Asymmetric Synthesis of Axially Chiral C N Atropisomers
Abstract
Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C N atropisom- ers. This review offers an overview of the various method- ologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C N axes. The preparation of different families of C N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.
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Asymmetric Synthesis of Axially Chiral CN Atropisomers Patricia Rodríguez-Salamanca,[a] Rosario Fernández,*[b] Valentín Hornillos,*[a, b] and José M. Lassaletta*[a] Dedicated to Professor Joan Bosch on the occasion of his 75th birthday Chemistry—A European Journal www.chemeurj.org Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (1 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 5/48] 1
Abstract: Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a CC stereogenic axis, there is a growing interest in less common and more challenging axially chiral CN atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral CN axes. The preparation of different families of CN based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text. 1. Introduction Atropisomers, the most recognized class of compounds featuring axial chirality, comprise conformers with restricted rotation around a single bond that allow their isolation in a stable form. The configurational stability of these compounds depends on the rotational energy barrier and is generally determined by the number and size of substituents at the ortho,ortho positions relative to the stereogenic axis. The presence of larger substituents led to higher energy barriers and thus more configurationally stable products. In order to isolate atropisomers by analytical methods, a half-life for their interconversion of at least 1000 s is required, which is equivalent to a barrier of rotation of 90–100 kJ mol1.[1] Atropisomerism was first reported in 1922 by Christie and Kenner after their isolation of 6,6’-dinitro-[1,1’-biphenyl]-2,2’- dicarboxylic acid atropisomers by using brucine as a resolution agent.[2] Nonetheless, the importance of axial chirality in organic synthesis began to be widely recognized after 1980, when BINAP was implemented as a highly efficient ligand in asymmetric hydrogenation reactions.[3] During the subsequent decades, enantiomerically pure atropisomers have become desirable synthetic targets and tools in the field of asymmetric catalysis with long-winded application as organocatalysts and ligands for enantioselective transition-metal-catalyzed transformations.[4] Furthermore, axially chiral biaryl scaffolds are present in numerous natural products and biologically active molecules in which the configuration of each enantiomer plays an important role in determining the final biological activity.[5] A family of nonbiaryl atropisomers that have attracted considerable attention in recent years comprises those with restricted rotation around a C(sp2)N(sp2) axis.[6] These chiral scaffolds are also present as key motifs in biologically active compounds (Figure 1A). In 1931, Adams described the first example of a compound with CN axial chirality, a pyrrole derivative that could be obtained in enantiomerically pure form by resolution with brucine (compound I).[7] More recently, the groups of Curran and Clayden set the bases for the study, synthesis, and applications of CN atropisomers[8] and, in recent years, a growing number of members of this family have been described. Many of them are natural products or present varied biological activities.[9] For example, quinazolinone derivative methaqualone II has sedative and hypnotic properties and has also been illegally used as a recreational drug,[10] while aniline derivative metolachlor III is one of the most important grass herbicides for use in maize.[11] Other relevant representatives include ancisheynine IV, a naphthylisoquinoline alkaloid isolated from Ancistrocladus heyneanus,[12] or murrastifoline A, B and F alkaloids, extracted from the root of Murraya koenigii plants, which constitute a family of axially chiral carbazolederived CN compounds,[13] whose configurational properties were studied by Bringmann in 2001 (compound V).[14] More recently, axially chiral metabolites ()-marinopyrrole Via and ()-marinopyrrole Vib were isolated by cultivation of an obligate marine Streptomyces strain and have shown excellent antibiotic activity against methicillin-resistant staphylococcus aureus.[15] Particularly relevant is the axially chiral quinazolinone derivative AMG 510 (Sotorasib) VII, a potent KRASG12C inhibitor[16] that has been recently approved as an anti-cancer medication for the treatment of non-small-cell lung cancer (NSCLC). Remarkably, several types of axially chiral heterobiaryls show activity as kinase inhibitors. Selected representatives are quinazolinedione VIII, a reversible inhibitor of Bruton’s tyrosine kinase (BTK),[17] benzimidazole IX, a phosphoinositide 3-kinase PI3 Kβinhibitor,[18] and pyridone X, a potent p38 kinase inhibitor.[19] Interesting bioactivities have also been found in axially chiral N-aryl triazole derivatives. For example Lenisurad X is a hURAD1 inhibitor used for the treatment of goat,[20] while analogue XII is a glycine transporter GlyT1 inhibitor.[21] These types of compounds have also demonstrated their potential as [a] P. Rodríguez-Salamanca, Dr. V. Hornillos, Prof. J. M. Lassaletta Instituto de 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, Dr. 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) E-mail: [email protected] © 2022 The Authors. Chemistry - A European Journal 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. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (2 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 6/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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chiral ligands for asymmetric catalysis, as exemplified by the selected examples VIII–XI shown in Figure 1(B).[22] While the synthesis of axially chiral biaryls has been widely explored, the enantioselective construction of CN heterobiaryls and other axially chiral compounds featuring a CN stereogenic axis has been much less investigated and remains as a quite challenging task.[23] Their rotational stability generally relies on the steric factors of the substituents around the CN axis as well as the structure of the nitrogen moiety. Thus, most of these axially chiral CN atropisomers contain substituents in the ortho position of the aromatic unit attached to nitrogen. The structural properties of the CN axis often led to a decrease in the configurational stability, which increases the difficulty of their enantioselective synthesis. The aim of the present review is to provide an updated outline of the different strategies and methodologies developed for the asymmetric synthesis of compounds with restricted rotation around a CN bond, with special emphasis on catalytic asymmetric methodologies. The manuscript includes methods for the synthesis of axially chiral anilides XII, indole and carbazole derivatives XIII, pyrroles and triazoles XIV, benzimidazoles XV, imides XVI, six-membered lactam derivatives XVII, quinazolinones XVIII, and thiazinones XIX, among others (Figure 2). Early contributions based on diastereoselective approaches using auxiliaries from the chiral pool, classical resolutions, cocrystallizations or chromatographic separations are presented for each group of compounds, but then the review emphasizes the different strategies developed for their catalytic asymmetric synthesis. These can be roughly classified according to the retrosynthetic pathways shown in Figure 3. Thus, target products featuring a CN stereogenic axis can be accessed by N- functionalization of aniline derivatives, either intramolecularly (Figure 3A) or by cyclization (Figure 3B). There are also methodologies involving atroposelective de novo construction of heterocyclic (Figure 3C) or aromatic (Figure 3D) moieties of the final product. Modern CH activation/functionalization strategies (Figure 3E) are also suitable tools for the atroposelective synthesis of these compounds. Alternatively, there are also approaches that focus on the direct generation