Ligands For Asymmetric Catalysis Research Articles

P-Stereogenic Phosphorus Ligands in Asymmetric Catalysis.

Chiral phosphorus ligands play a crucial role in asymmetric catalysis for the efficient synthesis of useful optically active compounds. They are largely categorized into two classes: backbone chirality ligands and P-stereogenic phosphorus ligands. Most of the reported ligands belong to the former class. Privileged ones such as BINAP and DuPhos are frequently employed in a wide range of catalytic asymmetric transformations. In contrast, the latter class of P-stereogenic phosphorus ligands has remained a small family for many years mainly because of their synthetic difficulty. The late 1990s saw the emergence of novel P-stereogenic phosphorus ligands with their superior enantioinduction ability in Rh-catalyzed asymmetric hydrogenation reactions. Since then, numerous P-stereogenic phosphorus ligands have been synthesized and used in catalytic asymmetric reactions. This Review summarizes P-stereogenic phosphorus ligands reported thus far, including their stereochemical and electronic properties that afford high to excellent enantioselectivities. Examples of reactions that use this class of ligands are described together with their applications in the construction of key intermediates for the synthesis of optically active natural products and therapeutic agents. The literature covered dates back to 1968 up until December 2023, centering on studies published in the late 1990s and later years.

Nickel-Catalyzed Atroposelective Cross-Electrophile Coupling of Aryl Halides: A General and Practical Route to Diverse MOP-Type Ligands.

We report a highly cross- and atroposelective coupling between ortho-(chloro)arylphosphine oxides and ortho-(bromo)aryl ethers. This previously unknown asymmetric nickel-catalyzed reaction offers a direct route to highly enantioenriched axially chiral biaryl monophosphine oxides that are difficult to access by other means. These products can be readily reduced to generate chiral MOP-type ligands bearing complex skeletal backbones. The utility of these chiral ligands in asymmetric catalysis is also demonstrated.

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.

Enantioselective Rhodium‐Catalyzed C−H Arylation Enables Direct Synthesis of Atropisomeric Phosphines

AbstractAtropisomeric phosphines hold considerable significance in asymmetric catalysis, yet their synthesis presents a formidable challenge owing to intricate multistep procedures. In this context, a groundbreaking methodology has been presented for their preparation. This innovative approach entails an atroposelective rhodium‐catalyzed C−H activation employing aryl and heteroaryl halides, chelated by a P(III) center. The essence of this strategy lies in its ability to directly construct chiral phosphine ligands in a single step, thereby exhibiting exceptional efficiency in terms of atom and redox economy. Illustrative examples serve to demonstrate the immense potential of in situ‐formed ligands in asymmetric catalysis. Mechanistic experiments have further provided invaluable insights into this transformation.

Enantioselective Rhodium-Catalyzed C-H Arylation Enables Direct Synthesis of Atropisomeric Phosphines.

Atropisomeric phosphines hold considerable significance in asymmetric catalysis, yet their synthesis presents a formidable challenge owing to intricate multistep procedures. In this context, a groundbreaking methodology has been presented for their preparation. This innovative approach entails an atroposelective rhodium-catalyzed C-H activation employing aryl and heteroaryl halides, chelated by a P(III) center. The essence of this strategy lies in its ability to directly construct chiral phosphine ligands in a single step, thereby exhibiting exceptional efficiency in terms of atom and redox economy. Illustrative examples serve to demonstrate the immense potential of in situ-formed ligands in asymmetric catalysis. Mechanistic experiments have further provided invaluable insights into this transformation.

Chiral 1‐Phosphabarrelene‐Pyridines as Suitable Ligands for the Rh/Ir‐Catalyzed Asymmetric Hydrogenation of Olefins

AbstractHerein, we report the synthesis of chiral phosphabarrelene‐pyridine ligands. Their synthesis benefit from modified reaction conditions to overcome the low yields normally associated with the [4+2] cycloaddition reaction of phosphinines with hexafluoro‐2‐butyne, which is a key to install the P‐stereocenter in the phosphabarrelene. Their potential as chelating ligands in asymmetric catalysis was assessed in the Rh‐ and Ir‐catalyzed hydrogenation of cyclic β‐enamides and β‐dehydroamino acid derivatives. The catalytic system containing a tert‐butyl substituent at the ortho position of the phosphabarrelene moiety successfully hydrogenates a range of cyclic β‐enamides (ee's between 92% to 94%) and β‐dehydroamino acid derivatives (ee's between 93% to 95%). Moreover, the reactions can be carried out in the environmentally friendly 1,2‐propylene carbonate as solvent with no loss of enantioselectivity. Mechanistic studies with the Rh/P,N catalytic systems agree with the Landis‐Halpern mechanism and explain the influence of the substituent at the phosphabarrelene on enantioselectivity. Finally, the hydrogenation reactions can be carried out at large scale maintaining high enantioselectivities.

Py-2NO ligand enabled Ni(ii)-catalyzed asymmetric Michael addition reaction of indoles with β,γ-unsaturated α-keto esters

This work diversified the Py-2NO ligand library recently developed by our group and further expanded the application of chiral Py-2NO ligands in asymmetric catalysis.

