Bioactive CN Atropisomers.

In the last several years, atropisomers owing to the rotational restriction around a C-N single bond (C-N axially chiral compounds) have attracted significant attention in the field of synthetic organic chemistry. In particular, the highly enantioselective synthesis of various C-N axially chiral compounds and their application to asymmetric reactions have been reported by many groups. On the other hand, studies on the structural chemistry of C-N axially chiral compounds have attracted scant attention in comparison with synthetic studies. For over 25 years, our group has explored asymmetric synthesis of C-N axially chiral compounds and their synthetic application. In the course of these synthetic studies, we found several notable structural properties in relation to the C-N bond rotation and an association of enantiomers (the relationship between the rotational stability and the structure or electronic effect, the chirality-dependent halogen bond, and the self-disproportionation of enantiomers). Furthermore, on the basis of these structural properties, the development of acid-mediated molecular rotors and the synthesis of isotopic atropisomers possessing high stereochemical purity and rotational stability were achieved. Through this Perspective, I wish to make the chemistry community aware that C-N axially chiral compounds are attractive molecules from the viewpoints of both synthetic organic chemistry and structural chemistry.

Heterocyclic compounds are an important class of compounds in the field of pharmaceutical and synthetic organic chemistry. The Schiff bases contain azomethine linkages which are obtained by the condensation of aldehyde/ketone with amines. Among the various types of Schiff bases, the chalcone-based Schiff bases play a vital role in the treatment of various ailments and various applications, which can be synthesized by using different types of chalcones as the starting materials. These types of compounds were synthesized by using various techniques like conventional means of synthesis, microwave-assisted reaction, heterocyclic catalyst-mediated synthesis and also by means of trituration. The chalcone or bis-chalcone-based Schiff bases and their derivatives contain -C=N linkage which exhibits various activities including antimicrobial, anticancer, antioxidant, antidiabetic and immunosuppressant activities. Beyond these activities, these types of Schiff bases are also used in various chemical industries and fluorescent sensors, which also play a major role in the field of synthetic organic chemistry and coordination chemistry as intermediates. This review discusses the numerous synthetic strategies along with their applications in the field of medicine. Thus, this review will be helpful in developing more effective drug-like scaffolds for use in future drug design. Keywords: Schiff bases, Chalcone-based Schiff bases, Antimicrobial, Anticancer, Antioxidant, Biological Applications

Review: 174 refs.

Biaryl atropisomers are key structural components in chiral ligands, chiral functional materials, natural products, and bioactive compounds, and their asymmetric syntheses have been reported by many groups. In contrast, although the scientific community has long been aware of atropisomers due to rotational restriction around N-C bonds, they have attracted scant attention and have remained an unexplored research area. In particular, their catalytic asymmetric synthesis and the synthetic applications were unknown until recently. This Account describes studies conducted by our group on the catalytic enantioselective syntheses of N-C axially chiral compounds and their applications in asymmetric reactions.In the presence of a chiral Pd catalyst, the reactions of achiral secondary ortho-tert-butylanilides with 4-iodonitrobenzene proceeded in a highly enantioselective manner (up to 96% ee), affording N-C axially chiral N-arylated ortho-tert-butylanilides in good yields. The application of the present chiral Pd-catalyzed N-arylation reaction to an intramolecular version gave N-C axially chiral lactams with high optical purity (up to 98% ee). These reactions were the first highly enantioselective syntheses of N-C axially chiral compounds with a chiral catalyst. Since the publication of these reactions, N-C axially chiral compounds have been widely accepted as new target molecules for catalytic asymmetric reactions. Furthermore, chiral-Pd-catalyzed intramolecular N-arylations were applied to the enantioselective syntheses of N-C axially chiral quinoline-4-one and phenanthridin-6-one derivatives. We also succeeded in the enantioselective syntheses of various N-C axially chiral compounds using other chiral Pd-catalyzed reactions. That is, optically active N-C axially chiral N-(2-tert-butylphenyl)indoles, 3-(2-bromophenyl)quinazolin-4-ones, and N-(2-tert-butylphenyl)sulfonamides were obtained through chiral Pd-catalyzed 5-endo-hydroaminocyclization, monohydrodebromination (reductive asymmetric desymmetrization), and Tsuji-Trost N-allylation, respectively. The study of the catalytic asymmetric synthesis of axially chiral indoles has contributed to the development of not only N-C axially chiral chemistry but also the chemistry of axially chiral indoles. Subsequently, the catalytic asymmetric syntheses of various indole derivatives bearing a C-C chiral axis as well as an N-C chiral axis have been reported by many groups. Moreover, axially chiral quinazlolin-4-one derivatives, which were obtained through chiral Pd-catalyzed asymmetric desymmetrization, are pharmaceutically attractive compounds; for example, 2-methyl-3-(2-bromophenyl)quinazolin-4-one product is a mebroqualone possessing GABA agonist activity.Most of the N-C axially chiral products have satisfactory rotational stability for synthetic applications, and their synthetic utility was also demonstrated through application to chiral enolate chemistry. That is, the reaction of various alkyl halides with the enolate prepared from the optically active anilide, lactam, and quinazolinone products proceeded with high diastereoselectivity by asymmetric induction due to the N-C axial chirality.At the present time, N-C axially chiral chemistry has become a popular research area, especially in synthetic organic chemistry, and original papers on the catalytic asymmetric syntheses of various N-C axially chiral compounds and their synthetic applications have been published.

