Construction of Axially Chiral Compounds via Asymmetric

Article Cite This: Acc. Chem. Res. 2018, 51, 534−547

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Construction of Axially Chiral Compounds via Asymmetric Organocatalysis Yong-Bin Wang and Bin Tan* Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China CONSPECTUS: Axially chiral compounds have received much attention from chemists because of their widespread appearance in natural products, biologically active compounds, and useful chiral ligands in asymmetric catalysis. Because of the importance of this structural motif, the catalytic enantioselective construction of axially chiral scaffolds has been intensively investigated, and great progress has been accomplished. However, the majority of methodologies in this field focus on the use of metal catalysis, whereas approaches involving organocatalysis have started to emerge only recently. This Account describes certain advances in the organocatalytic asymmetric synthesis of axially chiral compounds involving the following strategies: kinetic resolution, desymmetrization, cyclization/addition, direct arylation, and so on. We began our investigation by developing a highly efficient strategy for the kinetic resolution of axially chiral BINAM derivatives involving a chiral Brønsted acid-catalyzed imine formation and transfer hydrogenation cascade process, thereby providing a convenient route to generate chiral BINAM derivatives in high yields with excellent enantioselectivities. The desymmetrization of 1-aryltriazodiones (ATADs) through an organocatalyzed tyrosine clicklike reaction wherein a nucleophile was added to the ATAD afforded an interesting type of axially chiral N-arylurazole in an excellent remote enantiocontrolled manner. We then focused on a direct construction strategy involving cyclization and the addition strategy given the inherent limitations of the kinetic resolution in terms of the chemical yield and the desymmetrization in terms of the substrate scope. By utilizing the catalytic enantioselective Paal−Knorr reaction, we disclosed a general and efficient cyclization method to access enantiomerically pure arylpyrroles. The direct heterocycle formation and the stepwise method, which was executed in a one-pot fashion containing enantioselective cyclization and subsequent aromatization, were successfully applied for the construction of diverse axially chiral arylquinazolinones catalyzed by chiral Brønsted acids. We discovered the asymmetric organocatalytic approach to construct axially chiral styrenes through the 1,4-addition of arylalkynals in good chemical yields and enantioselectivities. Such structural motifs are important precursors for further transformations into biologically active compounds and useful synthetic intermediates and may have potential applications in asymmetric syntheses as olefin ligands or organocatalysts. To further tackle this challenge, we accomplished the phosphoric acid-catalyzed enantioselective direct arylative reactions of 2-naphthol and 2-naphthamine with quinone derivatives to deliver efficient access to a class of axially chiral BINOL and NOBIN derivatives in good yields with excellent enantioselectivities under mild reaction conditions. Most importantly, we discovered that the azo group can effectively perform as a directing and activating group for organocatalytic formal aryl C−H functionalization via formal nucleophilic aromatic substitution of azobenzene derivatives. Thus, a wide range of axially chiral arylindoles were synthesized in good yields with excellent enantioselectivities. We anticipate that this strategy will foster the development of many other transformations and motivate a new enthusiasm for organocatalytic enantioselective aryl functionalization. Moreover, SPINOLs are fundamental synthetic precursors in the construction of other chiral organocatalysts and ligands. We have successfully developed a phosphoric acid-catalyzed enantioselective approach for SPINOLs. This approach is highly convergent and functional-group-tolerant for the efficient generation of SPINOLs with good results, thus delivering practical access to this privileged structure.

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INTRODUCTION Axial chirality, which refers to stereoisomerism resulting from the nonplanar arrangement of four groups in pairs about a chirality axis (IUPAC), including atropisomerism, chiral allenes, spiranes, spiroindanes, and so on,1 is ubiquitous in organocatalysts,2−4 chiral ligands,5−7 bioactive molecules,8−10 and natural products,11 as illustrated in Figure 1. Atropisomerism, which is enantiomerism caused by restricted bond rotation and was discovered by Christie and Kenner in 1922, is the most representative subclass of axial chirality.1 Neglect of the © 2018 American Chemical Society

importance of axial chirality changed drastically in 1980 when BINAP was developed as a predominant axially chiral ligand for enantioselective transition-metal-catalyzed reactions.5 To date, numerous efficient ligands bearing axially chiral backbones have been synthesized and widely applied in transition-metalmediated asymmetric catalysis, as evidenced by many reviews.5−7 The axially chiral unit was also deemed an important Received: November 30, 2017 Published: February 8, 2018 534

