, and fabrication of functional materials. This review comprehensively summarizes recent advancements in the catalytic asymmetric synthesis of axially chiral quinazolinones, with a particular focus on the construction strategies for the three major structural types: the C–N axis, N–N axis, and C–C axis. Key synthetic methodologies, including atroposelective halogenation, kinetic resolution, condensation–oxidation, and photoredox deracemization, are discussed in detail. In addition, the review provides an in-depth analysis of the applications of various catalytic systems, such as peptide catalysis, enzymatic catalysis, metal catalysis, chiral phosphoric acid catalysis, and others. Despite the substantial progress made thus far, several challenges remain, including the expansion of the substrate scope, enhanced control over stereoselectivity, and further exploration of practical applications, such as drug discovery and asymmetric catalysis. These insights are expected to guide future research towards the development of novel synthetic strategies, the diversification of structural variants, and a comprehensive understanding of their biological activities and catalytic functions. Ultimately, this will foster the continued growth and evolution of this rapidly advancing field.

1. Introduction

Quinazolinones and their derivatives represent a class of extremely important nitrogen-containing heterocyclic compounds, commanding significant attention in the domains of organic synthesis and medicinal chemistry [1,2,3]. Their distinctive molecular structures endow these compounds with diverse biological activities, extensively covering aspects such as antitumor [4], antiinflammatory [5], antifungal [6,7], and more. Moreover, quinazolinone derivatives also exhibit broad application prospects in the field of materials science. For instance, their outstanding properties in optoelectronic materials [8], fluorescent materials [9], etc., have opened up new avenues for the design and development of novel functional materials (Figure 1). Given the significance of the quinazolinone structure, in recent years, comprehensive reviews have been carried out extensively on both its synthetic methodologies and pharmaceutical applications [10,11,12,13,14]. Thus, conducting in-depth investigations into the synthesis methods, structure–activity relationships of quinazolinone compounds, and their applications in various fields is of great significance. It not only greatly benefits the advancement of medicinal chemistry and materials science but also lays a crucial foundation for the innovation and progress of related disciplines.

Axial chirality, a unique form distinct from traditional central chirality, has captured the attention of numerous researchers due to its special structure and properties. Thanks to the persistent research and unwavering efforts of chemists, the catalytic asymmetric synthesis of axially chiral compounds, a research area at the forefront of science and rife with challenges, has witnessed remarkable and substantial breakthroughs over the past decade [15,16,17,18]. Chemists have been actively exploring and constantly seeking novel catalytic systems, meticulously optimizing reaction conditions, and conducting in-depth analyses of reaction mechanisms. Through these endeavors, they have successfully established a series of highly efficient and selective catalytic asymmetric synthesis strategies, laying a solid foundation for the synthesis of axially chiral compounds. These achievements have significantly enriched the theoretical framework and methodologies of organic synthetic chemistry while also providing a powerful impetus for the innovative development of related fields, such as medicinal chemistry and materials science.

Quinazolinone, as a typical class of heterocyclic compounds, has an axially chiral skeleton that is extensively present in natural products and drug molecules [19,20,21]. The unique axial chirality of these molecules imparts distinctive spatial conformations and electronic properties. This characteristic plays an indispensable role in constructing the intricate structures of natural products and drives the synthesis of numerous active substances essential for maintaining the normal physiological functions of organisms. In drug design, these molecules have also attracted significant attention and become core structural units in developing a variety of high-efficiency and low-toxicity drugs. In organic synthesis, the axially chiral quinazolinone framework stands out as an exceptionally advantageous ligand in asymmetric allylation reactions, owing to its outstanding chiral modulation capabilities (Figure 2) [22,23]. It can precisely guide the reaction progression and exerts efficient control over the stereochemical architecture of the products. This furnishes a powerful approach for synthesizing intricate organic molecules with specific chiral configurations, substantially driving the evolution of organic synthetic chemistry towards greater selectivity and sophistication.

