Introduction

Stereoselective catalytic formation of chiral compounds is one of the critical tasks of modern organic synthesis . The catalytic formation of compounds with a center of chirality has been the focus of countless works and can now be considered a matured area. On the other hand, the generation of compounds comprising a stereogenic plane or axis is much less developed. Axially chiral compounds are well known as chiral ligands in asymmetric catalysis, with notable examples of binaphthyl-based derivatives such as BINAP, SEGPHOS, or binaphthyl-based phosphoric acid derivatives, which are among the privileged catalyst frameworks . Axially chiral biaryls have also been found to be useful in materials . Although much less widely occurring than centrochiral compounds, there are also naturally occurring axially chiral compounds. Axially chiral compounds are becoming increasingly relevant also in drug discovery and medicine . However, a lack of reliable synthetic methods for their preparation hindered the broader application of axially chiral compounds. In recent decades, there has been increased interest in the catalytic syntheses of axially chiral compounds by catalytic , especially organocatalyzed, methods . Asymmetric organocatalysis offers efficient and environmentally benign access to numerous chiral compounds . Therefore, an increasing number of researchers are now investigating the organocatalytic formation of compounds with axial stereogenic axes across various structural motifs . Remarkably, these compounds are not limited to the C(sp2)–C(sp2) axis, but new developments in the formation of C–N, C–B, or even N–N stereogenic axes have been achieved. To help the research community distill and abstract the relevant new knowledge, this review has been prepared, which aims to provide an update on the last five years of this burgeoning area with some relevant links to key earlier works. The material in this article is divided according to the major activation mode of the organocatalyst, from covalent activation via enamine and iminium activation to NHC-catalyzed reactions. The major part is devoted to chiral Brønsted acid catalysis as it seems so far the most widely used activation principle for the generation of axially chiral compounds. Hydrogen-bond-donating catalysts and various other activation modes complete the discussion of recent advances in organocatalytic atroposelective syntheses.

Review Atroposelective reactions via enamine and iminium activation

Iminium activation was utilized in the synthesis of axially chiral styrenes. Tan and co-workers developed an atroposelective strategy toward axially chiral alkenylarenes 3 based on an organocatalytic Michael addition to alkynals 2 (Scheme 1) . The authors identified the Jørgensen–Hayashi-type catalyst C1 as the most efficient organocatalyst. In this way, a range of axially chiral styrenes were obtained in high yields and enantiomeric purities. The reaction was based on an iminium activation of propargylic aldehydes with catalyst Int-1. Another critical feature was the ability of the organocatalyst to promote the Z-selective isomerization of Int-2 to Int-3.

Scheme 1: Formation of axially chiral styrenes 3 via iminium activation.

In a related fashion, Wang and co-workers developed an atroposelective heterocycloaddition . The iminium-activated alkynals 4 reacted with aminoarylaldehydes 5 to form axially chiral 2-arylquinoline derivatives 6 (Scheme 2). Using the pyrrolidine derivative C2 as the most efficient organocatalyst, a range of quinoline derivatives were obtained in high yields and enantiomeric purities. The postulated mechanism consists of iminium activation, atroposelective aza-Michael addition, and intramolecular aldol reaction to form the cationic intermediate Int-6. Release of the catalyst C2, reduction with NaBH4, and dehydration with acetic acid leads to the desired product 6.

Scheme 2: Synthesis of axially chiral 2-arylquinolines 6.

Recently, an organocatalytic atroposelective intramolecular (4 + 2) annulation of enals with ynamides 8 to afford axially chiral 7-arylindolines 9 was reported . The reaction mechanism, rationalized by DFT calculations, is believed to occur through catalyst C3 activation of the substrate 8, dehydration, and deprotonation with tautomerization leading to the enamine intermediate Int-9. As the assumed rate-determining step the intramolecular nucleophilic addition takes place, followed by further cyclization and finally, release of the organocatalyst to form the axially chiral product 9. Various aryl-substituted indolines 9 were obtained in good yields and high enantiomeric purities (Scheme 3).

Scheme 3: Atroposelective intramolecular (4 + 2) annulation leading to aryl-substituted indolines.

