Lewis Acid-Base Interactions as a Racemization Strategy for the Atroposelective Synthesis of (Hetero)biaryls via Dynamic Kinetic Resolution

Lewis Acid-Base Interactions as a Racemization Strategy for the Atroposelective Synthesis of (Hetero)biaryls via Dynamic Kinetic Resolution José A. Carmona+,[a] Carlos Rodríguez-Franco+,[a] Rosario Fernández,[b] José M. Lassaletta,*[a] and Valentín Hornillos*[a, b] Due to their molecular topology, atropisomers serve as highly valuable chiral frameworks for diverse applications across academic research and industry. Despite the availability of numerous established catalytic methods for their synthesis, there is still a high demand for the development of novel and resourceful strategies. In this concept article, we will detail our studies on the use of transient Lewis acid-base interactions (LABI) as a dynamization strategy for the synthesis of (hetero)biaryl atropisomers by Dynamic Kinetic Resolution (DKR). The formation of cyclic transition states, resulting from the interaction between an acidic functionality and a basic counterpart, plays a key role in facilitating racemization by substantially reducing the barrier to atropisomerization. In this scenario, we have employed transformations aimed at neutralizing the acidic nature of the Lewis acid, ultimately leading to the formation of configurationally stable enantioenriched compounds. The design of substrates and the employment of stereoselective strategies based on transition metal and biocatalysis for their resolution is detailed. Specific emphasis on the preparation of axially chiral motifs commonly found in catalysis or medicinal chemistry will also be given. Introduction Atropisomerism arises from the restricted rotation around a single bond, such as CC, CN, NN, or CB.[1] This restriction is typically caused by electronic or steric effects of adjacent substituents, resulting in a pair of conformational stereoisomers known as atropisomers. Among many others, classical examples of well-known atropisomers present in natural products and bioactive substances include Vancomycin, a marketed glycopeptidic antibiotic prescribed for bacterial infections, Michellamine B, an alkaloid with HIV viral replication inhibition properties, Steganacin, an antileukemic lignan lactone that hampers tubulin formation, and Marinopyrrole A, a marine-derived compound with substantial antibiotic and anticancer activities (Figure 1A).[2] Biaryl atropisomers also serve as pivotal structural components in chiral ligands, which have garnered extensive utility in asymmetric catalysis. Well-known representative examples include C2- [a] Dr. J. A. Carmona,+C. Rodríguez-Franco,+Prof. J. M. Lassaletta, Prof. V. Hornillos Instituto Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA) C/ Américo Vespucio 49, 41092 Sevilla, Spain E-mail: [email protected] [email protected] [b] Prof. R. Fernández, Prof. V. Hornillos Departamento de Química Orgánica Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA) C/ Prof. García González 1, 41012 Sevilla, Spain [+]These authors contributed equally to this work; co-first authors. © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Figure 1. Examples of natural products and chiral ligands featuring axial chirality. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 201/207] 1 ChemCatChem 2024,16, e202400701 (1 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem www.chemcatchem.org Concept doi.org/10.1002/cctc.202400701 symmetric binaphthyls, such as the recognized ’privileged structures’BINOL and BINAP, alongside derivatives like BINAM or BINOL-derived phosphoramidites. Moreover, non-C2-symmetric variations such as MOP, MAP, or QUINAP have also demonstrated myriad applications within this field (Figure 1B).[3] There has been a significant effort in developing methodologies for the catalytic asymmetric synthesis of atropisomers, particularly over the past decade.[4] This encompasses various motifs, including (hetero)biaryls, styrenes, and CN, CB, and NN atropisomers prepared by transition metal-, organocatalytic- , and biocatalytic processes. The demand for efficient methods for the enantioselective synthesis of these compounds has led to the development of a variety of strategies, with direct coupling to generate the stereogenic axis being the most straightforward approach. However, this approach is far from being of general application, prompting the development of alternative methodologies, such as central-to-axial chirality transfer processes or de novo construction of aromatic rings through cycloaddition or cyclization reactions. Another set of strategies focuses on desymmetrizing and resolving preformed biaryls into enantioenriched compounds, emphasizing the significance of DKRs. Among the strategies based on DKR, the use of bridged biaryl lactones introduced by Bringmann stands out.