of the CN stereogenic axis (Figure 3F). Finally, examples of desymmetrization strategies based on transformations in either the aromatic (Figure 3G) or the heterocyclic (Figure 3H) part of heterobiaryls are also presented and discussed. Patricia Rodriguez-Salamanca received in 2017 her Master in Organic Chemistry from the Autonomous University of Madrid, where she worked on iron-catalyzed hydroborylative cyclization of enynes. She commenced her PhD studies in the group of Asymmetric Catalysis at the Instituto de Investigaciones Químicas (CSIC-US) in 2018, exploring novel methodologies for the atroposelective synthesis of axially chiral biaryls involving dynamization processes. Rosario Fernández received her Ph.D. (1985) at the University of Sevilla. She was a NATO postdoctoral fellow at the University of Paris-Sud (Orsay, France) from 1986 to 1987. In 1987, she returned to the University of Sevilla, where she was promoted to Associate Professor. In 2008 she became a Full Professor at the same University. She has been recognized with the ‘Excelencia Investigadora’ Award from the Royal Society of Chemistry (2019). Her current research interests include asymmetric synthesis and enantioselective catalysis, in both aspects, asymmetric metal catalysis and organocatalysis. Valentín Hornillos (Toledo, 1978) obtained his Ph.D. from the University Complutense de Madrid in 2009, working on the synthesis of fluorescent lipid drugs. In 2007, he also spent four months in the Novartis laboratories in Vienna. 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 the IIQ, CSIC in Seville as a Talent Hub Fellow. Since 2019, he has been a Ramón y Cajal researcher at the University of Seville. His research interests include the development of new transition metal-catalyzed enantioselective processes. José María Lassaletta received his Ph. D. in 1990 at the University of Seville. He then performed postdoctoral stages at the ’Instituto 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). He has been recognized with the ’Felix Serratosa’Lecture (2011) and the ’Ignacio Ribas’Medal from the Royal Society of Chemistry (2017). His current interests focus on asymmetric homogeneous catalysis and the development of synthetic methodologies. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (3 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 7/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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Figure 1. A) Naturally occurring and bioactive CN-bonded axially chiral compounds. B) Selected ligands and complexes featuring CN axially chirality. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (4 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 8/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
Figure 2. Representative families of atropisomers featuring a CN chiral axis. Figure 3. Strategies for the catalytic asymmetric synthesis of axially chiral CN atropisomers. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (5 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 9/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
2. Atropisomeric cyclic derivatives: anilides and related analogues. 2.1. Early examples and conventional resolution approaches In the case of anilides, a bulky ortho substituent, such as the tert-butyl group, is frequently used to attain configurational stability. In 1994, Curran et al.[24] advanced the requirement of using large ortho substituents next to the CN axis to increase their rotational barrier and thus prevent racemization at room temperature. Initially, they focused on the study of the configurational stability of racemic anilides 1and their subsequent derivatization reactions, such as the 1,3 dipolar cycloaddition with benzonitrile oxide to afford a mixture of diastereomers 2a and 2b in a 97:3 ratio (Scheme 1). These preliminary results fixed the bases for the development of a range of approaches for the synthesis of these compounds in enantiomerically pure form. Thus, Simpkins and co-workers[25] performed a kinetic resolution (KR) of racemate 3 to obtain enantioenriched α-methylated product 4together with unreacted 2-(tert-butyl)anilide ()-3in 88% ee. The reaction proceeds through the generation of an enolate using substoichiometric amounts of a chiral lithium amide base, followed by quenching with MeI (Scheme 2). Although the kinetic resolution was not optimized, the strategy paved the way for the development of more efficient methods to obtain highly enantioenriched axially chiral anilides. Taguchi[26] and co-workers employed a chiral pool approach to obtain enantiomerically pure anilide derivatives. Thus, the reaction of N-allyl-o-(tert-butyl)aniline 6with 2 equivalents of lactic acid derivative 5afforded a 3:1 separable mixture of diastereomeric carboxamides 7a and 7b. Subsequently, the former was easily transformed into anilide 8, obtained in 97% enantiomeric excess, as shown in scheme 3. Following a related strategy, Simpkins and co-workers[27] also used a chiral pool approach based on lactic acid. Starting from α-acetoxy anilide 9, readily available after condensation of acetate 5with o-(tert-butyl)aniline, alkylation with MEMCl afforded a mixture of stereoisomeric anilides 10a and 10b in 41% and 25% yield, respectively. Subsequently, these products were reduced using a SmI2-LiCl system to afford enantioenriched products 11 with a slight loss of stereochemical integrity. This reaction was general for a wide variety of acetates and the method was also effective for the removal of α-bromo and αbenzyloxy functionalities (Scheme 4). Furthermore, Taguchi co-workers[28] developed a chiral pool approach to access highly enantioenriched atropisomeric anilides based on the resolution of amide esters 13a and 13b, easily available from oxalyl chloride, (R)-pantolactone alkoxide 12 and N-allyl-(ortho-tert-butyl)aniline 6(Scheme 5). Noteworthy, the chiral pantolactone 12 could be recovered and reused, and the efficient resolution of 13a and 13b by recrystallization makes large-scale preparation possible. The authors further performed the synthesis of enantiomerically pure α-ketoamides 14 and α,β-unsaturated anilides 15 from amide ester 13a, without loss of stereochemical integrity. In 2000, Uemura and co-workers[29] reported the asymmetric synthesis of atropisomeric anilides through a kinetically controlled enantiotopic lithiation of prochiral chromium arene complex 16 (Scheme 6). Deprotonation with chiral lithium amide base 17, followed by quenching with an electrophile (alkyl halides or carbonyl compounds) afforded axially chiral amides 18 with selectivities up to 97% ee. The high stereoselectivity could be associated with the conformal orientation of the prochiral chromium complex, where the amido carbonyl Scheme 1. Seminal studies toward the synthesis of axially chiral anilides. Enantiomers of 2a and 2b not shown. Scheme 2. Kinetic resolution for the synthesis of 2-(t-butyl)anilides. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (6 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 10/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
oxygen is oriented trans to the chromium atom in the complexed aryl group. Exposure of complex 18 to sunlight resulted in the removal of the ligand from the coordination sphere of chromium, providing pure anilides 19 without loss of optical purity. Building upon the above findings of Simpkins and Taguchi, the group of Curran[30] described an efficient method to obtain axially chiral enantiopure anilides based on a crystallizationinduced asymmetric transformation (Scheme 7). Upon reaction with dimethyl-L-tartrate, racemic anilide 20 was converted into a 1:1.1 mixture of diastereomeric ketals 21. Further selective recrystallization increased the diastereomeric ratio to 20:1. The enantiomeric excess of the final product 20 obtained after cleavage with SmI2or hydrolysis under basic conditions was determined by the diastereomeric ratio of 21, assuming that these transformations proceed faster than the interconversion of the rotamers (racemization). On the other hand, the diastereomeric ratio drops when the crystallization occurs too rapidly. In these compounds, the nitrogen atom exhibits a pyramidal structure, with the ortho-tert-butyl group adopting a syn orientation relative to the vicinal N lone pair. In 2009, Clayden et al. reported a kinetic resolution for the synthesis of atropisomeric ureas 23 based on the vanadiumcatalyzed enantioselective oxidation of ortho-thiophenyl precursors 22 (Scheme 8).[31] Sulfoxidation proceeds with moderate enantioselectivities (up to 78% ee for ligand L1 and R1=tBu, R2=Cy,) and low selectivity factors except for one substrate (R1=tBu, R2=Me, S=300). The half-life for racemization of the substrates was determined to be between 8 weeks [R1=CH- Scheme 3. Chiral pool approach to axially chiral anilide derivatives. Scheme 4. Synthesis and reduction of axially chiral acetoxy anilides. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (7 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 11/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