Sparr and co-workers developed an atroposelective synthesis for tetra-ortho-substituted biaryls 11 by non-canonical polyketide cyclizations . This work was based on an earlier report of the team on the aldol cyclization of naphthyl-substituted unsaturated ketoaldehydes . The process was inspired by the biocatalytic synthesis of aromatic polyketides by polyketide synthase from poly β-carbonyl substrates. Pyrrolidine-based organocatalyst C4 was able to promote a twofold atroposelective arene-forming 6-enolendo aldol condensation (Scheme 4).

Scheme 4: Atroposelective formation of biaryl via twofold aldol condensation.

Sparr also realized a central-to-axial chirality conversion via catalyst-controlled oxidative aromatization . In this way, the axially chiral starting material 12 comprising an additional stereogenic center was converted into oligonaphthylenes 13 with two, three or even four stereogenic axes. Based on the organocatalyst used, the transformation produced either the (Ra,Sa)-isomer using pyrrolidine tetrazole catalyst C6 or the (Sa,Sa)-diastereoisomer using quaternary ammonium salt C5 (Scheme 5). Catalyst-controlled formation of twofold and higher-order stereogenicity in axially chiral arenes was discussed in this account article .

Scheme 5: Strategy towards diastereodivergent formation of axially chiral oligonaphthylenes.

Hayashi realized an organocatalytic domino sequence that afforded axially chiral biaryls . The transformation relied on an organocatalytic Michael/Henry cascade. The enamine-type Michael addition was catalyzed by the Hayashi–Jørgensen organocatalyst C7 (Scheme 6). Then, a series of one-pot reactions was carried out to provide the final biaryl products 17.

Scheme 6: Atroposelective formation of chiral biaryls based on a Michael/Henry domino reaction.

In a related strategy, Hayashi´s team realized an organocatalytic Michael/aldol cascade leading to chiral dihydronaphthalene derivatives 20a–e . Through a series of one-pot reactions, aromatization was achieved with concomitant central-to-axial chirality conversion and formation of axially chiral products 21a–e (Scheme 7). This critical aromatization was later studied in more detail, and the team was able to achieve enantiodivergent aromatization, which led to different atropoisomers based on the oxidation reagent used . The use of NBS and AgOTf led to the formation of the (Sa)-atropoisomers, whereas NIS afforded the (Ra)-atropoisomers.

Scheme 7: Organocatalytic Michael/aldol cascade followed by oxidative aromatization.

Non-biaryl atropoisomers are characterized by at least one non-aryl substituent on the stereogenic axis. Among them, compounds featuring a conformationally stable C(sp2)–C(sp3) stereogenic axis are of interest and have been recently investigated by Jørgensen and co-workers. The authors employed an enantioselective aminocatalytic cycloaddition between 5H-benzo[a]pyrrolizine-3-carbaldehydes 22 and naphthyl-substituted nitroalkenes, α,β-unsaturated ketoesters, or α,β-unsaturated aldehydes 23 . This transformation led to a series of axially chiral cycl[3.2.2]azines 24 in good yields and high enantiomeric purities (Scheme 8). The proposed mechanism comprises enamine activation, condensation with nitroolefin 23, ring closure, and catalyst elimination to provide the axially chiral product 24.

Scheme 8: Atroposelective formation of C(sp2)–C(sp3) axially chiral compounds.

NHC-catalyzed atroposelective reactions

Organocatalysis with N-heterocyclic carbenes (NHC) became one of the main types of covalent activation strategies, which grew into a very diverse area, allowing the synthesis of a wide array of interesting structures. Also, in atroposelective synthesis, NHC-catalysis recently led to an array of intriguing transformations.

Axially chiral styrenes 26 were assembled via the NHC-catalyzed reaction of propargylic aldehydes 25, sulfinic acids, and phenols . The crucial step of this transformation is the 1,4-addition of the sulfinic anion to the triple bond of acylazolium intermediate Int-16 followed by E-selective protonation of Int-17 (Scheme 9).

Scheme 9: NHC-catalyzed synthesis of axially chiral styrenes 26.

