Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

In recent years, the synthesis of axially chiral compounds has received considerable attention due to their extensive application as biologically active compounds in medicinal chemistry and as chiral ligands in asymmetric catalysis. Chiral phosphoric acids are recognized as efficient organocatalysts for a variety of enantioselective transformations. In this review, we summarize the recent development of chiral phosphoric acid-catalyzed synthesis of a wide range of axially chiral biaryls, heterobiaryls, vinylarenes, N-arylamines, spiranes, and allenes with high efficiency and excellent stereoselectivity.


Introduction
Axial chirality is one of the most important properties of nature, resulting from the nonplanar arrangement of four groups in pairs about a chirality axis. These include atropisomerism [1], chiral allenes, spiranes, spiroindanes, and so on [2,3]. Recently, there emerged an enormous demand for enantiopure compounds, not only for pharmaceutical and fine chemical industries, but also for fragrance, flavor, agrochemical, and food industries [4]. Consequently, the importance of axially chiral compounds has been widely recognized in both academic and industrial chemical societies [5]. Therefore, asymmetric synthesis of axial chiral compounds has been paid much attention [6], and great progress has been made in recent years. For example, many remarkable activities have been undertaken to develop strategies such as dynamic kinetic resolution, atroposelective coupling, cycloaddition, and chirality conversion for the construction of axial chirality [7][8][9][10][11][12][13][14].
Axial chirality is also found in chiral stationary phases for enantioselective separation, dopants in liquid-crystalline materials, chiroptical molecular switches, microporous soluble polymers, and interlocked nanotubes ( Figure 3) [24]. In addition, axially chiral allenes and spiranes [25] are well-known scaffolds widely used in natural products, ligands, organocatalysts, and functional materials as well as versatile chiral building blocks in organic synthesis [14,26,27].
Chiral phosphoric acids represent an important and widely used class of catalysts for a variety of enantioselective transformations, especially for carbon-carbon and carbon-heteroatom bond-forming reactions [15,28]. They are important for the development of axially chiral compounds, which are involved in the design of chiral catalysts and ligands. Currently, chiral phosphoric acids are widely used in stereoselective oxidative/ cross-coupling of two aryl counterparts, asymmetric control of aromatic ring formation, atroposelective functionalization of biaryl compounds, and so on [17,29,30]. In this context, Akiyama (2004) described that chiral phosphoric acids (CPAs) have great potential for catalysis of a wide range of reactions to achieve good to perfect enantioselectivities. This is due to their ability to act as synergistic bifunctional catalysts bearing both Brønsted acidic and Lewis basic sites, with the 3,3′-substituents playing a crucial role in achieving excellent enantioselectivity [31]. The widespread use of phosphoric acids and phosphates as chiral acids, chiral anions, and ligands is one of the most important achievements of modern enantioselective catalysis. The atropochiral BINOL, H 8 -BINOL and SPINOL [32] derived phosphoric acids ( Figure 4) [33,34] play a crucial role in asymmetric catalysis, the construction of numerous axially chiral biaryls/heterobiaryls [21,[35][36][37][38], and other useful asymmetric transformations [5]. Although chiral phosphoric acids have shown promising properties in asymmetric catalysis and play a significant catalytic role in the development of axially chiral compounds with biaryls, heterobiaryls, atropisomeric arylalkenes, allenes, and spiranes, there are only few comprehensive reviews in this area.
Therefore, the aim of this review is to provide readers with an overview of recent advances in the asymmetric phosphoric acidcatalyzed synthesis of axially chiral compounds and to suggest that much more attention should be paid to these catalysts in order to promote asymmetric synthesis.

Enantioselective synthesis of atropisomeric biaryls
Direct C-H functionalization strategies for the atroposelective aryl-aryl cross-coupling using various transition-metal catalysts has rarely been successful for the enantioselective construction of hindered biaryls [39] due to the discord between the temperature tolerance of the rotational axis and the high temperature required for C-H activation and suffered from poor chemoselectivity [40]. However, the realization of this redoxneutral aryl-aryl cross-coupling is a formidable challenge. Therefore, the discovery of efficient catalysts and ligands to achieve high stereoselectivity is a fundamental issue in catalytic asymmetric synthesis [14]. In this section, we will present pioneering examples of chiral phosphoric acid-catalyzed asymmetric syntheses of axially chiral biaryls. In 2013, Kürti and co-workers reported a chiral phosphoric acid-catalyzed aryl-aryl-bond formation process for the regio-and atroposelective synthesis of 2,2′-diamino-1,1′-binaphthalenes (BINAMs) from achiral N,N′-binaphthylhydrazines (Scheme 1). In the presence of chiral phosphoric acids (CPA 1), the reaction undergoes a simple [3,3]-sigmatropic rearrangement, giving the corresponding products 2 in good yield (up to 88%) and enantioselectivity (up to 93:7 er). The density functional calculations showed that the chiral phosphoric acid proton forms an H-bond with nitrogen atoms of 1 and the phosphate acts as a chiral counterion, resulting in a [3,3]-sigmatropic rearrangement with controlled stereoselectivity [14,41].