(SiMe3)2, R2=Me] and 500 years (R1=tBu, R2=Me), discarding any possibility of developing dynamic kinetic resolutions (DKR). 2.2. Atroposelective N-functionalization of aniline derivatives The groups of Taguchi[32] and Curran[33] independently described the catalytic asymmetric synthesis of atropoisomeric anilides 25 Scheme 5. Chiral pool approach for the synthesis of atropisomeric anilides. Scheme 6. Asymmetric synthesis of atropisomeric anilides. Scheme 7. Axially chiral enantiopure anilides by crystallization-induced asymmetric transformation. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (8 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 12/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
and 27 by palladium-catalyzed allylation of achiral precursors 24 and 26, using diphosphine ligands (S)-Tol-BINAP L2 and (S)- BINAP L3, respectively (Scheme 9). Excellent yields were observed in both cases, but the enantioselectivities were rather low, a fact that was attributed to poor facial discrimination during the nucleophilic attack of the soft anilide anion on the π-allyl system, which occurs from the opposite side of the coordinated chiral ligand. Aiming to overcome these difficulties, Taguchi et al.[34] described the synthesis of optically active atropoisomeric anilide derivatives 29 through a catalytic asymmetric inter- and intramolecular N-arylation of achiral anilides 24, using in this Scheme 8. Kinetic resolution of sulfanyl ureas. Scheme 9. Palladium-catalyzed asymmetric allylic alkylation for the synthesis of atropoisomeric anilides. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (9 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 13/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
was used in the enantioselective amination of 1,3-benzenedi- amines 65 with azodicarboxylate derivatives (Scheme 22B). A wide variety of substrates with different acyl, aryl, sulfonyl and alkoxycarbonyl protecting groups in the secondary amine were well tolerated. However, the enantioselectivity drops when benzoyl groups are incorporated at this position. Importantly, the use of different azodicarboxylates as the aminating reagents afforded the corresponding product in excellent yields and enantioselectivities. The obtained axially chiral anilides 66 presented the highest configurational stabilities reported to date. 3. N-Aryl Five-Membered Heterocycles 3.1. Pyrrole, indole/indoline, and carbazole derivatives The enantioselective synthesis of N-aryl pyrrole, indole/indoline, and carbazole atropisomers has received increasing attention in recent years, for potential applications as chiral ligands and intermediates in natural product synthesis. In these systems, the rotation about the CN axis becomes easier than in biaryl compounds because of the relatively larger CNC angles associated with a five-membered heterocyclic ring. 3.1.1. Early examples In 2001, Bringmann et al.[49] reported the first total synthesis of the natural product Murrastifoline-F 68 through an oxidative CN homocoupling of carbazole precursor 67 with Pb(OAc)2. Due to the restricted rotation around the CN bond, the two enantiomers of the coupling product were observed through liquid chromatography-circular dichroism (LC-CD). After cleavage of the methoxy groups and further derivatization with Mosher’s acid, the resulting diastereomers 69 were separated by preparative thin-layer chromatography, allowing the determination of their absolute configurations with the M-isomer being the major product (Scheme 23). Comparison with the Murrastifoline-F natural product isolated from the root extract of the curry leaf plant Murraya koenigii (Rutaceae), allowed to determine the presence of a 56:44 mixture in favor of the M- enantiomer in the natural source mixture. Few years later, Uemura and co-workers reported the stereoselective synthesis of axially chiral N-aryl indoles 72 through a nucleophilic substitution reaction of haloarene chromium complexes 71, featuring planar chirality, with indoles 70 (Scheme 24, A).[50] The stereochemistry of the CN axis was determined by the position of the substituent R1. When the indole ring was unsubstituted or 3-methyl substituted, the Scheme 22. Atroposelective CPA-catalyzed CH amination of N-aryl-2-naphthylamides and anilides. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (16 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 20/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
resulting chromium moiety was oriented anti with respect to the indole aryl ring, whereas when it was 2-methyl substituted, the benzene ring of the indole was oriented syn toward the chromium tricarbonyl group, even for sterically hindered indole compounds. It was also found that in product 72b containing a 1,3-dioxolanyl group, the chromium tricarbonyl group migrated from the N-aryl to the indole arene ring to yield complex 73 after heating in toluene (Scheme 24, B). When the 1,3-dioxolane group was changed to a methyl group, migration did not occur. X-Ray analysis revealed that the 1,3-dioxolane was oriented toward the chromium tricarbonyl group in the migrated product, suggesting that the former might play a role in assisting the transfer of the tricarbonyl chromium group by coordination. 3.1.2. Atroposelective cyclization In 2017, Tan and co-workers described the first catalytic asymmetric Paal-Knorr reaction between functionalized 1,4- diketones 74 and anilines 75 to obtain axially chiral N- arylpyrroles 76. High enantiomeric excesses were observed by using again BINOL-derived phosphoric acid C10 as the catalyst (Scheme 25).[51] Based on previous knowledge on the Paal-Knorr Scheme 23. Total synthesis of Murrastifoline-F. Scheme 24. Stereoselective synthesis of axially chiral N-aryl indoles. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (17 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 21/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
reaction mechanism, the authors envisaged the ability of the chiral phosphoric acid to assist in the intramolecular nucleophilic addition step. It was also found that the reaction could be further speeded up by adding Fe(OTf)3as a Lewis acid cocatalyst. Remarkably, the ortho Z group in anilines 75 was not restricted to tert-butyl: iodine, bromo, and phenyl groups could also be employed, giving the expected products in good to excellent enantiomeric excesses. Mechanistically, the formation of an enamine key intermediate was proposed to control the stereoinduction. Finally, the authors also observed an unexpected solvent-dependent inversion of the enantioselectivity. Kitagawa et al. reported in 2010[52a] and further expanded in 2016[52b] a Pd-catalyzed 5-endo-hydroaminocyclization of orthoalkynilanilines 77 for the synthesis of axially chiral indoles 78, obtained in moderate to good enantioselectivities by using (R)- SEGPHOS L10 as the chiral ligand (Scheme 26). This transformation represents the first transition metal-catalyzed asymmetric synthesis of such a structural motif. The reaction works well for aromatic alkynes but was sluggish for highly deactivated (R=2-NO2C6H4) and aliphatic derivatives (R=n-C4H9). In these cases, the addition of AgOTf was necessary to increase the reactivity by generating more active cationic palladium species. It was also found that the presence of an orthosubstituent in the aromatic alkyne was important to improve the enantioselectivity (60% ee for R=Ph, 80–83% ee for orthosubstituted substrates). The authors attributed this observation to the dynamic axial chirality generated around the C- (alkynyl)C(phenyl) bond. Because chirality transfer occurs during the NC bond formation step, substrates with a bulky ortho-substituent transferred more effectively the chiral information from the ligand through the C(alkynyl)C(phenyl) bond. In 2015, Nakazaki and co-workers developed a methodology to access N-arylisatins with CN axial chirality by means of an enantioselective intramolecular N-arylation reaction (Scheme 27).