Asymmetric Nickel-Catalyzed Reactions

The enantioselective synthesis of organic compounds is one of the key issues to be resolved in the field of synthetic organic chemistry because chiral organic compounds are important as pharmaceutical products, agrochemicals, and fine chemicals. Until fairly recently, transition metal complexes and enzymes had been utilized primarily as catalysts for enantioselective synthesis. List, Lerner, and Barbas reported an aldol reaction catalyzed by ( S )‐proline, and MacMillan reported MacMillan's catalyst for the Diels–Alder reaction. Following these two seminal reports, organocatalysis has emerged as a novel asymmetric methodology viable for a number of transformations. Metal‐based catalysts, which are sensitive to oxygen and water, are therefore prepared in situ from a metal salt and a chiral ligand and employed directly. In contrast, asymmetric organocatalysts are generally stable and thus easy to handle. Recently, chiral organocatalysts were found to complement metal‐based catalysts. In this chapter, an overview of chiral organocatalysts, including the seminal work, is presented, focusing on the recently developed chiral Brønsted acid catalysts. The catalysts discussed include proline and derivatives, MacMillan's catalyst, peptide catalysts, ketone catalysts, phase‐transfer catalysts, amine catalysts, guanidinium salt catalysts, hydrogen‐bond catalysts, and Brønsted acid catalysts.

Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis of various biologically important molecules and therefore, gain tremendous attention worldwide. A wide range of synthetic routes to access these versatile molecules have been developed in the past decades. Transition metal-catalyzed cross-dehydrogenative coupling (CDC) has emerged as one of the utmost front-line research areas in current synthetic organic chemistry due to its high atom economy, efficiency, and viability. In this review, an up-to-date summary including scope, limitations, mechanistic studies, stereoselectivities, and synthetic applications of transition metal-catalyzed double Cvinyl-H bond activation for the synthesis of conjugated dienes has been reported since 2013. The literature reports mentioned in this review have been classified into three different categories, i.e. (a) Cvinyl-Cvinyl bond formation via oxidative homo-coupling of terminal alkenes; (b) Cvinyl-Cvinyl bond formation via non-directed oxidative cross-coupling of linear/cyclic alkenes and terminal/internal alkenes, and (c) Cvinyl-Cvinyl bond formation via oxidative cross-coupling of directing group bearing alkenes and terminal/internal alkenes. Overall, this review aims to provide a concise overview of the current status of the considerable development in this field and is expected to stimulate further innovation and research in the future.

In the periodic table of elements, indium is located within group 13, and has the atomic number 49. Indium is classified as one of the chemical elements of post-transition metals. Indium is silvery-white in color, soft, and possesses a high level of malleability. Although indium is a relatively rare element, it is indispensable in industry applications worldwide. German metallurgists discovered indium in 1863. It was not until the early 1990s, however, that scientists in the field of synthetic organic chemistry attempted genuine studies to explore the roles of indium or indium-related reagents. Focusing on indium or indium-related reagents, many recent investigations have led to significant advances in synthetic organic chemistry. Various applications have been examined and a growing number of useful chemical transformations using indium or indium-related reagents are being revealed and reported. Chemical transformations of the reactive functional groups are an essential point, particularly for the successful implementation of a sequence of multiple-step chemical schemes. For this purpose, a variety of strategic reaction methodologies have been developed, including those utilizing indium or indium-related reagents. Indium metal was discovered to be useful for the protection and deprotection of functional groups, while trivalent indium Lewis acids have been effective in a wide variety of chemical transformations. This chapter describes an efficient oxone-mediated esterification of aldehydes using indium(III) triflate, which is also one of the trivalent indium Lewis acids. Esterification is performed primarily on aromatic and heterocyclic aldehydes. The results show the effectiveness of this esterification methodology and suggest the potential in the further development of these reagents, which could enhance the field of synthetic organic chemistry.

