Atropisomeric molecules are present in many natural products, biologically active compounds, chiral ligands and catalysts. Many elegant methodologies have been developed to access axially chiral molecules. Among them, organocatalytic cycloaddition and cyclization have attracted much attention because they have been widely used in the asymmetric synthesis of biaryl/heterobiaryls atropisomers via construction of carbo- and hetero-cycles. This strategy has undoubtedly become and will continue to be a hot topic in the field of asymmetric synthesis and catalysis.
Atropisomers are common in natural products and some drugs (Scheme 1) 
, such as ancistrocladinium A 
, michellamines A and B 
, korundamine A 
, vancomycin, etc. 
. When two specific groups connected by a σ bond cannot rotate freely due to electronic effects or steric hindrance between them, a pair of immobilized isomers can be separated. The earliest atropisomer was isolated and determined by Christie and Kenner 
, but the definition was not fully developed until Oki’s work 
. Nowadays, the atropisomers are generally divided into three or four classes according to the type of bond axis (Scheme 2) 
Scheme 1. Axially chiral natural products.
Scheme 2. Different type of atropisomers.
Biaryl is a structure consisting of two full-carbon aromatic rings connected by a single bond. The chiral ligand 2,2’-bis(diphenylphosphaneyl)-1,1’-binaphthalene (BINAP) with this framework was first applied to the asymmetric hydrogenation performed by Noyori et al. 
. This application opened the door to the study of biaryls as ligands and catalysts. Since then, binaphthol (BINOL) and other biaromatic ligands have been synthesized and used as privileged chiral ligands in the field of asymmetric metal catalysis. Then, in 2004, Akiyama 
and Terada 
independently developed BINOL-derived chiral phosphoric acid catalysts and successfully catalyzed the asymmetric Mannich reaction with these catalysts, which is an important breakthrough for the application of biaryls in the field of organocatalysis.
Heterobiaryl has one or more heteroatoms on the aromatic ring, which allows it to participate in reactions through the action of heteroatoms and other molecules without dependence on substituents. This property often makes this skeleton catalyst uniquely able to catalyze some reactions. In 1991, the first heterobiaromatic N,P-ligand (1-(1-isoquinolinyl)-2-naphthyl)diphenylphosphine (QUINAP) was successfully synthesized 
, followed by a series of other ligands based on this skeleton, such as 1-(isoquinolin-1-yl)naphthalen-2-amine (IAN), and some heterobiaryls with good organocatalytic properties were synthesized 
, which greatly expanded the choice of catalysts 
In addition to traditional benzamides and styrenes, nonbiaryl anilide derivatives containing C-N axial chirality have been developed over the past two decades 
. These structures exist widely in natural products and have wide application in medicine 
. Diaryl ether, another type of nonbiaryls containing C-O-C bonds, was proved by Mislow et al. in 1982 
, but its synthesis was not reported until 1998 by Kinoshita et al. 
. At present, there is still a large room for research on this kind of compounds, and new progresses have been developed for the synthesis of these compounds by using organocatalytic strategies in recent years 
Due to its unique steric hindrance, atropisomer has an irreplaceable role in metal catalysis and organocatalysis 
. As a result, its asymmetric synthesis has become a hot topic in the field of organic synthesis 
. The existing synthetic methods mainly include coupling, aromatic ring construction, chiral separation/desymmetrization and chiral transformation 
. Cycloaddition and cyclization are common methods in the ring construction, which are efficient and environmentally friendly synthetic methods 
. Organocatalytic cycloaddition and cyclization adhere to this concept, using efficient and environmentally friendly small molecular organocatalysts to achieve this goal.
Organocatalysis is no stranger to chemists; its mild conditions, low expense and easy to obtain, environmental-friendliness, excellent atomic economy make it an ideal and feasible catalytic strategy, as well as in the construction of atropisomers. Most of these reactions are catalyzed by Brønsted acid or Lewis base 
, which can form intermolecular hydrogen bonds, facilitate the reaction by giving or receiving protons, and control the reaction direction of substrate through steric hindrance of groups or an inductive effect of hydrogen bonds, so as to obtain single configuration of atropisomers. In the process of organocatalytic cycloaddition/cyclization, it is usually necessary to go through multiple intermediates and involve the formation of multiple bonds, so the requirements for organocatalysts are more stringent. Under the joint efforts of various research groups, many kinds of organocatalysts have been developed and applied in synthetic chemistry 
2. Chiral Phosphoric Acids (CPAs)
The chiral part of chiral phosphoric acid mainly consists of BINOL, H8
-BINOL, SPINOL and TADDOL (Scheme 3) 
. Different catalysts can be derived from different substituents on aromatic rings. Each CPA catalyst has a slight difference in steric hindrance and inductive effect 
. The functional part of the catalyst contains both hydroxyl sites as proton donors and oxygen sites as proton acceptors 
. These enable CPA catalyst to adapt to a variety of reactions, and to change its skeleton and substituents according to the needs of different reactions, so that it can be better combined with the substrates and catalyze the reaction.
Scheme 3. Classification of CPAs.
Tan et al. made an early start in using CPAs to catalyze asymmetric cycloaddition/cyclization to construct axially chiral molecules. In 2017, they reported an asymmetric Paal–Knorr reaction to synthesize arylpyrroles, giving up to 95% yield and 98% ee (Scheme 4) 
. This general and efficient reaction has mild condition and wide adaption to many substituent groups. Remarkably, during screening solvents, they found that the configuration of the product depended on the solvent, wherein cyclohexane and ethanol gave opposite results. After further optimization, the product of S
-configuration could be stably obtained, although its yield and enantioselectivity were relatively low. Moreover, both of the reaction efficiency and enantioselectivity were promoted when Fe(OTf)3
was used as an additive, wherein the phosphoric acid C1
was activated by the Lewis acid. Further investigation shows 1a
is first condensed with 2
, and after undergoing the equilibrium of intermediates, enamine II
is generated, and then the product is obtained by the second condensation cyclization. This process is different from the Paal–Knorr reaction mechanism previously thought.
Scheme 4. Asymmetric Paal–Knorr reaction to synthesize N-arylpyrroles.
In the same year, Tan et al. reported a cyclization strategy catalyzed by CPA for the construction of arylquinazolinones (Scheme 5) 
. They successfully synthesized arylquinazolinones with excellent yields and enantioselectivities using N-aryl anthranilamides and benzaldehyde as substrates under CPA catalysis. In the reaction process, N-aryl anthranilamides were first condensed with benzaldehyde, and the condensation products formed hydrogen bonds with CPA. Under the induction of CPA, amido N atom conducted nucleophilic attack on imine C atom, and a proton exchange occurred with CPA to complete the ring closure.
Scheme 5. Tan’s arylquinazolinone synthesis and its reaction mechanism.