Although the research on axially chiral quinazolinones is still in a stage of continuous development and refinement, the phased achievements over the past decade have fully demonstrated their broad application prospects. In axially chiral quinazolinone molecules obtained through catalytic asymmetric synthesis, there often exist one or more chiral axes, which can be mainly classified into three basic types, namely the C–N axis, N–N axis, and C–C chiral axis (Figure 3). We have observed that this emerging field remains underexplored. In this review article, we zeroed in on the stereostructural features of axially chiral quinazolinones. We examined their distinctive advantages and challenges in asymmetric synthesis and deliberated on the strategies for synthesizing axially chiral quinazolinones with specific configurations via precise stereocontrol. This effort aimed to provide deeper theoretical insights for drug design and synthesis.

Moreover, we delved into the recently emerged synthetic approaches for axially chiral quinazolinones, such as green synthesis techniques, including photocatalysis and enzyme catalysis. We elaborated in detail on the reaction mechanisms, advantages, and limitations of these methods. By contrasting them with traditional synthesis routes, we highlighted the features of emerging technologies in terms of atomic economy, process simplification, and environmental sustainability. This comparison offers synthetic chemists an array of additional options and novel perspectives. Additionally, we discussed the early developments of chiral ligands and catalysts derived from axially chiral quinazolinones in asymmetric catalytic reactions. This not only broadens the research purview but also enhances the potential applications of axially chiral quinazolinones.

In fact, as early as 2006, the Natsugari group reported the diastereoselective synthesis of 3-(2-substituted aryl)quinazolin-4-one compounds through an acid-catalyzed reaction involving chiral amino acids (Scheme 1) [24]. Using 2-amino-N-(2-chloropyridin-3-yl)benzamide 1 and N-Boc-alanine 2 as the starting materials, the group first carried out a conventional dehydroamidation reaction to obtain tert-butyl (1-((2-((2-chloropyridin-3-yl)carbamoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate 3. Subsequently, the axially chiral quinazolinone core was constructed via dehydration cyclization methods. The researchers conducted a profound study on the stereochemical properties of the products by means of X-ray analysis and temperature-dependent interconversion experiments. The results showed that the (aR*, S*) configuration (4R*) was more stable than the (aS*, S*) configuration (4S*), and both isomers exhibited high stereochemical stability. This research not only provided practical intermediates for the synthesis of bioactive compounds but also contributed invaluable information to the chemical research of axially chiral quinazolinones. In the main text of this review, we will no longer focus on the method of synthesizing axially chiral quinazolinones with the aid of chiral auxiliaries but will only discuss the relevant content based on the strategy of asymmetric catalysis.

2. Catalytic Asymmetric Synthesis of Axially Chiral Quinazolinones

2.1. Quinazolinones with C–N Axial Chirality

The emergence of quinazolinones with C–N axial chirality can be attributed to the connection of the nitrogen atom of the quinazolinone ring to a planar structure bearing a group at the ortho-position. This configuration restricts the rotation of the two planes around the C–N sigma bond. Among various structural types of quinazolinones, the atropisomers of this particular type exhibit the greatest diversity. Moreover, they are the first to have been reported as being synthesized via catalytic asymmetric approaches.

In 2015, the Miller group reported the synthesis of axially chiral quinazolinones via the atroposelective bromination of 3-arylquinazolin-4(3H)-ones catalyzed by a peptide C1 (Scheme 2). This approach enabled high enantioselective induction across a broad spectrum of substrates [25]. The reason lies in the fact that the racemization rate of the starting material can impact the outcome of the dynamic kinetic resolution. Therefore, slowly adding NBS facilitated the complete racemization of the starting material. For quinazolinones bearing alkyl substituents, the reaction yields reached 75–86%, with enantiomeric excess (ee) ranging from 86% to 94%. X-ray crystallography and 2D-NOESY experiments were employed to probe into the structures of the catalyst and the peptide–substrate complex.