[53] Cyclization of amide 79 using Pd(OAc)2/(S)-DM- SEGPHOS L11 as the catalyst afforded N-aryloxindole 80 in 81% ee. This product was transformed into dibrominated derivative 81, which was enantioenriched to >99% ee by recrystallization and subsequently transformed into N-arylisatin 82 under mild conditions without erosion of the enantiomeric purity. Finally, this material was subjected to a diastereoselective 1,2-addition of MeLi, which took place from the less hindered face of the isatin, the one opposite to the tert-butyl group, to afford the 3,3-disubstituted oxindole scaffold 83, in good yield and high diastereoselectivity. The group of Lin described the first three-component cascade heteroannulation reaction of 2,3-diketoesters 84,orthosubstituted aryl anilines 85 and 1,3-cyclohexanediones 86 using a chiral spirocyclic phosphoric acid organocatalyst C11 (Scheme 28).[54] Under optimal conditions, substituents with different electronic properties in the aromatic ring of the 2,3- diketoester were tolerated, giving axially chiral N-arylindoles 87 in excellent yields and enantioselectivities. The reaction also tolerates structural modifications in anilines (R2) and 1,3-cyclo- hexanediones (R3), thus expanding the scope of the method. Scheme 25. Catalytic asymmetric Paal-Knorr reaction for the synthesis of axially chiral N-arylpyrroles. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (18 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 22/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
Very recently, Wang, Lan, Li and coworkers also reported an interesting approach to axially chiral N-isoquinolyl indole derivatives 90.[55] Using the isoquinoline N atom as a directing group, a RhIII-catalyzed CH activation of anilines 88 was used for an oxidative [3+2] annulation with alkynes 89 (Scheme 29). Using Cramer's CpOMeRhIII/AgSbF6catalyst C12 and Ag(I) salts as the oxidant, the reaction proceeds under mild conditions with high enantioselectivity and high functional group tolerance. Interestingly, good to excellent regioselectivities were observed for alkyl-aryl alkynes and substituted 1,3-enynes when AgOPiv or MeSO3Ag were used as the oxidants, respectively. Finally, Yan and co-workers have recently reported on the synthesis of complex azepine derivatives featuring a CN stereogenic axis incorporated into a bridged heterobiaryl skeleton.[56] Starting from alkynyl naphthol substrates 91 bearing a carbazole moiety, reaction with N-bromosuccinimide (NBS) in the presence of squaramide organocatalyst C13 afforded the products 92 in good yields and with excellent enantio- and diastereoselectivities (Scheme 30). The bifunc- Scheme 26. Pd-Catalyzed enantioselective synthesis of axially chiral indoles. Scheme 27. Palladium-catalyzed intramolecular N-arylation for the synthesis of enantioenriched N-aryloxindoles. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (19 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 23/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
tional activation by the catalyst facilitates a highly stereocontrolled electrophilic bromination to generate reactive bromo-functionalized tetrasubstituted chiral vinylidene orthoquinone methide (VQM) intermediates. Subsequently, intramolecular electrophilic aromatic substitution at the C1 position of the carbazole moiety affords the final products, which exhibited interesting optical properties and Ru3+-induced fluorescence responses that suggest potential applications in optoelectronic materials and heavy metal ion detection. 3.1.3. Atroposelective C–H activation/functionalization In 2019, Shi and co-workers described a palladium-catalyzed CH alkynylation of aryl pyrroles 93 with bromoalkynes 94 for the synthesis of pyrrole derivatives 95 displaying axial chirality (Scheme 31).[57] This elegant approach, inspired by the seminal work by the group of Yu[58] and applied previously to the resolution of biaryls,[59] is based on the transient directing group formed by condensation of the formyl group of 93 with L-tert- leucine L12, thus enabling a regio- and atroposelective CH activation to afford the alkynylated products in excellent yields and enantioselectivities up to >99% ee. These products exhibit high configurational stability, as no erosion of ee values was observed, even after heating at 120°C. Nevertheless, sterically bulky substituents in the ortho position to the axis are needed to maintain the configurational stability and to ensure good enantioselectivities. Xie, Zhang and co-workers developed later a similar PdII- catalyzed atroposelective CH olefination of N-aryl indoles 96 with electron-poor alkenes 97 (Scheme 32A).[60] The authors reported on three different situations depending on the substitution pattern of the starting material: For atroposelective CH olefination/desymmetrization reactions [Z=H, R2(meta)= R2(meta’)], a wide variety of alkenylated products 98a could be prepared in good yields and high enantioselectivities using Pd(OAc)2as the precatalyst, L-valine L13 as the ligand and benzoquinone (BQ) as an external oxidant. Similar results were also obtained in the catalytic CH olefination/dynamic kinetic resolution of configurationally labile N-aryl indoles. Finally, for Scheme 28. Organocatalyzed heteroannulation reaction for the synthesis of N-arylindole esters. Scheme 29. Rhodium(III)-catalyzed CH activation of anilines for the synthesis of axially chiral N-isoquinolyl indole derivatives. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (20 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 24/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
racemic, configurationally stable substrates with more sterically demanding substituents, a catalytic CH alkenylation via kinetic resolution was developed. In this last case, the alkenylated N- aryl indoles 98b were obtained with excellent selectivity factors of up to 459 by using tert-leucine L12 as the ligand and AgTFA as the oxidant. All synthesized products present high configurational stability at rt. Very recently, Ackermann and co-workers recently reported developed a similar kinetic resolution of N- naphthyl indole carbaldehydes 99 into alkenylated products 100, but an electrocatalytic approach was used to avoid the need of an external oxidant (Scheme 32B).[61] Excellent selectivity factors of up to S=355 were achieve in the reaction with a variety of electron-poor olefins, including, acrylates, vinyl phosphonates, vinyl sulfones, maleimides and fluorinated alkenes. Interestingly, an unprecedented allylic selectivity was observed with 1,1-disubstituted alkenes, and the atroposelective allylation could also be performed to obtain products 101 with excellent selectivity factors of up to S=169. Subsequently, Wang et al. presented an alternative method to construct CN axial chirality through a RhIII-catalyzed Satoh- Miura-type reaction of N-aryloxindoles 102 and alkynes 103. Using catalyst C14 with a spirocyclic cyclopentadienyl ligand, chiral N-aryloxindoles 104 were obtained with high yields and enantioselectivities (Scheme 33).[62] This dual CH activation reaction tolerates both electron withdrawing and electron donating groups in the N-phenyl ring and in the diaryl alkynes. Mechanistic studies revealed that the CH activation step proceeds by a carboxylate-assisted concerted metalation-depro- tonation mechanism affording a six-membered rhodacyclic intermediate in which the bulky isobutyrate additive helps to better differentiate the two enantiotopic CH bonds. Very recently, Kwon and co-workers[63] reported a Pictet- Spengler reaction of N-aryl indoles 105 with paraformaldehyde for the atroposelective synthesis of N-aryl-tetrahydro-β-carbo- lines 107 (R4=H, Scheme 34). Previous studies on acid-catalyzed atroposelective C-2 functionalization of unprotected indoles indicated the need for a bifunctional activation that includes acidic activation of the electrophile and interaction between the phosphate counterion and the indole NH. The absence of a NH group in these substrates, however, was addressed by Scheme 30. Organocatalytic construction of complex azepines featuring CN axial chirality. Scheme 31. Palladium-catalyzed atroposelective CH alkynylation. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (21 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 25/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