In 2017, Tan and co-workers developed an organocatalytic atroposelective synthesis of axially chiral biarylamino alcohols from the reaction of quinone ester (3) and various 2-naphthylamines 4. In the presence of CPA 2, the axially chiral biarylamino alcohols 5 were obtained in moderate to good yields (up to 85%) and high to excellent enantioselectivities (up to 99% ee) (Scheme 2). The electronic properties of the substitu- ents on the 2-naphthylamine showed remarkable effects on the chemical yield but had negligible impact on the enantioselectivity [42].
The direct arylation reaction of quinones 6 and 2-naphthols 7 was described by Tan and co-workers in 2015. The corresponding axially chiral biaryl diols 8 were prepared in good yields (60-90%) and excellent enantioselectivities (90-99% ee) in the presence of CPA 2 (Scheme 3). The stereoselectivity of the reaction is only moderately affected by the position and electronic properties of the substituents on the aromatic ring [36]. Experiments showed that chiral phosphoric acid CPA 2 acted as a bifunctional organocatalyst, that activates 2-naphthols and quinone derivatives via multiple H-bonds and promotes the first step of the enantioselective conjugative addition to generate intermediate I-1 and transfers the its central chirality informa-tion to the axial chirality to give the chiral biaryldiols (Scheme 3) [14].
In 2013, Akiyama and co-workers described the enantioselective preparation of multisubstituted biaryls by the desymmetrization strategy, which was further enhanced by the subsequent asymmetric reaction (kinetic resolution) in the presence of chiral phosphoric acid CPA 3. In this work, various EWGand EDG-containing substrates were incorporated, and chiral biaryls 10 were obtained with good to excellent selectivities of 81-93% ee by desymmetrization and 63-96% ee by kinetic resolution. The subsequent asymmetric bromination reaction afforded monobrominated biaryls with excellent enantioselectivities up to 99% ee (Scheme 4). The experimental and computational studies showed that the highly organized hydrogenbonding network between a substrate, a chiral phosphoric acid catalyst (CPA 3), and a brominating reagent (N-bromophthalimide) plays a crucial role in achieving the excellent selectivities [43].
The axially chiral biaryl-2-amines, N-heteroarenes [44] and derivatives are ubiquitous structural motifs and have profound applications in biochemistry and asymmetric catalysis [45]. These chiral biaryls can be prepared by asymmetric C-H activation. The C-H activation or functionalization can be achieved by a metal-catalyzed chiral phosphoric acid ligand-assisted method, which offers distinct possibilities to provide various chiral biaryl compounds by changing different directing groups (DGs) [46]. Since the important reports by Akiyama and Terada [31,47], chiral phosphoric acids have received much attention in the efficient construction of chiral molecules not only by using them as organocatalysts, but also by applying them as ligands in transition-metal catalysis due to their multifunctionality (Brønsted acidity/basicity, hydrogen-bonding units, and counter-anions toward metals) [48,49]. In 2019, Shi, Lin, and co-workers achieved an enantioselective synthesis of axially chiral quinoline-derived biaryl atropisomers via Pd-catalyzed C-H olefination of 8-phenylquinoline (11) using a novel chiral spirophosphoric acid (CPA 4). A wide range of quinolinederived biaryls 13 with various substituents was synthesized in good to excellent yields (up to 99%) with excellent enantioselectivities (up to 98% ee) (Scheme 5). A working model for the origin of enantioselectivity in C-H olefination was provided by density functional theory calculations [46].
Recently, Shi, Lin and co-workers reported the atroposelective synthesis of axially chiral biaryls by Pd(II)-catalyzed free amine-directed atroposelective C-H olefination using chiral spirophosphoric acid CPA 5 as an efficient ligand and Ag 2 CO 3 as the oxidant. The C-H olefination of various biaryl-2-amines with acrylates and styrenes was carried out and afforded the desired products 15 in good yields (up to 96% yield) with high enantioselectivities (up to 96% ee). The electronic properties of the side chains of the biaryl compounds have a significant effect on the reactivity, but little on the enantiocontrol. In general, biaryl-2-amines with electron-donating groups showed higher reactivity than those with electron-withdrawing groups (Scheme 6). CPA 5 activates the reaction by creating a rigid and narrow chiral pocket, thus leading to better noncovalent interactions with the substrates. Moreover, the SPA ligand loading of 1 mol % is effective for this reaction under mild conditions [50].