Nickel‐Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide

AbstractSulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni‐catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and β‐sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98 % ee. The product exhibits tremendous potential in various applications, including diastereoselective Diels–Alder reactions, coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.

Nickel-Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide.

Sulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni-catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and β-sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98 % ee. The product exhibits tremendous potential in various applications, including diastereoselective Diels-Alder reactions, coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.

Synthesis of Planar‐Chiral [2.2]Paracyclophane‐Based Oxazole‐Pyrimidine Ligands and Application in Nickel‐Catalyzed 1,2‐Reduction of α,β‐Unsaturated Ketones

Comprehensive SummaryThe planar‐chiral ligands have been widely applied as a class of unique and significant ligands in asymmetric catalysis. Among them, chiral [2.2]paracycyclophane has emerged as a privileged type of planar‐chiral framework and has been utilized as an important toolbox due to their structural stability. Herein, we design and synthesize [2.2]paracyclophane‐derived oxazole‐pyrimidine ligands (abberviated as PYMCOX). These N,N‐ligands with stable properties, rigid structure and large steric hindrance performed successfully in nickel‐catalyzed asymmetric 1,2‐reduction of α,β‐unsaturated ketones, affording the chiral allylic alcohols with up to 99% yield and 99% ee. Meanwhile, this reduction reaction could be conducted on gram‐scale without loss of activity and enantioselectivity, and the chiral ligand could be conveniently recovered with high yield.

Cr-Catalyzed Asymmetric Cross Aza-Pinacol Couplings for β-Amino Alcohol Synthesis.

Chiral β-amino alcohols are crucial structural motifs found in pharmaceuticals, natural products, and chiral ligands in asymmetric catalysis. Despite previous advances, the development of catalytic approaches to access β-amino alcohols bearing vicinal stereocenters from readily available chemicals remains a prominent challenge. Herein, we describe the Cr-catalyzed asymmetric cross aza-pinacol coupling of aldehydes and N-sulfonyl imines. This protocol proceeds in a radical-polar crossover manner from the intermediacy of an α-amino radical instead of a ketyl radical. Key to the success is using a chiral chromium catalyst, which plays a triple role in the chemoselective single-electron reduction of the imine, fast radical interception to inhibit radical addition to imines, and chemo- and stereoselective addition to aldehydes instead of imines. This method provides a modular and efficient approach to accessing diverse β-amino alcohols bearing vicinal stereocenters.

Enantioselective Amino- and Oxycyanation of Alkenes via Organic Photoredox and Copper Catalysis.

The β-amino nitrile moiety and its derivatives frequently appear in natural product synthesis, in drug design, and as ligands in asymmetric catalysis. Herein, we describe a direct route to these complex motifs through the amino- and oxycyanation of olefins utilizing an acridinium photooxidant in conjunction with copper catalysis. The transformation can be rendered asymmetric by using a serine-derived bisoxazoline ligand. Mechanistic studies implicate olefin-first oxidation. The scope of amines for the aminocyanation reaction has been greatly expanded by undergoing a cation radical intermediate as opposed to previous N-centered radical-initiated aminocyanations. Furthermore, alkyl carboxylic acids were included as nucleophiles in this type of transformation for the first time without any decarboxylative side reactions.

Asymmetric Synthesis of Chiral‐at‐P Alkenylphosphonamidates through Nickel‐Catalyzed C−P Coupling of Phosphoramidites and Alkenyl Halides

AbstractP‐stereogenic compounds are widely used as ligands in asymmetric catalysis and are present in a myriad of bioactive compounds and pharmaceuticals. Yet, their stereocontrolled preparation remains challenging. Herein, we report a novel strategy towards versatile chiral‐at‐P alkenylphosphonamidates through a one‐pot Ni‐catalyzed C−P coupling/diastereoselective hydrolysis of readily available phosphoramidites and alkenyl halides. Remarkably, a chemo‐ and diastereodivergent behavior was observed upon subtle changes in the reaction conditions. Additionally, selective derivatizations of chiral alkenylphosphonamidates demonstrate their versatility as building blocks for the synthesis of structurally diverse P‐stereogenic compounds.

Asymmetric Synthesis of Chiral-at-P Alkenylphosphonamidates through Nickel-Catalyzed C-P coupling of Phosphoramidites and Alkenyl Halides.

P-stereogenic compounds are widely used as ligands in asymmetric catalysis and are present in a myriad of bioactive compounds and pharmaceuticals. Yet, their stereocontrolled preparation remains challenging. Herein, we report a novel strategy towards versatile chiral-at-P alkenylphosphonamidates through a one-pot Ni-catalyzed C-P coupling/diastereoselective hydrolysis of readily available phosphoramidites and alkenyl halides. Remarkably, a chemo- and diastereodivergent behavior was observed upon subtle changes in the reaction conditions. Additionally, selective derivatizations of chiral alkenylphosphonamidates demonstrate their versatility as building blocks for the synthesis of structurally diverse P-stereogenic compounds.