introducing an ortho-amino hydrogen bond donor (R3) into the bottom aromatic ring. Thus, the use of chiral phosphoric acid C15 afforded excellent yields and enantioselectivities with a variety of substrates that contain electron-donating or electronwithdrawing groups. In addition to paraformaldehyde, the reaction also works with different activated benzaldehydes 106, which additionally allows to control both central and axial chirality elements (4:1 to 10:1 d.r., >99% ee). Very recently, Meggers and co-workers described an atroposelective alkylation of N-arylpyrroles 108 achieved by nucleophilic addition to N-acryloyl-1H-pyrazoles 109 using a chiral-at-rhodium Lewis acid catalyst C16 possessing a unique helical (chiral-at-rhodium) chirality (Scheme 35).[64] Different substitution patterns were tolerated in the coupling partners affording structurally diverse axially chiral N-arylpyrroles 110 in high yields and excellent atroposelectivivities (up to >99% ee). N-arylpyrroles with different R3groups on the phenyl ring could be used with excellent results. Thus, halogen-containing substrates and those with free hydroxy, amino, or strong deactivating nitro groups were tolerated. The thermal configurational stability was analyzed in products with the smaller R3 substituents. Even in these cases, no erosion of the enantiomeric excess was observed after heating at 80°C for 18 h. 3.1.4. Atroposelective construction of the CN stereogenic axis Direct NC coupling in hindered systems usually requires harsh reaction conditions that compromise the configurational stability of the CN axis. Looking for a synthetic solution to this Scheme 32. Atroposelective CH olefination of N-aryl indoles. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (22 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 26/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
Scheme 33. Satoh-Miura-type reaction of N-aryloxindoles and alkynes. Scheme 34. Atroposelective synthesis of N-aryl-tetrahydro-β-carbolines. Scheme 35. Atroposelective alkylation using a chiral at-rhodium catalyst. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (23 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 27/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
problem, the group of Colobert, Wencel-Delord and co-workers introduced in 2018 the use of hypervalent iodine reagents as highly electrophilic coupling partners for the distereoselective synthesis of axially chiral N-arylated indolines 113 via Cucatalyzed Ullmann coupling (Scheme 36A).[65] Taking advantage of the high reactivity of sterically encumbered chiral iodanes 111, the reaction with indolines 112 could be performed at low temperature furnishing these axially chiral CN motifs in a highly atroposelective manner. A traceless sulfoxide auxiliary placed in the ortho-position of the iodine substituent was chosen to control the stereochemical course of the reaction. It was found that CuIsalts performed better than CuII salts, and that the nature of the iodane counteranion had a minor impact on selectivity. Structurally diverse iodane and indolines worked well under the optimized conditions, leading to higher selectivities for the more sterically hindered substrates. A proposed mechanism suggested that the chemoselectivity was controlled by a π,π-stabilizing interaction between the p-tolyl group of the chiral auxiliary and the aromatic part of the indoline. More recently, the same group reported on the development of a catalytic asymmetric version of the same reaction (Scheme 36B).[66] Thus, the reaction between indolines 115 and dissymmetric mesityl-aryl iodanes 114 bearing an unsubstituted primary amide was efficiently catalyzed by a Cu(I)/bisoxazoline L14 chiral complex, leading to N-aryl indolines 116. The reaction tolerates both Br and F substituents at different positions of the indoline ring, which is important for further functionalization and biological applications. The nature of the R1group in the hypervalent iodine reagent is of critical importance: substrates with reduced steric hindrance deliver nearly racemic products. On the other hand, halogen-substi- tuted iodanes are suitable reaction partners, affording the corresponding indolines in good yields and enantioselectivities. The crystal structure of one of the products (R1=R2=OMe, R3= 7Br, R4=H) showed an intermolecular hydrogen bond between the N atom of the indoline and the amide motif, which highlights the importance of the latter in the efficiency of the reaction. Moreover, preliminary mechanistic studies revealed the occurrence of a nonlinear amplification involving multimetallic copper species, together with a very fast initial rate of the reaction. Conversely, Tan et al. reported an acid-catalyzed atroposelective CH amination of azonaphthalenes 117 with carbazoles 118 for the synthesis of axially chiral N-arylcarbazoles 119, reaching good to excellent enantioselectivities by using spinolderived chiral phosphoric acid C10 as the catalyst (Scheme 37A).[67] This was the first organocatalytic method for the synthesis of such chiral motifs and represents an alternative to metal-catalyzed cross-coupling reactions for CN bond formation. Since this reaction is redox neutral, no external Scheme 36. Axially chiral N-arylated indolines by Cu-catalyzed Ullmann coupling. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (24 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 28/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
oxidant was needed. A sterically hindered group at the C2 position of the carbazole substrate ensures configurational stability on the resulting products. Replacement of the R2group in the ester functionality consistently gave the desired products in excellent yields and with a similar high enantiocontrol. The electronic nature and position of the R1groups also had a limited effect on enantioselectivity. The authors propose a CPA- assisted central to axial chirality transfer process through H- bond activation and rearomatization. Indoles 120 were also effective in this transformation, although a bulky R3substituent at C3 was required to generate the desired products 121 and a different catalyst C17 was required to obtain optimal results (Scheme 37, B). Furthermore, it was found that the introduction of a methyl group at C3 of the azonaphthalene 117 significantly increased the yield and also had a positive impact on the enantioselectivity. More recently, Wang and co-workers reported on a highly atroposelective synthesis of axially chiral N-arylindolocarbazoles 123.[68] To this end, the authors developed a Rh(II)-catalyzed intermolecular NH insertion of diazonaphthoquinone 121- derived carbenes into indolocarbazole precursors 122. The reaction proceeds under mild conditions to afford moderate to good yields and excellent enantioselectivities by using phthalimido-derived dirhodium catalyst Rh2(S-PTAD)2C18 (Scheme 38). The reaction exhibits a wide substrate scope, providing satisfactory results for a variety of diazonaphthoquinones and indolocarbazoles, regardless of the electronic and steric nature of the substituents. Moreover, the methodology can be used for late-stage functionalization of natural products and bioactive molecules and for the synthesis of novel chiral phosphoric acids (CPAs). 