DOI: 10.1021/acs.accounts.7b00602 Acc. Chem. Res. 2018, 51, 534−547

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Accounts of Chemical Research

Figure 1. Selected examples of axially chiral organocatalysts, ligands, natural products, and bioactive molecules.

structural element of many natural products11 and bioactive molecules, enantiomers of which usually exhibit different pharmacological activities and metabolic processes in vivo and in vitro.8−10 In 2004, Akiyama and Terada first introduced

axially chiral BINOL-derived phosphoric acids into asymmetric catalysis, which brought a milestone in the area of axially chiral organocatalysts and asymmetric Brønsted acid catalysis.4 Current developments in chiral metal ligands and organo535


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Accounts of Chemical Research Scheme 1. Dynamic Kinetic Resolution of Atropisomers through Peptide-Catalyzed Bromination

Scheme 2. Kinetic Resolution of the BINAM Derivatives

Organocatalysis has been recognized as a versatile and powerful synthetic tool for the preparation of valuable chiral building blocks. A wide range of chiral organocatalysts, including Brønsted acids, N-heterocyclic carbenes (NHCs), amines, peptides, thiourea catalysts, phosphines, and phase-transfer catalysts, have permitted a large number of enantioselective transformations to proceed smoothly.2−4,17 However, the construction of structurally diverse axially chiral backbones via organocatalysis remains a challenge at the forefront of synthetic chemistry.18 This Account highlights our efforts to construct axially chiral compounds involving optically active atropisomers and spirobicyclic frameworks through asymmetric organocatalysis.

catalysts have witnessed wide utilization and growth of axial chirality. The increasing demand for enantioenriched axially chiral compounds in asymmetric catalysis and drug discovery has stimulated the development of efficient methods for these privileged scaffolds. Although the conventional chiral resolution of racemates and chiral-auxiliary-assisted reactions are generally used for the construction of axially chiral compounds in enantiomerically pure form, asymmetric catalysis meets the demands of high efficiency and economic value.11−14 Initial attempts focused on enzymatic and transition-metal-mediated reactions.12−15 The development of axially chiral ligands facilitated the discovery of enantioselective metal-catalyzed reactions that are capable of delivering new and more efficient axially chiral ligands,12,14,16 which can be considered to be an evolutionary process. Compared with relatively mature transition-metal-catalyzed reactions, flourishing asymmetric organocatalysis is a rising star.

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(DYNAMIC) KINETIC RESOLUTION STRATEGY The (dynamic) kinetic resolution of racemic starting materials has been one of the most powerful and reliable strategies for 536


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Accounts of Chemical Research Scheme 3. Process of Kinetic Resolution of BINAM Derivatives

Scheme 4. Desymmetrizaion/Kinetic Resolution of Biaryls

2,2′-Dihydroxy-1,1′-binaphthyl (BINOL),4,28 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN),29 and 1,1′-binaphthyl-2,2′diamine (BINAM) derivatives are essential axially chiral biaryls in asymmetric catalysis and chiral catalyst preparation. In general, organocatalytic kinetic resolution strategies are used for the construction of these predominant skeletons and exhibited major breakthroughs in this field.13 In 2013, Maruoka’s group reported the kinetic resolution of chiral NOBINs utilizing phase-transfer-catalyzed N-allylation with excellent results.30 Almost simultaneously, we finished the highly enantioselective kinetic resolution of BINAMs through a Brønsted acidcatalyzed imine formation and transfer hydrogenation cascade process (Scheme 2).31 Racemic N-sulfuryl-BINAM (rac-13) and aryl aldehydes were selected as the substrates for this approach, wherein Hantzsch esters 15 were used as the hydride source in the presence of chiral phosphoric acids (CPAs). The initial investigation indicated that the desired sequence of transformations catalyzed by 14 was effective, and the optimization process generated satisfactory results. Under the optimal conditions, a variety of rac-BINAM derivatives produced the corresponding products (aS)-16 with modest to excellent enantiomeric excesses (ee’s) and recovered substrates with excellent enantiomeric excess (ee) (S 7−340). This kinetic resolution exhibited excellent compatibility with different types of Nprotecting groups (sulfonyl, aroyl, 2-naphthylmethyl, Fmoc, and amido) and functional groups (Br, Cl, TMS) at the 6- and/ or 6′-positions of rac-13.