The peptide catalyst was capable of modulating the site selectivity of the bromination reaction, and the first bromination step played a pivotal role in determining the stereochemistry. The brominated product can be transformed into other valuable axially chiral products 7 and 8 through dehalogenation cross-coupling or selective amination reactions while maintaining the enantioselectivity. Significantly, this work constituted the first reported case of catalytic asymmetric synthesis of axially chiral 3-aryl quinazolinones. The accomplishment of this peptide catalyst in the atroposelective bromination reaction is highly promising. It is expected to furnish an efficient methodology for the synthesis of an even wider array of compounds with potential biological activities.

In 2016, the group conducted more in-depth crystallographic and NMR studies on this class of polypeptide catalysts [26]. The data obtained clearly demonstrated that the conformational diversity of the catalyst was of crucial significance for achieving high enantioselectivity in the electrophilic bromination reaction.

In 2022, the Lewis group harnessed directed evolution engineering to modify a flavin-dependent halogenase, RebH, and successfully generated a variant capable of performing site and atroposelective halogenations of 3-(3-aminophenyl)-4(3H)-quinazolinone 9 (Scheme 3) [27]. Directed evolution made use of a combined approach of random mutagenesis and site-saturation mutagenesis. After screening for conversion and enantioselectivity, variant 3-T catalyzed 10 synthesis with >98% ee, a 25-fold increase in the conversion rate, demonstrating excellent site selectivity. They were consistently demonstrated across a diverse range of other substrates with varying steric hindrances and electronic properties. To understand the underlying mechanisms, computational modeling and docking simulations were employed. These analyses provided a rational explanation for the impact of key mutations on substrate binding.

In 2016, the Kitagawa group reported the catalytic enantioselective synthesis of C–N axially chiral quinazolinones and their derivatives via a palladium-catalyzed asymmetric reductive desymmetrization reaction (Scheme 4). In the presence of the (R)-DTBM-SEGPHOS (C2) and Pd(OAc)₂ catalysts, 3-(2,6-dibromophenyl)quinazolin-4-one 11 underwent a reaction with NaBH₄ [28]. Through reductive asymmetric desymmetrization and kinetic resolution processes, the resulting product could achieve an enantiomeric excess as high as 99%. The enantioselectivity of this reaction was significantly influenced by multiple factors, including the substituent at the C4′ position, the dosage of NaBH₄, and the reaction temperature. Eventually, an attempt was made to convert mebroqualone into methaqualone. However, during this conversion, the enantiomeric excess decreased, presumably due to the relatively low rotational energy barrier of the chiral axis in the aryl-Pd intermediate.

Notably, in 2018, this group carried out a thorough study on the α-alkylation reaction of C–N axially chiral quinazolinone derivatives bearing different ortho-substituted phenyl groups [29]. They discovered that the diastereoselectivity of the reaction was closely associated with the steric hindrance of the ortho-substituents. Specifically, the greater the steric hindrance, the higher the diastereoselectivity. Additionally, they found that C–N axially chiral compounds containing ortho-fluorophenyl moieties 2-alkyl-3-(2-fluorophenyl)quinazolin-4-one possessed sufficient rotational stability to allow for enantiomeric separation [30]. This finding offered a novel perspective on the discussion of the bioisosterism between fluorine and hydrogen in the context of drug design.

Selective functionalization of complex multifunctional compounds is of profound significance in the realms of catalysis and medicinal chemistry. Metal-catalyzed cross-coupling reactions represent a potent means for constructing diverse molecular frameworks. In 2022, the Miller group reported an enantioselective copper-catalyzed C–O cross-coupling reaction (Scheme 5). By leveraging a novel guanidinylated dimeric peptide ligand C3, they were able to synthesize axially chiral quinazolinones featuring resorcinol moieties 15 [31]. Through meticulous optimization of reaction conditions, when resorcinol-substituted quinazolinone 13 and aryl bromide 14 were employed as substrates, the product 15 with good yield and excellent stereocontrol was obtained (the yield was 59% under the optimal conditions, and the ee was 90%). In the copper-catalyzed cross-coupling reaction, a potential pathway involved the formation of a bidentate copper-based catalyst. Cesium carbonate acted to deprotonate the bromoarene 14, thereby triggering oxidative addition. Then, an atroposelective process occurred, where the intermediate coordinated with a hydroxyl group and underwent deprotonation. Finally, through reductive elimination, the product 15 was formed, and the active catalyst was released and regenerated. This reaction showcased substantial substrate generality and allowed for gram-scale synthesis, as well as product derivatization. As such, this study established a solid foundation for late-stage functionalization reactions within complex molecular settings.