3.1.5. Atroposelective desymmetrization of achiral heterobiaryls Kamikawa and co-workers reported the desymmetrization of planar-prochiral (π-arene)chromium complexes 124 via an enantioselective ring-closing metathesis catalyzed by (R)-Mo- alkylidene catalyst C10, generating N-arylindoles 125 with both planar and axial chirality (Scheme 39).[69] These substrates contain η6-diisopropenyl-2-N-indolyl ligands, in which the orientation of the aryl ring of the indole is anti with respect to the Cr(CO)2group. The presence of electron-donating groups on the phosphine moiety was crucial to obtain good reactivity and high enantioselectivity. For substrates with poorer electrondonating groups on the allylphosphine, the reaction did not occur. The proximal isopropenyl groups slow down the rotation around the (π-arene)-indolyl single bond, and their orientation is therefore fixed in the anti-configuration. Mechanistically, the first metathesis takes place between the catalyst and the P-allyl group, which is the less sterically hindered olefin. The ringclosing metathesis is then favored because the more electrondonating PR2group increases the electron density at the two isopropenyl groups through the chromium atom. As ligation of Scheme 37. Atroposelective CH amination of arenes for the synthesis of chiral N-aryl carbazoles and indoles. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (25 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 29/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
maleimides 161 with N-Boc protected oxindoles 164 for the synthesis of adducts 165 (Scheme 49B). The bifunctional character of the catalyst containing a tertiary amine was essential to interact with the acidic proton at C3 of the oxindole and simultaneously as H-bond donor to coordinate the imide carbonyl, ensuring in this way a well-defined geometry in the transition state. Under optimal conditions, it was shown that the presence of diverse electron-withdrawing and electrondonating groups at the oxindole core did not affect the reactivity of the system. Furthermore, no loss of reactivity or stereoselectivity was observed with para or meta substituents in the maleimide. On the other hand, excellent results were obtained with halogenated maleimides, although a lower reactivity was observed for the larger ones. A related strategy for the atroposelective synthesis of spirocyclic N-aryl succinimides 167 has also been recently reported.[82] The method is also based on a desymmetrization of maleimides 161, making use in this case of a NHC-catalyzed Stetter-aldol/oxidation sequence from dialdehydes 166 (Scheme 50). Using triazolium salt C27 as the carbene precursor in the presence of DIPEA as the base and thiourea as an additive, a variety of products were obtained in good yields and enantioselectivities. Lastly, axially chiral N-aryl succinimides 170 have been prepared from N-aryl 5-norbornene-2,3-dicarboximides 168 using a nickel-catalyzed enantioselective hydrocyanation with cyanohydrin 169 as a hydrogen cyanide surrogate (Scheme 51).[83] The desymmetrization process proceeds with generation of central and remote NC axial chirality, reaching high levels of enantioselectivity by using (R)-DM-SEGPHOS ligand ent-L11. The absence of a nonlinear effect (NLE) suggests that a monomeric [NiL11] complex is the catalytically active species, and control experiments confirmed the key role of the carbonyl groups of the substrate. Finally, computational DFT studies revealed that reductive elimination is the enantiodetermining step. Scheme 49. A: Scandium-catalyzed Michael addition of 3-substituted-2-oxindoles to arylmaleimide derivatives. B: Organocatalytic atroposelective desymmetrization of maleimides. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (32 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 36/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
4. N-Aryl/Vinyl Six-Membered Heterocycles 4.1. Axially chiral lactams The above-mentioned intermolecular anilide N-arylation by Taguchi and co-workers (Scheme 10) could also be applied in an intermolecular fashion to anilide derivatives 171 for the atroposelective synthesis of cyclic products 172.[34] Good ee’s and excellent yields were observed by using a modified catalyst system comprising Pd(OAc)2/(S)-BINAP L2 (Scheme 52A). This methodology was later applied by the authors to the synthesis of dihydroquinolinone derivatives 173 using a Pd(OAc)2/(R)- SEGPHOS L10 catalyst (Scheme 52B).[84] The synthesis of 174 precursor of a norepinephrine transporter (NET) inhibitor, was then carried out by diastereoselective α-alkylation of the corresponding lactam enolate, where the attack of the electrophile occurs preferentially from the opposite side or the orthotert-butyl group, generating finally a quaternary carbon. anti- Markovnikov hydration of the allyl group followed by trans-tert- butylation was then performed under mild conditions to afford the target product. In 2010, Tan and co-workers described an intramolecular hetero-Michael reaction of alkynylamide 175 for the synthesis of axially chiral lactam 176. Using Brönsted base-catalyst C28, this transformation proceeds via isomerization into chiral allene intermediates followed by cyclization (Scheme 53).[85] Limitations in the preparation of related atropoisomeric six-mem- bered lactams were encountered due to difficulties in the synthesis of suitable alkyne substrates. Tanaka and co-workers have also described an atroposelective Rh(I)-catalyzed [2+2+2] cycloaddition reaction of diynes 177 with ortho-substituted phenyl isocyanates 178 for the synthesis of axially chiral N-aryl-2-pyridones 179 (Scheme 54A).[86] The optimal cationic catalyst was generated in situ from [Rh(cod)2l]BF4and (R)-BINAP ent-L2. Under the optimized conditions, it was observed that an increase of the steric hindrance of the alkyl substituent at the 2-position of substrates 178 led to higher ee values but at expenses of yield. Conversely, substituents such as 2-OMe and 2-Cl afforded good yields but moderate ee’s. On the other hand, malonate-derived- diynes, 1,3-diol-derived diynes, 1,6-diynes and ethylene-linked 1,7-diynes could all participate in the reaction although moderate enantioselectivities were reached. Using the same approach, Takeuchi et al. later described that the alternative catalyst formed in situ from [Ir(cod)Cl]2and chiral diphosphines can also be used in the same transformation, reaching optimal enantioselectivities by using L17 as the ligand (Scheme 54B).[87] The use of iridium instead of Scheme 50. NHC-catalyzed synthesis of axially chiral N-Aryl succinimides. Scheme 51. Synthesis of axially chiral N-Aryl succinimides: Ni-catalyzed desymmetrization of norbornene derivatives by hydrocyanation. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (33 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 37/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
rhodium or nickel has advantages, as the catalyst does not require preactivation. Under optimized conditions, the reaction worked well for a wide range of isocyanates 178. As in the precedent case, the higher the steric hindrance of R, the lower the observed yield. The reaction tolerates ortho-halophenyl isocyanates, with the bromo derivative giving a yield lower than that of the chlorine, although good enantioselectivities were observed in both cases. Alternatively, Ollivier and co-workers used in the same reaction an anion metathesis between the rhodium catalyst [Rh(cod)Cl]2and a chiral silver phosphate C29 in order to generate in situ a catalytically active [Rh- (I)][phosphate] chiral complex (Scheme 54C).[88] An H2atmos- phere was initially used to accelerate decoordination of the cyclooctadiene ligand, but similar results were also obtained without H2premix, although a higher temperature was required to generate the catalytically active species. The presence of bulky R substituents in 178 provided better ee’s under optimized conditions, but the use of halogenated derivatives (R =Cl, Br) was detrimental to both yield and enantioselectivity. Regarding the scope of the diynes 177, good results were obtained when Z was a diester, cyclic acetal, and N-tosyl group, but lower yields and selectivities were observed for an unsubstituted tether, indicating the underlying positive gemdialkyl effect on the reaction. Gu and co-workers developed a copper-catalyzed enantioselective Ullmann-type amination reaction for the construction of CN atropisomers (Scheme 55).