the synthesis of enantiopure compounds in past decades. A series of kinetic resolutions for chiral biaryls have been reported,12,14,15 as summarized in detail by Ma and Sibi.13 The present study introduces some organocatalytic examples using the kinetic resolution strategy given its connection to the proposed work. In 2010, Miller’s group reported the innovative and successful access to axially chiral biaryls (aR)-4 through tripeptide-catalyzed enantioselective bromination involving a dynamic kinetic resolution (Scheme 1).19 The barrier for atropisomer interconversion of rac-1 was low, thereby allowing the dynamic process of the kinetic resolution. Bromines were asymmetrically introduced at the ortho positions and blocked the rotation of the axis, leading to isolation of the enantiomers. In the proposed mechanism, the spatial configuration of intermediate 5, which was locked by the salt bridge and hydrogen bonds between 1 and the catalyst 2, determined the axial chirality of the products. This work brought a milestone in the organocatalytic enantioselective construction of axially chiral compounds.20 By extension of this strategy to axially chiral arylquinazolinones,21−23 benzamides,24,25 isoquinoline Noxides,26 and arylquinolines,27 high enantioselectivies were achieved under catalysis by peptides or cinchona-alkaloidderived bifunctional organocatalysts. In these examples, the hydrogen bonds between the substrates bearing the indispensable hydroxyl group and catalysts (5−8) bearing H-bond acceptors and donors on the chiral scaffolds were critical for chiral induction. 537


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Accounts of Chemical Research Scheme 5. Desymmetrization of 1-Aryltriazodiones with 2-Naphthols

Scheme 6. Desymmetrizaion of 1-Aryltriazodiones with Indoles

the yield and the enhancement of the enantioselectivity. By employing Akiyama’s strategy, Armstrong and Smith 36 improved the enantioselectivities of desymmetric nucleophilic aromatic substitution reactions, which delivered axially chiral biaryls with good results. In 2016, we reported the asymmetric synthesis of axially chiral N-arylurazoles via organocatalytic desymmetrization of 1aryltriazodiones (ATADs) proceeding without a kinetic resolution process (Scheme 5).37 Urazoles 25 obtained from the tyrosine clicklike reaction were recognized as a type of axially chiral skeleton containing an N−Ar chiral axis in the initial work. However, the strong background reaction and remote axial enantiocontrol were a formidable challenge for the enantioselective desymmetrization of ATADs. The tertiary amine−thiourea bifunctional organocatalyst 24, which could simultaneously activate the nucleophile and electrophile via hydrogen bonding, was finally found to be effective in the remote enantioselective control of the desymmetrization process. A variety of both 2-naphthol derivatives and 4substituted phenols were deemed to be efficient nucleophiles for this transformation, thereby affording (aS)-25 in good yields with excellent ees under the optimized conditions. The ortho group of the ATADs was not restricted only to the tertbutyl group. In addition, iodo, bromo, and phenyl groups at the ortho position also proved to be compatible with this reaction. The use of 2-substituted indoles, which are rarely used as nucleophiles in asymmetric organocatalysis with good enantiocontrol, generated only poor results in the presence of catalyst 24. Thus, we turned our focus to chiral phosphoric acid catalysts, as these can perform bifunctional actions to simultaneously activate indoles and ATADs (Scheme 6). As expected, the well-defined CPA 27 smoothly promoted the

Control experiments indicated that the transfer hydrogenation process catalyzed by 14 was the enantioselectivitydetermining process in the kinetic resolution (Scheme 3), which agrees with the fact that organocatalytic enantioselective reduction of imines through transfer hydrogenation emerged as a powerful synthetic tool for the construction of chiral amines.31 Akiyama and collaborators also introduced enantioselective transfer hydrogenation in the dynamic kinetic resolution of other biaryls.32 Additionally, Zhao’s group successfully accomplished the kinetic resolution of BINOLs and NOBINs through NHC-catalyzed atroposelective acylation.33 These developed methods featured a general strategy that employs prominent reactions for the efficient preparation of useful axially chiral compounds through kinetic resolution.

