キラルブレンステッド酸触媒の創製と新展開

CONSPECTUS: The asymmetric reduction of ketimines is an important method for the preparation of amines in optically pure form. Inspired by the biological system using NAD(P)H, Hantzsch ester has been extensively employed as a hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation of ketimines to furnish amines with high to excellent enantioselectivities. We focused on 2-substituted benzothiazoline as a hydrogen donor in the phosphoric acid catalyzed transfer hydrogenation reaction of ketimines for the following reasons: (1) benzothiazoline is readily prepared just by mixing 2-aminobenzenethiol and aldehyde, (2) both reactivity (hydrogen donating ability) and enantioselectivity would be controlled by tuning the 2-substituent of benzothiazoline, and (3) benzothiazoline can be stored in a refrigerator under inert atmosphere without conceivable decomposition. Both the 2-position of benzothiazoline and the 3,3'-position of phosphoric acid are tunable in order to achieve excellent enantioselectivity. Benzothiazoline proved to be useful hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation reaction of ketimine derivatives to afford the corresponding amines with high to excellent enantioselectivities by tuning the 2-substituent of benzothiazoline. Ketimines derived from acetophenone, propiophenone, α-keto ester, trifluoromethyl ketone, and difluoromethyl ketone derivatives proved to be suitable substrates. Benzothiazoline could be generated in situ starting from 2-aminobenzenethiol and aromatic aldehyde in the presence of ketimine and chiral phosphoric acid and successfully worked in the sequential transfer hydrogenation reaction. The reductive amination of dialkyl ketones also proceeded with high enantioselectivities. Use of 2-deuterated benzothiazoline led to the formation of α-deuterated amines with excellent enantioselectivities. The kinetic isotope effect (kH/kC = 3.8) was observed in the competitive reaction between H- and D-benzothiazoline, which explicitly implies that the cleavage of the C-H (C-D) bond is the rate-determining step in the transfer hydrogenation reaction. Benzothiazoline yielded products with higher enantioselectivity in the transfer hydrogenation reaction of ketimines, particularly ketimines derived from propiophenone derivatives, than Hantzsch ester. DFT study elucidated the mechanism, as well as the difference in selectivity, between benzothiazoline and Hantzsch ester. The chiral phosphoric acid activates ketimines and benzothiazoline by means of the Brønsted acidic site (proton) and the Brønsted basic site (phosphoryl oxygen), respectively, to accelerate the hydride transfer reaction.

Recent advances in chiral phosphoric acid catalyzed asymmetric organic reactions: An overview

Uhle’s ketone and its derivatives are highly versatile intermediates for the synthesis of a variety of 3,4-fused tricyclic indole frameworks, i.e. indole alkaloids of the ergot family, that are found in various bioactive natural products and pharmaceuticals. Therefore, the development of a convenient preparative method for this structural motif as well as its opportune/useful derivatization have been the subject of longstanding interest in the fields of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent and less recent methods for the preparation of Uhle’s ketone and its derivatives as well as its main reactivity towards the synthesis of bioactive substances. Regarding the preparation, it can be roughly classified into two categories: (a) using 4-unfunctionalized and 4-functionalized indole derivatives as starting materials to construct a fused six-member ring, and (b) constructing the indole ring through intramolecular cycloaddition. Principally, the reactivity of the cyclic Uhle’s ketone shown here is derived from the classical electrophilicity of the carbonyl carbon or the acidity of the α-hydrogen and, though less intensively investigated, chemical reactions that induce ring expansion to form novel ring skeletons.1 Introduction2 Synthesis2.1 Disconnection A: Cyclization Reaction of the Opportune 3,4-Disubstituted Indole2.2 Disconnection B: Intramolecular Friedel–Crafts Cyclization2.3 Disconnection B: Intramolecular Cyclization via Metal–Halogen Exchange2.4 Disconnection C: Intramolecular Diels–Alder Furan Cycloaddition2.5 Disconnection D: Intramolecular Dearomatizing [3 + 2] Annulation3 Reactivity3.1 Use of Uhle’s Ketone for Lysergic Acid3.2 Use of Uhle’s Ketone for Rearranged Clavines3.3 Use of Uhle’s Ketone for Medicinal Chemistry4 Conclusion and Outlook

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.