[2a,6] This strategy involves catalytic ring-opening of configurational labile biaryl lactones with nucleophiles to obtain configurationally stable and enantioenriched biaryls. The bridging ring decreases the barrier to rotation in compounds that have a configurationally stable open form. This strategy has been significantly developed, with applications in the synthesis of natural products and bioactive compounds. Nonetheless, racemization can also occur through the formation of cyclic intermediates generated by ring-closing and ring-opening events.[8–10] This was first evidenced in the DKR of biaryl lactols or hydroxy aldehydes, where racemization is triggered by the formation of biaryl hemiaminal intermediates during the reaction with aromatic amines.[8] Alternatively, the labilization of the stereogenic axis can also be facilitated by the formation of cyclic transition states. In this regard, our group has successfully demonstrated the use of LABI, formed through subtle interactions between strategically located acidic moieties (even as weak as a carbonyl group) and basic counterparts, to promote the racemization of stereogenic axes in heterobiaryl systems.[11–18] The formation of quasizwitterionic transition states facilitates racemization by substantially reducing the barrier to atropoisomerization, which would otherwise be significantly higher without the stabilizing LABI interactions. In this context, we have developed transformations aimed at neutralizing the acidic nature of the Lewis acid, thereby increasing the barrier to atropisomerization and ultimately yielding configurationally stable, enantioenriched compounds. In this concept article, we summarize the achievements collected in our group on the basis this strategy, particularly focusing on substrate design. This includes considerations such as the choice of the Lewis basic function, ring size, and the presence of ortho substituents in the substrates. Additionally, we explore how the predicted interactions in the cyclic transition states influence the ease of racemization. Bringmann’s Biaryl ‘Lactone Concept’ and Related Systems In 1992, Bringmann and colleagues discovered that the introduction of a lactone bridge between the ortho positions of tri-ortho- substituted biaryl systems results in a notable decrease in the atropisomerization barrier.[6a] The stabilization of the stereogenic axes could subsequently be reinstated through atroposelective bridge cleavage using reduction, transesterification, or amidation reactions. Bringmann applied this strategy in the total synthesis of axially chiral natural products and bioactive compounds. However, for many years, the main limitation was the necessity of stoichiometric amounts of chiral nucleophiles. In 2016, the group of Wang introduced the first highly efficient catalytic enantioselective version of the method, through a transesterification reaction (Scheme 1).[7] Using a chiral bifunctional thiourea as an organocatalyst, a broad array of configurationally stable products were obtained with outstanding yields and enantiomeric excesses. Since then, there has been a growing number of catalytic methodologies for the ring-opening of Bringmann’s lactones or related lactams, utilizing both organocatalysis and transition-metal catalysis.[8] Furthermore, the bridge does not need to be permanently formed for racemization to occur. Racemization can also be induced from a non-bridged starting material, by the formation José María Lassaletta received his Ph. D. in 1990 at the University of Seville. He then performed postdoctoral stages at the ’Institu- to de la Grasa y sus Derivados’(CSIC) and the University of Konstanz, (Germany), with Prof. R. R. Schmidt. In 1995 he moved to the ‘Instituto de Investigaciones Químicas’ (CSIC, Seville), where he was promoted to Tenured Scientist (1996), Research Scientist (2005), and Research Professor (2009). His current interests focus on asymmetric catalysis, with a focus on ligand design and discovery of innovative activation modes. Valentín Hornillos obtained his Ph.D. from the University Complutense de Madrid in 2009, working on the synthesis of fluorescent lipid drugs. From 2010 until 2015, he was a postdoctoral fellow in the group of Professor Ben Feringa at the University of Groningen and in 2015 he moved to ‘Instituto de Investigaciones Químicas’ (CSIC, Seville) as a Talent Hub Fellow. In 2019, he became a Ramón y Cajal researcher at the University of Seville, where he was promoted to Associate Professor in Organic Chemistry in 2024. His research interests include the development of new transition metal-catalyzed enantioselective processes. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 202/207] 1 ChemCatChem 2024,16, e202400701 (2 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Concept doi.org/10.1002/cctc.202400701 18673899, 2024, 18, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400701 by Readcube (Labtiva Inc.), Wiley Online Library on [26/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License of cyclic intermediates through ring-closing/ring-opening events. In this context, in 2016 Akiyama introduced a strategy that builds upon Bringmann’s ‘lactone concept’ and involves in situ ringopening and ring-closing of biaryl hemiaminal ethers to perform DKR:[9] Starting from non-bridged hydroxy imines, a reduction via asymmetric transfer hydrogenation (ATH) was performed with a Hantzsch ester as the reductant and a chiral phosphoric acid as the catalyst (Scheme 2). This reductive amination exhibited an enantio-divergent characteristic, resulting in the predominance of the (R)-isomer with 2-hydroxyanilines, while the reverse isomer was favored with 3-hydroxyanilines. In 2018, Wang reported a similar Ir-catalyzed redox-neutral amination, employing a ’borrowing hydrogen’strategy for the atroposelective synthesis of axially chiral aminophenols (Scheme 3).[10] This approach involves the in situ oxidation of biaryl diols by an Ir(η5-Cp*)(dpen) catalyst, leading to the formation of an iridium hydride and the lactol. Subsequent condensation with various anilines enabled reductive amination with good overall yields and excellent enantioselectivities. Our group also employed this strategy for the synthesis of axially chiral diamines, utilizing the formation of bridged biaryl aminals to facilitate racemization. The rapid equilibrium favoring the open amino-imino form enabled a DKR scenario, yielding various analogs of the homologated BINAM ligand through Rucatalyzed ATH (Scheme 4).[11] A computational analysis of the racemization mechanism was conducted, unveiling the higher stability of the hemiacetals/hemiaminals intermediates compared to their open counterparts. Furthermore, the calculated barrier for atropoisomerization of the aminal model is higher, yet this is compensated by their increased stability relative to the hemiaminals. Atropisomerization through Lewis Acid-Base Interactions in Cyclic Transition States This section describes an alternative approach to the ‘lactone concept’, wherein racemization is achieved without the need of forming and cleaving a covalent bond. Instead, it relies on a Scheme 1. Catalytic atroposelective transesterification of Bringmann’s lactones. Scheme 2. DKR via ATH of biaryl hemiaminal ethers. Scheme 3. DKR via atroposelective redox-neutral amination of biaryl diols. Scheme 4. DKR via atroposelective ATH of biaryl aminals. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 203/207] 1 ChemCatChem 2024,16, e202400701 (3 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Concept doi.org/10.1002/cctc.202400701 18673899, 2024, 18, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400701 by Readcube (Labtiva Inc.), Wiley Online Library on [26/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License weak interaction between a Lewis basic and an acidic functionality at the ortho-ortho’ positions. When solely assessing steric factors, one might expect tri-ortho substituted biaryl compounds to be configurationally stable. However, the interaction of the Lewis pair effectively reduces the rotational barrier of the stereogenic axis by forming six- or five-membered cyclic transition states, thereby facilitating the interconversion of both atropisomers of the substrate. Consequently, by strategically designing the substrates and selecting appropriate transformations to disable the LABI, this strategy enables the achievement of efficient DKRs (Scheme 5). In 2016, the groups of Clayden and Turner reported that the incorporation of N-oxide and aldehyde functional groups at the 2,2’-positions of tri-ortho-substituted heterobiaryl scaffolds enabled a significant reduction in atropisomerization barriers (16.3 kcal·mol1and 15.7 kcal·mol1for the reported examples, Scheme 6).[12] This stabilizing interaction facilitated rapid interconversion between atropisomers through a six-membered cyclic transition states, enabling a DKR scenario. A biocatalytic atroposelective reduction of the carbonyl group yielded the corresponding heterobiaryl alcohols in good yields and nearly perfect enantioselectivities. In this case, without considering the steric differences between the carbonyl and hydroxymethyl groups, the LABI interaction reduces the rotational barrier by approximately 12 kcal·mol1. Two control experiments were conducted to demonstrate the interaction. The synthesis of isosteric ortho fluorinated aldehyde and alcohol unveiled a notable increase in the rotational barrier of the former, while it remained nearly unchanged for the latter. Furthermore, a plausible transition state for atropisomerization was proposed by computational studies, characterized by a stabilizing NO···CHO interaction that promotes pyramidalization of the aldehyde at the transition state. The main limitation of the method arises when transitioning to tetra-ortho-substituted systems derived from naphthylisoquinoline N-oxide. In this case, the reaction efficiency is compromised due to a lower racemization rate, resulting in a non-dynamic scenario. To demonstrate the utility of the products, the resulting alcohols were employed as organocatalysts in the asymmetric allylation of benzaldehydes, achieving enantiomeric excesses of up to 80% with a catalyst loading of 0.1 mol% (not shown). In 2022, Yuan and Wang further exploited this system to conduct a DKR.