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DESYMMETRIZATION STRATEGY The enantioselective desymmetrization of meso- or prochiral precursors is a remarkably valuable transformation in organic synthesis that involves axially chiral skeleton construction13,14 because it breaks the symmetry of the molecule without incorporating new stereogenic centers.34 According to Akiyama, desymmetric bromination, which was catalyzed by CPA 18, afforded axially chiral multisubstituted biaryls (aS)-19 with good to excellent enantioselectivity (Scheme 4).35 In the monobromination process, the CPA controlled the enantioselectivity via a highly organized hydrogen-bonding network among an advantageously configurational substrate, a catalyst, and a brominating reagent (3). The kinetic resolution of rac-19 can also generate good results. In the desymmerization of achiral 17, when a slight excess of 3 (1.1−1.2 equiv) was added, a kinetic resolution process was observed in the further bromination of (aR)-19, which resulted in a slight decrease in 538


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Accounts of Chemical Research Scheme 7. Paal−Knorr Reaction for the Synthesis of Axially Chiral Arylpyrroles

Scheme 8. Mechanism of the Enantioselective Paal−Knorr Reaction

enantioselectivity (Scheme 7).38 To further improve the enantioselectivity, Lewis acids, which activate CPAs to facilitate many challenging transformations in accordance with Yamamoto’s combined-acid39 and Luo’s binary-acid catalysis principle,40 were introduced into this catalytic system. Screening of Lewis acids revealed that Fe(OTf)3 (10 mol %) was able to promote the CPA-catalyzed Paal−Knorr reaction very well and clearly improved the enantioselectivity. Under the optimized conditions, good results were obtained for all of the tested substrates regardless of the electronic properties and position of the substituents on the aromatic ring of 29 and 30. The rotation-blocking groups at the ortho positions of 30 were not restricted to only tert-butyl groups, as bromo, iodo, and phenyl groups also effectively controlled the enantioselectivity. The products shifted from (aR)-32 to their opposite enantiomers following a solvent change from CCl4/cyclohexane to CCl4/EtOH (Scheme 8). This phenomenon was worth investigating further. The key intermediates 33, which served as the tautomers and were isolated from the transformation, suggested that the desired arylpyrrole formation may go through enamines 33 followed by acid-catalyzed dehydrative cyclization. This work presented a general and efficient method to access enantiomerically pure arylpyrroles through the enantioselective Paal−Knorr reaction. In addition to the direct aromatic ring formation, a stepwise method involving cyclization and subsequent aromatization for axial chirality was also deemed efficient and applicable. According to Rodriguez and Bonne, the organocatalytic 1,4addition of carbon nucleophiles to 37 triggered an intramolecular O-alkylation resulting in trans-dihydrofurans, which

reaction to deliver (aR)-28 with excellent enantioselectivity. Under the optimized conditions, the reaction was extended to include various 2-substituted indoles with excellent results, thereby demonstrating that the bulkiness and electronic properties of the substituents on the indoles had only a minimal effect on the efficiency and enantioselectivity of this transformation. In summary, this work represented a convenient desymmetric approach to an interesting class of axially chiral urazole derivatives with excellent remote enantiocontrol.

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CYCLIZATION STRATEGY Axially chiral skeletons are already present in the substrates in the above-mentioned strategies, thereby affording the desired products in the preferred configuration. Cyclization reactions are generally used for the construction of axially chiral compounds because most atropisomers contain at least one aromatic ring stick on the chiral axis.1,12,14 Axially chiral arylpyrroles as essential motifs are widely found in natural products, bioactive entities, and ligands. The direct construction method is highly demanded, whereas the effective synthesis of enantiopure arylpyrroles has always relied on the conventional resolution. The Paal−Knorr reaction, which converts amines into pyrroles with 1,4-diketones through acid-mediated dehydrative annulation, is one of the most common approaches for the construction of pyrroles. However, the asymmetric catalytic Paal−Knorr reaction had been unknown until our present work. A well-defined catalyst 31 smoothly promoted the reaction of 29 and 2-(tert-butyl)aniline to produce axially chiral arylpyrroles (aR)-32 with moderate 539


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Accounts of Chemical Research Scheme 9. Enantioselective Construction of Furan Atropisomers through Stepwise Reactions

Scheme 10. Enantioselective Synthesis of Axially Chiral Arylquinazolinones through Cyclization with Aldehydes and Oxidants

delivered the final axially chiral furans through oxidative centralto-axial chirality conversion.41 Numerous 1,3-cyclohexanones 35 and 2-naphthols 36 as C,O-dinucleophiles proved to be compatible with the sequential transformation, by which enantiopure (aS)-39 and (aS)-40, respectively, were produced with great efficiencies (Scheme 9). Various functional groups at the ortho position of the nitrostyrene were well-tolerated in the reaction with 2-naphthol. Notably, the authors clearly proposed the highly efficient central-to-axial chirality transfer mechanism,

which demonstrated that the oxidants phenyliodine diacetate (PIDA, cp = 84−92%) and MnO2 (cp = 89−100%) proceeded with opposite chirality transfer manners in the oxidation process. Following the application of this strategy, Rodriguez and Bonne also successfully developed an enantioselective approach for axially chiral 4-arylpyridines.42 These excellent works shed light on the research of atropisomer construction through central-to-axial chirality transfer. 540


