Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

Abstract

Axially chiral heterobiaryl frameworks are privileged structures in many natural products, pharmaceutically active molecules, and chiral ligands. Therefore, a variety of approaches for constructing these skeletons have been developed. Among them, de novo synthesis, due to its highly convergent and superior atom economy, serves as a promising strategy to access these challenging scaffolds including C-N, C-C, and N-N chiral axes. So far, several elegant reviews on the synthesis of axially chiral heterobiaryl skeletons have been disclosed, however, atroposelective construction of the heterobiaryl subunits by de novo synthesis was rarely covered. Herein, we summarized the recent advances in the catalytic asymmetric synthesis of the axially chiral heterobiaryl scaffold via de novo synthetic strategies. The related mechanism, scope, and applications were also included.

1. Introduction

A common form of axial chirality is atropisomerism, which results from the inhibition of σ bond rotation caused by steric hindrance or the electronic effect of the flanking substituents [1,2]. When the half-life of interconversion is at least 1000 s under the specific temperature, and the rotational barrier is higher than 23.3 kcal mol⁻¹, the two atropisomers could be separated [3]. Although Christie and Kenner resolved the stable isomers of 6,6′-dinitro-2,2′-diphenic acid as early as 1922 [4], the importance of atropisomerism was only realized after the pioneering work of Noyori and Takaya in 1980, in which atropisomeric chiral BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) was successfully applied as a ligand for rhodium-catalyzed asymmetric hydrogenation of α-(acylamino) acrylic acids [4,5]. Since then, atropisomerically chiral catalysis has received remarkable attention, and axially chiral heterobiaryl frameworks have, thus, been recognized as a privileged structure in many natural products, pharmaceutically active molecules, and chiral ligands (Figure 1) [6,7,8,9,10,11,12,13]. For example, natural products with the heterobiaryl skeleton, such as Ancistrocladinium A, Rivularin D₃, Murrastifoline F, and Marinopyrrole A, were isolated from marine blue-green alga Rivularia firma, Murraya koenigii, and actinomycete strain CNQ-418, and some of these products exhibit excellent activities in antimicrobial bioassays (Figure 1A) [14,15,16]. In addition, axial heterobiaryl compounds are also present in many FDA-approved drugs, and they have been proven to have a positive contribution to pharmacokinetics including absorption, distribution, metabolism, excretion, and potency via interaction with the target protein, which made heterobiaryl molecules more and more prevalent in drug discovery and drug development (Figure 1B) [17,18,19,20,21]. In addition, axially chiral heterobiaryl subunits, such as isoquinoline containing phosphine and atropisomeric isoquinoline N-oxide, have been successfully employed as powerful chiral ligands to construct various chiral molecules through transition-metal catalyzed asymmetric transformation (Figure 1C) [22,23,24,25,26,27].

In view of these significant applications, efficient approaches for synthesizing these axially chiral heterobiaryl skeletons are highly desirable [12,28,29,30]. However, it is well understood that construction of the axially chiral heterobiaryl scaffolds is very challenging, due to the following issues: (i) when heteroaryl sub-units are used as the coupling partners in the cross-coupling or oxidative dimerization reactions, the strong coordination ability of heteroatoms has a non-negligible impact on these transformations [30,31]; (ii) the low steric hindrance of nitrogen lone pair can lead to the poor conformational stability of some pyridine-derived atropisomers [12]; (iii) in addition to configurational instability and the low rotation barrier, the increased distance between the ortho-substituents around the axis makes the atroposelective synthesis of five-membered heterobiaryl molecules more challenging [32]. Nevertheless, a series of outstanding strategies to prepare axially chiral biaryls have been developed. These diverse methodologies can be divided into four main categories (Figure 2): (A) atroposelective coupling of two aromatic sub-units [33,34,35,36], (B) transformation of prochiral heterobiaryl molecules into axially chiral skeletons [37,38,39,40], (C) central-to-axial chirality conversion [41,42,43], and (D) de novo construction of axially chiral molecules [44,45,46]. To date, several elegant reviews have been disclosed, in which the authors focused on the atroposelective coupling of two units [47,48], atroposelective transformation of prochiral heterobiaryls [11,49,50,51], and central-to-axial chirality conversion [52,53]. Although de novo synthesis of axially chiral heterobiaryl exhibits highly convergent and superior atom economy, atroposelective construction of the heterobiaryl subunits by de novo synthesis was rarely covered. Moreover, the broader substitution patterns of de novo synthesis could increase the structural diversity, which is in turn, conducive to the application of heterobiaryl molecules in the development of chiral ligands for asymmetric synthesis and bioactive molecules for drug discovery. Thus, the synthesis of axially chiral heterobiaryl compounds from acyclic precursors through cyclization reaction has gained more and more attention recently.

In this review, we summarized the recent research progress and trend of axial chiral heteroaryl synthesis by means of de novo construction. The construction of heterobiaryl via two or more steps [54,55,56,57] and the synthesis of nonbiaryl atropisomers containing a heteroaryl scaffold [58,59,60] are out of the scope of this review. This mini-review is divided into the following parts: (1) transition metals catalyzed de novo synthesis of axially chiral heterobiaryl scaffolds; (2) organic small molecules catalyzed de novo synthesis of axially chiral heterobiaryl scaffolds.