Moreover, Shi, Lin and co-workers reported the first Pd(II)-catalyzed directed atroposelective C-H allylation of 2-(naphthalen-1-yl)aniline derivatives 14 with methacrylates 16 via β-H elimination using (S)-CPA 4 as a ligand (Scheme 7) [51]. The directing group (NH 2 ) facilitated the C-H activation on the other aromatic ring and ensured its coordination with Pd to form palladacycle I-2 to restrict bond rotations and promote exclusive allylic selectivity via β-H 1 elimination as opposed to styrenyl selectivity. In addition, the methacrylates were used as allyl surrogates to overcome the reactivity problem caused by steric hindrance of 1,1,-disubstituted alkenes, and the electronwithdrawing esters enhance the migratory insertion to form palladacycle I-2. The CPA generates the chiral environment and played a crucial role in favoring of atropisomerism. A series of axially chiral biaryl-2-amines with 1,1-disubstituted alkenes 17 was efficiently synthesized in moderate to excellent yields (42-96%) with excellent enantioselectivities (up to >99% ee).

Synthesis of atropisomeric arylindoles
The indole scaffold is found in many natural products, drugs, and bioactive molecules. Moreover, the introduction of axial chirality into the indole scaffold is receiving attention due to its widespread use [45,52]. In 2019, Li and co-workers developed a synthetic strategy for the atroposelective construction of phenylindole 20 by the chiral phosphoric acid-catalyzed crosscoupling of quinones 18 and indoles 19. In this reaction, the chiral phosphoric acid (R)-CPA 6 acts as a bifunctional catalyst to activate indoles and quinones through a dual H-bond activation mode to form the intermediate I-3, and aromatization with central-to-axial chirality transfer occurs to afford the axially chiral phenylindoles in good yield (76-92%) with good to excellent enantioselectivity (88-96% ee, Scheme 8a). The position and electronic properties of the substituents on the aromatic rings of the indole have limited influence on the reactivity Scheme 9: Asymmetric arylation of indoles enabled by azo groups. and remarkable effects on the enantioselectivity. For example, in the case of indole 20b, the enantioselectivity was drastically reduced due to steric hindrance present at the 2-position of the indole, which plays a crucial role in the stability of axial chirality.
In 2019, Li and co-workers further investigated the feasibility of 5-hydroxyindoles 22 with iminoquinones 23 under optimized reaction conditions. In the presence of 5 mol % (R)-CPA 7, the desired biaryldiol products 23 were obtained in moderate to good yields (58-95%) with excellent enantioselectivity (90-95% ee, Scheme 8b) [53]. The synthesized axially chiral phenylindoles have the potential to be used as chiral ligands in asymmetric catalysis [54] and are ubiquitous in natural products with considerable bioactivity [55,56].
Organocatalytic aryl C-H activation via a nonradical process represents an enormous challenge in organic synthesis, although the nucleophilic aromatic substitution with cleavage of the electrophilic aryl C-H bond has only recently been developed by transition-metal-catalyzed aryl C-H activation [57].
In the presence of a chiral phosphoric acid, the azo group has recently been revealed to be a useful moiety that may efficiently activate an aromatic ring for formal nucleophilic aromatic substitution, resulting in the cleavage of the aryl C-H bond and direct arylation of the nucleophile [58]. In 2018, Tan and co-workers showed that azo groups enable the organocatalytic asymmetric arylation of indoles. The nucleophilic aromatic substitution between the azobenzene derivative 24 and indoles 25 was carried out in the presence of 2.5 mol % chiral phosphoric acid (CPA 8, Scheme 9a), leading to the intermediate I-4, Scheme 10: Proposed mechanism for the asymmetric arylation of indoles.
which was subsequently aromatized to give the intermediate I-5 (Scheme 10). The axially chiral arylindole 26 was synthesized from intermediate I-5 via chirality transfer with high isolated yield (up to 98%) and excellent enantioselectivity (up to >99% ee, Scheme 9a) [59]. The authors also reported that the reaction of 2-substituted indoles with azobenzenes proceeded smoothly in the presence of the chiral phosphoric acid catalyst (R)-CPA 9. At a catalyst loading of 0.2 mol %, the intermediate I-5 was simultaneously cyclized to I-6, followed by β-H elimination and chirality transfer to afford another type of axially chiral indoles 27 (Scheme 10) bearing aniline groups by direct arylation and rearrangement in moderate to good yields with excellent enantioselectivities of mostly 99% ee (Scheme 9b) [59]. The electronic properties and position of the substituents on the azobenzene ring did not affect the yields, whereas the electronic properties of the substituents on the indole ring did.
In 2019, Lin and co-workers reported the asymmetric threecomponent cascade reaction of 2,3-diketo esters 28, aromatic amines 29, and 1,3-cyclohexanediones 30 to prepare axially chiral arylindoles 31 in a highly enantioselective manner. A wide range of substrates was subjected to the reaction in the presence of the chiral phosphoric acid CPA 9 to afford axially chiral N-arylindoles 31 in good yields (up to 93%) with good to exceptional enantioselectivities (up to 99% ee, Scheme 11). The chiral spirocyclic phosphoric acid catalyst developed by our group is critical for increasing the enantioselectivity in this cascade reaction [38]. This catalyst can facilitate the aldol reac-tion to generate a stereocenter (I-7), which can then be converted to axial chirality (I-8 to I-10) and finally aromatized to give 31 (Scheme 11) [60].
