Design Of Chiral Ligands Research Articles

Overcoming Copper Reduction Limitation in Asymmetric Substitution: Aryl-Radical-Enabled Enantioconvergent Cyanation of Alkyl Iodides.

Cu-catalyzed enantioconvergent cross-coupling of alkyl halides has emerged as a powerful strategy for synthesizing enantioenriched molecules. However, this approach is intrinsically limited by the weak reducing power of copper(I) species, which restricts the scope of compatible nucleophiles and necessitates extensive ligand optimization or the use of complex chiral scaffolds. To overcome these challenges, we introduce an aryl-radical-enabled strategy that decouples the alkyl halide activation step from the chiral Cu center. We demonstrate that merging aryl-radical-enabled iodine abstraction with Cu-catalyzed asymmetric radical functionalization enables the conversion of racemic α-iodoamides to enantioenriched alkyl nitrile products with good yield and enantioselectivity. The rational design of chiral ligands identified a new class of carboxamide-containing BOX ligands. Mechanistic studies support an aryl-radical-enabled pathway and the unique hydrogen-bonding ability in the newly designed BOX ligands. This aryl-radical-enabled asymmetric substitution reaction has the potential to significantly expand the scope of Cu-catalyzed enantioconvergent cross-coupling reactions.

Ionic Hydrogen Bond-Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols.

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S-, P-, Si- and B-stereocenters over the past decades, the catalyst-controlled strategies to govern the formation of N-stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen-stereogenic compounds through a desymmetrization approach. Intriguingly, the pro-chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene-bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N-oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N-oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Ionic Hydrogen Bond‐Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols

AbstractThe control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S‐, P‐, Si‐ and B‐stereocenters over the past decades, the catalyst‐controlled strategies to govern the formation of N‐stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen‐stereogenic compounds through a desymmetrization approach. Intriguingly, the pro‐chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene‐bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N‐oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N‐oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Enantioselective organocatalytic strategies to access noncanonical α-amino acids.

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.

Recent advances in Rh(I)-catalyzed enantioselective C-H functionalization.

Chiral carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds are pervasive and very essential in natural products, bioactive molecules, and functional materials, and their catalytic construction has emerged as one of the hottest research fields in synthetic organic chemistry. The last decade has witnessed vigorous progress in Rh(I)-catalyzed asymmetric C-H functionalization as a complement to Rh(II) and Rh(III) catalysis. This review aims to provide the most comprehensive and up-to-date summary covering the recent advances in Rh(I)-catalyzed C-H activation for asymmetric functionalization. In addition to the development of diverse reactions, chiral ligand design and mechanistic investigation (inner-sphere mechanism, outer-sphere mechanism, and 1,4-Rh migration) will also be highlighted.

Enantiodivergent Hydrogenation of Exocyclic α,β‐Unsaturated Lactams Enabled by Switching the N‐Chirality of Iridium Catalyst

AbstractCentral chirality is an important chiral element used in the design of chiral ligands and catalysts. Mostly, the attention of organic chemists is focused on developing of chiral ligands with stable stereogenic centers. However, the N‐chirality in chiral ligand design has been rarely explored due to its flexibility. Here we demonstrate the design, synthesis, and application of a class of simple P,N‐ligands with flexible N‐chirality and their derived iridium complexes with fixed N‐chiral stereocenters. Both fixed configurations of the N‐stereocenter of the iridium complexes could be selectively formed from the same chiral ligand. This pair of diastereoisomeric iridium complexes showed good performance in the enantiodivergent asymmetric hydrogenation of exocyclic α,β‐unsaturated lactams. The N−H group plays an impressive role in catalytic activity. Computational studies emphasized the importance of N‐chirality and N−H group.

Enantiodivergent Hydrogenation of Exocyclic α,β-Unsaturated Lactams Enabled by Switching the N-Chirality of Iridium Catalyst.

Central chirality is an important chiral element used in the design of chiral ligands and catalysts. Mostly, the attention of organic chemists is focused on developing of chiral ligands with stable stereogenic centers. However, the N-chirality in chiral ligand design has been rarely explored due to its flexibility. Here we demonstrate the design, synthesis, and application of a class of simple P,N-ligands with flexible N-chirality and their derived iridium complexes with fixed N-chiral stereocenters. Both fixed configurations of the N-stereocenter of the iridium complexes could be selectively formed from the same chiral ligand. This pair of diastereoisomeric iridium complexes showed good performance in the enantiodivergent asymmetric hydrogenation of exocyclic α,β-unsaturated lactams. The N-H group plays an impressive role in catalytic activity. Computational studies emphasized the importance of N-chirality and N-H group.