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Accounts of Chemical Research Scheme 11. Atroposelective Synthesis of Arylquinazolinones through Cyclization and C−C Bond Cleavage

Scheme 12. Computed Rotation Barriers and Half-Lives of Styrenes

Scheme 13. Atroposelective Construction of Styrene Atropisomers through Michael Reaction

Similar to arylpyrroles, axially chiral arylquinazolinones constitute a privileged structural scaffold found in a large number of natural products, bioactive compounds, and chiral ligands. Miller’s work involving dynamic kinetic resolution through peptide-catalyzed bromination yielded several axially chiral arylquinazolinones with good results.21−23 However, the organocatalytic direct construction approach to access enantiopure arylquinazolinones remained underexplored until our present work. N-Arylanthranilamides 41 were able to react with aldehydes catalyzed by chiral Brønsted acids to generate centrally chiral 2,3-dihydroquinazolinones 45, which could be converted to axially chiral N-arylquinazolinones 44 with central-to-axial chirality transfer upon dehydrogenation with oxidants.43 DDQ was identified as a suitable oxidant for this cascade reaction, which proceeds smoothly with 41 and aryl aldehydes to afford highly enantiopure arylquinazolinones

under the catalysis of CPA 43 (Scheme 10). Compared with Rodriguez and Bonne’s stepwise method, this transformation performed well regardless of when the oxidant was added, thereby allowing its use in multicomponent processes. Under the standard conditions, 41 and 42 with different functional groups were well-tolerated. The ortho group, which blocked the rotation of the axes, was not restricted only to the tert-butyl group, as I, Br, Ph, and POPh2 also exhibited efficiency. Several control experiments demonstrated that the introduction of chirality into the catalytic cyclization process and the oxide hydrogenation were responsible for the central-to-axial chirality transfer. Following the application of our developed methodology, the first enantioselective total synthesis of eupolyphagin was achieved in six steps in an overall yield of 32%. Interestingly, in the case of cyclohexanal, the 2-cyclohexyl ((aR)-44b) or 2-H ((aR)-44c) arylquinazolinone was obtained 541


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Accounts of Chemical Research Scheme 14. Enantioselective [3,3]-Rearrangement for BINAMs

Scheme 15. Enantioselective Synthesis of Axially Chiral Biaryldiols from Quinones and 2-Naphthols

when DDQ or PIDA, respectively, was added following the catalytic cyclization. However, acyclic aliphatic aldehydes afforded only poor results in this transformation. To tackle this problem, a new direct construction approach using the Brønsted acid-catalyzed carbon−carbon bond cleavage strategy was developed. The reaction of Narylanthranilamides with acetylacetone catalyzed by the Brønsted acid produced 2-methylarylquinazolinones. A deep investigation found that 4-methoxypentenone was more reactive than acetylacetone and that N-triflylphosphoramides 48 could well control the enantioselectivity of the axially chiral products (aS)-49 (Scheme 11). The subsequent transformations of (aS)-49a to (aS)-50 further enlarged the scope of axially chiral arylquinazolinones.

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enantioselective synthetic approach to axially chiral styrenes, which remains underexplored.44 We first focused on evaluating the addition reaction between nucleophilic 1,3-diones and 2-iodophenylpropiolaldehyde for the enantioselective construction of axially chiral styrenes. However, only a few organocatalytic enantioselective transformations involving alkynals have been exploited. After deep research, chiral secondary amine 55 was deemed a suitable catalyst for the transformation to yield axially chiral styrenes (aR)-56 with complete Z/E selectivity (>20:1) and moderate ee (Scheme 13).44 Under the optimized conditions, a series of 3-arylalkynals 54 bearing different substituents on the phenyl ring smoothly produced axially chiral styrenes with moderate to good results. In addition to 1,3-diones, 1,3-keto esters and malononitriles as nucleophiles also efficiently generated (aR)56 with good to excellent results. The subsequent transformations to several complex chiral compounds, including 57a and 57b, without a decrease in the enantioselectivities demonstrated the synthetic utility of the axially chiral styrenes. Inspired by this work, the discovery of other promising strategies for enantiopure styrenes is in high demand, considering the importance of axially chiral styrenes.