Zhou and co-workers published an excellent paper in 2019 on the conversion of central to axial chirality in an enantioselective [3 + 2] annulation of 1-styrylnaphthols 32 with azonaphthalenes 33. Under defined conditions, the cycloaddition product 34 was prepared in high yield (99%) with exclusive diastereoselectivity and 99% ee in the presence of the chiral phosphoric acid CPA 2. Subsequently, using the chiral phosphoric acid-catalyzed [3 + 2] formal cycloaddition and a moderate DDQ oxidation method over 34, enantiomerically enriched 2,3diarylbenzoindoles 35 were successfully prepared by performing a central-axial chirality conversion by oxidative aromatization. With excellent diastereoselectivities (all >20:1) and enantioselectivities (87-99% ee), the target products 35 containing different groups were obtained in high yield (up to 94%) (Scheme 12). In this transformation, electron-donating and withdrawing groups were tolerated [7].
to give I-12, and then oxidized to give 39. In addition, the intermediate I-12 was cyclized to form the intermediate I- 13 followed by β-H elimination to give another axially chiral arylindole framework 40 (Scheme 14). Both products 39 and 40 were obtained in moderate to excellent yields (up to 99%) and good to excellent enantioselectivity (83-99% ee, Scheme 13). Moreover, the reactions provide easy access to the privileged NOBIN (2-amino-2'-hydroxy-1,1'-binaphthyl) structures 41. The additional insights into the origins of enantiocontrol were described by DFT calculations. Owing to the presence of axially chiral indole-based biaryl scaffolds such as naphthylindoles and phenylindoles in bioactive molecules and chiral catalysts [62][63][64], the construction of this scaffold has recently become valuable and attracted the attention of chemists [2,64]. In this context, Shi and co-workers reported a new strategy for the enantioselective synthesis of axially chiral naphthylindoles via the asymmetric addition reaction of racemic naphthylindole 42 with azodicarboxylate 43 under chiral phosphoric acid catalysis. In the presence of CPA 2, 42 and 43 reacted and underwent dynamic kinetic resolution to afford naphthylindoles 44 with axial chirality in moderate to good yields (50-98%) and high enantioselectivity (91:9 to 98:2 er, Scheme 15) [65].
The control experiments showed that the N-H group in naphthylindoles, the OH group in phenol, and the carboxylate group in azodicarboxylate play a crucial role in both the reactivity and enantioselectivity of the reaction due to the formation of hydrogen bonds with CPA. In addition, the chiral phosphoric acid catalysts generate the chiral environment and showed the pleasing role in favoring atropisomerism [65].
The atroposelective synthesis of a new class of 3,3'-bisindoles 51 with axial and central chirality by dynamic kinetic resolution of 2-substituted 3,3'-bisindoles via asymmetric nucleophilic addition reactions using isatin-derived imines 50 as electrophiles was reported by Tan, Shi and co-workers in 2020. Enantioenriched 3,3'-bisindoles with a biologically essential chiral 3-aminooxindole unit can be readily prepared by these methods. CPA 9 utilizes hydrogen bonding to activate both Scheme 14: Proposed reaction mechanism for the atroposelective arene functionalization of nitrosonaphthalenes.
In 2020, Shi and co-workers reported the chiral phosphoric acid (CPA)-catalyzed enantioselective addition reaction of 3,3'-bisindoles 47 and ninhydrin-derived 3-indolylmethanols 52 for the synthesis of 3,3'-bisindoles 53 with single axial chirality. In the presence of CPA 15, the axially chiral 3,3′-bisindoles 53 were synthesized via a dynamic kinetic resolution (DKR) process in overall moderate yields (up to 79%) and good enantioselectivities (up to 94:6 er, Scheme 18) [68]. The authors investigated the high rotation barrier and stability of the axially chiral products and found that 3,3'-bisindole scaffolds with a single axial chirality are quite stable because of the bulkiness of the ninhydrin group. They also investigated the rotational barrier of substrate 47 and confirmed that it could be rapidly racemized during the reaction process, suggesting that dynamic kinetic resolution could be used to accomplish enantioselective synthesis of axially chiral 3,3'-bisindoles. The mechanistic studies showed that the N-H group of 3,3′-bisindoles 47 played a crucial role in carrying out the addition reaction with substrates 52 possibly by forming a hydrogen bond with CPA 15. Moreover, the N-H group of ninhydrin-derived 3-indolylmethanols 52 was crucial in increasing the reactivity and enantioselectivity, but it is not important for ninhydrin-derived substrates to carry out the addition reaction. This suggests that this substrate could produce an ion-pair interaction with CPA 15 in addition to the hydrogen-bonding interaction.