NHC-catalysis also proved useful in the atroposelective construction of triaryl derivatives with two stereogenic axes. Wei, Du, and co-workers developed a synthesis of 1,2-diaxially chiral triarylpyranones 29 via an NHC-catalyzed (3 + 3) annulation . A broad scope was demonstrated, comprising more than 50 diversely substituted compounds (Scheme 10).

Scheme 10: NHC-catalyzed synthesis of biaxial chiral pyranones.

Wong, Zhao, and co-workers disclosed the intriguing formation of bridged biaryls featuring eight-membered lactone rings 32 . This serendipitously discovered transformation relies on the catalysis with azolium precatalyst C12 (Scheme 11a). The reaction also allowed the synthesis of indol-derived bridged biaryls 35 (Scheme 11b). The proposed mechanism, supported by DFT calculations, comprises propargylic substitution towards Int-20 with NHC-derived enolate Int-19 followed by lactonization to Int-21 and Int-22 (Scheme 11c).

Scheme 11: Formation of bridged biaryls with eight-membered lactones.

Chi and co-workers showed that desymmetrization of urazoles can lead to axially chiral derivatives . The NHC-catalyzed (3 + 2) annulation between α,β-unsaturated aldehydes 36 and urazoles 37 generates atropoisomers 38 with a C–N stereogenic axis (Scheme 12).

Scheme 12: The NHC-catalyzed (3 + 2) annulation of urazoles 37 and ynals 36.

Wei, Du, and co-workers developed an atroposelective formal (3 + 3) annulation of 4-nitrophenyl 3-arylpropiolates 39 with 2-sulfonamidoindolines 40 . The NHC catalyst derived from triazolium salt C14 afforded the best results in terms of chemical yields as well as enantioselectivities (Scheme 13).

Scheme 13: NHC-catalyzed synthesis of axially chiral 4‑aryl α‑carbolines 41.

Axially chiral compounds with an N–N stereogenic axis can be synthesized by an NHC-catalyzed (3 + 3) annulation . The key feature of this transformation is the cycloaddition of α,β-unsaturated azolium intermediates with thioureas. In this way, a range of diversely substituted N–N axially chiral pyrroles and indoles 44 are obtained (Scheme 14).

Scheme 14: NHC-catalyzed construction of N–N-axially chiral pyrroles and indoles.

Zhu and co-workers developed a method for the atroposelective formation of arenes 48 by an NHC-catalyzed formal (4 + 2) cycloaddition . The triazolium pre-catalyst (R,S)-C11 was the most efficient in providing a range of biaryls in high yields and enantiomeric purities. The reaction was initiated by the formation of acylazolium intermediate Int-24 that underwent a 1,6-addition with the enol form of the carbonyl substrate to give Int-25. Cyclization was realized via an intramolecular aldol reaction to Int-26 (Scheme 15).

Scheme 15: NHC-catalyzed oxidative Michael–aldol cascade.

Ye and co-workers developed atroposelective formation of benzothiophene-fused biaryls via formal (4 + 2) annulation . The NHC catalyst C12 was the most efficient for realizing the de novo formation of a new aryl ring within the newly formed axially chiral biaryl 51 from enals 49 and 2-benzylbenzothiophene- or benzofuran-3-carbaldehydes 50 (Scheme 16).

Scheme 16: NHC-catalyzed (4 + 2) annulation for the synthesis of benzothiophene-fused biaryls.

Another demonstration of the atroposelective formation of compounds with a C–N stereogenic axis was developed by Jindal, Mukherjee, Biju, and co-workers . The authors developed an NHC-catalyzed desymmetrization of N-aryl maleimides 53, which afforded a range of axially chiral N-aryl succinimides 54. The tentative mechanism comprises the formation of the Breslow intermediate Int-31 from the catalyst carbene and aldehyde 52, which then adds to the electron-deficient double bond of maleimide giving rise to Int-32 (Scheme 17).

Scheme 17: NHC-catalyzed desymmetrization of N-aryl maleimides.

Chi and co-workers developed an atroposelective deracemization of biaryl hydroxy aldehydes 55a–k . NHC catalyst C18 afforded a range of axially chiral benzonitriles 56a–k in high yield and enantiomeric purities (Scheme 18). The reaction likely proceeds via the initial formation of racemic imines, which is followed by the formation of aza-Breslow-type intermediates with the chiral NHC-catalyst and subsequent deprotonation toward the nitrile product.