In 2017, the Tan group reported a versatile and highly efficient approach for the enantioselective synthesis of axially chiral aryl quinazolinones, with chiral phosphoric acid (CPA) C4 serving as the catalyst (Scheme 6) [32]. Employing N-aryl aminobenzamides 16 and aldehydes 17 as substrates, this method enabled the synthesis of diverse axially chiral aryl quinazolinone compounds under mild reaction conditions. Impressively, it delivered excellent yields, reaching up to 99%, along with good to outstanding enantioselectivities, with ee values as high as 97%. Moreover, the group achieved the atroposelective synthesis of alkyl-substituted aryl quinazolinones 21 by utilizing a Brønsted acid C5-catalyzed carbon–carbon bond cleavage strategy.

These reactions probably proceeded via the typical Brønsted acid-catalyzed aminal formation process (Scheme 7). Initially, imines or enamines were generated from the condensation of 16 or 19 with aldehyde or 4-methoxypentenone, respectively. This was followed by intramolecular amidation, leading to the formation of N,N-aminal cyclization intermediates. Finally, the desired aryl quinazolinones were obtained either through dehydrogenation in the presence of an oxidant or via C–C bond cleavage under acidic conditions. It is evident that the enantioselectivity was established during the intramolecular nucleophilic attack, catalyzed by a chiral Brønsted acid. However, the mechanisms of asymmetric induction and chirality transfer from central to axial chirality remain unclear.

In 2023, the He group pioneered a strategy for the synthesis of axially chiral N-vinylquinazolinones via asymmetric allylic substitution-isomerization (AASI) (Scheme 8). By skillfully integrating transition-metal catalysis and organocatalysis, they successfully prepared a series of trisubstituted (24) and tetrasubstituted (26) axially chiral N-vinylquinazolinone enantiomers [33]. These products not only boasted good yields but also exhibited high enantioselectivities. Notably, through astute manipulation of the reaction substrates and base types, they achieved precise control over the configuration of the tetrasubstituted products, enabling them to selectively yield either the (Z) or (E) form. During the exploration of the reaction mechanism, they determined that when the reaction was propelled by an inorganic base, it was predominantly governed by thermodynamic factors. Conversely, in reactions involving an organic base, the formation of the product configuration was a kinetically controlled process, with hydrogen bonding playing an ancillary yet significant role. Furthermore, an array of transformation reactions of the axially chiral N-vinylquinazolinones were conducted, vividly demonstrating the remarkable practicality of this synthetic method.

In acid-catalyzed asymmetric reactions, substrates bearing basic nitrogen heteroatoms frequently exert an impact on the reaction outcome and mechanism. This often results in suboptimal control over enantioselectivity. In 2024, the Miller group devised a one-step catalytic method for the synthesis of 3-aryl-4(3H)-quinazolinones (Scheme 9). Employing the chiral phosphoric acid catalyst C8, an ee as high as 96% and a yield of 95% could be attained for specific substrates [34]. However, when the substrate contained a basic nitrogen heteroatom, the enantioselectivity catalyzed by C8 dropped significantly. On the other hand, although the catalyst based on phosphothreonine (pThr) C9 exhibited poor selectivity towards carbocyclic substrates, it can achieve a selectivity of 80% ee for pyridyl analogs. The catalyst framework based on pThr reveals remarkable potential in handling substrates with basic nitrogen-containing functional groups. This is particularly true when it is paired with a weak acid, as this allows it to interact with these functional groups while still preserving the catalyst’s catalytic activity.

