Atropisomerism is a stereochemical behavior portrayed by three-dimensional molecules that bear rotationally restricted σ bond. Akin to the well-represented point-chiral molecules, atropisomerically chiral compounds are finding increasing utilities in many disciplines where molecular asymmetry is influential. This provides steady demand on atroposelective synthesis, where numerous synthetic pursuits have been rewarded with conceptually novel and streamlined methods while expanding the structural diversity of atropisomers. This review summarizes key achievements in stereoselective preparation of biaryl, heterobiaryl, and nonbiaryl atropisomers documented between 2015 and 2020. Emphasis is placed on the synthetic strategies for each structural class, while examples are cited to illustrate the potential applications of the accessed atropochiral targets.

Recent Advances in Catalytic Asymmetric Construction of Atropisomers.

Transition-metal-catalyzed enantioselective C-H functionalization has become a powerful strategy for the formation of C-C or C-X bonds, enabling the highly asymmetric synthesis of a wide range of enantioenriched compounds. Atropisomers are widely found in natural products and pharmaceutically relevant molecules, and have also found applications as privileged frameworks for chiral ligands and catalysts. Thus, research into asymmetric routes for the synthesis of atropisomers has garnered great interest in recent years. In this regard, transition-metal-catalyzed enantioselective C-H functionalization has emerged as an atom-economic and efficient strategy toward their synthesis. In this Perspective, the approaches for the synthesis of atropisomers by transition-metal-catalyzed asymmetric C-H functionalization reactions are summarized. The main focus here is on asymmetric catalysis via Pd, Rh, and Ir complexes, which have been the most frequently utilized catalysts among reported enantioselective C-H functionalization reactions. Finally, we discuss limitations on available protocols and give an outlook on possible future avenues of research.

Synthesis of Atropisomers by Transition-Metal-Catalyzed Asymmetric C-H Functionalization Reactions.

Transition metal-catalyzed enantioselective functionalization of C-H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the synthesis of complex chiral molecules. Despite significant progress, traditional directing group-enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C-H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.

Transition Metal-Catalyzed Enantioselective C−H Functionalization via Chiral Transient Directing Group Strategies

Atropisomers beyond the C–C axis (denoted as X–Y herein) are important addition to the repertoire of axially chiral compounds, which have received much attention in recent years. Compared with conventional C–C axial chirality around biaryl and olefin axes, atropisomerism portrayed by C–N, C–O, C–B, or N–N bond was deemed to be challenging due to the relatively low rotational barriers. However, the intrinsic shorter bond length and electron-repelling effect lead to a congested hetero X–Y axis, resulting in stable axially chiral frameworks. The past two decades, especially the past few years have witnessed a rapid progress of this emerging area. A range of catalytic atroposelective approaches have been reported for the efficient synthesis of these challenging skeletons. The X–Y axially chiral compounds are valuable molecules, and they may be used as new ligands or catalysts in asymmetric catalysis or evaluated for their potential biological activities. We believe that the chemistry of atropisomers beyond C–C axial chirality will be forthcoming and blooming in the near future, taking up an important position in organic chemistry and beyond. Atropisomers beyond the C–C axis (denoted as X–Y herein) are important addition to the repertoire of axially chiral compounds, which have received much attention in recent years. Compared with conventional C–C axial chirality around biaryl and olefin axes, atropisomerism portrayed by C–N, C–O, C–B, or N–N bond was deemed to be challenging due to the relatively low rotational barriers. However, the intrinsic shorter bond length and electron-repelling effect lead to a congested hetero X–Y axis, resulting in stable axially chiral frameworks. The past two decades, especially the past few years have witnessed a rapid progress of this emerging area. A range of catalytic atroposelective approaches have been reported for the efficient synthesis of these challenging skeletons. The X–Y axially chiral compounds are valuable molecules, and they may be used as new ligands or catalysts in asymmetric catalysis or evaluated for their potential biological activities. We believe that the chemistry of atropisomers beyond C–C axial chirality will be forthcoming and blooming in the near future, taking up an important position in organic chemistry and beyond. 

Atropisomers beyond the C–C axial chirality: Advances in catalytic asymmetric synthesis

Axially chiral indole-based frameworks have been recognized as a class of important five-membered heterobiaryls and developing catalytic asymmetric approaches for constructing these frameworks in an enantioselective manner is highly desirable. In recent years, synthetic chemists have paid much attention to this research field, and rapid developments have occurred. At this point, a range of axially chiral indole-based scaffolds have been constructed via various catalytic asymmetric reactions based on different strategies. Thus, the catalytic asymmetric construction of axially chiral indole-based frameworks has become an emerging area. This minireview summarizes the rapid advances in this field and gives some insights into future developments, which will help this research field to thrive.

Catalytic Asymmetric Construction of Axially Chiral Indole-Based Frameworks: An Emerging Area.

Construction of N-C Axial Chirality through Atroposelective C-H Olefination of N-Arylindoles by Palladium/Amino Acid Cooperative Catalysis.

A silver-catalyzed, K2S2O8-mediated protocol to access regioselective acylarylation of unactivated alkenes was developed. The reaction between N-allyl-indoles and α-oxocarboxylic acids proceeded smoothly and involved an acyl radical addition/C–H cyclization cascade. The protocol showed a broad substrate scope and good tolerance of functional groups. The reaction proceeded with both internal and terminal alkenes to furnish many functional pyrrolo[1,2-a]indoles bearing the ketone carbonyl group, and this feature also provides the potential to construct structurally complex N-containing heterocycles.

K2S2O8-mediated acylarylation of unactivated alkenes via acyl radical addition/C–H annulation cascade of N-allyl-indoles with silver cocatalysis

Herein, we present the first Pd(II)-catalyzed atroposelective dual C–H annulative strategy for the assembly of axially chiral aldehyde frameworks using commercially available amino acid as the transient auxiliary and chiral pool. This reaction accommodates a broad substrate scope to give atropisomeric aldehydes bearing both C–C and N–C chiral axes in good yields (up to 95%) with excellent enantioinduction (up to 99%). The utility of this synthetic methodology was testified by various practical late-stage transformations, thereby accomplishing diversity-oriented synthesis of structurally diverse biaryl atropisomers and several functionalized axially chiral species such as bifunctional organocatalysts. Moreover, a series of mechanistic studies have provided more details for this catalytic transformation.

Pd(II)-Catalyzed enantioconvergent twofold C–H annulation to access atropisomeric aldehydes: a platform for diversity-oriented-synthesis

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Construction of N-C Axial Chirality through Atroposelective C-H Olefination of N-Arylindoles by Palladium/Amino Acid Cooperative Catalysis.

K2S2O8-mediated acylarylation of unactivated alkenes via acyl radical addition/C–H annulation cascade of N-allyl-indoles with silver cocatalysis

Pd(II)-Catalyzed enantioconvergent twofold C–H annulation to access atropisomeric aldehydes: a platform for diversity-oriented-synthesis