ADDITION STRATEGY

Modification of alkynyl groups is one of the most common methods for the synthesis of alkenes. Styrenes 52, which were obtained from 3-arylalkynals 51 through 1,4-addition, exhibited a relatively high computed rotational barrier, thereby indicating that the atropisomers of the substituted styrenes might be stable enough for isolation and application (Scheme 12). Simple styrenes are the predominant principal building blocks for chemical synthesis and catalysis. Thus, they are very attractive and highly desirable for the development of the

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DIRECT ARYLATION STRATEGY Direct construction of the chiral axis through metal-catalyzed cross-coupling and oxidation has been the most common 542


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Accounts of Chemical Research Scheme 16. Atroposelective Synthesis of Axially Chiral NOBIN Analogues with 2-Naphthylamines

Scheme 17. Enantioselective Synthesis of Axially Chiral 3-Arylindoles through Direct Arylation

approach for the asymmetric synthesis of atropisomers.12,14 In comparison, only a few organocatalytic examples have been reported. In 2013, the groups of Kü r ti 45 and List 46 independently reported the asymmetric synthesis of enantiopure (aS)-BINAM derivatives through the CPA-catalyzed [3,3]-rearrangement of N,N′-diarylhydrazines 58, which was a significant improvement of Sannicolò’s work47 (Scheme 14). The enantioselectivity determined by the C−C bond-forming step was notably affected by both the steric and electronic effects of the substituents on 58. These two prominent works paved the way for the practicable construction of biaryls through the direct formation of chiral axes promoted by organocatalysts. In addition to intramolecular rearrangement, intermolecular nucleophilic aromatic substitution is another direct arylation approach to atropisomers. The combination of readily available carbon-nucleophilic 2-naphthols and carbon-electrophilic quinones allowed the development of a direct enantioselective arylation strategy to construct non-C2-symmetric axially chiral biaryldiols. In our work, an ester group was incorporated into the quinone skeleton to address the challenges involving enantioselectivity control and product axial rotation restriction. CPAs were deemed suitable catalysts for this transformation.48 BINOL-derived CPA 64 was found to be the catalyst of choice to produce (aR)-65 with 93% ee under the optimal conditions (Scheme 15). In this catalytic system, different quinone esters and various substituents at different positions of the 2-naphthol were well-tolerated. Changing the ester group to a useful halogen group at the quinone moiety had almost no negative influence on the reaction efficiency and stereoselectivity. The obtained axially chiral biaryldiols were verified as excellent

ligands for the titanium-catalyzed enantioselective addition of diethylzinc to aldehydes, thereby indicating the potential utility of the products. In the proposed mechanism, 64 performed as a bifunctional organocatalyst to promote the enantioselective conjugate addition of the 2-naphthol to the quinone derivative to form centrally chiral intermediate 66 through multiplehydrogen-bonding activation. The subsequent aromatization of 66 to form (aR)-75 efficiently transferred the chirality from central to axial. Xu, Kürti, Sun, and co-workers found that Nsulfonyl-protected iminoquinones also smoothly reacted with phenols to afford BINOL analogues with good enantioselectivity.49 To construct enantiomerically enriched NOBIN analogues with this strategy, 2-naphthylamines were selected as nucleophiles instead of 2-naphthols. Readily available 2naphthylamines had scarcely been investigated prior to our work. Under the above-mentioned conditions, the reaction of 2-naphthylamines and quinone esters afforded unexpected Naryl-2-naphthylamines without the formation of NOBIN analogues.50 Interestingly, when N-sulfonyl iminoquinones 67 were used as the electrophiles in place of the quinone esters, the desired NOBIN analogues (aS)-69 were obtained by Carylation of 2-naphthylamines 68 catalyzed by 64 with good results considering the yield and ee (Scheme 16). Under the optimized conditions, numerous 2-naphthylamines smoothly yielded (aS)-69 in moderate to good yields with excellent enantioselectivities. The electronic properties of the substituents on the aromatic ring of the 2-naphthylamine exhibited significant effects on the chemical yield rather than on the enantioselectivity. Additionally, various substituents on 67 and the amino groups of 68 were well-tolerated in this catalytic 543