[13] In their study, a cascade reaction with aminobenzamides catalyzed by CPA induces the loss of the Lewis acidic character of the carbonyl group, leading to the formation of configurationally stable products (Scheme 7A). The reaction proceeded through imine formation followed by annulation, enabling the simultaneous installation of both a stereocenter and a stereogenic axis in an enantio- and diastereoselective fashion. Notably, the protocol exhibited excellent tolerance towards functional groups on the heterobiaryl scaffold as well as various modifications on the aminobenzamide, consistently delivering a single diastereoisomer in good yields and with excellent enantioselectivities in nearly all cases. Some of the products were tested as ligands in a model Sc-catalyzed asymmetric 1,2-addition of N-methylindole to 1-phenylisatin, achieving the corresponding product with excellent yield (up to 94%) and enantioselectivity (up to 90% ee) (not shown). Very recently, Wang and Li reported a DKR approach involving the CPA-catalyzed atroposelective one-step condensation reaction of the same configurationally labile heterobiaryl aldehydes with hydroxylamines (Scheme 7B).[14] This methodology constitutes the first atroposelective synthesis of axially chiral biaryls via a direct catalytic condensation reaction. A wide variety of configurationally stable heterobiaryl oxime ethers Scheme 5. LABI strategy for the atroposelective synthesis of (hetero)biaryls by DKR. Scheme 6. Clayden and Turner's DKR by atroposelective biocatalytic reduction of heterobiaryl aldehydes. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 204/207] 1 ChemCatChem 2024,16, e202400701 (4 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Concept doi.org/10.1002/cctc.202400701 18673899, 2024, 18, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400701 by Readcube (Labtiva Inc.), Wiley Online Library on [26/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License could be obtained in moderate to excellent yields and enantioselectivities, with an E/Zratio >20:1 in all reported examples. To elucidate the reaction mechanism, DFT calculations were conducted, unveiling that the CPA simultaneously activates both the carbonyl and hydroxylamine, thereby controlling the stereochemical course of the reaction. In 2018, our group reported a LABI-based DKR of heterobiaryl ketones.[15] In this case, a less acidic ketone carbonyl was employed, in combination with a nitrogen from an isoquinoline/ pyridine moiety as a Lewis base, to promote atropoisomerization through the formation of five-membered cyclic transition states. A zinc-catalyzed asymmetric hydrosilylation, employing a chiral diamine as a ligand, was used for synthesizing the corresponding heterobiaryl carbinols, achieving good diastereomeric ratios and excellent enantioselectivities (Scheme 8). The potential of the resulting enantiomerically enriched carbinols was demonstrated by synthesizing several appealing derivatives, which may potentially function as catalysts or ligands in asymmetric synthesis. Various experiments were conducted to demonstrate the lack of configurational stability of the ketone substrates. These findings were further corroborated by performing DFT calculations which revealed a substantial difference in energy between the rotational barriers of the ketone and the obtained alcohols. Thus, although the rotational barrier of a model heterobiaryl ketone TSαwas determined to be 22.1 kcal·mol1, the Relaxed Potential Energy Scan (PES) indicated the absence of the interaction responsible for atropisomerization in the corresponding carbinol, leading to a rotational barrier exceeding 35 kcal·mol1. These calculations also enabled the acquisition of a DFT-optimized geometry of the transition state for the isomerization of the substrate. A distance of 1.63 Å was found for the N···(O)Me interaction, indicating the formation of a quasizwitterionic transition state. This interaction is responsible of the widening of angles φ1 and φ2, to 137.1°and 133.4°, respectively, compromising the configurational stability of the stereogenic axis. Our group further extended this strategy to quinoline derivatives, once again utilizing aldehydes as a Lewis acid.