Access to Enantiomerically Pure P-Stereogenic Primary Aminophosphine Sulfides under Reductive Conditions.

Stereochemically pure phosphines with phosphorus-heteroatom bonds and P-centered chirality are a promising class of functional building blocks for the design of chiral ligands and organocatalysts. A route to enantiomerically pure primary aminophosphine sulfides was opened through stereospecific reductive C-N bond cleavage of phosphorus(V) precursors by lithium in liquid ammonia. The chemoselectivity of the reaction as a function of reaction time, substrate pattern, and chiral auxiliary was investigated. In the presence of exclusively aliphatic groups bound to the phosphorus atom, all competing reductive side reactions are totally prevented. The absolute configurations of all P-stereogenic compounds were determined by single-crystal X-ray diffraction analysis. Their use as synthetic building blocks was demonstrated. The lithium salt of (R)-BINOL-dithiophosphoric acid proved to be a useful stereochemical probe to determine the enantiomeric purity. Insights into the coordination mode of the lithium-based chiral complex formed in solution was provided by NMR spectroscopy and DFT calculations.

10 Gram-scale synthesis of TY-Phos ligand and its application in carbene insertion of Si-H bonds

The design of chiral ligands has always been one of the most prominent research areas in asymmetric catalysis. This method reports on the 10 g-scale synthesis of one class of Sadphos: TY-Phos ligand. The ligand preparation could be carried out on a scale of 10 g with a reasonable yield, and the preliminary exploration of its application in the enantioselective insertion of carbenes into Si−H bonds is reported.

Natural Product-Inspired Chiral Ligand Design: Aloperine and N-Substituted Aloperines-Induced Pd-Catalyzed Asymmetric Hydroarylation of Ketimines.

A naturally occurring alkaloid aloperine was utilized as a chiral skeleton for the development of new ligands/catalysts in asymmetric synthesis. A number of N-substituted aloperines have been prepared, and a Pd-catalyzed asymmetric hydroarylation of ketimines using these chiral 1,3-diamine ligands was reported. A range of chiral sulfonyl amides were prepared in high yields and enantioselectivities. The stereoselectivity and structure relationships of aloperines have been studied. In addition, preliminary studies on the desymmetrization of meso-anhydride have also shown that these diamines have good potential in organocatalysis. These discoveries would provide a new future development for natural product-inspired chiral ligand design and developments.

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

Recent Advances in Asymmetric Hydrogenation Catalysis Utilizing Spiro and Other Rigid C-Stereogenic Phosphine Ligands

Transition-metal-catalyzed asymmetric reactions have been a powerful tool in organic synthesis for many years. The design of chiral ligands with the right configuration is fundamental to induce high regio- and stereoselectivity to catalytic reactions and to achieve high turnover numbers and high yields. A challenge is the control of prochiral centers with similar electronic properties in a similar steric environment within the same molecule. Over the last 10 years, a range of novel rigid C-stereogenic chiral phosphine ligands has been developed and successfully applied in various types of asymmetric transformations. Many of these ligands are of a di-, tri-, or multidentate nature. The purpose of this Perspective is to highlight recent synthetic achievements (since 2010) with spiro-phosphines and other rigid phosphines and discuss some mechanistic aspects of the catalytic reactions.

Bicyclic Bridgehead Phosphoramidite-Based Hybrid Diphosphorus Ligands: Design, Synthesis, and Application in Catalytic Asymmetric Hydrogenation.

A strategy for chiral ligand design has been developed that allows for incorporation of an achiral bicyclic bridgehead phosphoramidite to generate a class of hybrid diphosphorus ligands for high activity and asymmetric control. Using this concept, a series of chiral phosphine-phosphoramidite ligands bearing the sole chirality at the ligand backbone have been prepared and successfully employed in the Rh-catalyzed asymmetric hydrogenation of 2-vinylanilides for the synthesis of optically active anilines bearing an ortho-tertiary benzylic stereocenter.