2. The De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds Catalyzed by Transition Metal Catalysts

This section covers: (1) Intermolecular cyclization and cycloaddition reactions catalyzed by transition metal catalysts; (2) Transition metals-catalyzed intramolecular cyclization reactions.

2.1. Intermolecular Cyclization and Cycloaddition Reactions Catalyzed by Transition Metal Catalysts

2.1.1. Enantioselective Synthesis of Five-Membered Ring Axially Chiral Heteroaromatic Skeletons

The conformational instability and lower rotation barrier make the synthesis of atropisomeric species bearing the five-membered rings challenging, nevertheless, some elegant methodologies have been reported in recent years. In 2017, Tan’s group discovered an efficient strategy for highly atroposelective synthesis of enantiomerically pure aryl pyrroles through an asymmetric Paal–Knorr reaction between 1,4-dione 1 and substituted anilines 2 catalyzed by the combination of chiral phosphoric acid and Fe(OTf)₃ (Scheme 1) [61]. Although using chiral phosphoric acid as a single catalyst only resulted in moderate enantioselectivity, the ee value was improved from 78% to 88% when Fe(OTf)₃ was added as a Lewis acidic catalyst to activate phosphoric acid [62]. Significantly, an unexpected solvent-dependent inversion of the enantioselectivity was also discovered in this conversion. When the solvent was switched from CCl₄ to MeOH, the enantioselectivity was changed from 72% ee to −52% ee under otherwise identical conditions. In addition, various functionalized aryl pyrroles could be accessed through enamine intermediate Int 2, followed by acid-catalyzed dehydrative cyclization (3a–3d). The presence of Int 2 formed in the reaction mixture was confirmed by NMR and HRMS. Furthermore, axially chiral phosphine ligand 3d could also be achieved in 88% ee through simply changing tertiary butyl (t-Bu) groups in amine 2 into diphenylphosphine analogs.

Inspired by Tan’s work, Zhu and co-workers revealed a catalytic enantioselective heteroannulation between α-isocyanoacetates 4 and α-aryl-α,β-alkynic ketones 5 catalyzed by Ag₂O in the presence of a cinchona-based phosphine ligand L2, which afforded axially chiral 3-arylpyrroles 6 in high yields with excellent enantioselectivities (Scheme 2) [63]. It is worth noting that 6a bearing a quinoline system could be furnished in 91% ee. The authors proposed a possible mechanism in which nucleophilic addition of 4 and 5 provided the allene Int 4, which was followed by intramolecular cyclization to generate Int 5. Subsequently, the protonation of Int 5 afforded Int 6. Finally, the 1,5-H shift of Int 6 offered the corresponding axially chiral 3-arylpyrroles 6. To demonstrate the utility of the reaction, the chiral olefin oxazole ligand 6d, which could be potentially used for a catalytic asymmetric conjugate addition reaction, was prepared from the aryl pyrrole 6c through a four-step transformation.

Chen and co-workers reported the synthesis of 3-pyrrole-containing axially chiral scaffolds via an atropenantioselective Barton−Zard reaction of ethyl α-isocyanoacetate 8 and nitroolefin 7 catalyzed by Ag₂O in the presence of cinchona-derived phosphine ligand L3 (Scheme 3) [64]. This work presented a central-to-axial chirality transfer process, in which Michael addition of 8 to β-nitrostyrenes 7 generated Int 7 with three central stereogenic centers. Subsequently, intramolecular cyclization and aromatization via the elimination of HNO₂ could afford the axially chiral compound 9.

The atroposelective azide−alkyne cycloaddition to offer axially chiral aryl triazoles was recently disclosed by Xu and co-workers via an Ir(I)/squaramide cooperative catalytic procedure (Scheme 4) [65]. It was found that the metal catalyst, reaction solvent, and temperature all play a key role in the increase in enantioselectivity. The cyclization process could be rationalized by the following mechanism: the crucial vinylidene ortho-quinone methide (VQM) Int 9 could be formed from 1,5-hydrogen migration triggered by the interaction between 10, [Ir(COD)CI]₂ and L4. The cycloaddition between chiral Ir(I) coordinated azide, and Int 9 produced the chiral aryl triazole products. The L4 serves both as an organic catalyst to activate ortho-hydroxy aryl alkyne 10 by hydrogen-bonding interaction between squaramide and oxygen atom in Int 9, and as a ligand to chelate with metal Ir. The aryl triazole skeleton bearing aryl, trimethylsilyl, heteroaryl, and alkyl substituent could also be achieved in excellent yield and high enantioselectivity with this protocol.