Scheme 18: NHC-catalyzed deracemization of biaryl hydroxy aldehydes 55a–k into axially chiral benzonitriles 56a–k.

Zhang, Wang, Ye, and co-workers utilized NHC-catalysis for the atroposelective synthesis of axially chiral diaryl ethers 59 and 61 . This transformation was realized via desymmetrization of prochiral 2-aryloxyisophthalaldehydes 57a,b with a range of aliphatic and aromatic alcohols 58a–g, as well as heteroaromatic amines 60 (Scheme 19). Chiral diaryl ethers of this type received increased attention lately. Biju, Gao, Zhang, and Zeng groups all reported high degrees of yields and enantioselectivities in similar desymmetrization reactions .

Scheme 19: NHC-catalyzed desymmetrization of 2-aryloxyisophthalaldehydes.

The dynamic kinetic resolution (DKR) of racemic 2-arylbenzaldehydes 62 with α-bromoenals 63 led to axially chiral products 64 . Triazolium salt C20 as an NHC pre-catalyst was the most efficient for achieving high yields and enantiomeric purities in this process (Scheme 20).

Scheme 20: NHC-catalyzed DKR of 2-arylbenzaldehydes 62.

Chiral Brønsted acid-catalyzed atroposelective reactions

Chiral Brønsted acids became prominent organocatalysts that also promote the syntheses of axially chiral compounds. The amination of aromatic biaryls 65a–g with dibenzylazodicarboxylate catalyzed by organocatalyst C21 was studied in 2019 (Scheme 21) . A broad range of aniline and phenol substrates was studied. The best results were accomplished with products containing a Boc-protected amino group on the aniline or 2-aminonaphthalene frame (66a–g), achieving very good yields and excellent enantioselectivities. Compound 66d was incorporated into a thiourea organocatalyst framework and successfully tested in kinetic resolution with 73% enantioselectivity.

Scheme 21: Atroposelective biaryl amination.

The chiral phosphoric acid (CPA) (R)-C22 was used to catalyze the formation of a C–N chiral axis in the axially chiral product 68 from biarylamines 67 and di-tert-butyl azodicarboxylate (Scheme 22) . An added benefit to these products is that they possess an intramolecular hydrogen bond acting as a stabilizing factor and products 68 were prepared in good to very good yields and excellent enantiomeric purities. Based on the authors’ design, previous findings from the literature, and experimental results, a reaction mechanism was proposed . Hydrogen bonding as well as π–π interaction with the catalyst (R)-C22 activates both substrates in the stable intermediate Int-35. This stabilized state ensures the concerted control of enantioselectivity during the nucleophilic addition, and the subsequent aromatization completes central-to-axial chirality conversion delivering products 68.

Scheme 22: CPA-catalyzed atroposelective amination of 2-anilinonaphthalenes.

Dynamic kinetic resolution of naphthylindoles 69 was performed by reaction with bulky electrophiles such as azodicarboxylates 70 or o-hydroxybenzyl alcohols 72 (Scheme 23) . These reactions were catalyzed by both BINOL-derived (TRIP) CPA (S)-C23 and SPINOL-derived CPA (S)-C24, providing axially chiral products 71 and 73, respectively. Control experiments showed the importance of the N–H group on the indole ring and the presence of both carboxylate groups in the azodicarboxylate as crucial to forming hydrogen bonds with the organocatalyst. Benzylation of this nitrogen or substitution of just one of the carboxylate groups led to no product being observed. A series of naphthylindoles 71 was tested for potential biological activity and showed promising results in one case, providing high cytotoxicity toward the MCF-7 cancer cell line. The stable axial chirality of the products 71 and 73 was confirmed by calculations of the rotational barriers ranging from 30.2 to 46.3 kcal/mol.

Scheme 23: Atroposelective DKR of naphthylindoles.