Visible light catalysis activates substrates under mild conditions via single electron transfer (SET) or energy transfer (EnT) mechanisms. This process generates highly reactive radical intermediates that trigger reactions. It is characterized by mild reaction conditions, high selectivity, and environmental friendliness. Despite significant advancements in the photo-induced construction of central chirality, constructing axially chiral molecules through photocatalysis still confronts several challenges [35].

In 2024, the Jiang group reported a modular approach for the synthesis of axially chiral N-aryl quinazolinones through photoredox-catalyzed deracemization (Scheme 10) [36]. A highly reductive Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ photosensitizer, in cooperation with a chiral phosphonic acid, effectively averted the disproportionation of the push–pull radical intermediate, thereby guaranteeing outstanding chemoselectivity. Within this catalytic system, 2,3-dihydroquinazolin-4(1H)-one 30 was initially oxidized by an excited-state photosensitizer, yielding a nitrogen radical cation I. Subsequently, a sequence of hydrogen atom transfer and single-electron reduction occurred, generating an anionic intermediate III. Finally, the stereocenter was re-established through asymmetric protonation. The authors speculated that the steric hindrance caused by the N-aryl 2-substituent of the quinazolinone may enable R-30 to undergo oxidation by DDQ, which can facilitate the transfer from central to axial chirality with excellent enantioselectivity (Scheme 11). As a result, 2-azaarene-functionalized axially chiral quinazolinone compounds 31 were constructed with excellent yields and enantioselectivities. Notably, this work represents the first successful synthesis of quinazolinone molecules featuring a C–N axis at the 1-position (33). This achievement significantly enriches the structural diversity of chiral quinazolinone compounds. Simultaneously, it furnishes novel insights for the construction of axially chiral molecules via photocatalysis.

As shown in

Table 1. Summary of the construction strategies of quinazolinones with C–N axial chirality.

Substrates	Products	Catalysts	Synthesis Strategies	References
		Peptide	Atroposelective halogenation	[25]
		Enzyme	Atroposelective halogenation	[27]
		Pd(OAc)2 Chiral ligand	Desymmetrization	[28]
		CuI Chiral ligand	Desymmetrization	[31]
		CPA	Condensation oxidation	[32]
		[Ir(cod)Cl]2 Chiral ligand or Lewis base	N-H functionalization	[33]
		CPA	Condensation	[34]
		[Ir]/CPA	Photoredox deracemization	[36]

, a large number of starting materials and catalytic strategies are used in the construction strategies of quinazolinones with C–N axial chirality. Their construction strategies focus on the molecular structure, exploiting the inherent active sites of substrates or introducing specific functional groups. By carefully optimizing the reaction conditions and precisely choosing appropriate catalysts or chiral inducers, it becomes feasible to satisfy the distinct needs of different applications.

2.2. Quinazolinones with N–N Axial Chirality

For an extended period, research concerning the C–C axis and C–N axis thrived and achieved remarkable outcomes. In stark contrast, the catalytic asymmetric synthesis of N–N axis chirality was not documented until 2021 [37]. In that year, the Lu group reported the first instance of asymmetrically constructing N–N axis chiral quinazolinones with a Lewis base catalyst (Scheme 12). Through a quinuclidine-catalyzed N-allyl alkylation reaction, a diverse range of 3-aminoquinazolinones 36 featuring N–N axis chirality was smoothly synthesized under mild reaction conditions [38]. These products not only exhibited high yields but also demonstrated outstanding enantioselectivities.

Density functional theory (DFT) calculations were carried out to elucidate the origin of enantioselectivity, offering valuable guidance for the design of such molecules. The proposed catalytic cycle followed the well-established mechanism in Morita–Baylis–Hillman (MBH) chemistry. Initially, quinidine initiated the reaction by adding to the MBH adduct via an SN₂’ pathway. Subsequently, substrate 34 underwent another SN₂’ process, reacting with the quinidinium intermediate. This step was the stereochemistry-determining step. N–N axially chiral compounds hold great potential in the realms of medicinal chemistry and asymmetric catalysis. This accomplishment blazed a new trail in the domain of axial chirality chemistry, bearing significant implications across multiple fields, including organic synthesis and drug development. Nevertheless, due to constraints imposed by synthetic methodologies, the stability of isomers, and the scope of application research, there remains substantial scope for future exploration.