At around the same time, structurally similar axially chiral 1,2,3-triazole derivatives were furnished by Li and Cui utilizing an Rh/chiral phosphoramidite ligand L5 catalyst system through azide-internal-alkyne cycloaddition with high yield (up to 99%) and excellent enantioselectivities (up to 99% ee) (Scheme 5) [66,67]. Combining density functional theory calculations and control experiments, Li and co-workers presumed that the excellent regioselectivity of the catalytic system is closely related to the hydrogen-bond effect between the Cl-atom in [Rh(COD)Cl] and the H-atom in the hydroxyl group of phenol. Interestingly, in Li’s case, the utility of 15e was also illustrated by converting it into new phosphine chiral ligands 15f and 15h. The latter compound (15h) was then employed as a chiral ligand for an asymmetric Tsuji–Trost allylation reaction to prepare chiral allylic alkylation product 19 in 99% ee.

2.1.2. Enantioselective Synthesis of Fused Bicyclic Heteroaromatic Chiral Skeletons

The catalytic asymmetric Paal–Knorr reaction, heteroannulation, and azide−alkyne cycloaddition are effective strategies to produce atropisomers featuring pentatomic heteroaromatic molecules. Recently, the atroposelective [2 + 2 + 2] cycloaddition of nitriles 21 with (o-halophenyl) diynes 20 was successfully developed to access the heterobiaryl compounds 22 (chiral) and 23 (achiral) (Scheme 6) [68]. (S)-H₈−BINAP L6 was selected as the ligand to control the stereochemistry of the products. It was supposed that the equilibrium between intermediates Int 11 and Int 12 could be controlled by introducing the coordinating group (CO₂Me, Cl, and OMe) at ortho-substituent (R²) to form Int 12. Oxidative cyclization of Int 12 and insertion of nitrile 21 could give axially chiral product 22. However, when the R² was substituted by a less-coordinating group (such as CH₃, etc.), the cationic rhodium(I) center could be coordinated by the alkyne moiety of 20 and nitrile of 21, which was followed by oxidative cyclization, insertion of the pendant alkyne, and reductive elimination affording the achiral 6-arylpyridine 23.

Inspired by the C-H activation approach to form heterocyclic compounds, Li and co-workers reported an innovative way to access isoquinolines bearing an indole sub-unit via rhodium (III)-catalyzed oxidative [3 + 2] annulation between internal alkynes 25 and aniline-substituted isoquinolines 24 (Scheme 7) [69]. Further study of the mechanism showed that the C-N reductive elimination and dynamic kinetic annulation were the decisive steps for controlling the stereo configuration. In addition, the N-isoquinolylindole 26 could be transformed into various derivatives (26f–26i) through oxidative C=C cleavage, reductive reaction, Sonogashira reaction, and Suzuki coupling.

Recently, the de novo construction of indole-based frameworks has gained increasing attention since Kitagawa and co-workers disclosed the first example of axially chiral indoles [70]. Most reported methods focus on the mono-catalysis strategy to produce the heteroarene skeleton. In sharp contrast, there are rarely reports on the construction of axially chiral indoles via dual catalysis. In 2022, Shao’s group utilized organic catalysts (L8 and the L9)/transition-metal (AgNO₃) combined dual catalytic system for de novo synthesis of the axially chiral indole-based scaffold 29 with good yields and excellent enantioselectivities, by employing 2-naphthylamines 28 and N, O-acetals 27 as the starting materials (Scheme 8) [71]. This transformation offered a rare example of the combination of two chiral phosphoric acids with a metal catalyst in a single reaction to enable inaccessible molecules through intermolecular cycloaddition-isomerization. Impressively, 29g, featuring two C-N axes, could be obtained by this method, which is challenging to access by existing strategies.

Later, the asymmetric [4 + 2] annulative coupling reaction of arylalkynes 32 with different sulfonium ylides 31 mediated by L11, Zn(OAc)₂, and AgSbF₆ to furnish C-N axially chiral 4-indole 1-naphthols with wide substrate universality (33a–33d) was also established by Li’s group (Scheme 9) [72]. Furthermore, this report indicated that sulfonium ylides 31 could be applied as a versatile platform in the asymmetric C-H bond activation process.

Later, the asymmetric [4 + 2] annulative coupling reaction of arylalkynes 32 with different sulfonium ylides 31 mediated by L11, Zn(OAc)₂, and AgSbF₆ to furnish C-N axially chiral 4-indole 1-naphthols with wide substrate universality (33a–33d) was also established by Li’s group (Scheme 9) [72]. Furthermore, this report indicated that sulfonium ylides 31 could be applied as a versatile platform in the asymmetric C−H bond activation process.

2.2. Intramolecular Cyclization Reaction Catalyzed by Transition Metal Catalysts

Enantioselective Synthesis of Heteroaromatic Chiral Skeleton with Fused Ring

Intramolecular cyclization reactions catalyzed by transition metal catalysts are considered powerful methods for delivering a variety of atropisomeric indoles with a chiral axis. In 2010, N-(ortho-tert-butylphenyl)-2-(phenylethynyl) aniline 34 was used to construct indole compounds with N-C axial chirality through intramolecular hydroamino cyclization catalyzed by PdCl₂ in the presence of (R)-SEGPHOS by Kitagawa and co-workers (Scheme 10) [70].