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Accounts of Chemical Research Scheme 18. Enantioselective Synthesis of Axially Chiral Arylindoles through Direct Arylation and Rearrangement

Scheme 19. Proposed Mechanism for Organocatalytic C-Arylation with Azobenzenes and Rearrangement

2-Methyl- and 2-isopropylindoles also smoothly reacted with azobenzenes catalyzed by 74 as the optimal catalyst, of which the loading was as low as 0.2 mol %. Unlike the abovementioned transformation, another type of axially chiral indole, (aS)-75 bearing aniline groups, was obtained in moderate to good yields with excellent ee’s (Scheme 18). The yields were not obviously affected by the electronic properties and position of the substituents on the azobenzene but were affected by the electronic properties of the substituents on the indole. Following the introduction of 2,3-disubstituted indoles, the products shifted from axially chiral (aS)-75 to centrally chiral polycyclic pyrroloindole derivatives 80 bearing two contiguous quaternary chiral centers in excellent yields and ee’s (Scheme 19). Among these three types of transformations, the initial stereoselective nucleophilic addition promoted by a Brønsted acid and primary rearomatization was the common step that thermodynamically produced more stable arylhydrazine intermediates 78 (Scheme 19). Several control experiments suggested that axially chiral (aS)-75 and polycyclic pyrroloindoles 80 came from the same intermediate, 79, which was obtained from intermediate 78 through the intramolecular cyclization process. In the case of 2-substituted indoles bearing a bulky group, the cyclization was blocked by the bulky substituent, thereby resulting in the further rearomatization of intermediate 78 to preferentially produce (aR)-73 with centralto-axial chirality transfer. This work represented an unprecedented arylation approach involving organocatalytic formal nucleophilic aromatic substitution and aryl C−H bond cleavage. In addition to affording structurally diverse axially

system. This work presented a rare example of 2-naphthylamines acting as carbon nucleophiles in the organocatalytic enantioselective transformation, which gave effective access to enantiopure NOBIN analogues. In the above-mentioned reactions, quinones and iminoquinones acted as arylation reagents through conjugate addition. Electrophilic and nucleophilic aromatic substitutions as textbook organic reactions were alternative, more straightforward arylation methods. In contrast, nucleophilic aromatic substitution with cleavage of the electrophilic aryl C−H bond was merely developed in recent years through transition-metalcatalyzed aryl C−H activation51 or a radical process;52 the organocatalytic one via a nonradical process is an enormous challenge in organic synthesis. As the present study sought suitable activating and directing groups, the azo group was identified as a useful moiety that could effectively activate an aromatic ring in the presence of a Brønsted acid for formal nucleophilic aromatic substitution resulting in the cleavage of the aryl C−H bond and the direct arylation of the nucleophile.53 This discovery presented a completely new and intriguing arylation approach. In the transformation with indoles, the products and optimal catalysts were substratedependent. When 70 and 2-tert-butylindoles 71a were employed, an axially chiral direct arylation product, 3-arylindole (aR)-73, was obtained with an excellent result catalyzed by 72. In addition, the substituents on the aryl rings of 70 and 71a exhibited no significant effect on the yield and enantioselectivity (Scheme 17). In addition to a tert-butyl group at the 2-position of the indole, 1-methylcyclopropyl, tert-pentyl, and phenyl groups all proved to be compatible with this transformation. 544


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Accounts of Chemical Research Scheme 20. Cyclization of Ketones and Ketals To Form SPINOLs

Scheme 21. Cyclization of Ketals for SPINOLs Bearing o-Aryl Groups

deficient substituents at the para position of the phenol performed smoothly to afford C2-symmetric and non-C2symmetric SPINOLs with high enantioselectivies in good to excellent isolated yields (Scheme 20). However, the reaction rate and enantiocontrol were obviously retarded following the introduction of an aryl group at the ortho position of the phenol (Scheme 21). Further screening of the catalysts indicated that (aR)-74 instead of (aS)-82 was the optimal catalyst, which smoothly promoted the reaction with over 90% ee in good yield. The optimal conditions were compatible with different electronic properties of the o-aryl group.

and centrally chiral indole derivatives, this strategy provides an opportunity for the direct construction of many other prominent axially chiral backbones and will foster the development of many other organocatalytic enantioselective arylation methods.

