Catalytic Asymmetric Reaction Research Articles

Recent advances in catalytic asymmetric synthesis.

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Atroposelective Construction of Naphthylpyrazoles by Chiral Phosphoric Acid Catalyzed Enantioselective Cross‐Coupling of Pyrazoles with Naphthoquinone Esters

AbstractThe catalytic asymmetric reaction of 5‐aminopyrazoles with naphthoquinone esters has been established. A wide range of unprecedented axially chiral naphthylpyrazole derivatives (29 examples) have been synthesized in moderate to excellent yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) by utilizing chiral phosphoric acid as a catalyst. This protocol features mild reaction conditions, a broad substrate scope, good scalability and facile derivatization. Moreover, preliminary mechanistic investigation was conducted to elucidate the mechanism.

Enantioselective Synthesis of Axially and Centrally Chiral Styrenes via Nickel-Catalyzed Desymmetric Hydrocyanation of Biaryl Dienes.

Herein, a highly regio-, enantio-, and diastereoselective nickel-catalyzed desymmetric hydrocyanation of biaryl dienes for the simultaneous construction of axial and central chiralities is presented, which offers a convenient approach to a variety of tirenes containing the union of an axially chiral biaryl and a centrally α-chiral nitrile under mild conditions using a commercially available catalyst. The synthetic utility is highlighted by the development of a novel axially chiral phosphine ligand and biphenyl-based chiral diene ligand and their potential applications in the field of asymmetric catalytic reactions.

Brønsted Acid Catalyzed Intramolecular Allylic Substitution Reaction of Allylic Alcohols: A Facile Synthesis of 2-Vinylchromans

AbstractBrønsted acid catalyzed intramolecular allylic substitution reaction of secondary and tertiary allylic alcohols has been developed. A variety of 2-vinylchromans were efficiently prepared in moderate to excellent yields. The given method features wide substrate scope, operational simplicity, and mild, metal-free reaction conditions. The practicability of the method was demonstrated by a gram-scale reaction and further derivations of the product. Preliminarily studies on a catalytic asymmetric reaction were also undertaken.

Catalytic Asymmetric Synthesis of Chiral α,α-Dialkyl Aminonitriles via Reaction of Cyanoketimines.

Chiral aminonitriles not only are broadly useful building blocks but also increasingly appear as structural motifs in bioactive molecules and pharmaceuticals. The catalytic asymmetric synthesis of chiral aminonitriles, therefore, has been intensively investigated, as reflected in numerous reports of catalytic asymmetric Strecker reactions. Despite such great progress, the catalytic asymmetric synthesis of chiral α,α-dialkyl aminonitriles in a highly selective and efficient manner is still a formidable challenge. Here, we report a new approach for the catalytic asymmetric synthesis of chiral α,α-dialkyl aminonitriles via reaction of cyanoketimines with enals. We demonstrate that this reaction could be carried out with as low as 20 ppm catalyst loading.

Applications of Organosilanes in Visible Light‐induced Catalytic Asymmetric Reactions

AbstractOver the past decades, visible light‐mediated photocatalysis has found a mainstream of applications in synthetic chemistry. Organosilanes have been proven to be a useful class of electron donors to generate the highly active radical species via photoinduced single electron transfer oxidation/fragmentation sequence, which may undergo follow‐up radical coupling or addition process. This minireview highlights the comprehensive advances of organosilanes in photoredox catalyzed asymmetric organic synthesis, with particular emphasis placed on reaction mechanisms. We hope that this review will inspire further design and development of new reactions with such class of readily accessible reagents.

Asymmetric photoredox catalytic formal de Mayo reaction enabled by sensitization-initiated electron transfer.

Visible-light-driven photoredox catalysis is known to be a powerful tool for organic synthesis. Its occurrence critically depends on the twice exothermic single-electron transfer processes of photosensitizers, which are governed by the redox properties of the species involved. Hence, the inherently narrow range of redox potentials of photosensitizers inevitably constrains their further availability. Sensitization-initiated electron transfer has recently been found to effectively overcome this substantial challenge. However, feasible and practical strategies for designing such complicated catalytic systems are rather scarce. Herein we report an elaborate dual-catalyst platform, with dicyanopyrazine as a visible light photosensitizer and a pyrenyl-incorporated chiral phosphoric acid as a co-sensitizer, and we demonstrate the applicability of this sensitization-initiated electron transfer strategy in an asymmetric formal de Mayo-type reaction. The catalysis platform enables otherwise thermodynamically unfavourable electron transfer processes to close the redox cycle and allows for precise access to valuable enantioenriched 1,5-diketones with a wide substrate range.