The above work opened a new field of the catalytic asymmetric synthesis of axially chiral indole-based framework utilizing ortho-alkynylaniline. For example, in 2020, Zhu’s group revealed the strategy of enantioselective Cacchi reaction through a Pd(OAc)₂/(R, R)-QuinoxP* L12 catalyzed cascade process to provide enantioenriched 2,3-disubstituted indoles 38 possessing a chiral C2-aryl axis with excellent enantioselectivities (Scheme 11) [73]. Furthermore, the newly formed indole ring possessed unique properties, for example, high aromaticity and a planar 2D structure, and was electronically rich which enables it to be a good hydrogen-bond donor that can be easily functionalized. Therefore, based on these inherent characteristics, Li and co-workers achieved axially chiral biindolyls using a unified chiral Rh (III) catalyst through intermolecular C-H activation followed by intramolecular alkyne cyclization (Scheme 12) [74]. Unlike other reported methodologies, this conversion does not require an inorganic base as an additive and achieved the enantiomeric 2,3′-biindolyls under very mild reaction conditions with excellent enantioselectivity. Later, the same group performed the de novo construction of 3-arylindoles via an enantioselective Cacchi reaction between aryl bromides 43 and o-alkynylanilines 42 in the presence of Pd(TFA)₂, ferrocene-based N, P-ligands L13 under the assistance of Ba(OH)₂ 8H₂O and B(OH)₃ (Scheme 13) [75].

Similar work was disclosed in the same year, in which 2-phenylethynyltrifluoroacetanilide 45 and 1-iodo-2-isopropoxynaphthalene 46 were used by Wang’s group as the reaction substrates for directly accessing naphthyl-C3-indoles with a free NH moiety (Scheme 14) [76]. Remarkably, it offered a strategy for improving the enantioselectivity by adjusting the steric hindrance of the substituted group on the O-atom of 1-iodonaphthalen-2-ol. In addition, it was found that dissolving the inorganic base in H₂O could facilitate the formation of product by offering a homogeneous catalytic system. In 2021, Xu’s group also reported a cyclization reaction between o-ethynylanilines 48 and cyclobutanones 49 catalyzed by [Pd(allyl)Cl] in the presence of a chair phosphoramidite ligand L14 to access indanone-substituted indole 50 with concomitant formation of C-N bond, C-C bond, and an all-carbon quaternary stereocenter (Scheme 15) [77].

Methoxymethyl sulfides 51 were also employed to construct the axially chiral bibenzothiophenes 52 through asymmetric cyclization–dimerization (Scheme 16) [78]. The alkynophilicity of Int 15 was enhanced by the box ligand L15, which promotes the occurrence of dimerization affording 52 with broad functional group tolerance.

Compared with these achievements for the synthesis of C-C and N-C axially chiral compounds, the methodology for the synthesis of N-N atropisomers was still in its infancy. In 2022, structurally diverse indole-heterocycle (carbazole and pyrrole) bearing a chiral N-N axis was accessed via intramolecular arylation of enamine 53 catalyzed by Pd(OAc)₂ and DTBM-SEGPHOS (L16) (Scheme 17) [79]. Several compounds containing a core structure of active molecules were compatible with this protocol. Generally, the reaction delivered the corresponding product with high diastereoselectivities (54e–54g). However, because of the reduced steric hindrance, the similar indole/benzo[d] [1,2,3]-triazole atropisomer 54d was provided as a racemic product.

In this section, a series of heterobiaryl frameworks have been provided with excellent yield and ee values catalyzed by (Rh, Ag, Ir, Pd, and Fe) with the assistance of chiral phosphoric acid ligand, phosphine ligand, and chiral rhodium (III) cyclopentadienyls. Significantly, chiral phosphoric acid can be activated by a Lewis acid to promote many challenging transformations. In addition, pentatomic heteroaromatics bearing pyrrole, 1,2,3-triazole could be accessed by the classical reaction. However, the synthesis of oxygen and sulfur-containing heterobiaryl catalyzed by transition metal catalysts was rarely developed.

3. Synthesis of Axially Chiral Heterobiaryl Scaffold Catalyzed by Organocatalysts through De Novo Synthesis

Asymmetric organocatalysis has been employed as a powerful tool to furnish chiral products in an enantioenriched form. To date, a variety of organocatalyst-catalyzed synthetic approaches have been reported for constructing axially chiral heterobiaryl molecules via new ring formation. These tactics could be divided into two major themes: (1) Intermolecular cyclization reactions catalyzed by organocatalysts; (2) Intramolecular cyclization reactions catalyzed by organocatalysts.