A survey of the literature reveals that both coumarin and the 1,2,3-triazole nucleus have important and well-recognized biological and pharmaceutical activities. Furthermore, these fused scaffolds have demonstrated biological significance, making the design and development of coumarin-1,2,3-triazole hybrids a topic of great interest in the field of synthetic organic chemistry and medicinal chemistry. The wide-ranging applications of coumarin and triazole have stimulated interest among researchers to develop various methodologies for synthesizing new molecules incorporating these moieties. Consequently, numerous research and review articles have been published on the subject. In this review, we present some research conducted over the past five years on bioactive coumarin-1,2,3-triazole hybrids, with an emphasis on the synthesis of these compounds and their biological applications in the treatment of infectious diseases, cancer, and Alzheimer’s disease.

Abstract3,4‐Fused tricyclic indole frameworks are found in various bioactive natural products and pharmaceuticals. The development of an efficient synthetic method for this structural motif has therefore attracted attention in the field of synthetic organic chemistry and medicinal chemistry. Herein, we summarize recent advances in the synthesis of 3,4‐fused tricyclic indoles. This class of synthetic methods can be roughly classified into two categories: methods using functionalized indole derivatives as starting materials to construct a fused medium‐sized ring (Types A–D: Category I), and methods of constructing a 3,4‐fused tricyclic indole skeleton via indole ring formation (Types E–G: Category II). In this focus review, synthetic methods for 3,4‐fused tricyclic indoles classified as Category II methods are highlighted, following a brief overview of the Category I methods.

: Pyrimidobenzothiazoles and its derivatives are important structural scaffolds in the field of synthetic organic chemistry and medicinal chemistry. The review is focused on one pot multicomponent approaches for generating pyrimidobenzothiazoles and its derivatives along with their interesting biological profile over the last ten years. Several eco-benign and cost effective approaches such as nano catalyst, ionic liquid, metal, solid acid, catalyst free, solvent free, etc. for its synthesis have been discussed in this review. Different synthetic strategies of pyrimidobenzothiazole derivatives have been compiled and discussed using 2-aminobenzothiazole, 1,3 diketones, substituted aldehydes, alkynoic acid, bis-methyl thiomethylene malononitrile, Baylis Hillman acetates, etc.

The past two decades have witnessed unprecedented development and advancement of chiral phosphoric acid catalysis. Therefore, it is not surprising that the attempts to synthesize enantioenriched axially chiral compounds via chiral phosphoric acid catalysis have achieved fruitful results in recent years although this area of research is still in its infancy. A number of structurally important heterocycles with chiral atropisomerism have been successfully designed and prepared by chiral phosphoric acid promoted transformations involving diverse strategies: including direct coupling, de novo formation of a heterocyclic ring and functionalization of prochiral or racemic substrates. In this minireview, we would like to highlight the advances in the field of atropisomeric heterocycles construction enabled by chiral phosphoric acid catalysis. In addition, this Minireview is organized based on the different types of atropisomeric heterocyclic frameworks generated covering quinoline, pyrrole, indole, benzimidazole, quinazolinone, isoindolinone, urazole, pyrazole and so on. We hope that this Minireview will motivate continuous interest on chiral phosphoric acid catalyzed atroposelective reactions.

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

The facile synthesis of a porous heterogeneous BINOL-derived chiral phosphoric acid BiCz-POF-1 using the mild, FeCl3-promoted oxidative polymerization is reported. For the first time, carbazole is introduced at the 3,3'-positions of the chiral BINOL-derived phosphoric acid to (1) offer steric hindrance for achieving a high enantioselectivity and (2) serve as a cross-linker for the construction of the porous solid catalyst. BiCz-POF-1 exhibits remarkable catalytic activity and enantioselectivity toward transfer hydrogenation of 1,4-benzoxazine, 1,4-benzoxazinone, and 2-phenylquinolone. Combined with its facile synthesis and excellent recyclability, BiCz-POF-1 represents a new class of heterogeneous chiral phosphoric acid that has wide potential utility in enantioselective organocatalysis.

Herein, recent developments in the field of organocatalytic asymmetric transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asymmetric catalysis relies on metal‐free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asymmetric reduction of α,β‐unsaturated carbonyl compounds, imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asymmetric transfer hydrogenations.