[16] In this case, the transient Lewis pair resulted in a 6-membered cyclic transition state, in which the angles involved in the stability of the stereogenic axis are not widened. In this scenario, to perform DKR was more challenging, not only because of the six-member geometry in the cyclic transition structure encompassing the bonding interaction, but also because both aryl units are six member rings, leading to greater steric repulsion in it. Indeed, calculations revealed that the racemization of 1-formyl-2’- (dimethylamino)biphenyls, which exhibit related features (TSβ, Scheme 9), is not facile due to an unfavorable balance of repulsive and attractive forces in the N(sp3)···CHO Lewis interaction. However, for 8-arylquinoline derivatives, the planar geometry of the heterocycle sufficed to mitigate the steric Scheme 7. DKR by CPA-catalyzed imine formation/asymmetric annulation (A) and CPA-catalyzed atroposelective one-step condensation with hydroxilamines (B). Scheme 8. DKR by Zn-catalyzed asymmetric hydrosilylation of isoquinolinyl ketones. Scheme 9. DKR of 1-(quinolin-8-yl)-2-naphthaldehydes and derivatives. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 205/207] 1 ChemCatChem 2024,16, e202400701 (5 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Concept doi.org/10.1002/cctc.202400701 18673899, 2024, 18, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400701 by Readcube (Labtiva Inc.), Wiley Online Library on [26/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License repulsive interaction in the transient N(sp2)···CHO Lewis pair formed (TSγ). An asymmetric allylation reaction catalyzed by an ortho-cyclometalated iridium-DM-BINAP complex was then employed to perform the DKR. This methodology takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses (Scheme 9A). The resulting heterobiaryl carbinols could be transformed into potential P,N-ligands for asymmetric catalysis (not shown). These quinoline derivatives could also be resolved through biocatalytic reduction of the carbonyl group using commercially available ketoreductases (Scheme 9B). In this case, the careful selection of the appropriate enzyme enables the synthesis of either the (S) or the (R) enantiomer of the resulting heterobiaryl alcohol with exceptional levels of enantioselectivity.[17] Another way to alleviate steric repulsions in 6-membered transition states for atropisomerization involves transitioning from (6,6)-(hetero)aromatic ring systems to (6,5)-analogues. In this scenario, the steric repulsions of the ortho-ortho’substituents are alleviated by geometric factors. The presence of a fivemembered ring (e.g., pyrrole or indole fragment) instead of a phenyl ring makes the angles surrounding the stereogenic axis significantly wider than the prototypical 120°angles in the (6,6)- systems. Consequently, the distances between the ortho groups are also longer. A particularly attractive system among them comprises N-arylindoles, wherein the nitrogen is directly incorporated into the stereogenic axis. The structural properties of the CN axis further contribute to a decrease in configurational stability, rendering their enantioselective synthesis more challenging. Consequently, methodologies for the synthesis of CN atropisomers have been less explored, but have gained significant interest in recent years.[4g] In this context, our group has explored the resolution of N- arylindoles bearing formyl and N-dimethylamino groups at the ortho positions, which serve as Lewis acid and basic groups, respectively (Scheme 10).[18] DFT calculations revealed the feasibility of the Me2N···CHO interaction to facilitate racemization (TSδ). The calculations revealed a NC bond distance of 2.25 Å, with a low rotational barrier of 18.6 kcal·mol1for the model substrate. This stands in contrast with the above-mentioned biphenyl derivative (TSβ), where such interaction is insufficient to facilitate racemization due to repulsive steric interactions between the carbonyl oxygen atom and the nearest NMe group with a barrier of 24.2 kcal·mol1observed for the latter. By taking advantage of a biocatalytic reduction of the carbonyl using commercially available KREDs, a series of axially chiral N- arylindole aminoalcohols were obtained with excellent conversions and enantioselectivities under very mild reaction conditions. For comparison, the rotational barrier of the reduced alcohol, which lacks the stabilizing interaction, was calculated to be 30.8 kcal·mol1(TSɛ), confirming the configurational stability of the products. These axially chiral aminoalcohols could also be transformed into potential ligands for asymmetric catalysis. On the other hand, the indole ring can also be attached at the 3-position to generate the stereogenic axis, giving rise to a related family of (6,5)-atropisomers. Accordingly, our group has conducted the DKR of sulfenylated 3-arylindole-2-carbaldehydes through Rh-catalyzed asymmetric reductive aldol reaction (Scheme 10).