Synthesis of miscellaneous atropisomeric heterobiaryls
Axially chiral pyrazole scaffolds are commonly found in natural products and drugs and are often used as valuable building blocks in organic synthesis [69]. Herein, Li and co-workers developed a new asymmetric synthesis of atropisomeric pyrazole derivatives 56 via an enantioselective reaction of azonaphthalene 54 with pyrazolone 55 using 5 mol % chiral phosphoric acid CPA 16. Substrates bearing electron-donating and elec-tron-withdrawing groups gave the desired axially chiral pyrazole derivatives 56 in good yields (up to 99%) with excellent enantioselectivities (up to 98% ee, Scheme 19). Density functional theory calculations revealed that the chiral phosphoric acid acts as a proton-transfer shuttle to assist proton transfer from the OH group of pyrazolone-enol intermediates to the N-N double bonds of azonaphthalenes [70].
On the other hand, N-arylcarbazole frameworks are also abundant in pharmaceuticals, agrochemicals, natural products, and functional OLED materials [71,72]. Therefore, the construction of axially chiral N-arylcarbazoles is desirable. In this sense, Tan and co-workers (2020) developed the first chiral phosphoric acid-catalyzed atroposelective C-H amination of arenes for the synthesis of N-arylcarbazole structures. The atroposelective N-arylcarbazoles 58 were prepared by C-H amination of azonaphthalene derivatives 54 and carbazole derivatives 57 via asymmetric addition and chirality transfer. In the presence of CPA 9, axially chiral N-arylcarbazoles were obtained in moderate to good yields (51-97%) with good to excellent enatioselectivity (87-96% ee, Scheme 20a) [73].
More importantly, the same group reported the synthesis of axially chiral N-arylindole atropisomers from azonaphthalene 54 and indole substrates 59 in the presence of chiral phosphoric acid CPA 17. The atropisomeric adducts were obtained in moderate to good yields (up to 93%) with good to excellent enantioselectivity (up to >99% ee, Scheme 20b). Therefore, this synthetic method (nucleophilic aromatic substitution reaction) is crucial for the development of alternative C-N bond-forming reactions to conventional metal-involved cross-couplings, providing axially chiral N-arylcarbazoles 60 in good yields with remarkable enantiocontrol through a rearomatization-enabled central to axial chirality transfer pathway [73].
Citing the crucial role of di-carbazole-substituted arenes in OLED materials [74], Tan and co-workers have recently developed structural motifs with two chiral N-aryl axes from 2,6diazonaphthalene 61 and carbazoles 62. For this reaction, a high loading of 20 mol % CPA 18 with a 1-pyrenyl group at the Scheme 21: Atroposelective cyclodehydration reaction. 6,6'-position of the spiro backbone was preferred as the best catalyst for this transformation. Encouragingly, the double atroposelective C-H amination reaction took place and afforded the desired 1,5-dicarbazole naphthalene derivative 63 in moderate yield with >90% enantioselectivity (Scheme 20c) and tolerable diastereoselectivity (4:1) [73].
The optically enriched benzimidazoles are N-heterocycles which are of great interest as drug-like molecules [75], and exhibit biological activities such as anticancer, antiviral, antifungal, and antibacterial effects [76]. In this context, Miller and co-workers reported the performance of C 2 -symmetric chiral phosphoric acids (C 2 -type) and phosphothreonine-embedded, peptidic phosphoric acids (pThr-type CPAs) to catalyze a wide range of atroposelective cyclodehydration reactions for the synthesis of benzimidazoles. In the presence of CPA 7, the corresponding products 65 were obtained with the highest selectivity (up to 96% ee) at full conversion while catalyst CAT 1 (Scheme 21) afforded 65 with up to 94% ee at 96% conversion. The highly substituted axially chiral benzimidazoles 65 were all formed with excellent enantioselectivity when either CAT 1 (93-97% ee) or CPA 7 (93-96% ee) was used as catalyst (Scheme 21). The authors described that, BINOL-derived CPAs and pThr-type CPA scaffolds were found to be effective for atroposelective cyclodehydrations. Both the DFT and catalyst correlation studies showed that the steric repulsion between the large 3,3′-substituent of the C2-type CPAs catalyst and the bottom aromatic ring of the substrate seems to determine the enantioselectivity [77].