In 2022, the Li group reported the first synthesis of N–N axially chiral quinazolinone derivatives via an organocatalytic N-acylation reaction (Scheme 13). They utilized benzamides bearing a quinazolinone skeleton 37 and cinnamic anhydride 38 as starting materials [39]. Quinazolinones with diverse substituents reacted with the anhydride, affording N–N axially chiral products 39 with yields ranging from 57% to 99%, ee values spanning from 85% to 97%, and a diastereomeric ratio (dr) exceeding 19:1. The stability of the products was intimately associated with the steric hindrance of the substituent at the 2-position of the quinazolinone. Additionally, the electronic properties of the substituent exerted a certain influence on its stability. Theoretical calculations revealed that multiple non-covalent interactions existed in the transition state, and these interactions jointly governed the stereoselectivity of the reaction in a synergistic manner. This research accomplishment has significantly expanded the diversity of N–N axially chiral quinazolinone compounds, thereby opening up an entirely new avenue for subsequent relevant research. Moreover, the data obtained throughout the research process and the outcomes of theoretical calculations offer robust support for further advancements in this field.

Almost concurrently, the Li group disclosed a highly significant research finding. Employing chiral quaternary ammonium salts C13 as phase-transfer catalysts, they successfully accomplished an efficient atroposelective N-alkylation of N-(4-oxoquinazolin-3(4H)-yl)amides 37 (Scheme 14). Under rather mild reaction conditions, this approach enabled the preparation of diverse N–N axially chiral quinazolinone derivatives [40]. The yields were gratifying, and the enantioselectivities were remarkable. The feasibility and practicality of this method in real-world applications were comprehensively validated through large-scale reactions and product transformation experiments. Furthermore, a detailed DFT-based investigation into the reaction mechanism demonstrated that the hydrogen bonds established between the chiral ammonium salt and the substrate, along with the π–π interactions, were of pivotal importance in the enantioselective course of this reaction. These interactions meticulously govern the reaction pathway, steering the reaction towards the formation of products with a particular configuration. As a result, it furnishes a robust theoretical foundation for comprehending and optimizing such reactions.

In 2023, the Biju group reported an atroposelective synthesis of N–N axially chiral 3-aminoquinazolinones 42, which was catalyzed by N-heterocyclic carbenes (NHCs) C14 (Scheme 15). Conducted under mild conditions, this reaction showcased excellent functional group compatibility [41]. It allowed for the facile preparation of diverse N–N axially chiral 3-aminoquinazolinone derivatives, with high yields and remarkable enantioselectivities. The reaction mechanism unfolded as follows: Initially, the NHC catalyst nucleophilically attacked cinnamaldehyde 43, giving rise to a Breslow intermediate I. Subsequently, in the presence of an oxidant, an acylazolium cation II was generated. This cation was then subjected to a nucleophilic attack by a nitrogen anion from one side, followed by an elimination reaction that led to the formation of the target product. Simultaneously, the carbene catalyst was regenerated and set free for further catalytic cycles. Notably, the researchers also delved into a series of derivatization reactions of the synthesized axially chiral quinazolinones. These included hydrogenation reactions and palladium-catalyzed cross-coupling. These derivatization studies significantly broaden the application landscape of this synthetic approach, thereby offering more potential avenues for research and development in relevant fields.

In 2022, the Teng group introduced a chiral phosphoric acid-catalyzed bicyclic formation strategy for the enantioselective synthesis of N–N axially chiral 3,3′-biquinazolin-ones (Scheme 16) [42]. Starting with 2-amino-N’-(2-aminobenzoyl)benzhydrazide 45 and benzaldehyde 46, following the optimization of reaction conditions, diverse substrates can be transformed into the target products in good yields with excellent enantioselectivities. Importantly, this reaction proceeded under metal-free conditions, circumventing potential issues associated with metal catalysts. The products featured stable configurations and were amenable to further derivatization reactions.