Asymmetric hydrophosphonylation reaction of aldimines with dialkyl phosphites proceeds catalytically by means of a phosphoric acid diester, derived from (R)-BINOL, as a chiral Brønsted acid to afford alpha-amino phosphonates with good to high enantioselectivities (up to 90% ee). The use of the aldimines derived from cinnamaldehyde derivatives and sterically demanding dialkyl phosphites was essential for achieving high enantioselectivity as well as high yield. To elucidate the reaction mechanism and the origin of the high enantioselectivity, DFT calculation (BHandHLYP/6-31G*) was carried out. The reaction proceeds via the nine-membered zwitterionic transition state (TS) with the chiral phosphoric acid, where aldimine and phosphite could be activated by the Brønsted acidic site and Lewis basic site, respectively. The si-facial attacking TS could be less favored by the steric repulsion of 3,3'-aryl groups on the chiral phosphoric acid with the bulky phosphite. When using the aldimine derived from benzaldehyde, the re-facial attacking TS is destabilized to decrease the enantioselectivity in agreement with the experimental results.

Chiral phosphoric acids (CPAs) have emerged as versatile catalysts for asymmetric catalysis, capable of transforming a wide selection of substrates with high stereoselectivities. However, the mechanistic role of higher aggregates in CPA-catalyzed reactions remains poorly understood, although increasing evidence suggests that dimeric and trimeric CPA species can promote challenging transformations. This work provides comprehensive experimental evidence demonstrating that special [CPA/imine]2 species critically enhance the reactivity and selectivity in CPA-catalyzed Mannich-type reactions with imines bearing an N-2-hydroxyphenyl moiety. Using low-temperature NMR spectroscopy, diffusion-ordered spectroscopy (DOSY), and molecular dynamics (MD) simulations, we revealed that imines with a N-2-hydroxyphenyl moiety promote the formation of dimeric [CPA/imine]2 aggregates, while monomeric CPA/imine complexes dominate, with imines lacking this moiety. [CPA/imine]2 formation is favored under low-temperature and high-concentration conditions. Dimers with sufficient structural flexibility provide enhanced reactivity, acidity, and selectivity. In contrast, at higher temperatures, where no [CPA/imine]2 aggregates are formed, the Mannich-type reaction proceeds inefficiently. A nonlinear effect analysis provided evidence of asymmetric amplification in the present Mannich-type reaction, proving the participation of aggregated species in the reaction pathway. Together, these results highlight the importance of controlling catalyst aggregation as a strategy to optimize the reactivity and selectivity in asymmetric organocatalysis.

金属配合物和有机小分子双体系联合催化的不对称接力催化反应是一新兴热点研究领域. 接力催化可以由易得的起始原料生成结构复杂的化合物, 实现单一催化剂无法实现的新反应, 并且避免了对不稳定中间体的分离纯化, 提高了反应的步骤经济性和原子经济性. 手性磷酸是近年来研究最为热门的有机小分子催化剂之一, 其与金属催化剂结合催化也得到了深入的研究. 本工作即针对金属催化剂和手性磷酸结合的接力催化反应的研究进展, 做一简要评述.

An inventive approach to the development of chiral Brønsted acid catalysis, to enable catalysts which possess strong acid functionalities, has been accomplished. Among the various organic Brønsted acids surveyed, phosphoric acids have become the focus of our attention as potential chiral Brønsted acid catalysts because of their unique structural and chemical features. The desirable features of phosphoric acids as chiral Brønsted acid catalysts are summarized as follows. 1) Phosphoric acids are expected to have relatively strong yet appropriate acidity. 2) The phosphoryl oxygen would function as a Brønsted basic site and hence it is anticipated that it would convey acid/base dual function even to monofunctional phosphoric acid catalysts. 3) An acidic functionality is available even with the introduction of a ring system which effectively restricts the conformational flexibility of the chiral backbone. 4) Substituents can be introduced to the ring system to provide an efficient chiral environment for enantioselective transformations. It is anticipated that an efficient substrate recognition site would be constructed around the activation site due to the acid/base dual function and the steric and electronic influence of the substituents introduced at the ring system. In this context, we developed 1,1′-bi-2-naphthol (BINOL)-derived monophosphoric acids as chiral Brønsted acid catalysts. The chiral phosphoric acids thus developed functioned as efficient enantioselective catalysts for a variety of carbon–carbon bond forming reactions via activation of a series of functionalities, affording enantioenriched products in excellent selectivities. In this article, we review our recent achievements in developing enantioselective reactions using the chiral phosphoric acid catalysts. The contents are arranged according to the type of functionality, including imines, hemiaminal ethers, aldehydes, and electron-rich double bonds, followed by specific reaction types.