3.1. Intermolecular Cyclization Reaction catalyzed by Organocatalysts

3.1.1. Enantioselective Synthesis of Heteroaromatic Chiral Skeleton with a Five-Membered Ring

In 2022, Shi and co-workers established a chiral phosphoric acid catalyzed Paal–Knorr reaction of N-aminoindole 55 with 1,4-diketones 56 affording N-N axially chiral indoles and pyrroles (Scheme 18) [80]. The stereoselectivity of this transformation was generated by the bulky substituted group at the C2-position of N-aminoindoles or N-aminopyrroles, which restricted the free rotation of the N-N axis. The free amino group of 55 underwent an asymmetric annulation reaction with 1,4-diketone 56 catalyzed by chiral phosphoric acid to produce intermediate Int 16. Int 16 then cyclized intramolecularly affording Int 17. Dehydration of Int 17 gave the final axially chiral product 57. Furthermore, the methodology could also be extended to the synthesis of axially chiral 1,1′-bipyrrole 57a. The preliminary application of N-N axially chiral bispyrroles as organocatalysts was also demonstrated by a [4 + 2] cycloaddition between 58 and 59 to provide chiral product 60 in 92% ee. At the same time, Zhao’s group disclosed a chiral phosphoric acid catalyzed Paal–Knorr reaction of N-aminopyrroles 61 with 1,4-diketones 56 to access 1,1′-bipyrroles 62. Interestingly, it was found that Fe(OTf)₃ could induce enantiodivergence, as in the presence of Fe(OTf)_3, the reaction delivered enantiomeric (S)-62, while the same reaction without Fe(OTf)₃ produced its enantiomer (R)-62 [81].

Shortly after this, Mei’s group reported a procedure to construct C1-symmetric biaryl amino ethers (a privileged chiral backbone) via an asymmetric Attanasi reaction of azoalkenes 64 with 1,3-dicarbonyl compound 63 catalyzed by chiral phosphoric acid L19 (Scheme 19) [82]. In addition to the synthesis of a range of axially chiral biaryl amino ethers, various further conversions starting from 65e were also carried out. For example, 65f bearing biaryl C-C axis and N-N axis was produced by N-allylic alkylation of 65e. Deprotection of the Boc group in 65e afforded 65g with a free amino group in excellent yield. Thioureas derivatives 65h, 65i, 65k could be obtained with retention of the enantioselectivities from 65g. In addition, the hydrogenation of 65g could also provide the parent NPNOL (1-(1-aminopyrrol-2-yl) naphthalen-2-ol) scaffold 65j in excellent yield and enantioselectivity.

3.1.2. Enantioselective Synthesis of Heteroaromatic Chiral Skeleton with Fused Ring

Since quinoline derivatives exist widely in pharmacological molecules and natural products, many synthetic strategies have been developed for their construction. Recently, Jiang’s and Cheng’s group uncovered successively effective protocols to produce atropisomeric quinoline scaffold 68, 70, and 72 through a Friedländer reaction between 2-aminoaryl ketones 66 and ketone derivatives (ethyl acetoacetate 67, acetylacetone 69 and cyclohexanone 71) catalyzed by chiral phosphoric acids L20 and L21 in good yields with high enantioselectivities (Scheme 20, Scheme 21 and Scheme 22) [83,84,85]. Notably, when quinoline-containing heteroatropisomers 68 and 72 were treated with m-CPBA, the quinoline N-oxide could be generated with retained optical integrity [83,85]. In addition, the organocatalyzed aza-Michael/aldol cascade reaction between 2-aminoaryl ketones 73 and ynals 74 to access axially chiral quinoline-3-carbaldehydes 75 was also reported in 2021. Quinoline-carbaldehydes 75 were obtained in high yield with the assistance of diluted HCl(aq) which could promote aromatization in the last step (Scheme 23) [86,87]. Similarly, when 2-substituted phenols in 3-(naphthalene-1-yl) propionaldehyde were protected with a large protecting group such as 2,4,6-Me₃-Bn, the axially chiral 2-arylquinolines 78 could be accessed by chiral amine (L23)-catalyzed heteroannulation between 77 and 2-aminobenzaldehyde 76 (Scheme 24) [88].

In 2020, Tan and co-workers uncovered a highly efficient approach to providing the chair IAN (Isoquinoline and 2-Amino Naphthalene) analogs [89]. The reaction proceeds through organocatalytic asymmetric heteroannulation of ortho-alkynyl-naphthylamines 79, to generate vinylidene orthoquinone methide (VQM) intermediates Int 19, which was then attacked by amine 80 to form Int 20. The intramolecular aldol condensation of Int 20, followed by dehydration delivered biologically important atropisomeric C2-arylquinoline skeleton 81 (Scheme 25) [90]. The benzyl (Bn) protecting group in 81e was successfully removed by catalytic hydrogenation of 81f, which could further react with isothiocyanate to produce the fascinating atropisomeric thiourea 81g.

Later, Wang and co-workers presented the amine L25-catalyzed higher-order [8 + 2] cycloaddition of pyridinium ylides 83 with 82 via Michael addition and intramolecular cyclization, furnishing an array of 3-arylindolizines 84 with broad functional group compatibilities (Scheme 26) [91].

Simultaneously, Du’s group successfully prepared axially chiral 4-aryl α-carbolines 87 through N-heterocyclic carbene (L26) catalyzed formal [3 + 3] annulation of 2-sulfonamidoindolines 86 with 4-nitrophenyl 3-arylpropiolates 85 (Scheme 27) [92]. The late-stage functionalization of the product was also demonstrated by the coupling reactions between 87e and 2-(tributylstannyl) pyridine and piperidine under mild conditions.