In the chiral phosphoric acid-catalyzed system, the compound 45 first underwent a condensation reaction with benzaldehyde 46, forming an imine intermediate through nucleophilic addition and dehydration. Driven by the chiral environment of the catalyst, this intermediate then underwent two consecutive intramolecular nucleophilic cyclization reactions, creating a central chiral scaffold in the resulting intermediate. Finally, oxidation by an oxidizing agent triggered a structural rearrangement, during which the central chirality was transferred to the N–N axis of the product, yielding the axially chiral 3,3′-bisquinazolinone 47 with high stereoselectivity. This work not only offers a novel approach for constructing N–N axially chiral compounds but also provides new research perspectives, giving it significant importance in relevant research areas.

In 2024, the Liao group pioneered an unprecedented silver-catalyzed asymmetric [3+2] cycloaddition reaction involving prochiral N-quinazolinone 48 maleimides and isocyanoacetates 49 (Scheme 17). Leveraging this reaction, they successfully synthesized a series of structurally novel and intricate N–N axially chiral compounds [43]. The yields were highly satisfactory, and the stereoselectivity achieved was impressive.

In the cyclization process, squaramide C16, functioning as a monodentate ligand, exhibited distinct advantages. It engaged in strong non-bonding interactions with the substrate while maintaining a relatively low degree of distortion. These two crucial factors worked synergistically, enabling the reaction to efficiently yield endo-selective cycloaddition products. In sharp contrast, the Trost ligand C17, a bidentate ligand, showed different characteristics in the reaction. When isocyanoacetate coordinated with silver, the distortion was relatively minimal, and there was a favorable overlap between the Ag-C σ-orbital. These favorable conditions drove the reaction towards the formation of exo-selective [3+2] cycloaddition products. Significantly, this work represents a groundbreaking achievement, as it is the first to enable the concurrent construction of N–N axial chirality and point chirality within the same reaction system. Moreover, it successfully realized ligand-regulated stereodivergent synthesis, thereby opening new avenues for the synthesis of chiral compounds.

Recently, the Shi group created an innovative design by using indolyl o-aminobenzamides as novel platform molecules and successfully accomplished the catalytic asymmetric synthesis of indole derivatives bearing N–N/C–C double axes (Scheme 18) [44]. Under meticulously optimized reaction conditions, the team employed chiral phosphoric acid C18 to catalyze the reaction between indolyl o-aminobenzamides 51 and 1-naphthaldehyde 52. Through a one-pot, asymmetric formal (5+1) cycloaddition/oxidation process, a diverse range of indolyl quinazolinones with N–N/C–C double axes were efficiently synthesized. These products not only exhibited high yields but also demonstrated excellent diastereoselectivity and enantioselectivity. It is worth noting that the products boasted remarkable configurational stability, with the double axes presenting a high rotational energy barrier. Additionally, these products could be further converted into novel chiral ligands for application in asymmetric catalytic reactions. The success of this strategy not only expanded the family of bi-axial atropisomers but also furnished an innovative approach for the synthesis of related compounds, thereby holding significant importance within the realm of organic synthesis.

As elaborated in

Table 2. Summary of the construction strategies of quinazolinones with N–N axial chirality.

Substrates	Products	Catalysts	Synthesis Strategies	References
		Lewis base	N–H functionalization	[39]
		Lewis base	N–H functionalization	[40]
		PTC	N–H functionalization	[41]
		NHC	N–H functionalization	[42]
		CPA	Condensation oxidation	[43]
		Ag2CO3 Chiral ligand	Desymmetrization	[44]
		CPA	Condensation oxidation	[45]

, an extensive range of catalysts and diverse reaction strategies have been successfully established and utilized in the construction of quinazolinones featuring N–N axial chirality. This rich variety not only reflects the complexity and flexibility of the synthesis process but also demonstrates the continuous exploration and innovation in this research field.

