Bin Tan

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.

Spirooxindoles have become a privileged skeleton given their broad and promising activities in various therapeutic areas. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of spirooxindoles via organocascade strategies. Various organocatalysts with distinct activation modes have found application in constructing these sophisticated compounds. This review focuses on the enantioselective synthesis of spirooxindoles via organocascade strategies and is organized on the basis of three primary starting materials and then further subdivided according to the types of organocatalyst. These methods are of importance for the synthesis of complex natural products and the design of new pharmaceutical compounds. We believe that compounds based on spirooxindole skeletons have the potential to provide novel therapeutic agents and useful biological tools.

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

A novel organocatalytic asymmetric [3+2] cycloaddition reaction between methyleneindolinones and allylic compounds yielding complex spirocyclopentaneoxindoles has been developed. It provides extraordinary levels of enantioselective control involving a chiral phosphine as a nucleophilic organocatalyst. Simple precursors were used under mild conditions to construct oxindole derivatives with high enantiopurity and structural diversity. This method should be useful in medicinal chemistry and diversity-oriented syntheses of these intriguing compounds.