[89] Using diamide L18 as the optimal ligand, a series of biaryl bromo anilides 180 afforded the corresponding lactams 181 in excellent selectivities. Different substitution patterns in the biaryl skeleton and in the aniline fragment were well tolerated. Ortho-substituted alkyl substrates (R3) in the latter, however, afforded lower yields due to steric hindrance, but the enantioselectivities remained excellent. Racemization studies indicated the need to work under mild conditions (below 60°C), to avoid racemization. In 2016, Kitagawa et al.[90] reported on the atroposelective synthesis of CN axially chiral N-aryl phenanthridin-6-ones 183 via Pd-catalyzed intramolecular Buchwald-Hartwig amination from bromo amides 182 (Scheme 56). Using (R)-DTBM-SEGPHOS L4 as ligand, ortho-ethyl and ortho-methyl substituted products Scheme 52. Asymmetric intramolecular N-arylation for the synthesis of atropoisomeric lactams. Scheme 53. Base-catalyzed isomerization–Michael addition for the synthesis of axially chiral lactams Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (34 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 38/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
were obtained with moderate yield and enantioselectivity (25 and 68% ee respectively) although racemization of the products was also observed. Surprisingly, the use of bulky ortho-tert-butyl substituents led to poor yield and enantioselectivity, although these results could be improved by heating the reaction at 130°C. This behavior was attributed to a high rotational barrier around the CN chiral axis in the Pd-amine diastereomeric intermediates. Very recently, Hong, Zhou and co-workers have developed an elegant approach for the synthesis of axially chiral N- arylphenanthridinones.[91] The strategy relies on cooperative palladium/chiral norbornene (Pd/NBE*) catalysis, in what can be Scheme 54. Atroposelective cycloaddition of diynes with isocyanates for the synthesis of axially chiral N-aryl-2-pyridones. Scheme 55. Ullmann-type amination to obtain axially chiral lactams. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (35 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 39/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
considered as a variant of the Catellani reaction with an intramolecular amidation as the termination event. Thus, starting from ortho-substituted iodoarenes 184 and orthobromoanilides 185, an optimized catalyst formed by Pd(OAc)2, tri(2-furyl)phosphine (TFP) and 2-ethyl ester-substituted norbornene C30 provided the desired products 186 in good yields and excellent enantioselectivities (Scheme 57). The process, supported by DFT calculations, starts with the oxidative addition of the Pd0catalyst to iodoarene 184, NBE* C30 insertion, and CH activation leading to palladacycle intermediate A. Oxidative addition to 185 followed by reductive elimination and extrusion of the NBE transient mediator C30 affords the key PdII intermediate B, featuring a transient CC stereogenic axis from which the final CN stereogenic axis originates with high levels of stereoselectivity during the final intramolecular amidation step via intermediate Cand the final axial-to-axial chirality transfer to the NC axis. Very recently, He and co-workers[92] described the synthesis of axially chiral pyridones 189 through an iridium-catalyzed enantioselective allylic amination of cinnamyl carbonates 187 with the unsubstituted precursors 188, followed by a stereospecific central-to-axial chirality transfer process (Scheme 58). As a remarkable singularity, the CN bond is built on an N-styryl moiety instead of the common N-aryl unit. The reaction proceeds smoothly using an iridacycle catalyst generated in situ with a chiral phosphoramidite ligand L19. The CH amination procedure tolerates different para- and meta-substituted carbonates bearing electron-neutral, electron-donating, and electronwithdrawing groups, as well as difunctionalized derivatives, affording the corresponding products in excellent yields and enantioselectivities. Bulky substituents and heterocyclic rings were also tolerated, but a lower ee was obtained with orthosubstituted derivatives. Remarkably, the electronic properties of substituents on 2-quinolinol substrates have an important impact on enantioselectivity with electron-withdrawing groups Scheme 56. Atroposelective synthesis of phenanthridin-6-ones. Scheme 57. Axial-to-axial chirality transfer approach for the synthesis of axially chiral N-arylphenanthridinones. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (36 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 40/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
at C4, resulting in a decrease in enantiocontrol. Density functional theory (DFT) studies revealed that the stereospecificity during the central-to-axial chirality transfer ([1,3]-H transfer) can be explained by the stabilizing H-bonding interaction between the base and the amide carbonyl group in the favored transition structure. 4.2. Quinazolinone derivatives N-Aryl quinazolinone derivatives are privileged heterocyclic structures in medicinal chemistry as they possess a wide spectrum of biological activities.[93] Their high rotational barrier compared to other axially chiral CN compounds also makes them good chiral ligands candidates for asymmetric catalysis. Until 2006, quinazolinone derivatives could only be obtained in enantiomerically pure form after chromatographic separation in chiral stationary phases[94] or classical resolution with chiral resolving agents. For example, Virgil and co-workers[95] described in 1998 the synthesis of different racemic quinazolinone ligands 191a,b from 2-chloroanilines 190 (Scheme 59) and the resolution of the former, which was accomplished by means of chiral palladium dimer 192, a conventional resolving agent for monophosphines. Enantiomerically pure quinazoline complex 193 and unreacted (S)-(+)-191a were obtained with high enantioselectivities. A more convenient strategy for larger-scale synthesis was applied to the resolution of analogue 191b with (S)-camphorsulfonic acid (benzenesulfonyl)hydrazone 194 as the resolving agent. In 2006, Natsugari and co-workers reported a method for the atroposelective synthesis of quinazolinone derivatives 197, obtained by condensation of precursors 195 with chiral amino acids and subsequent dehydrative cyclization of the resulting compounds 196 (Scheme 60).[96] The diastereoselectivity was found to depend on the type of substrate and reaction conditions employed. Using TMSCl/Et3N (path a) the reaction gave almost equal amounts of diastereomers (S,R)-197 and (S,S)-197, which could be easily separated by flash chromatography. The second method (path b) consists of the alternative cyclization of amidine 199 under milder conditions. This in turn was prepared from 196 by treatment with I2, PPh3, and DIPEA, followed by reaction of the resulting product 198 with piperidine. In this case, the reaction occurred to yield (S,R)-197 in good yield and much better diastereoselectivity (d.r, up to 9:1). Miller described an efficient method to access a wide range of substituted tribrominated 3-arylquinazolin-4(3H)-ones 201 through an atroposelective tribromination reaction of precursors 200 (Scheme 61).[97] High enantioselectivities were achieved by using a tertiary amine-embedded β-turn peptide catalyst C31. Even in the absence of ortho-substituents in the phenol ring, quinazolinones 200 present a modest rotational barrier around the CN axis (18.8 kcal/mol for R1=Me, R3=H) Therefore, the slow addition of NBS over 2.5 h was necessary for an efficient DKR to occur. A screening of truncated peptide catalysts provided evidenced that the β-turn secondary structure is important to achieve high levels of enantioinduction in this reaction. Under optimized conditions, it was possible to achieve good yields and high enantioselectivities for substrates possessing alkyl substituents at the 2-position (R1) or electrondonating and withdrawing groups at the phenol ring (R3), suggesting a weak effect of distal substitution on enantioselectivity. However, electron-withdrawing groups or lack of substitution at the 2-position (R1) led to products with a lower rotational barrier around the chiral axis, resulting in lower levels of enantioselectivity. Mechanistically, the chiral axis is set after the first bromination reaction at ortho-position. Based on the results previously described by Miller, Kitagawa et al. reported in the following year a reductive desymmetrization of chiral quinazolinone derivatives 202 into Scheme 58. Atroposelective synthesis of N-styryl pyridones. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (37 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 41/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