Precision in stereochemistry: the integral role of catalytic asymmetric Biginelli reaction in crafting enantiomerically pure dihydropyrimidinones.

One well-known multicomponent reaction that is helpful in the synthesis of dihydropyrimidinones (DHPMs), important molecules in organic synthesis and medicinal chemistry, is the Biginelli reaction. Because of their wide range of biological activities, DHPMs are regarded as essential chemicals. A great deal of research has been done in the last few decades to find ways to produce enantiomerically pure DHPMs because of their notable and focused target-oriented biological activities. In this reaction, numerous structural variants and catalysts have been employed in a range of solvents to yield an enormous number of Biginelli-type compounds. In the present review, the available catalysts in the literature including ionic liquids, Lewis acids, and organocatalysts for the Biginelli reaction and synthesis of a large number of asymmetric compounds since 2003 are summarized.

Organocatalytic Atroposelective Construction of Pentatomic Heterobiaryl Diamines through Arylation of 5-Aminoisoxazoles with Azonaphthalenes.

An efficient catalytic asymmetric Michael-type reaction of azonaphthalenes with 5-aminoisoxazoles has been developed. The reaction was based on the utilization of a chiral phosphoric acid as the catalyst, delivering a large panel of axially chiral heterobiaryl diamines in generally good yields with excellent enantioselectivities. The gram-scale reaction and postmodification of the chiral product demonstrated their potentials in the synthesis of chiral catalysts and ligands. This approach not only provides a useful method for the construction of pentatomic heterobiaryl scaffolds but also offers new members to the axially chiral diamine family with promising applications in synthetic and medicinal chemistry.

Catalytic Asymmetric Construction of Chiral Amines with Three Nonadjacent Stereocenters via Trifunctional Catalysis.

Pharmaceuticals and biologically active natural products usually contain multiple stereocenters. The development of catalytic asymmetric reactions for the direct construction of complex motifs containing three nonadjacent stereocenters is a particularly important and formidable challenge. In this paper, we report an unprecedented method for the direct asymmetric construction of complex chiral amines with 1,3,5- or 1,3,4-stereocenters from readily available achiral and racemic starting materials. The reaction was made possible by the development of highly efficient chiral ammonium catalysts that serve three distinct functions: promoting efficient kinetic resolution by chiral recognition of racemic electrophiles, promoting asymmetric C-C bond forming reactions by recognizing enantiotropic faces of achiral nucleophiles, and mediating a highly stereoselective protonation of carbanions. Using these trifunctional catalysts, the reaction of imines and tulipane derivatives proceeded in a highly regio-, chemo-, and stereoselective manner to produce synthetically useful yields of complex chiral amines. We believe that trifunctional catalysis can be applied in a variety of asymmetric transformations for the streamlined asymmetric synthesis of complex chiral molecules with multiple stereocenters.

Design and Application of New Pyridine-Derived Chiral Ligands in Asymmetric Catalysis.

ConspectusThe innovation of chiral ligands has been crucial for the asymmetric synthesis of functional molecules, as demonstrated by several types of widely applied "privileged" ligands. In this context, chiral pyridine-derived ligands, by far some of the oldest and most widely utilized ligands in catalysis, have attracted considerable research interest in the past half-century. However, the development of broadly applicable chiral pyridine units (CPUs) has been plagued by several intertwining challenges, thus delaying advancements in many asymmetric reactions.This Account aims to summarize the recent progress in new CPU-containing ligands, focusing on a rationally designed, modular, and tunable CPU developed in our laboratory. A significant problem thwarting conventional designs is the paradox between broad reactivity and stereoselectivity; that is, while enhanced stereoselectivity may be achieved by introducing chiral elements close to the N atom, the concomitant increase in local steric hindrance often limits catalytic activity and scope. Our newly developed CPU features a rigid [6-5-3] fused-ring framework and a tunable spirocyclic ketal side wall. The well-defined three-dimensional structure minimizes local (inner layer) steric hindrance and tunes the peripheral environment (outer layer) by remote substituents, thus securing reactivity and stereoselectivity. Different chelating ligands were readily assembled using this chiral structural module, with applications in mechanistically diverse transition-metal-catalyzed reactions. Thus, a series of chiral 2,2'-bipyridine ligands were successfully employed in the development of a general, efficient, and highly enantioselective nickel-catalyzed intermolecular reductive addition, Ullmann coupling of ortho-chlorinated aryl aldehydes, and carboxylation of benzylic (pseudo)halides with CO2. Notably, these chiral 2,2'-bipyridine ligands exhibited superior catalytic activity in the reactions compared to common N-based ligands. In addition, highly enantioselective iridium-catalyzed C-H borylation was developed using a CPU-containing N,B-bidentate ligand. Furthermore, mechanistically challenging, additive-free, and broad-scope transfer hydrogenative direct asymmetric reductive amination was achieved using a half-sandwich iridium catalyst supported by a chiral N,C-bidentate ligand. The new ligands demonstrated excellent performance in securing high catalytic activity and stereoselectivity, which, when combined with experimental and computational mechanistic investigations, supported the "double-layer control" design concept.Considering the broad applications of pyridine-derived ligands, the research progress described herein should inspire the creation of novel chiral catalysts and drive the development of many catalytic asymmetric reactions.