Recently, the asymmetric cycloaddition of 3-alkynylindoles 88 with azonaphthalenes 89 catalyzed by 9-phenanthryl-substituted chiral phosphoric acid L20 for the atroposelective preparation of new indole-based biaryl skeletons was developed by Zhou and co-workers (Scheme 28) [93]. A series of substituted indoles and naphthalenes could be used in the reaction for furnishing axially chiral arylindole derivatives 90 with excellent stereoselectivities. According to DFT calculations and control experiments, it was proposed that the new indole-based biaryl skeletons could be delivered via the dearomatization of an indole-triggered intramolecular aza-Michael addition cascade process. Moreover, the product 90e could be converted into 90f after a four-step transformation. Interestingly, 90f could be engaged as a ligand to catalyze asymmetric allylation reaction between 91 and 92 to generate 93 with 99% yield and 39% ee.

In addition to employing aryl alkynes in the construction of axially chiral biaryls, Zhou’s group also creatively used aryl ethylenes as the starting materials for the same goal. In this case, the asymmetric addition of phenol-derived enecarbamates 94 and azonaphthalenes 95 produced Int 21, which, upon intramolecular cyclization and elimination of a carbamate, generated Int 23. Lastly, β-H elimination of Int 23 produced the axially chiral product 96 (Scheme 29) [94]. Further studies indicated that the catalyst L24 plays a decisive role in controlling the enantioselectivity and the reactivity. Axially chiral product 96f could be smoothly converted into 96g in the presence of phosphorus oxychloride and DMF.

In the same year, an N-heterocyclic carbene (L27) catalyzed [4 + 2] annulation of enals 97 with 2-benzylbenzothiophene 98 was developed for enantioselective de novo construction of ortho-substituted biaryl 99 (Scheme 30) [95]. A novel axially chiral benzothiophene-fused biaryl 99 could be obtained through central-to-axial chirality conversion via a decarbonylation-aromatization cascade process. Moreover, biaryl products 99f, 99h, and 99k could be converted into synthetic useful biaryls 99g, 99j, and 99l through a simple transformation in one or two steps.

Furthermore, a chiral spirocyclic phosphoric acid (L28)-catalyzed three-component cascade reaction of 2,3-diketoesters (101), aromatic amines (102), and 1,3-cyclohexanediones (103) has also been applied to construct the axially chiral N-arylindoles 104 (Scheme 31) [96]. This process went through the initial aldol condensation between enamine intermediate Int 25 with Int 24 mediated by L28, which was followed by dehydrative cyclization, 1,4-elimination, and tautomerization to generate the desired product 104. In addition, product 104e could be used as a novel ligand in a Pd-catalyzed asymmetric Tsuji–Trost allylation reaction. In a related report, Fu’s group demonstrated that axially chiral N-aryl benzimidazoles scaffolds could be produced via the reaction of 1,3-dicarbonyl compounds 109 with 1,2-diamines 108 via carbon-carbon bond cleavage catalyzed by CPA (chiral phosphoric acid) L9 (Scheme 32) [97]. The enantioselectivity of 110 could be improved by using molecular sieve as the additive. In addition, 1,2,3,4-tetrahydroquinolin-8-yl, isoquinoline-5-yl, and quinoline-5-yl benzimidazole derivatives could be achieved under this condition with high yield (up to 86%) and excellent enantioselectivity (up to 98% ee). Further studies indicated that enamine Int 28 was the key intermediate in this transformation. In addition, the reduction of ester 110e with LiAlH₄ could deliver alcohol 110g, which, upon treatment with SOCl₂, followed by NaH triggered intramolecular cyclization, producing cyclic product 110h.

3.2. Intramolecular Cyclization Reaction Catalyzed by Organo-Catalysis

3.2.1. Enantioselective Synthesis of Heteroaromatic Chiral Skeleton with a Five-Membered Ring

Diverse atropisomeric heterobiaryl molecules including axially chiral N,N- and N,S- 1,2-azole scaffolds were synthesized utilizing modified vinylidene ortho-quinone methide precursors 111 and 113 via a ring formation method catalyzed by cinchona alkaloids-derived squalamine L29 and L30 (Scheme 33) [98]. This work, developed by Yan’s group, simultaneously controlled the atroposelective installation of a stereogenic axis and the formation of a heterocyclic ring. The corresponding axially chiral naphthyl-isothiazole S-oxides 112 were synthesized by this methodology via a kinetic resolution process with high S factors in the presence of N-bromophthalimide (NBP). Meanwhile, when hydrazone 113 instead of 111 was employed as the starting material, in the presence of a slightly different catalyst (L30), naphthyl-pyrazoles 114 could be furnished in the absence of NBP.

3.2.2. Enantioselective Synthesis of Heteroaromatic Chiral Skeleton with a Fused Ring

In recent years, vinylidene ortho-quinone methides precursors were engaged as the powerful building blocks to construct different kinds of atropisomeric heterocycles. In 2018, Irie’s group described an unprecedented approach to access novel benzocarbazole derivatives 116 through enantioselective hydroarylation of alkynes 115 under transition-metal-free conditions (Scheme 34) [99]. It was found that chiral vinylidene o-quinone methide (VQM) intermediate Int 29 could be generated by a proton shift of 115 catalyzed by cinchonine L31 or cinchonidine L32.