In 2020, Fu and co-workers described the chiral phosphoric acid-catalyzed atroposelective construction of axially chiral N-arylbenzimidazoles involving a carbon-carbon bond cleavage under optimal reaction conditions. In the presence of CPA 2, Scheme 22: Atroposelective construction of axially chiral N-arylbenzimidazoles [78]. Axially chiral arylpyrroles are the core scaffold for a variety of natural products, bioactive compounds and pharmacological agents [79] as well as for a variety of chiral phosphine ligands [80]. As a result, the preparation of axially chiral arylpyrroles has been one of the most important areas of investigation in synthetic chemistry. In the last decade, the optical activity of arylpyrroles has been explored by optical resolution of racemates using chiral resolving agents or chiral column chromatography [81]. Although Zhang et al. developed the first catalytic asymmetric Paal-Knorr reaction for accessing highly enantioenriched axially chiral arylpyrroles in 2017 [82], a complicated catalytic system and narrow substrate range limited its application. Therefore, the use of chiral phosphoric acids to modulate axial chirality enables the preparation of highly enantioenriched axially chiral arylpyrroles. In this context, Tan and co-workers discovered in 2019 a highly effective approach using organocatalytic atroposelective desymmetrization and kinetic resolution to obtain enantioenriched axially chiral arylpyrroles. The axially chiral arylpyrroles 73 were prepared in high yields (up to 99%) and with excellent enantioselectivities (up to 98% ee) from the reaction of 71 and diethyl ketomalonate (72) under remote control of CPA 19 as chiral phosphoric acid catalyst (Scheme 24). The hydrogen bonding between the ketomalonate and CPA 19 proved to be the most important Scheme 23: Proposed reaction mechanism for the atroposelective synthesis of axially chiral N-arylbenzimidazoles.

Scheme 24:
Atroposelective synthesis of axially chiral arylpyrroles [21]. interaction in the formation of the chiral pocket for the induction of chirality and could considerably improve the stereocontrol of the reaction [21].
The axially chiral arylquinazolinones form the backbones of a large number of natural products and biologically active compounds as well as chiral ligands [83]. Nevertheless, a simple chiral phosphoric acid-catalyzed enantioselective approach to access optically pure arylquinazolinones has never been developed in the last decades. However, in 2017, Tan and co-workers reported the enantioselective synthesis of axially chiral arylquinazolinones 76 from the reaction of N-arylanthranilamides 74 and benzaldehyde (75) by accelerating imine formation (I- 19), and under the catalysis of a chiral phosphoric acid, intramolecular nucleophilic addition occurs to form I-20, followed by oxidative dehydrogenation with 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ). In the presence of 10 mol % chiral phosphoric acid CPA 7, the axially chiral arylquinazolinones 76 were obtained in high yield (up to 99%) with high enantioselectivity (83-97% ee, Scheme 25). Both the position and the electronic properties of the substituents on the aromatic ring had a minor influence on the reaction efficiency and enantioselectivity of this transformation [35].
Quinolines are widely used in natural and synthetic products and exhibit remarkable pharmacological properties [84]. To synthesize this valuable scaffold, Cheng and co-workers performed for the first time in 2019 an atroposelective Friedländer heteroannulation reaction of 2-aminoaryl ketones 77 with α-methylene carbonyl derivatives 78 catalyzed by a chiral phos-Scheme 26: Synthesis of axially chiral aryquinoline by Friedlander heteroannulation reaction and its proposed reaction mechanism [85]. phoric acid. In the presence of (R)-CPA 9, the Friedlander heteroannulation reaction between aromatic amines 77 and the carbonyl derivative 78 was carried out to form imine I-21, which tautomerized to generate intermediate I- 22. Under CPA 9 catalysis, the intermediate I- 22 is converted to I-23, which after dehydration forms the desired enantioenriched products, polysubstituted 4-arylquinolines 79 in high yield (up to 94%) with good to excellent enantioselectivities (up to 97% ee, Scheme 26). The chiral phosphoric acid catalyst played an important role in the asymmetric induction by establishing a favorable chiral environment in the cyclization step through supporting hydrogen bonds [85].

Enantioselective synthesis of axially chiral arylalkene and N-arylamines
Although many elegant strategies have been developed to enable the atroposelective construction of axially chiral biaryls and heterobiaryls [87][88][89], the synthesis of axially chiral styrenes or vinylarenes has rarely been developed [90,91], due to their low rotational barrier and weak configurational stability. Moreover, the application of an organocatalytic kinetic resolution strategy to access axially chiral styrenes has rarely been reported. In this regard, Shi and co-workers reported the first atroposelective access to oxindole-based axial chiral styrenes or vinylarenes by kinetic resolution of racemic oxindole-based styrenes 83 and azalactones 84. In the presence of CPA 20, racemic oxindole-based styrenes reacted with azalactones via hydrogen bonding, and the azalactones underwent asymmetric ring opening to form axially chiral oxindole-based styrenes 85 in up to 53% yield with good diastereoselectivities (up to 94:6 dr) and enatioselectivities (up to 95% ee). Moreover, the racemic oxindole-based styrenes underwent kinetic resolution to afford other axially chiral styrenes 86 in moderate yields (up to 54%) with excellent enantioselectivities (up to 96% ee) and high selectivity factors (SF up to 106) [92]. This strategy is critical for accessing axially chiral the oxindole-based styrenes and provides a robust method for the synthesis of bisamide derivatives that are both axially and centrally chiral (Scheme 28).
The nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines. and chiral ligands due to the restricted rotation around an N-C single bond. There are few strategies for the catalytic atroposelective construction of N-C nonbiaryl atropisomers, which mainly consist of enantioselective cyclization [35], N-functionalization [93], and desymmetrization [94] of the existing achiral N-C bond. In this context, Bai and co-workers (2019) developed the direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines 92 with azodicarboxylates 93 to prepare N-C atropisomers of nonbiaryl naphthalene-1,2-diamine 94. In the presence of chiral phosphoric acids (CPA 15), the desired product 94 was obtained in moderate to high isolated yield (up to 95%) and enantioselectivity (up to 94% ee, Scheme 31). However, the reactivity and stereoselectivity decreased the closer the substituents were to the reaction site, probably due to steric effects. On the other hand, the substrates with electron-withdrawing groups would decrease the electron cloud density, limiting the reactivity and thus reducing the yield. In general, the electronic properties of the substituents did not affect the stereoselectivity of the reaction. The mechanistic study revealed that, CPA 15 simultaneously activates N-phenyl-2-naphthylamine and azodicarboxylate through a dual hydrogen bond activation mode and a π-π interaction strategy (Scheme 31) [2].
Diarylamines and related scaffolds are among the most common potentially atropisomeric chemotypes in medicinal chemistry. For example, the drugs binimetinib and bosutinib contain diarylamines that exist as rapidly interconverting atropisomers, Scheme 29: Synthesis of axially chiral alkene-indole frame works [45].

Scheme 30:
Proposed reaction mechanism for axially chiral alkene-indoles. and a VEGFR inhibitor from Wyeth contains a potentially atropisomeric N-arylquinoid [95,96]. In 2020, Gustafson and co-workers reported the first chiral phosphoric acid-catalyzed atroposelective electrophilic halogenation of N-arylquinoids 95, a class of compounds similar to diarylamines. In this reaction, CPA 21 was an effective catalyst, providing stereochemically stable brominated product N-arylquinoids 96 in high yield (up to 95%) and atroposelectivity (up to 98:2 er, Scheme 32). Remarkably, these products existed as stereochemically stable class 3 atropisomers under protic and aprotic conditions due to a strong intramolecular N-H-O hydrogen bond that locks one of the axes into a planar conformation and proposed that the quinoid-nitrogen axis exists in a planar exo conformation [97].

Enantioselective synthesis of axially chiral allenes and spiranes
The enantioselective construction of spirocyclic centers is an exciting synthetic challenge that plays a prominent role in the discovery of new catalysts and complex molecules [98]. Spirocyclic frameworks are present, for example, in biologically active natural products (e.g., fredericamycin A and acutumine [99]), SPINOL-based ligands and catalysts [100], and organometallic complexes with important applications. The use of chiral catalysts for spirocyclization reactions brings asymmetry at the site of the spirocyclic center while tolerating different electronic and steric functional groups [98].
In this context, Tan and co-workers succeeded in the enantioselective synthesis of axially chiral SPINOLs 98 from ketals 97 by an intramolecular fashion in the presence of 1 mol % chiral phosphoric acid CPA 22 to afford the axially chiral product (R)-98 in high yield (62-95%) with good to excellent enantioselectivity (90-96% ee, Scheme 33) [17]. The electronic properties and steric bulk of the substituents on the catalysts as well as the axial chiral backbone have a very strong influence on the reactivity and enantioselectivity as shown in Scheme 33. The syn- thesis of the products (R)-98 at a gram scale was carried out without loss of chemical yields and stereoselectivities under optimized conditions. The authors also found that the excellent stereocontrol was due to the simultaneous interaction between the bifunctional phosphoric acid and the intermediate formed in the reaction via hydrogen bonds.
Axially chiral allenes and derivatives occur in overwhelming numbers in natural products, pharmaceuticals, functional materials, and useful intermediates in organic synthesis [101]. Therefore, great efforts have been made to synthesize these axially chiral scaffolds [102]. In this regard, Wang and co-workers reported the organocatalytic asymmetric synthesis of tetrasubstituted α-amino allenoates by a dearomative γ-addition reaction of 2,3-disubstituted indoles 99 to β,γ-alkynyl-α-imino esters 100 [103]. In the presence of chiral phosphoric acid CPA 13, a series of tetrasubstituted α-amino allenoates 101 was prepared in moderate to excellent yields (69-99%), dr (9:1 to >20:1), and excellent enantioselectivity (91-99% ee, Scheme 34). The mechanistic studies showed that the substituents at the second and third positions of the indole play a crucial role in the chemo-and stereoselectivity. Moreover, the chiral phosphoric acid group attains a bifunctional role by activating both partners via hydrogen bonds, and the chiral backbone of the catalyst controls the stereoselectivity through steric effects and π-π interactions.