Asymmetric Carbene Transformations for the Construction of All-Carbon Quaternary Centers.

Asymmetric catalytic carbene reactions have been well documented in the last few decades for the expeditious assembly of chiral molecules with structural diversity. However, the enantioselective construction of all-carbon quaternary centers remains a challenge in this area. In this review article, two types of asymmetric carbene reactions that beyond cyclopropanation, cyclopropenation, and Büchner reaction, have been summarized for the construction of all-carbon quaternary centers: 1) using carbene species as a 1C synthon that reacts with a trisubstituted prochiral center; 2) sequential installation of two different C-C bonds on the carbene position, which features a gem-difunctionalization reaction. Especially, the asymmetric metal carbene gem-dialkylation process, which has emerged as a practical and versatile method for the expeditious assembly of complex architectures from readily available chemical resources, is a complementary approach for the expeditious assembly of all-carbon quaternary centers.

Asymmetric cyclization catalyzed by a chiral phosphoric acid–gold(I) hybrid complex as a multifunctional catalyst

Abstract We herein report the development of a novel hybrid complex containing gold(I) and a chiral phosphoric acid moiety to generate a multifunctional catalyst. While the use of chiral phosphoric acid as a bifunctional catalyst is a common strategy in asymmetric organic synthesis, chiral phosphoric acid–transition metal hybrid complexes as multifunctional catalysts have not been investigated. Thus, we designed and synthesized a novel gold(I) hybrid complex as a multifunctional catalyst that promotes asymmetric catalytic reactions through multipoint nonclassical noncovalent interactions in substrates that lack classical hydrogen-bond donors. In addition, we demonstrate its usefulness as a multifunctional catalyst by successfully developing the first catalytic asymmetric synthesis of dihydrocyclohepta[b]indoles. Experimental and theoretical studies revealed that this asymmetric catalytic reaction involves the kinetic resolution of the reaction intermediate, and that the favored diastereomeric transition state for yielding enantiomeric products is formed through multipoint nonclassical noncovalent interactions originating from the acid–base nature of the chiral phosphoric acid moiety.

Cu-Catalyzed Direct Asymmetric Mannich Reaction of 2-Alkylazaarenes and Isatin-Derived Ketimines.

The first direct catalytic asymmetric Mannich reaction of 2-alkylazaarenes and ketimines was realized with a chiral Cu-bis(oxazoline) complex as the catalyst. The asymmetric addition of 2-alkylpyridines to isatin-derived ketimines proceeded smoothly to afford α,β-functionalized 2-substituted pyridines bearing 3-amino-3,3-disubstituted oxindole motifs with excellent results (≤99% yield, 99:1 dr, and 98% ee). The catalytic system was also extended to 2-alkylbenzothiazoles as nucleophiles for the asymmetric Mannich reaction of ketimines.

Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon.

A robust and practical difluoroalkylation synthon, α,α-difluoroenol species, which generated in situ from trifluoromethyl diazo compounds and water in the presence of dirhodium complex, is disclosed. As compared to the presynthesized difluoroenoxysilane and in situ formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting in dramatically improved enantioselectivity under mild conditions. As demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine-derived urea, and chiral phosphoric acid (CPA), respectively, this relay catalysis strategy provides an effective platform for applying asymmetric fluorination chemistry. Moreover, this method features a novel 1,2-difunctionalization process via installation of a carbonyl motif and an alkyl group on two vicinal carbons, which is a complementary protocol to the metal carbene gem-difunctionalization reaction.

Enantioselective Synthesis of Planar-Chiral Sulfur-Containing Cyclophanes by Chiral Sulfide Catalyzed Electrophilic Sulfenylation of Arenes.