2.3. Quinazolinones with C–C Axial Chirality

As another structural variant of axially chiral quinazolinones, C–C axial chirality assumes an indispensable role. In 2021, the Zhu group devised a palladium-catalyzed coupling cyclization reaction involving N-alkyl-2-isocyano benzamides 54 and 2,6-disubstituted aryl iodides 55 (Scheme 19) [45]. This reaction efficiently constructed novel axially chiral 2-aryl quinazolinones 56, featuring gratifying yields and remarkable atroposelectivities. Particularly, when specific substrates were employed, it became feasible to prepare 2,3-diaryl quinazolinones 56d containing two chiral axes. The resulting products exhibited moderate diastereoselectivity and commendable enantioselectivity. This innovative approach paved a new path for the synthesis of axially chiral aryl–heteroaryl compounds. The products show promising potential applications in bioactivity screening, as well as in the design of chiral catalysts and ligands. This novel methodology presents a fresh route for the synthesis of axially chiral aryl–heteroaryl compounds, heralding new possibilities in relevant research fields.

In the same year, the Jiang group successfully developed three distinct strategies, enabling the highly enantioselective synthesis of a series of 2-aryl axially chiral quinazolinone compounds (Scheme 20) [46]. The enantiomeric excess of the resultant products could reach up to 94%. The three strategies included chiral transfer from the center to the axis, palladium-catalyzed dynamic kinetic resolution, and phase transfer-catalyzed asymmetric alkylation. Remarkably, these quinazolinone-based biaryl compounds (67,69) could be readily converted into highly valuable P,N-ligands and demonstrated excellent chiral control capabilities during the asymmetric catalytic process. The design of this synthesis method for quinazolinone ligands laid a solid foundation for the construction of novel P,N-ligand skeletons via asymmetric catalysis. This approach is anticipated to drive new advancements in organic synthesis and catalysis within related fields.

As illustrated in

Table 3. Summary of the construction strategies of quinazolinones with C–C axial chirality.

Substrates	Products	Catalysts	Synthesis Strategies	References
		Pd(OAc)2 Chiral ligand	Coupling cyclization	[45]
		CPA	Condensation oxidation	[46]
		Pd(OAc)2 Chiral ligand	Dynamic kinetic resolution	[46]
		PTC	N–H functionalization	[46]

, both have made remarkable breakthroughs in the synthesis of axially chiral aryl-heteroaryl compounds, as well as in the research of related areas in organic synthesis and catalysis. These achievements not only significantly expand the synthetic methodologies for axially chiral compounds, but also the successful development of ligands derived from novel axially chiral compounds holds great promise.

3. Conclusions and Prospects

In this review, we embarked on the discussion by centering on the structural types of the constructed quinazolinones, which included the C–N axis, N–N axis, and C–C axis. We also highlighted efforts to construct multiple axes and chiral elements simultaneously. In terms of reaction strategies, we discussed approaches such as atroposelective halogenation, kinetic resolution, and tandem condensation–oxidation. Additionally, we examined the application of novel catalytic systems, including visible light-driven racemization and enzyme catalysis via directed evolution. Despite significant progress, the number of successfully developed structural types remains limited, and the scope of applicable substrates is still narrow. As a result, current advancements have yet to fully address the critical needs for quinazolinones as candidate molecules for drug development.

Given the potential pharmaceutical activities of pyridine and indole as parent nuclei, we anticipate the emergence of additional azaarenes conjugated to axially chiral quinazolinones in the near future. Future research should focus on applied studies in fields such as medicinal chemistry and asymmetric catalysis. In drug development, it is essential to comprehensively evaluate the biological activities of these compounds and assess their viability as potential drug candidates. For asymmetric catalysis, it is crucial to rigorously investigate the properties of these compounds when used as chiral ligands or catalysts. This scrutiny will help transition chiral quinazolinone compounds from fundamental research to practical applications. Furthermore, exploring a wide range of novel and efficient synthetic methodologies is of great importance. This exploration may involve testing various catalysts, reaction conditions, and substrate combinations. The ultimate goal is to overcome the limitations of current synthetic approaches, facilitating the synthesis of axially chiral quinazolinones with a broader range of structural diversity. Achieving this would effectively meet the structural requirements across multiple fields.