Microwave-assisted organic reactions have been applied as an effective technique in organic synthesis. Microwave irradiation often leads to shorter reaction times, increased yields, easier workup, matches with green chemistry protocols, and can enhance the region and stereo selectivity of reactions. In fact, the high usefulness of microwave-assisted synthesis encouraged us to increase the efficiency of several organic transformations and synthesis. High-speed microwave-assisted chemistry has attracted a considerable amount of attention in recent years and has been applied successfully in various fields of synthetic organic chemistry, proteins, peptides, drug discovery, and green chemistry. The various roles of microwave-assisted organic chemistry in green and sustainable chemistry are discussed, beginning with the strategies, technologies, and methods that were employed routinely at the time of the first reports of microwave applications. Microwave processing has several advantages over conventional sintering/heating, such as the reduction in cycle time, energy efficiency, eco-friendliness, and providing finer microstructures, leading to improved mechanical properties. Herein, we also describe the evolution of the microwave and some early applications of microwave assistance in the biomolecular sciences and treatment of solid malignant tumors.

Atropisomeric compounds and 1,3-disubstituted allenes are the most common examples of axial chirality in organic chemistry. However, there are less explored classes of axially chiral molecules that may also hold significant value in asymmetric synthesis. Here, we report a catalytic asymmetric synthesis of axially chiral methylenecyclopropanes by a [2 + 1]-cycloaddition of an alkene and a vinylidene equivalent. Computational models provide a rationale for the origin of asymmetric induction and indicate that key elements of stereocontrol differ from catalytic enantioselective cyclopropanation reactions using carbenes. Methylenecyclopropanes participate in a broad range of axial-to-central chirality transfer reactions that take advantage of addition to the alkene or ring-opening of the strained three-membered ring.

Chem-istry Is a Force for Good

ConspectusAsymmetric transition-metal catalysis stands as a cornerstone in the construction of molecules with stereogenic centers, profoundly impacting modern organic synthesis. Over the past decades, catalytic asymmetric synthesis has witnessed remarkable advancements, largely driven by the development of sophisticated chiral ligands. While chiral phosphorus ligands have experienced rapid growth and widespread application, chiral N-heterocyclic carbene (NHC) ligands remain underexplored, primarily due to the inherent challenges in designing and synthesizing suitable chiral frameworks. Given the unique topology and modular steric environment of NHCs, the development of novel NHC ligands holds significant promise.In our pursuit of broadly applicable and privileged catalysts with innovative structural motifs, we have developed a family of induced-fit chiral NHC ligands based on the privileged chiral fragment strategy using a C2-symmetric chiral aniline. These ligands are characterized by their ease of structural modification, bulky yet flexible nature, and versatile utility in asymmetric metal catalysis. Notably, they can be synthesized on a large scale from inexpensive starting materials without the need for column chromatography, offering a modular and straightforward preparation method that facilitates further exploration of their applications in asymmetric reactions. In this Account, we summarize recent progress in our group regarding the diverse and unique applications of these induced-fit NHC ligands in Pd-, Ni-, and Cu-catalyzed asymmetric reactions, encompassing reaction types, substrate scope, stereocontrol steps, and mechanistic insights. Our work is categorized into five sections based on reaction types: asymmetric cross-coupling reactions, asymmetric functionalization of alkenes, asymmetric hydrogen transfer reactions, asymmetric C-H functionalization reactions, and asymmetric nucleophilic addition reactions. These studies demonstrate the broad utility of the ligands in asymmetric catalysis, with their bulky yet flexible nature enabling adaptive stereocontrol across diverse elementary steps and challenging transformations.We anticipate that this Account will not only broaden the application of this class of chiral ligands but also inspire the design of new chiral NHC ligands for transition-metal-catalyzed asymmetric reactions. We believe that continued efforts focused on bulky yet flexible NHC ligands will offer practical solutions to critical challenges in chemical synthesis, further advancing the field of asymmetric catalysis.