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OTHERS

1,1′-Spirobiindane as a privileged C2-symmetric spirobicyclic framework has served as one of the most essential backbones of axially chiral organocatalysts and ligands. The two rings of 1,1′spirobiindanes lie in perpendicular planes and are rigidly connected at a quaternary center through a σ bond. This structural feature makes racemization of axially chiral 1,1′spirobiindanes impossible, and the asymmetric synthesis of this spirobicyclic framework difficult. Similar to atropisomers, chiral resolution of these racemates was previously the sole method for the enantioselective preparation of versatile axially chiral 1,1′-spirobiindane-7,7′-diols (SPINOLs),33,54 which are fundamental synthetic precursors for the construction of chiral catalysts and ligands containing 1,1′-spirobiindane scaffolds.5 Until our study, no reports tackled the challenge involving the direct construction of SPINOLs through asymmetric catalysis. Our group developed a CPA-catalyzed cyclization reaction for the asymmetric synthesis of SPINOLs in an enantiomerically pure form (Scheme 20).55 In the presence of SPINOL-derived CPA 82, the cyclization of 81 did not proceed at room temperature. However, (aS)-83 was produced in satisfactory yield and enantioselectivity when the temperature was raised to 120 °C. Under the optimized conditions, electron-donating alkyl and aryl groups on the aryl group were well-tolerated, whereas substrates bearing electron-withdrawing groups generated poor results with respect to yield. To expand the scope of the substrates, ketal 84 was evaluated under modified conditions. Under the optimal conditions, a broad scope of ketals bearing either electron-rich or electron-

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CONCLUSION Axially chiral compounds have received significant attention in recent years because of their wide applications in the total synthesis of natural products, drug discovery, and asymmetric catalysis. Axially chiral biaryl and 1,1′-spirobiindane-derived catalysts and ligands have specifically been the main force in high-performance organic and transition-metal-mediated asymmetric reactions. In addition to the chiral resolution and transition-metal-catalyzed reactions, diverse organocatalytic reactions, which include hydrogen-bonding catalysis and covalent catalysis, are powerful and economically feasible tools for the enantioselective construction of chiral skeletons. Attempts to construct enantiopure axially chiral compounds via asymmetric organocatalysis have achieved fruitful results. Many efficient and applicable enantioselective approaches for axial chirality have been developed, including several completely new organocatalytic strategies. However, a large number of axially chiral backbones still lack efficient preparation methods, especially asymmetric organocatalytic approaches, given their importance and difficulty for chemists. Additionally, numerous potentially useful axially chiral skeletons have yet to be discovered. Our group has been concentrating on the development of efficient methods for the asymmetric 545


Article

Accounts of Chemical Research

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construction of known and unknown useful axially chiral compounds via the use of chiral organocatalysts. We hope to discover some new reactions involving conceptually new synthetic chemistry such as organocatalytic enantioselective aryl C−H functionalization. In the meanwhile, we aim to develop some novel skeletons bearing axial chirality as useful chiral ligands/organocatalysts in the field of asymmetric catalysis or leading compounds in the field of drug discovery. We speculate that the mutual promotion present between organocatalysis and axial chirality will result in an evolutionary step in their development.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bin Tan: 0000-0001-8219-9970 Funding

The authors acknowledge financial support from the National Natural Science Foundation of China (Grants 21572095 and 21772081) and Shenzhen Special Funds for the Development of Biomedicine, Internet, New Energy, and New Material Industries (JCYJ20170412151701379 and KQJSCX20170328153203). B.T. acknowledges the Thousand Young Talents Program for financial support. Notes

The authors declare no competing financial interest. Biographies Yong-Bin Wang received his B.S. in 2010 and Ph.D. in 2015 from China Pharmaceutical University. He joined the faculty of Bin Tan’s group at South University of Science and Technology of China, where he is now a research assistant professor. His current research interests include asymmetric synthesis of axially chiral compounds using organocatalysis. Bin Tan received his B.S. from Hunan University of Science and Technology in 2001, his M.S. from Xiamen University in 2005, and his Ph.D. from Nanyang Technological University in 2010 with Prof. Guofu Zhong. He then did postdoctoral studies at The Scripps Research Institute with Prof. Carlos F. Barbas. At the end of 2012, he started his independent career as an associate professor at the South University of Science and Technology of China. His research focuses on the asymmetric construction of axially chiral compounds and corestructure-directed organocatalytic asymmetric synthesis.

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ACKNOWLEDGMENTS We thank all of our current and past co-workers who have contributed to our research on axial chirality chemistry.

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REFERENCES

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Construction of Axially Chiral Compounds via Asymmetric

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