Enantioselective Synthesis of Planar Chiral Macrocyclic Metacyclophanes by Pd-Catalyzed C–O Cross-Coupling

Despite the presence of planar chiral elements in natural products and in ligands for asymmetric catalysis, catalytic enantioselective methods for installing planar chirality remain underdeveloped relative to methods for installing central and axial chirality. Here, we report an enantioselective Pd-catalyzed C–O bond-forming macrocyclization to access enantioenriched planar chiral macrocyclic metacyclophanes incorporating 2,3,4-trisubstituted pyridines. A variety of bridging chains and substituents can be incorporated in the metacyclophanes under the same reaction conditions (14 examples, 59–85% yields, 79–92% ee) to generate enantioenriched meta-, metaortho-, and metapara- cyclophanes. The syn-/anti-conformational preferences of metacyclophanes were elucidated by the X-ray structures, 1H NMR analyses, and computational studies. We also found that the two enantiomers of the metacyclophane can be obtained using the same enantiomer of the chiral ligand by starting from two regioisomeric linear precursors. This work provides an entry into the design of enantioselective cross-coupling macrocyclizations to access planar chiral structures for applications in medicinal chemistry and catalysis.

Chiral Dienes: A Unique Class of Ligands in Asymmetric Catalysis.

Chiral Dienes: A Unique Class of Ligands in Asymmetric Catalysis.

A Scalable Synthesis of Chiral Himbert Diene Ligands for Asymmetric Catalysis

AbstractChiral dienes are important ligands in asymmetric catalysis but they are less accessible than other commonly used ligands such as chiral bisphosphines. Here, we show that intramolecular [4+2] cycloaddition of a simply attained chiral allenecarboxanilide readily affords pseudoenantiomeric bicyclo[2.2.2]octa‐2,5‐dienes containing an alkenyl bromide, which can be readily functionalized to give diverse chiral diene ligands. The synthesis is straightforward and easily conducted on multigram scales. These ligands exhibit high performance in nine types of enantioselective Rh(I)‐catalyzed 1,4‐addition or 1,2‐addition reactions.magnified image

Supramolecular axial chirality in [N-I-N]+-type halogen bonded dimers.

Axial chiral molecules are extensively used as skeletons in ligands for asymmetric catalysis and as building blocks of chiroptical materials. Designing axial chirality at the supramolecular level potentially endows a material with dynamic tunability and adaptivity. In this work, for the first time, we have reported a series of halogen-bonded dimeric complexes with axial chirality that were formed by noncovalent bonds. The [N-I-N]+-type halogen bond is highly directional and freely rotatable with good linearity and ultra-high bond energy; this bond was introduced to couple quinoline moieties with chiral substitutes. The resultant dimers were stable in solutions with thermo-resistance. Prominent steric effects from the 2' chiral pendant allowed the chirality to be transferred to aryl skeletons with induced preferred axial chirality and optical activities. Halogen-bonded complexation presented visible emissions to afford luminescent axial chiral materials, whereby circularly polarized fluorescence and phosphorescence were achieved. The [N-I-N]+-type halogen bond performed as a powerful tool to construct functional axial chiral compounds, enriching the toolbox for asymmetric synthesis and optics.

Enantioselective Synthesis of Both Axially and Planar Chiral Ferrocenes via Axial-to-Planar Diastereoinduction.

Ferrocenes with planar chirality have emerged as an important class of scaffolds for ligands in asymmetric catalysis; however, ferrocene molecules with polychiral structures have not been well explored. Herein, both axially and planar chiral ferrocenes were synthesized via palladium/chiral norbornene cooperative catalysis and axial-to-planar diastereoinduction. In this work, chiral norbornene was used to stereoselectively control the aromatic axial chirality, and further selectivity induced C(sp2)-H activation for ferrocene planar chirality. Based on density functional theory calculations, the catalytic model of chiral norbornene with the substrate and the axial-to-planar diastereoinduction process were confirmed.

A Quantum-Guided Molecular Mechanics Force Field for the Ferrocene Scaffold.

Ferrocene derivatives have a wide range of applications, including as ligands in asymmetric catalysis, due to their chemical stability, rigid backbone, steric bulk, and ability to encode stereochemical information via planar chirality. Unfortunately, few of the available molecular mechanics force fields incorporate parameters for the accurate study of this important building block. Here, we present a MM3* force field for ferrocenyl ligands, which was generated using the quantum-guided molecular mechanics (Q2MM) method. Detailed validation by comparison to DFT calculations and crystal structures demonstrates the accuracy of the parameters and uncovers the physical origin of deviations through excess energy analysis. Combining the ferrocene force field with a force field for Pd-allyl complexes and comparing the crystal structures shows the compatibility with previously developed MM3* force fields. Finally, the ferrocene force field was combined with a previously published transition-state force field to predict the stereochemical outcomes of the aminations of Pd-allyl complexes with different amines and different chiral ferrocenyl ligands, with an R2 of ∼0.91 over 10 examples.