Open AccessCCS ChemistryRESEARCH ARTICLE24 May 2022Inherently Chiral 6,7-Diphenyldibenzo[e,g][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform Yu Luo, Xilong Wang, Weiming Hu, Yan Peng, Chaoqin Wang, Ting Yu, Sidi Cheng, Jing Li, Yimiao He, Chunfang Gan, Shuang Luo and Qiang Zhu Yu Luo State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Xilong Wang State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Weiming Hu State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Yan Peng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Chaoqin Wang State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Ting Yu State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Sidi Cheng State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Jing Li State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 , Yimiao He Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 , Chunfang Gan Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 , Shuang Luo *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 and Qiang Zhu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049 Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, College of Chemistry and Materials, Nanning Normal University, Nanning 530001 https://doi.org/10.31635/ccschem.022.202201901 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Inherently chiral 6,7-diphenyldibenzo[e,g][1,4]diazocine (DDD) has been synthesized enantioselectively for the first time via chiral phosphoric acid (CPA)-catalyzed cyclocondensation of readily available [1,1′-biphenyl]-2,2′-diamine ( 1a) and benzil ( 2a) in 82% yield, with 98% ee under mild reaction conditions. The strategy could also be applied to racemic biaryl diamines through kinetic resolution. The unexpectedly high interconversion energy barriers between the enantiomers (ΔG = 39.5 kcal/mol) and the chemical stability rendered DDD an ideal platform for developing new chiral ligands and catalysts. Unique inherently chiral DDD-based phosphoramidites, phosphoric acid, mono- and diphosphine ligands were prepared from optically pure diphenol derivative DDDOL as a common precursor. Preliminary asymmetric reactions catalyzed by Pd or Rh in the presence of newly developed ligands exhibited comparable or even better enantioselectivities than the corresponding BINOL- or SPINOL-derived ligands. Density functional theory calculation revealed the origin of the enantioselectivity during the process. Download figure Download PowerPoint Introduction The term "inherent chirality" was first introduced by Böhmer et al.1 in 1994 to describe chirality observed in calix[4]arene substituted non-symmetrically. Free interconversion between the concave conformers was restricted due to steric hindrance arising from the lower-rim modification. Thus, the stabilized curvature devoid of symmetry was not superimposable on its mirror image that was chiral by definition. In other words, inherent chirality was established as an intrinsic character of a cyclic molecule, even if it lacks conventional chiral factors such as central, axial, planar, and helical chirality (Figure 1a, left). From then on, the terminology has been gradually applied to macromolecules and supramolecules possessing similar structural characteristics, such as rotaxanes, catenanes, fullerenes, cavitands, and capsular assemblies.2–5 Since inherently chiral calixarenes and other macromolecules have played an increasingly important role in chiral recognition and asymmetric catalysis,6,7 accessing these molecules in enantiomerically pure form is of great significance but also a formidable challenge. For example, enantioenriched calix[4]arene derivatives are mainly obtained by high-performance liquid chromatography (HPLC) separation of racemic mixtures using a chiral stationary phase or by forming diastereomers with a chiral auxiliary.8 Attempts of enantioselective catalytic synthesis of inherently chiral macrocycles led to very poor results (up to 35% ee).9 In 2020, Tong et al.10 reported the first successful asymmetric synthesis of macrocyclic heteracalix[4]aromatics through Pd-catalyzed intramolecular C–N coupling with high enantioselectivity (Figure 1a, right). Figure 1 | Inherently chiral compounds and their asymmetric catalytic synthesis. Download figure Download PowerPoint Cyclic molecules with rigid non-planar conformation smaller than calix[4]arene can also exhibit inherent chirality. For instance, replacing the four methylene linkages in calix[4]arene by four σ-bonds and changing the linking substitution site from meta to ortho positions of the phenyl units leads to an eight-membered ring system named tetraphenylene which has a unique saddle-shaped structure with extraordinary rigidity (ΔG approximately 80 kcal/mol!).11,12 Non-symmetrically substituted tetraphenylenes are inherently