Kinetic resolution by amino group protection of biaryls (R,S)-74a–r with azodicarboxylate catalyzed by CPA (R)-C23 provided axially chiral unprotected biaryls (S)-74a–r and axially chiral protected biaryls (R)-75a–r (Scheme 24) . Consistently high enantioselectivities and yields were reported with various binaphthyl and biphenyl substrates. Control experiments revealed the importance of hydrogen on the amino or hydroxy groups, supposedly through the bonding with the catalyst. Substitution of these groups or their hydrogens led to either halted reaction or significantly reduced enantiopurity of the products.

Scheme 24: CPA-catalyzed kinetic resolution of binaphthylamines.

Expanding the scope of available azodicarboxylates 77 and aromatic amines 76 in the C–H amination reaction with CPA C25, the authors were able to prepare axially chiral para-amination products 78 (Scheme 25) . Such amination products 78 were prepared with high levels of yields and showed remarkable enantiomeric purities. Interestingly, when a phenyl substituent was present on the amino group of the 1,3-benzenediamine, lower yields were reported, and substituting the amino group in position 3 for an N-methylamino or N,N-dimethylamino group led to a reduction in the enantioselectivity.

Scheme 25: Atroposelective amination of aromatic amines with diazodicarboxylates.

Shao et al. developed the first organocatalyzed atroposelective Friedländer heteroannulation . The SPINOL-derived chiral phosphoric acid C26 catalyzed the formation of axially chiral products 81 from diarylketones 79a–f and ketoesters 80a–c (Scheme 26). The substrate scope contained a broad range of substituents, including electron-donor groups and whole benzene rings. The authors were able to separate the enamine intermediate formed from diarylketone and ketoester.

Scheme 26: Atroposelective Friedländer heteroannulation.

Later, the BINOL-derived (TRIP) CPA (R)-C23 was used in a similar Friedländer reaction . Acetylacetone was utilized with diarylketones 82 containing arylethyl chains to form axially chiral products 83 (Scheme 27). The reaction mechanism proposed by the authors was analogous to that of the aforementioned atroposelective Friedländer reaction. Outstanding yields and enantioselectivities were accomplished during the substrate scope screening as well as in a model gram-scale reaction (83%, 91% ee).

Scheme 27: CPA-catalyzed formation of axially chiral 4-arylquinolines.

Annulation of biaryl ketones 84 with cyclohexanones 85 mediated by the second-generation chiral phosphoric acid C26 led to the formation of tetrahydroacridines 86 (Scheme 28) . This Friedländer reaction provided products 86 in moderate to good yields with consistently high enantiomeric purities and high diastereomeric ratios in a couple of cases. On a 1 mmol scale with reduced catalyst loading the reaction proceeded in a similar fashion with good yield and enantioselectivity (70%, 89% ee).

Scheme 28: CPA-catalyzed Friedländer reaction of arylketones with cyclohexanones.

The Povarov reaction of imines 87a–h and alkenylindoles 88a–i catalyzed by CPA (R)-C23 was utilized to give asymmetric products 89 and their subsequent oxidation with DDQ provided axially chiral quinolines 90 (Scheme 29) . Good retention of the stereoinformation acquired in the first transformation, moderate to excellent yields and consistently high degrees of enantiomeric purity were achieved. The reaction could also be carried out in a one-pot fashion with comparable results and without significant variation from the two-step procedure.

Scheme 29: CPA-catalyzed atroposelective Povarov reaction.

Utilization of the Povarov reaction and subsequent oxidation by DDQ was also done by Wang et al. in 2020 . In situ-formed imines from anilines 91 and benzaldehydes 92 were reacted with alkenyl-2-naphthols 93 in the presence of CPA (R)-C24 to form asymmetric products 94 and eventually axially chiral tetrahydroquinolines 95 through oxidation (Scheme 30). This approach led to the products 95 in high yields and enantiomeric purities. The tosyl group in the product was transformed through a series of reactions to a diphenylphosphine group and used as a ligand for Pd-catalyzed reactions.

Scheme 30: Atroposelective CPA-catalyzed Povarov reaction.