In the same year, 2-ethynylphenol derivatives 117 were employed as the substrates to furnish furan atropisomers 118 with various functional groups catalyzed by quinine-derived thiourea L33, through an atroposelective intramolecular [4 + 2] cycloaddition via ortho-quinone methide intermediates (Scheme 35) [100]. Control experiments indicated that the hydroxyl group played a key role in increasing yield and controlling the enantioselectivity in this transformation, as lacking either the right-hand phenolic hydroxyl group or both of the two free OH groups led to no reaction taking place. Further functional group transformations were realized by the reactions of 118f with NaBH₄ or Grignard reagent to afford 118g and 118h.

In 2019, Yan and co-workers developed a chiral Brønsted base quinine thiourea L34, catalyzed cycloaddition of ortho-alkynylanilines 119 for the synthesis of naphthyl-C2-indoles 120 (Scheme 36) [101]. Interestingly, when the cinchonine-derived thiourea catalyst L35 which had an identical stereoconfiguration with L34 was used as the catalyst, the opposite enantioselectivity could be achieved with 99% ee. It is worth noting that aniline bearing different protecting groups has a great influence on the enantioselectivity, even though the yields of the transformation were not affected. Furthermore, by this methodology, the indole derivatives such as 120a with CHO and 120b with chiral phosphine could be obtained with excellent ee values. In addition, 120b could be used as an organocatalyst to catalyze asymmetric aza-Baylis–Hillman reaction and [4 + 2] cyclization reaction affording the corresponding products 123 and 126 in good yield with high enantioselectivity.

Very recently, the same group disclosed a methodology for the construction of atropisomeric heterobiaryl structures including benzo[c][1,2]oxasilines 130 and isocoumarins 131 from simple starting materials 127 via asymmetric intramolecular annulation mediated by catalyst L36 and L37 (Scheme 37) [102]. Significantly, four isomers {(1R, 1S)-132d; (1R, 1R)-132d; (1S, 1S)-132d; (1S, 1R)-132d} of the annulation products from 127a could be achieved by using L38 as the catalyst through control of the reaction time and temperature. Control experiments showed that when the hydroxyl group of 127 was protected, axially chiral heterocyclic architecture could not be produced because the formation of the VQM intermediate 128 was inhibited.

Recently, the first example of 5-endo-dig annulation of o-anilino ynamides 134 was developed by Ye and co-workers to generate axially chiral N-arylindole framework 135 via Int 30 catalyzed by chiral phosphoric acid (R)-L39 (Scheme 38) [103]. Notably, when (S)-L39 was employed, the ent-135a could be obtained with an excellent ee value. The obtained products could be transformed into a range of other analogs in one to two steps. Furthermore, the corresponding thiourea 135g and phosphine 135h furnished by a two-step transformation, could serve as an organocatalyst or ligand for other applications, such as asymmetric addition reaction between 136 and N-Boc imine 137, and Pd-catalyzed allylic alkylation of 139 with 106, to produce 138 and 140 respectively.

Miller’s group disclosed an atroposelective cyclodehydration process of 1,1,1-trifluoro-3-(2-(phenylamino) phenyl) propane-2-one 141 with the assistance of C2-symmetric type catalyst L40 or peptide-based catalyst L41 (Scheme 39) [104]. The products with o,o′-disubstituted or 3H-imidazo [4,5-c]pyridines were obtained in moderate to excellent enantioselectivity. DFT calculations showed that the global conformation of the peptide L41 dominated the enantioselectivity of this transformation.

The above-mentioned studies clearly demonstrated that chiral phosphoric acid, chiral amine, chiral cinchona alkaloids, and N-heterocyclic carbene are highly efficient catalysts to promote the formation of heterobiaryl skeletons. Arylquinoline and heterocycles bearing O, S, Si, B, and N could be furnished by using 2-aminoaryl ketone and vinylidene orthoquinone methide precursor as the reaction substrate. Moreover, axially chiral helical compounds and heterobiaryls could be obtained with excellent yield and ee values.