chiral molecules, which have been studied extensively by Wong and coworkers.11,13–23 Although many methods have been developed to prepare racemic tetraphenylene derivatives; the enantioenriched ones are obtained mainly by HPLC separation or resolution of racemic mixtures. A breakthrough in the asymmetric synthesis of tetraphenylenes was realized by Shibata et al. in 2009, in which a novel Rh-catalyzed [2+2+2] cycloaddition of two phenylene-bridged 1,6,10-triynes was developed to deliver inherently chiral tetraphenylenes in up to 99% ee (Figure 1b).24,25 Overall, the study of inherently chiral small molecules, including their structural characteristics, enantioselective synthesis, and applications, has been long neglected. 6,7-Diphenyldibenzo[e,g][1,4]diazocine (DDD), an intuitively achiral eight-membered N-heterocycle, possesses an inflexible saddle-shaped configuration similar to that of tetraphenlene. Density functional theory (DFT) calculation suggests that the interconversion energy barrier is as high as 39.5 kcal/mol,26 indicating the existence of inherent chirality in this aza analog of tetraphenlene (Figure 1c, left). The first report for the synthesis of racemic DDD by thermal condensation of [1,1′-biphenyl]-2,2′-diamine and benzil dates back as early as 1892.27 In 1963, an optically pure 4,4′-diester derivative of DDD was obtained by resolution; a study of its enantiomeric stability showed that no reaction or racemization took place upon heating at 200 °C in mesitylene for 24 h.28 The ignored inherent chirality in DDD stimulated our interest in considering its enantioselective preparation and synthetic application. Our initial attempt relied on the hypothesis that a palladium-catalyzed double isocyanide insertion applying 2,2′-diisocyano-1,1′-biphenylbisisocyanide A would lead to a key dibenzo[e,g][1,4]diazocine-based palladium intermediate B. Transmetallation of B with aryl boronic acid, followed by reductive elimination would furnish 6,7-diaryldibenzo[e,g][1,4]diazocine, and in the presence of chiral ligand, enantioenriched DDD derivatives C will be obtained expectantly (Figure 1c, from A to C). Unfortunately, this hypothesized reaction sequence failed to give the desired product C in the presence of aryl boronic acid. Instead, another inherently chiral saddle-shaped product D was produced with high ee when cesium carboxylate was used (Figure 1c, from A to D).26 The failure of Pd-catalyzed enantioselective synthesis of DDD made us turn back to the century-old chemistry, condensation of [1,1′-biphenyl]-2,2′-diamine with benzyl. Inspired by recent achievements involving chiral phosphoric acid (CPA) in asymmetric catalysis,29–32 we hypothesized that optically pure DDD could be accessed by CPA-catalyzed asymmetric cyclocondensation of [1,1′-biphenyl]-2,2′-diamine and benzil under metal-free conditions (Figure 1d). When racemic biaryl diamines were used, it was possible to realize kinetic resolution to give value-added axially chiral diamines and DDD derivatives ready for ligand design. Experimental Methods In air, a 35 mL reaction tube was charged with [1,1′-biphenyl]-2,2′-diamines 1 (0.11 mmol), benzil 2 (0.1 mmol), and CPA (10 mol %). The tube was evacuated and filled with argon three times. Then, tetrahydrofuran (THF) or tetrahydropyran (THP) (0.1–0.2 mL) was added to the tube and sealed with a Teflon screwcap. The mixture was stirred at 35–75 °C for 24–72 h. After cooling to room temperature, the reaction mixture was directly loaded onto a low-pressure flash column (SYNTHWARE GLASS, C184171) packed with column chromatography silica gel (Qingdao Ocean, 100–200 mesh) by a minimal amount of CH2Cl2, and using petroleum ether/ethyl acetate as eluent to give the corresponding product 3. Following the procedure of phase separation mentioned in Supporting Information Figure S1, product 3 with increased optical purity was obtained. Results and Discussion To test our hypothesis, cyclocondensation of [1,1′-biphenyl]-2,2′-diamine ( 1a) with benzil ( 2a) catalyzed by CPA was investigated (Table 1). The result of the initial test with unsubstituted 1,1′-bi-2-naphthol (BINOL)-derived C1 (30 mol %) in dioxane at 65 °C for 24 h was encouraging, delivering the desired cyclization product 3aa in 63% yield with 22% ee (entry 1). Varying solvent revealed that the reaction proceeded more efficiently in THF; even the catalyst loading was reduced to 10 mol % (entry 4). Next, BINOL-based CPAs with substituents at the 3,3′-positions were screened. Except for bulky triphenylsilyl-substituted C3, 3,3′-diphenyl BINOL-CPA C2 and all of its aryl analogs were able to promote the cyclization but with low to moderate enantioselectivities (entries 5–14). Unfortunately, 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived CPAs were ineffective in this