De novo ring formation was utilized in the synthesis of N–N axially chiral N-pyrrolylindoles 98 and N-pyrrolylpyrroles 100 with the help of CPA C27 (Scheme 31) . Starting from either indoles 96 or pyrroles 99 and 1,4 diketones 97, respectively, the authors were able to achieve very good to near-perfect yields with consistently high enantioselectivities. Configurational stabilities of the products 98 and 100 were explored in toluene at 110 °C. Rotational barriers were calculated to be 47.7 and 52.2 kcal/mol, respectively, which suggests a high degree of configurational stability. One-mmol-scale reactions provided the corresponding products in comparable yields and enantioselectivities (87–96%, 94–97% ee). Based on a previous report on the CPA-catalyzed Paal–Knorr reaction, a reaction pathway was proposed . The first step is a CPA C27-catalyzed condensation giving rise to the imine intermediate followed by isomerization to the enamine stabilized by CPA. An enantioselective intramolecular cyclization followed by dehydration then afford the aromatic ring and desired product 98.

Scheme 31: Paal–Knorr formation of axially chiral N-pyrrolylindoles and N-pyrrolylpyrroles.

Concurrently, Gao et al. utilized a similar Paal–Knorr reaction for the synthesis of axially chiral biheteroaryls 103 (Scheme 32) . In the majority of the experiments Fe(OTf)3 was utilized as Lewis acid. The below-mentioned examples are only those, that did not require an additional co-catalyst containing transition metals but are purely of organocatalytic nature. In these experiments, the chiral phosphoric acid C28 catalyzed the reaction of aminopyrroles 101 and 1,4-diketones 102. Under the optimized reaction conditions, the yields were good to excellent, and high levels of enantioselectivities were achieved. The products showed no thermal racemization at 150 °C, what was supported by a calculated high rotational barrier of 49.9 kcal/mol.

Scheme 32: Atroposelective Paal–Knorr reaction leading to N-pyrrolylpyrroles.

The usefulness of chiral phosphoric acids also shows in the atroposelective Pictet–Spengler reaction of N-arylindoles 104 with various aldehydes 105 (Scheme 33) . Axially chiral products 106 were prepared in very high yields and exquisite enantiomeric purities. The presence of a methyl group in the aniline ring's ortho position proved to have a negative effect on the enantioselectivity, presumably due to the unfavorable steric interaction with the organocatalyst C21. A considerable drop in yield and enantioselectivity was also observed in the reaction with dibenzylaniline. Interactions with and steric effects of the CPA C21 guiding the orientation of the substrates dictate the stereocontrol of the reaction.

Scheme 33: Atroposelective Pictet–Spengler reaction of N-arylindoles with aldehydes.

The utilization of CPA (R)-C23 in a dynamic kinetic resolution through a Pictet–Spengler reaction, enabled the preparation of axially chiral 8-aryltetrahydroisoquinolines 108 starting from aminobiaryl scaffolds 107 and paraformaldehyde (Scheme 34) . For most substrates, excellent enantioselectivities and moderate to excellent yields were reported. However, the reaction did not tolerate a variety of substitutions on the amide group, probably because of its involvement in hydrogen bonding with the organocatalyst (R)-C23.

Scheme 34: Atroposelective Pictet–Spengler reaction leading to tetrahydroisoquinolin-8-ylanilines.

Expanding on earlier methodologies of Chen et al. and Wang et al. utilizing indole derivatives instead of β-naphthols, new atroposelective reactions of quinones and iminoquinones were developed . The reaction of quinones with an ester group 109 and indoles with alkyl substituents 110 catalyzed by CPA C29 provided products 112 with regioselectivity on the pyrrole ring of indole (Scheme 35). On the contrary, adding a hydroxy group to the benzene ring of indoles 111 and reacting them with tosyl-protected iminoquinone 109 with the help of CPA C30 led to the shift in regioselectivity providing different axially chiral products 113. All products were obtained with high degree of enantiomeric purity as well as significantly high yields. The CPA organocatalyst activates quinones with an acceptor hydrogen bond while indole acts as hydrogen-bond donor. On the other hand, a hydroxy group of hydroxyindole becomes a hydrogen donor and the iminoquinone nitrogen represents an acceptor to the hydrogen from the CPA, resulting in the regioselectivity change.