Ligand-Enabled Copper(I)-Catalyzed Asymmetric Radical C(sp3)–C Cross-Coupling Reactions

The first-row transition-metal-catalyzed asymmetric C(sp3)–C cross-coupling represents a powerful approach in the expedient synthesis of enantioenriched molecules. Recently, a series of chiral copper catalysts have been designed to promote a variety of asymmetric radical C(sp3)–C cross-coupling reactions with high efficiency and enantioselectivity. The key to success is the design of chiral ligands to initiate the reaction and achieve enantiocontrol over the highly reactive prochiral alkyl radical species. This Perspective will discuss the impressive advances and provide an outlook on the direction of further development.

Asymmetric Hydrogenation: Design of Chiral Ligands and Transition Metal Complexes. Synthetic and Industrial Applications.

AbstractThis personal account focuses on the development of atropisomeric ligands and chiral transition metal complexes and their applications to the asymmetric hydrogenation of alkenes, ketones and heteroaromatics using Ru(II) and Ir(III) catalysts in‐house developed. Particularly, effective scaled‐up development syntheses of SYNPHOS and DIFLUORPHOS have been successfully achieved and their steric and electronic profiling established. Going further, we demonstrated the utility of such homogeneous catalytic process highlighted with examples of industrial applications and total syntheses of biorelevant targets. Asymmetric hydrogenation provides a powerful tool for performing precise stereocontrolled transformations on valuable complex molecules.

Feng Ligand: Privileged Chiral Ligand in Asymmetric Catalysis

AbstractCatalysts and ligands possessing the great ability to tolerate over a wide range of mechanistically unrelated reactions are remarked as "privileged", which are rather scarce but extremely meaningful in asymmetric catalysis. Feng and co‐workers have developed a library of conformationally flexible, C2‐symmetric N,N'‐dioxide amide compounds with original design and featured structure (named as Feng ligand now). They were initially reported as chiral organocatalysts in 2005 and have been further developed as a new class of privileged chiral ligands since 2006. Tremendous success, including versatile coordination chemistry with plenty of metal sources (main‐group metals, transition metals, and rare‐earth metals), a truly broad scope of asymmetric reactions (more than 50 types), diverse areas of catalysis (organocatalysis, Lewis‐acid catalysis, bimetallic relay catalysis, and photocatalysis), numerous synthetic applications of bioactive compounds, has been achieved using Feng N,N'‐dioxide. Besides, they demonstrate that chiral ligands with conformationally flexible property can offer excellent chiral environment as well, which challenges the conventional idea preferring rigid structures in the design of chiral ligands. Herein, we briefly introduced the discovery of Feng ligand and the millstones during the development. We also covered the successful applications of Feng ligand by other scientists as well as novel chiral ligands inspired by them.

Chiral Imidazoline Ligands and Their Applications in Metal‐Catalyzed Asymmetric Synthesis†

AbstractAs a structural analog of oxazoline, imidazoline (4,5‐dihydroimidazole) has received much attention in the rational design of chiral ligands. The additional N‐substituent provides broader space for fine‐tuning of electronic and steric effects, and it offers a good handle for immobilizing onto solid supports. In the past decades, imidazoline ring has emerged as a powerful candidate for the design of chiral nitrogen‐containing ligands, as well as a significant alternative for oxazoline ring. Various chiral imidazoline ligands have been designed and utilized in asymmetric organic reactions. These new catalysts can not only be applied in classical reactions, but also be employed to develop new organic reactions with high enantioselectivities. This review provides an overview of chiral imidazoline ligands. Their applications in asymmetric synthesis are also summarized.

A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.

The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin–Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

P.524 Decreased medial prefrontal connectivity and lack of age-related gains in mentalizing in adolescents at clinical high risk transitioning to psychosis

Proline-based N,N′-dioxide ligands were designed on the basis of isosteric approach, and were successfully applied in enantioselective nucleophilic addition to aldehydes. In the presence of 10 mol% of chiral ligand 1b, enantioselective addition of diethylzinc to aldehydes provided the corresponding secondary alcohols in up to 90% isolated yield and up to 99% ee. Similarly, using 3e as chiral ligand, enantioselective arylation and alkynylation of aldehydes also proceeded readily, leading to the desired chiral alcohols in up to 92% isolated yield at 99% ee and 80% isolated yields and up to 84% ee, respectively. The current work would shed light on expanding the structure diversity in the design of chiral ligands and chiral catalysts.

Chiral Ugi-Type Amines: Practical Synthesis, Ligand Development, and Asymmetric Catalysis

Ugi’s amine has become one type of privileged chiral skeleton for chiral ligand design bearing central/planar chirality, and such ligands have exhibited tremendous success in various asymmetric cat...