case (entries 15–18). We found that H8-BINOL-based C16 could catalyze the reaction with slightly better ee than the BINOL analog C4 (entry 19 vs. entry 7). Intriguingly, the reaction was accelerated substantially at higher concentrations. When the amount of THF was minimized to 0.15 mL, 3aa was formed almost quantitatively with 68% and 76% ee in the presence of C16 and C18, respectively (entries 21–22). The enantioselectivity increased slightly to 81% ee when the reaction was carried out at 50 °C (entry 23). Accidentally, we found that the solubility of racemic and optically pure 3aa in isopropanol was quite different.33–35 After purification by column chromatography, 2 mL of isopropanol was added to the isolated product, followed by ultrasonic mixing for 2 min and precipitation of racemic 3aa. Subsequently, the product, which remained in solution, was obtained by removing solvent to give 3aa in 82% yield with excellent optical purity (98% ee, entry 24; see the detailed procedures in Supporting Information Figure S1). Interestingly, CPAs C18 and C19 had opposite asymmetric induction, although both catalysts had the same configuration (entry 23 vs entry 24).36–40 Table 1 | Optimization of the Reaction Conditionsa Entry Catalyst Solvent Yield (%) ee (%) 1 C1b Dioxane 63 −22 2 C1b DME 56 −14 3 C1b THF 77 −31 4 C1 THF 60 −21 5 C2 THF 54 61 6 C3 THF 0 / 7 C4 THF 61 64 8 C5 THF 78 −59 9 C6 THF 69 26 10 C7 THF 59 33 11 C8 THF 63 −16 12 C9 THF 52 −57 13 C10 THF 50 −57 14 C11 THF 76 −29 15 C12 THF 0 / 16 C13 THF 34 −3 17 C14 THF Trace −11 18 C15 THF 15 5 19 C16 THF 60 66 20 C17 THF 61 65 21c C16 THF 99 68 22c C18 THF 99 76 23 c, d C18 THF 98(82) e 81(98) e 24 C19 THF 51 −40 aReaction conditions: 1a (0.11 mmol), 2a (0.10 mmol), CPA (10 mol %) in 1.0 mL of solvent, 65 °C, 24 h, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. DME, 1,2-dimethoxyethane. b30 mol %. c0.15 mL of THF. d50 °C. ePhase separation. Following the identification of optimal reaction conditions and postreaction procedures (entry 23), the scope of benzils ( 2) was first explored in reactions with 1a. The substrates were insoluble in 0.15 mL THF; thus, we increased the volume to 0.2 mL of the solvent. As shown in Scheme 1, as expected, symmetric benzils with electron-withdrawing groups, including F, Cl, and Br, at the para-positions were more reactive than those with electron-donating groups. Although an extended reaction time and a higher temperature were required for OMe-substituted benzil, all of the corresponding products 3aa–3af were obtained in 68%–82% yields with excellent enantioselectivities (94–98% ee). The reaction was sluggish for ortho-methyl-substituted benzil 1g, which required 72 h at 65 °C to give 3ag in 73% yield with 72% ee without phase separation. Interestingly, in the case of 3ah, an optically pure product was precipitated after treatment with isopropanol instead of the racemate. For unsymmetric benzil 2i, cyclocondensation also proceeded smoothly ( 3ai, 72% yield, 96% ee). However, when phenyl methyl 1,2-diketone was applied, no enantioselectivity was observed for the corresponding cyclization product 3aj. Importantly, the unique pyridine-containing structure of 3ak, a potential chiral N,N-ligand,41 was accessed with 99% ee, albeit in low yield due to unidentified side-product formation. It's worth mentioning that when using symmetric tetraketone 2,2′-(1,4-phenylene)bis(1-phenylethane-1,2-dione) 2l in condensation with 1.0 equiv of 1a, 3al containing unreacted 1,2-diketone moiety was obtained in 82% yield with 80% ee. When 2l reacted with an excess amount of 1a, double condensation occurred smoothly, giving a mixture of diastereomers 3am in 98% ee and 3an as a meso-isomer in a 5∶1 ratio. Scheme 1 | The scope of benzyls.aaReaction conditions: 1a (0.11 mmol), 2 (0.10 mmol), (R)-C18 (10 mol %), THF (0.15 mL), 50 °C, 24 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. bTHF (0.2 mL). c40 °C. d36 h. e65 °C, 48 h. f65 °C, 72 h, without phase separation. g(R)-C19, 48 h, the optical product was precipitated. h(R)-C16. i1a (0.1 mmol), 2 (0.3 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. j1a (0.3 mmol), 2 (0.1 mmol), THP (0.1 mL), 35 °C, 72 h, without phase separation. kNo racemization and decomposition were observed upon heating in dry mesitylene at 250 °C for 24 h. THP, tetrahydropyran. Download figure Download PowerPoint Next, the compatibility of substituted [1,1′-biphenyl]-2,2′-diamines ( 1) was investigated (Scheme 2). When diamines ( 1) bearing OMe, Me, or F at the 4,4′ positions were applied, the corresponding cyclocondensation products 3ba, 3ca, and 3fa were obtained in moderate yields with excellent enantioselectivities catalyzed by C19 following the standard phase separation. However, diamines 1d and 1g substituted with strong