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 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

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.

In recent years, para-quinone methides (p-QMs) have emerged as attractive and versatile synthons in organic synthesis owing to their high reactivity. Consequently, p-QM chemistry has attracted increasing attention and remarkable advances have been achieved. Among the numerous transformations involving p-QMs, catalytic reactions play a pivotal role, and a variety of catalytic systems mediated by Lewis acids, Bronsted acids, bases, transition metals, N-heterocyclic carbenes, and other catalysts have been established for performing 1,6-conjugate addition reactions. Various molecular scaffolds have been constructed using p-QMs to obtain the core structures of numerous natural and synthetic substances of chemical and biomedical relevance. In this review, we provide a comprehensive overview of recent progress in this rapidly growing field by summarizing the 1,6-conjugate addition and annulation reactions of p-QMs with consideration of their mechanisms and applications.

https://pubs.rsc.org/en/content/articlepdf/2020/qo/d0qo00387e

Recent developments in 1,6-addition reactions of para-quinone methides (p-QMs)

Chiral indole derivatives such as indolines and indolenines are important heterocyclic frameworks which constitute the core structures of many natural products and bioactive molecules. So, intensive attentions from chemists have been paid to the construction of such frameworks. Among different approaches, organocatalytic asymmetric dearomatization (organo-CADA) reactions of indole derivatives have become powerful methods toward this goal. Consequently, a variety of enantioenriched heterocyclic frameworks containing indoline, indolenine and the related cores have been constructed via organo-CADA reactions of indole derivatives, and a series of important natural products with structural complexity and enantiopurity have been synthesized based on these methodologies. This review summarizes the progresses in organo-CADA reactions of indole derivatives since 2004 and their applications in total synthesis of natural products, and gives some insights into challenging issues in this research field, which will enlighten the future development of this field.

Progresses in organocatalytic asymmetric dearomatization reactions of indole derivatives

Axially Chiral Aryl-Alkene-Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

The regio- and enantioselective (3+3) cycloaddition of nitrones with 2-indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). Using this approach, a series of indole-fused six-membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3-nucleophilic asymmetric (3+3) cycloaddition of 2-indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.

Regio- and Enantioselective (3+3) Cycloaddition of Nitrones with 2-Indolylmethanols Enabled by Cooperative Organocatalysis

A chiral guanidine-catalyzed asymmetric [4 + 1] cyclization of benzofuran-derived azadienes with 3-chlorooxindoles has been established, which constructed chiral spirooxindole frameworks with in situ generation of a five-membered ring with high diastereoselectivities (up to >95:5 dr) and good enantioselectivities (up to 94:6 er). This reaction represents the first catalytic asymmetric [4 + 1] cyclization of benzofuran-derived azadienes, which will enrich the research field of catalytic asymmetric cyclizations of such reactants. In addition, this reaction provides a useful strategy for the enantioselective construction of five-membered ring-based chiral spirooxindole scaffolds.

Tian-Zhen Li

Papers

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

Axially Chiral Aryl-Alkene-Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

Regio- and Enantioselective (3+3) Cycloaddition of Nitrones with 2-Indolylmethanols Enabled by Cooperative Organocatalysis

Catalytic Asymmetric [4 + 1] Cyclization of Benzofuran-Derived Azadienes with 3-Chlorooxindoles.

Brønsted Acid-Catalyzed (4 + 3) Cyclization of N, N'-Cyclic Azomethine Imines with Isatoic Anhydrides.