Scheme 59. Classical resolution of racemic quinazolinones. Scheme 60. Diastereoselective dehydrative cyclization for the synthesis of quinazolinone derivatives. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (38 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 42/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
debrominated derivatives 203 using palladium catalysts based on (R)-DTBM-SEGPHOS L4 as the ligand (Scheme 62).[98] As an important strategic advance, the presence of an hydroxyl group at the C3 position of the phenyl ring, which hampered the synthesis of bioactive quinazolinone products in the previous method, is not required. During the optimization of the reaction, it was found that the enantioselectivity could be improved by decreasing the reaction temperature to 0°C. Furthermore, reducing the amount of NaBH4resulted in a considerable increase in the chemical yield of 203 at the expense of that of the fully dibrominated byproduct 204, although lower enantioselectivities were achieved. This result suggests that the enantioselectivity is determined not only by the desymmetrization process (the first dehydrodebromination), but also by a kinetic resolution of 203 (the second dehydrobromination). The outcome of the reaction was significantly influenced by the R2substituent, with alkyl groups affording a remarkable increase in enantioselectivity. However, the presence of methoxy or chlorine groups in R2was found to decrease enantioselectivity due to the influence of inductive effects. Later, the same research group developed a diastereoselective α-alkylation reaction of lithium enamines, prepared from mebroqualone derivatives 203 (R1=Et).[99] Under optimized conditions, the resulting α-alkylation products 205 were obtained in good yields and diastereomeric ratios (up to 99% yield and up to d.r.=26:1.) The diastereoselectivity was found to be strongly dependent on the bulkiness of the R2group. Thus, bulky alkyl halides, in particular isopropyl iodide, afforded Scheme 61. Atroposelective tribromination of N-arylquinazolinones. Scheme 62. Reductive desymmetrization of chiral quinazolinones. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (39 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 43/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
the best results. The relative (P,S)-configuration of the major diastereomer could be explained by the steric repulsion between the R3and the ortho-bromo groups. 4.3. Other six-membered heterocycles The synthesis of biaryls compounds 208 featuring both CC and CN axial chirality were reported by Hsung et al. in 2007. These products were obtained by a Rh(I)-catalyzed asymmetric [2+2+2] cycloaddition of ynamines 206 with 1,6-diynes 207 (Scheme 63).[100] Using (S)-DM-BINAP L8 as the ligand, cycloadditions of achiral 6-membered 2-oxazinone rings (n=1) afforded products with good yields and enantioselectivities, with the diastereomer 208b being formed preferentially (d.r. up to 8:1). In the case of ynamides containing 5-membered 2- oxazolidinones (n=0), the resulting chiral biaryls were also obtained in good yields and good to excellent enantioselectivities (82 to 99% ee), but with moderate diastereoselectivity (d.r. 1:1 to 1:6). The key step of the reaction is the chelation of the Rh metal by both the methoxy and carbonyl groups and the following cycloaddition yielding the major stereoisomer. Kitagawa and co-workers described the enantioselective synthesis of CN axially chiral quinolinone derivatives 211 by a palladium-catalyzed amination/cyclization of ynones 209 with ortho-tert-butyl aniline 210 (Scheme 64).[101] Low enantioselectivities and yields were observed when bidentate phosphines were used as ligands, while monodentate derivatives such as (R)-MOP L20 provided better results. As a limitation, ethynyl ketones with nonaromatic substituents were unproductive in the reaction. Murata and co-workers developed a cyclization reaction of ureas 212 for the synthesis of axially chiral uracil derivatives 213 through the combined use of (R)-ALBO as a chiral auxiliary and quinidine C32 as a chiral organic base catalyst (Scheme 65).[102] The chiral auxiliary was placed in the orthoposition of the substituted N-phenyl group to effectively control the enantioselective cyclization. It was also found that the absolute configuration of the stereocenter at C9 of the catalyst C32 is crucial to achieve high diastereoselectivity due to the formation of an intermolecular hydrogen bond between the hydroxyl group and the urea carbonyl group. Finally, removal of the (R)-ALBO auxiliary was successfully achieved to obtain the corresponding phenol derivative 214 under mild acidic conditions without significant racemization. Finally, NHC catalysis has been exploited by Jin and coworkers[103] for the atroposelective cycloaddition of thioureas 215 with ynals 216 for the synthesis of axially chiral N-aryl thiazines 217 (Scheme 66). Moderate yields, but excellent enantioselectivities were achieved using triazolium salt C33 as the NHC precatalyst, DMAP as the base and furan as the solvent in the presence of Sc(OTf)3and 5 Å MS as beneficial additives to improve the yield of the thiazine product. The reaction involves NHC-catalyzed addition of 215 to acylazolium intermediate I, Scheme 63. Asymmetric synthesis of heterobiaryl cyclic carbamates. Scheme 64. Hydroamination/cyclization sequence for the synthesis of axially chiral quinazolinones. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (40 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 44/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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
leading to key intermediate II, which undergoes a face-selective intramolecular lactam formation. The reaction tolerates various functionalities, and it was found that the size of substituent R2 on the N-phenyl moieties of the thiazine products plays a significant role in both chirality induction and stereochemical stability. As a limitation, aliphatic ynals are not suitable substrates in this reaction, leading to complex reaction mixtures. In conclusion, the development of new synthetic methods for accessing axially chiral CN atropisomers has emerged as a relevant goal in asymmetric catalysis. A minor number of these strategies have nonetheless been reported when compared with those for the synthesis of axially chiral biaryl scaffolds. Reasons for this difference include the lower configurational stability of the formers due to the high degree of freedom of their conformers and the reduced steric congestion around the CN axis, in particular for the more challenging 5-membered ring atropisomers. This review has covered enantioselective strategies for the synthesis of atropisomers that display a stereogenic CN bond, starting from the seminal work of Curran and Simpkins, and putting emphasis on catalytic asymmetric methods. The preparation of new families of atropisomers, Scheme 65. Atroposelective synthesis of axially chiral uracil derivatives. Scheme 66. Atroposelective synthesis of axially chiral thiazine derivatives. Chemistry—A European Journal Review doi.org/10.1002/chem.202104442 Chem. Eur. J. 2022,28, e202104442 (41 of 44) © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH Wiley VCH Donnerstag, 05.05.2022 2228 / 242598 [S. 45/48] 1 15213765, 2022, 28, Downloaded from https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202104442 by Universidad De Sevilla, Wiley Online Library on [30/08/2024]. 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