4. Conclusions and Perspective

In recent years, the atroposelective synthesis of biaryls has undergone significant progress with the rapid development of asymmetric reactions, which in turn realized a range of new methodologies for synthesizing various heterobiaryl scaffolds with C-N, C-C, and N-N chiral axes mediated by transition-metal and (or) organic catalysts. De novo synthesis of these motifs has thus become a representative and powerful strategy to provide axially chiral heterobiaryl skeletons containing indoles, pyrroles, triazoles, etc. Translation of de novo synthesis mediated by transition-metal into atroposelective variants has been established forming the indole-based framework and heterobiaryl atropisomers containing the C-N chiral axis. Meanwhile, the breakthrough in the use of organocatalysts in the de novo synthesis strategy enabled the direct forging of stereogenic aryl-(hetero)aryl bonds furnishing axially chiral helical compounds and atropisomeric quinoline scaffold through stereocontrolled annulation. Furthermore, the de novo synthesis strategy offers a new idea for the synthesis of heterobiaryls bearing an N-N chiral axis. The highly convergent and superior atom economy, in addition to a wide range of different reaction patterns, further broaden structural diversity in the products. A series of novel optically pure molecules were obtained based on these protocols, which offer opportunities for further asymmetric transformations and the discovery of new drug molecules. Nevertheless, there remain many challenges in this field. For example, compared to heterobiaryl molecules with C-N and C-C chiral axes, axially chiral compounds with an N-N chiral axis are much less developed because of the lower rotating energy barrier, and thus, are rarely reported. Also, presently, most reactions used to synthesize axially chiral biaryls skeletons are carried out at larger catalyst loadings (2 mol% to 20 mol%) with relatively complex starting materials, which hinders their application in industry and drug discovery. Therefore, new annulation reactions with readily accessible substrates under small catalyst loading remain highly desirable. Furthermore, the development of modern organic chemistry needs greener and more sustainable processes such as photocatalytic, electrocatalytic, and biocatalytic synthesis; however, these strategies are barely applied in the construction of axially chiral heterobiaryl skeletons. In addition, more attention should be paid to the application of heterobiaryl skeletons in asymmetric synthesis and drug development to further facilitate the discovery of new, greener, and highly efficient protocols for this topic.

Author Contributions

Conceptualization, X.M. and H.S.; Original draft was prepared by X.Z.; Review and editing was done by X.M., H.S. and Y.-Z.L. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures and Schemes

Figure 1. Representative heterobiaryl scaffolds in natural products, drug molecules, catalysts, and chiral ligands.

Figure 2. Representative synthesis method toward the heterobiaryl scaffold. Ar = aromatic ring or heteroaromatic ring; LG = leaving group.

Scheme 1. The synthesis of arylpyrroles by a catalytic asymmetric Paal–Knorr reaction.

Scheme 2. The synthesis of enantioenriched axially chiral 3-arylpyrroles.

Scheme 3. Access to 3-pyrrole-containing axially chiral skeletons catalyzed by Ag2O and L3.

Scheme 4. Asymmetric azide–alkyne cycloaddition with Ir(I)/squaramide cooperative catalysis.

Scheme 5. Rh-catalyzed azide-internal-alkyne cycloaddition.

Scheme 6. Rhodium-catalyzed atroposelective [2 + 2 + 2] cycloaddition.

Scheme 7. Atroposelective construction of indoles via C-H bond activation.

Scheme 8. Construction of axially chiral indoles by cycloaddition–isomerization.

Scheme 9. [4 + 2] Annulation of sulfoxonium ylides and ynamides.

Scheme 10. Atropisomeric indoles with an N-C chiral axis.

Scheme 11. Palladium-catalyzed enantioselective Cacchi reaction.

Scheme 12. Rh(III)-catalyzed asymmetric synthesis of biindolyls.

Scheme 13. Construction of atropisomeric 3-arylindoles.

Scheme 14. Asymmetric synthesis of naphthyl-C3-indoles.

Scheme 15. Pd-catalyzed enantioselective tandem C-C bond activation/Cacchi reaction.

Scheme 16. Dimerization of (ortho-alkynyl phenyl) (methoxymethyl) sulfides.

Scheme 17. Enantioselective synthesis of N-N bisindole atropisomers.

Scheme 18. Synthesis of N-N axially chiral indoles by de novo ring formation.

Scheme 19. Synthesis of axially chiral C2-arylpyrrole-derived amino ethers.

Scheme 20. Organocatalytic atroposelective Friedländer quinoline heteroannulation.

Scheme 21. Asymmetric synthesis of atropisomeric quinolines.

Scheme 22. Diastereoselective synthesis of 9-aryltetrahydroacridines.

Scheme 23. Atroposelective construction of 4-naphthylquinoline-3-carbaldehydes.

Scheme 24. The synthesis of axially chiral 2-arylquinolines.

Scheme 25. Atroposelective construction of IAN analogs.

Scheme 26. Organocatalytic higher-order [8 + 2] cycloaddition.

Scheme 27. Synthesis of axially chiral 4-aryl α-carbolines.

Scheme 28. Organocatalytic cycloaddition of alkynylindoles.

Scheme 29. Atroposelective construction of aryl-C3-benzoindoles.

Scheme 30. N-Heterocyclic carbene catalyzed [4 + 2] annulation.

Scheme 31. Three-component cascade reaction of aromatic amines.

Scheme 32. Organocatalytic atroposelective construction of N-aryl benzimidazoles.

Scheme 33. Atroposelective construction of axially chiral N,N- and N,S-1,2-azoles.

Scheme 34. Asymmetric synthesis of axially chiral benzocarbazole derivatives.

Scheme 35. Intramolecular [4 + 2] cycloaddition.

Scheme 36. The synthesis of axially chiral naphthyl-C2-indoles.

Scheme 37. Diversity-oriented enantioselective construction of atropisomeric heterobiaryls.

Scheme 38. Atroposelective cyclization of ynamides.

Scheme 39. The synthesis of axially chiral benzimidazole scaffold.

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