An efficient catalytic asymmetric electrophilic sulfenylation reaction for the synthesis of planar-chiral sulfur-containing cyclophanes has been developed for the first time. This was achieved by using a new Lewis base catalyst and a new ortho-trifluoromethyl-substituted sulfenylating reagent. Using the substrates with low rotational energy barrier, the transformation proceeded through a dynamic kinetic resolution, and the high rotational energy barrier of the substrates allowed the reaction to undergo a kinetic resolution process. Meanwhile, this transformation was compatible with a desymmetrization process when the symmetric substrates were used. Various planar-chiral sulfur-containing cyclophanes were readily obtained in moderate to excellent yields with moderate to excellent enantioselectivities (up to 97 % yield and 95 % ee). This approach was used to synthesize pharmaceutically relevant planar-chiral sulfur-containing molecules. Density functional theory calculations showed that π-π interactions between the sulfenyl group and the aromatic ring in the substrate play a crucial role in enantioinduction in this sulfenylation reaction.

Enantioselective Synthesis of Planar‐Chiral Sulfur‐Containing Cyclophanes by Chiral Sulfide Catalyzed Electrophilic Sulfenylation of Arenes

AbstractAn efficient catalytic asymmetric electrophilic sulfenylation reaction for the synthesis of planar‐chiral sulfur‐containing cyclophanes has been developed for the first time. This was achieved by using a new Lewis base catalyst and a new ortho‐trifluoromethyl‐substituted sulfenylating reagent. Using the substrates with low rotational energy barrier, the transformation proceeded through a dynamic kinetic resolution, and the high rotational energy barrier of the substrates allowed the reaction to undergo a kinetic resolution process. Meanwhile, this transformation was compatible with a desymmetrization process when the symmetric substrates were used. Various planar‐chiral sulfur‐containing cyclophanes were readily obtained in moderate to excellent yields with moderate to excellent enantioselectivities (up to 97 % yield and 95 % ee). This approach was used to synthesize pharmaceutically relevant planar‐chiral sulfur‐containing molecules. Density functional theory calculations showed that π‐π interactions between the sulfenyl group and the aromatic ring in the substrate play a crucial role in enantioinduction in this sulfenylation reaction.

Cu-Catalyzed Direct Enantioselective Vinylogous Mannich Reaction between β,γ-Unsaturated Pyrazoleamides and Ketimines.

A catalytic asymmetric vinylogous Mannich-type reaction between β,γ-unsaturated amides and ketimines has been developed in excellent regio-, diastereo-, and enantioselectivities. The methodology provides an efficient approach to construct chiral homoallylic amines with a 3-amino-2-oxindole scaffold. Moreover, the transformations of the chiral products, including the removal of the pyrazole group or Boc group, the reduction of the C-C double bond, and Suzuki coupling, have been investigated.

Catalytic Asymmetric Ring Opening Reactions of Vinylcyclopropanes

AbstractVinylcyclopropanes (VCPs) are important building blocks with multifaceted reactivity. Catalytic asymmetric ring opening of vinylcyclopropanes is a highly efficient process to access valuable chiral molecules with diverse functionalities that can be further functionalized for a series of synthetic purposes. VCPs are very well‐known substrates for cycloaddition reactions and this chemistry has been widely explored. On the contrary, despite of enormous synthetic potential, development of new innovative strategies for the catalytic, asymmetric ring opening of VCPs is somewhat underdeveloped. Recently, several significant examples have emerged in the literature for various asymmetric ring opening of both activated and unactivated vinylcyclopropanes that involve transition metal catalysis. These developments are relevant additions to the vinylcyclopropane chemistry. In this review, we aim to summarize all the catalytic asymmetric ring opening transformations reported till date and provide a comprehensive analysis of these research outcomes.

Substrate Directed Regio‐ and Enantioselective Ring‐Opening of Epoxides and Aziridines

AbstractThe oxirane and aziridine rings are valuable building blocks in modern synthetic chemistry and catalytic asymmetric ring opening reactions of these three membered ring systems have emerged as a powerful chemical tool for the synthesis of natural products and biologically active compounds. In this context, the regioselective ring‐opening of structurally or electronically unbiased epoxides and aziridines is challenging. Recently, metal‐catalyzed substrate directed strategies have successfully applied in the regio‐ and enantioselective ring opening of functionalized epoxy alcohols by the Yamamoto group. Subsequently, our group realized the ring opening reactions of functionalized 2,3‐aziridinyl alcohols with the dinuclear zinc complex. These enantioselective nucleophilic ring opening reactions of functionalized epoxy alcohols and aziridinyl alcohols allow for the facile synthesis of amino alcohol derivatives and the introduction of new concepts in catalysis.