Because of the importance of chiral tetrasubstituted allenes with aryl substituents, the asymmetric synthesis of these scaffolds has received much attention. In 2020, Lu and co-workers carried out the enantioselective dehydrative γ-arylation of α-indolyl-α-trifluoromethylpropargyl alcohol 105 and 1-naphthol (106) or 2-naphthol (107) catalyzed by chiral phosphoric acids CPA 13 and CPA 23, to produce a wide range of chiral tetrasubstituted allenes 108 and naphthopyrans 109 in high yield (≤98% yield) with excellent regio-and enantioselectivities (>99:1 er, Scheme 36) [105]. However, when substituents are present at the C-4 or C-7 position of the indole ring of the propargyl alcohol, the yield decreases, which could be due to steric effects. Since the chiral phosphoric acid catalysts can interact with these groups via double hydrogen bonds, control studies have shown that the free OH on naphthol/phenol and the NH groups on the α-indolyl-α-trifluoromethylpropargyl alcohol are very important for the reaction.
Li and co-workers developed a chiral phosphoric acid-catalyzed asymmetric remote 1,8-conjugate addition of thiazolones 111 and azlactones 112 to propargyl alcohols 110 for the synthesis of the chiral allenes 113 and 114, respectively. In the presence of 1 mol % CPA 24, 5H-thiazol-4-ones 111 and p-quinone methides generated in situ from propargyl alcohols 110 were incorporated and afforded the axially chiral tetrasubstituted allenes 113 with a chiral thiazolone moiety in high yield (65-97%), high enantioselectivity (76 to >99% ee) and diastereoselectivity (10:1 to >20:1 dr). In addition, the enantioselective 1,8-conjugate addition of azlactones 112 to paraquinone methides generated in situ from propargyl alcohols 110 were carried out in the presence of 1 mol % chiral phosphoric acid CPA 7 and afforded the chiral allenes 114 in high yields (65-97%) with good to excellent enantioselectivities (76-97% ee) and good diastereoselectivities (up to 20:1 dr, Scheme 37) [106]. The electronic nature and position of the substituents on the aromatic ring of the thiazolones or propargylic alcohols did not significantly affect the stereoselectivity of the reaction. Moreover, both electron-withdrawing and donating groups on the aromatic rings of propargyl alcohols or azlactones smoothly participated in the asymmetric 1,8-conjugate addition and afforded the corresponding chiral allenes in good yields with high enantioselectivity. The control experiments showed that the propargyl alcohol 110 was firstly converted to para-quinone methide (p-QM) in the presence of CPA and then led to the successful formation of the corresponding products through hydrogen-bonding interaction of para-quinone methide and thiazolones/azlactones with CPA.
rivatives 116 with an allene moiety, exhibiting both a quaternary stereocenter and axial chirality, were obtained in good yields (up to 82%) with high diastereoselectivities (up to >99:1 dr), and enantioselectivities (up to 96% ee, Scheme 38). Control experiments showed that the high to excellent stereoselectivity is the result of a dual hydrogen-bonding interaction between the substrates and the chiral phosphoric acid, with the substituent at the 1-position of the 2-naphthol playing a key role in controlling the regioselectivity [107].

Conclusion
In recent decades, chiral phosphoric acids have been recognized as privileged chiral catalysts and ligands and have therefore become an important tool in asymmetric organic synthesis. This review summarizes the state of the art in the chiral phosphoric acid-catalyzed asymmetric synthesis of axially chiral biaryls, heterobiaryls, arylamines, arylalkenes or styrenes, spiranes, and allenes. These axially chiral compounds have at-tracted considerable attention in recent years due to their wide application in the total synthesis of axially chiral natural products, functional materials, bioactive compounds, privileged chiral ligands, and have further potential applications in asymmetric catalysis and drug discovery. Accordingly, considerable efforts have been made to find new efficient routes for the enantioselective construction of various atropisomeric aryl-aryl or aryl-heteroaryl, enantioselective spiranes and allenes. Despite the advances mentioned above, much of this area of research is still relatively unexplored. Compared to the use of chiral phosphoric acids in the preparation of centrally chiral compounds, their application in the synthesis of axially chiral biaryls and heterobiaryls, axially chiral allene, atropisomeric aryl alkenes, and spirane moieties is still quite limited. Given the increasing importance of axially chiral compounds, novel chiral phosphoric acid-catalyzed asymmetric methods to address these challenges are highly desirable. Therefore, we believe that the future development of asymmetric syntheses using chiral phos- phoric acid catalysts will play a crucial role in the preparation of other complex organic molecules with axial chirality, which will be widely used in science and industry in the near future.

Funding
Financial support from the National Natural Science Foundation of China (22071213), Leading Talents of Special Support Program of Zhejiang Province High-level Talents (2020R52008) and Center of Chemistry for Frontier Technologies of Zhejiang University is gratefully acknowledged.