electron-withdrawing CF3 or CN groups were found unsuitable in condensation with 2a, resulting in low yields of 3da and 3ga. Less electron-deficient 4,4′-diester-substituted derivative 3ea was accessed in 80% yield with 82% ee. We found that substituents at the para positions of 1 had little effect on both yield and enantioselectivity. For example, the yield for electron-withdrawing F substituted 1h was slightly lower than that for 1k substituted with electron-donating OMe ( 3ha vs. 3ka). Both 3ia (Cl) and 3ja (Me) were obtained in excellent yields with high ee. Unsymmetrical isopropyl-substituted 1l could cyclize with 2a very efficiently; however, the enantiomeric purity of the corresponding product 3la could not be enriched by precipitation of the racemate (99% yield, 86% ee). It was not surprising that condensation of sterically hindered 1m with 2a was inefficient in terms of both yield and enantioselectivity ( 3ma, 42% yield, 60% ee). Scheme 2 | The scope of [1,1′-biphenyl]-2,2′-diamines.aaReaction conditions: 1 (0.11 mmol), 2a (0.10 mmol), (R)-C19 (10 mol %), THF (0.15 mL), 50 °C, 36 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b48 h. c(R)-C16, THF (0.2 mL), 65 °C. d(R)-C18. e1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 72 h. f1 (0.1 mmol), 2a (0.3 mol), THP (0.1 mL), 35 °C, 48 h. gWithout phase separation. Download figure Download PowerPoint Next, 6,6′-mono- and disubstituted [1,1′-biphenyl]-2,2′-diamines in which rotation around the aryl-aryl axis was hindered under varying degrees were investigated in condensation with 2a (Scheme 3). Racemic 6,6′-difluoro-[1,1′-biphenyl]-2,2′-diamine 1n reacted with 2a smoothly to give 3na in 86% yield with 85% ee through dynamic kinetic resolution (DKR) (for enantiomerization study of 1n see the Supporting Information Tables S2 and S3 and Figures S2 and S3). In addition, other biaryldiamines with unstable chiral axis such as 6-methyl-[1,1′-biphenyl]-2,2′-diamine 1o and 1-(2-aminophenyl)naphthalen-2-amine 1p were also fully converted to the corresponding products 3oa and 3pa in good yields, with 90% and 97% ee, respectively. After the DKR of biaryldiamines with unstabilized axial chirality, the kinetic resolution of stabilized biaryldiamines was studied. Unfortunately, only moderate enantioselectivities (50%–55% ee) were observed for DDD analogs 3qa– 3sa, and unreacted 1q– 1s were recovered in low enantiomeric purity (30–36% ee). However, when 6,6′-dimethoxy-[1,1′-biphenyl]-2,2′-diamine 1t was applied to condense with 2a in the presence of (R)- C18 as a catalyst, 3ta was isolated in 49% yield with a moderate 68% ee. Enantioenriched 3ta (35% yield, 99% ee) was obtained through the simple operation of phase separation in sacrificing an acceptable amount of the racemate. The absolute configuration of 3ta was confirmed by X-ray diffraction.a Notably, the other enantiomer of 3ta could be accessed by reaction of the recovered (R)- 1t (57% ee) with 2a in the presence (S)- C18 under otherwise identical conditions (see the detailed requirements in the Supporting Information). Therefore, both of the enantiomers of 3ta were accessed in excellent optical purity (99% ee). Scheme 3 | Kinetic resolution of racemic 1.aaReaction conditions: 1 (0.1 mmol), 2a (0.3 mol), (R)-C18 (10 mol %), THP (0.1 mL), 35 °C, 48 h, in a sealed tube, isolated yield, ee was determined by HPLC analysis using a chiral stationary phase. b(R)-C4, rt, 3 days. c(R)-C4, 35 °C, 48 h. d(R)-C4, rt, 4 days. e1t (0.5 mmol), 2a (1 mmol), THF (0.35 mL), 50 h. fphase separation. gs = ln[(1 − C)(1 − ees)]/ln[(1 − C)(1 + ees)], Conversion (C) = ees/(ees + eep). Download figure Download PowerPoint Scheme 4 | Preparation of DDD-based phosphoramidites, CPA, and phosphorus ligands. Conditions: (a) hexamethylphosphorous triamide (HMPT), toluene, 115 °C, 6 h; or hexaethylphosphoruo triamide (HEPT), toluene, 115 °C, 6 h; or (1) diisopropylamine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h; or (1) (R)-bis((R)-1-phenylethyl)amine, PCl3, NEt3, DCM, 0 °C, 7 h, (2) (-)-DDDOL, NEt3, DCM, rt, 18 h. (b) (1) POCl3, pyridine, 80 °C, 5 h, (2) H2O, 50 °C, 12 h, (3) 3 N HCl, 100 °C, 30 min. (c) (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) toluene, 100 °C, 24 h, Pd(OAc)2, DIPEA, HP(O)Ph2, DMSO, 100 °C, 14 h. (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, DIPEA, DMSO, °C, 18 h. (1) Tf2O, C5H5N, DCM, rt, 24 h, (2) Pd(OAc)2, dppp, DIPEA, HP(O)Ph2, DMSO, 100 °C, 24 h, (3) toluene, 100 °C, 24 h. DMSO, DIPEA, Download figure Download PowerPoint The structure of 3ta that the biaryl was approximately which was similar to that of The rigid configuration and of enantiomeric 3ta us to new ligands on this As shown in Scheme of 3ta as a key intermediate in 72% yield with of the ( (Scheme 4). a of ligands were readily prepared by from DDDOL