[19] In this case, the sulfur atom from a thioether group serves as a Lewis basic functionality, which, in combination with an aldehyde, enables a LABI-based DKR. Computational studies on the transition state for atropisomerization demonstrated not only a stabilizing RS···CHO interaction but also a CH···O hydrogen bond, providing significant additional stabilization (TSη). Furthermore, DFT calculations highlighted the necessity of a five-membered ring in the heterobiaryl scaffold for rapid interconversion between atropisomers, as evidenced by the significantly higher energy barrier (ΔΔG�=13.8 kcal·mol1) of an analogous system based on a biphenyl derivative (see TSζ, Scheme 10). This barrier also exceeds the one calculated for the transition structures featuring oxygen (N-oxide, 15–16 kcal·mol1, Scheme 6) or nitrogen (NMe2, 24.2 kcal·mol1, Scheme 9) functionalities, but notably correlated well with the interaction distance [1.96 Å for O···CHO,19 2.15 Å for N···CHO,20 2.64 Å for S···CHO], with the latter causing considerable distortion in the transition state. Furthermore, despite the challenges associated with the presence of the sulfenyl group, which could potentially coordinate to the metal center leading to catalyst deactivation or undesirable side reactions, the use of precatalyst Rh[(S,S)-Phe- BOX-ip](OAc)2(OH2) facilitated the reductive aldol reaction between the heterobiaryl aldehydes and tert-butyl acrylate, employing Me(TMSO)2SiH as reductant. This approach yielded configurationally stable 3-aryl indoles in good to excellent yields, with the highly stereoselective simultaneous installation of two stereocenters and a stereogenic axis, in up to 99% ee (Scheme 11). Only four of the eight possible diastereoisomers were observed, identified as two pairs of enantiomers, epimers at the chiral axis, with diastereomeric ratios of up to >20:1. This method, together with the above-mentioned Ir-catalyzed allylation, allowed to perform LABI-based DKR through CC bond formation. This innovative approach opens novel avenues for synthetic opportunities with the resulting products. Summary and Outlook In conclusion, the development of new synthetic strategies based on DKR to access chiral atropisomers has emerged as a significant goal in asymmetric catalysis. This concept review Scheme 10. DKR by biocatalytic reduction of N-arylindole carbaldehydes. Wiley VCH Donnerstag, 12.09.2024 2418 / 358995 [S. 206/207] 1 ChemCatChem 2024,16, e202400701 (6 of 7) © 2024 The Author(s). ChemCatChem published by Wiley-VCH GmbH ChemCatChem Concept doi.org/10.1002/cctc.202400701 18673899, 2024, 18, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cctc.202400701 by Readcube (Labtiva Inc.), Wiley Online Library on [26/11/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License encompasses DKR strategies based on Lewis acid-base interactions as a method to decrease the energy barrier for enantiomerization. Starting from the seminal works of Clayden and Turner, and ours, with a focus on substrate designs, the preparation of new families of atropisomers based on this strategy has been outlined. This includes derivatives of quinoline and isoquinoline (N-oxide), as well as N- and 3-aryl indoles. Methods based on transition metal-catalyzed and biocatalytic reactions that enable efficient DKR of these systems have been discussed. Interestingly, many of these compounds have found applications as chiral ligands for enantioselective catalysis. However, the development of novel methods based on this strategy remains challenging, prompting the search for new innovative designs. This concept review will provide researchers with an updated perspective on the state of the art in this field and we hope it will inspire the development of additional approaches for synthesizing new families of atropisomers. Acknowledgements We thank the Spanish Ministerio de Ciencia e Innovación (Grants PID2019-106358GB-C21, PID2022-143230NB-I00, contracts RYC-2017-22294 for V.H. and fellowship FPU18/02677 for C. R.-F.), European funding (ERDF), and Junta de Andalucía (Grants P18-FR-3531 and US-1260906). 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Lassaletta, Angew. Chem. Int. Ed. 2018,57, 3777. [16] J. A. Carmona, P. Rodríguez-Salamanca, R. Fernández, J. M. Lassaletta, V. Hornillos, Angew. Chem. Int. Ed. 2023,62, e202306981. [17] J. M. Coto-Cid, G. de Gonzalo, J. A. Carmona, J. Iglesias-Sigüenza, P. Rodríguez-Salamanca, R. Fernández, V. Hornillos, J. M. Lassaletta, Adv. Synth. Catal. 2024,366, 909. [18] P. Rodríguez-Salamanca, G. de Gonzalo, J. A. Carmona, J. López-Serrano, J. Iglesias-Sigüenza, R Fernández, J. M. Lassaletta, V. Hornillos, ACS Catal. 2023,13, 659. [19] C. Rodríguez-Franco, A. Ros, P. Merino, R. Fernández, J. M. Lassaletta, V. Hornillos, ACS Catal. 2023,13, 12134. Manuscript received: April 16, 2024 Revised manuscript received: May 23, 2024 Accepted manuscript online: May 27, 2024 Version of record online: July 8, 2024 Scheme 11. DKR by Rh-catalysed asymmetric reductive aldol reaction of sulfenylated 3-aryl indole-2-carbaldehydes. 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