in Next, CPA was prepared with a moderate DDD-based mono- and ligands were synthesized in in In addition, 4 could also as a to form ligand in 63% yield after three of It is worth mentioning that racemization decomposition was observed during these although conditions were applied, such as heating at °C for 18 h in Pd-catalyzed using in and using in of to the absolute of and were confirmed by X-ray (Scheme Scheme 5 | of in asymmetric Download figure Download PowerPoint these DDDOL derivatives in their as potential chiral ligands in asymmetric reactions were Rh-catalyzed asymmetric of 5 was to test with three other available as ligands (Scheme the reaction giving derivative 6 quantitatively in ee. The used and led to or slightly better Importantly, the moiety in DDD was upon even under high Next, the of as a ligand was in the of acid to 7 catalyzed by (Scheme Although and the ligand showed comparable asymmetric induction, the yield of 9 was better for the reaction using as a To our in the asymmetric reaction catalyzed by was to be an excellent ligand, delivering 12 in 98% yield with ee (Scheme The of in Pd-catalyzed reaction was also investigated to C–N derivatives (Scheme results for the reactions of with acetate catalyzed by in the presence of and that both of the ligands could promote the reaction in high yields but with poor enantioselectivities ( ee). We found that a methyl on the of acetate was for the of the corresponding ee). However, when acetate was used as the both the yield and ( yield, 42% ee). when a acetate derivative was applied, in which an chiral was the enantioselectivity for the ee ( after both of and Pd-catalyzed reaction in the presence of derivative containing both C–N axial chirality and chirality in excellent yield enantioselectivity ee) and It is that was produced in a lower yield with as the ligand under otherwise identical conditions. Although methods have been developed to axially chiral C–N compounds to the of our of and axis chirality through Pd-catalyzed has not been reported results that could be a chiral ligand to in catalyzed asymmetric Scheme 6 | Application of in the asymmetric of C–N axis configuration is from similar DCM, Download figure Download PowerPoint The result of these inherently chiral DDD-based ligands in of reactions us to study the of with ligands in To this mixing and in a that was from X-ray analysis of the revealed that the was smaller than that in and to that in (Scheme As we the of a ligand a role in the chiral of an asymmetric Therefore, to the of the in these palladium with asymmetric induction, a Pd-catalyzed of 15 was investigated (Scheme the same reaction in the presence of and ligand derivative 16 bearing axial chirality was obtained with 0 and 60% ee, respectively. When was 16 was obtained in ee. result that could be an ideal to and when chiral ligands for asymmetric catalytic Scheme 7 | and of Download figure Download PowerPoint Next, we explored the reaction and of enantioselectivity with 1a and benzil 2a as Since the first was not for the chirality the calculation with (Figure 2). The energy of the for the condensation was (Figure After by CPA ( ( the moiety of an intramolecular by the via the by the CPA with chiral were including two of ( The rotation barrier of the biaryl in was the energy between the diastereomers and was (Figure As a could be by

Development of efficient chiral catalyst continues to be an important challenge in the fields of synthetic organic chemistry and medicinal chemistry. Although metal-based Lewis acid catalysts had been extensively studied for the activation of carbonyl group and imine, chiral Brønsted acid has emerged in the beginning of 21st century. We synthesized chiral phosphoric acid, derived from (R)-BINOL, and demonstrated its catalytic activity in the Mannich-type reaction as a chiral Brønsted acid in 2004. Chiral phosphoric acid functioned as bifunctional catalyst bearing both basic site and Brønsted acidic site. The 3,3’-substituents play an important role. Since then, chiral phosphoric acid catalysis has become a popular research area, and its utility has been remarkably expanded. In this article, we will describe the development of chiral phosphoric acid and recent progress of the chiral phosphoric acid catalysis from our research group, in particular following topics; 1) transfer hydrogenation reaction of ketimines by use of benzothiazoline as a hydrogen donor, and oxidative kinetic resolution of indolines, 2) Friedel-Crafts alkylation reaction of indoles, and 3) enantioselective synthesis of chiral biaryls by bromination and transfer hydrogenation. In addition, several tips for using chiral phosphoric acid are also described.

Asymmetric domino reactions. Part B: Reactions based on the use of chiral catalysts and biocatalysts