Chiral Diphosphine Ligands Research Articles

Construction of axially chiral 2-arylpyrroles using catalytic asymmetric Suzuki-Miyaura cross-coupling: an efficient approach to esaxerenone.

A general and efficient method has been developed to access axially chiral 2-arylpyrroles using catalytic asymmetric Suzuki-Miyaura cross-coupling. A wide range of axially chiral arylpyrroles were obtained in high yields with good to excellent enantioselectivities. The key to success is the use of a combined catalytic system involving a palladium catalyst and chiral ferrocene diphosphine ligand for achieving effective enantiocontrol. More importantly, this axially chiral CF3-substituted 2-arylpyrrole serves as a key intermediate in the preparation of the anti-hypertensive and diabetic nephropathy drug esaxerenone. It was directly asymmetrically synthesized with high enantioselectivity (92% ee). Thus, a new strategy is provided for the catalytic asymmetric synthesis of esaxerenone.

Synthesis of Chiral Vicinal Amino Alcohol Derivatives via Lewis Acid‐Catalyzed Asymmetric Ring Opening of Aziridines with Alcohols and Carboxylic Acids

AbstractUnder the catalysis of a Cu(I) or Ag(I) salt with a chiral diphosphine ligand, the enantioselective nucleophilic ring opening of racemic 2‐styrenylaziridines via kinetic resolution or dynamic kinetic asymmetric transformation (DyKAT) and of meso aziridines via desymmetrization with alcohols was realized. The reaction provided a range of chiral vicinal amino ether derivatives in 47%‐98% yields and with 50%–98% ee. The reaction could be extended to aliphatic carboxylic acids as nucleophiles. The synthetic utility was demonstrated in a four‐step formal synthesis of a diastereomer of the antirythmetic agent vernakalant.

Structures and circularly polarized luminescence of copper(I) complexes with chiral diimine and achiral diphosphine ligands

Abstract Copper(I) complexes with chiral diimine and diphosphine ligands were prepared and their chiroptical properties were investigated. By adding chirality to the diimine ligand, CPL (circularly polarized luminescence) intensities emitted from the copper(I) complex were enhanced to a maximum absolute gem value of 3 × 10−3, which is considered large for a mononuclear copper(I) complex.

Development of a One-Step Synthesis of oxa-Spirocyclic Diphosphine Ligands Driven by Their Application in the Industrial Synthesis of Sacubitril.

Herein we have developed a highly practical and efficient one-step coupling protocol for the synthesis of chiral spiro diphosphine ligands, especially for the oxa-spiro diphosphine ligands O-SDP, which showed excellent reactivity and diastereoselectivity in the asymmetric hydrogenation of a key intermediate of Sacubitril. It should be noted that the one-step coupling protocol could be operated on a kilogram scale, and the resulting ruthenium catalyst of O-SDP could hydrogenate the key intermediate of Sacubitril on an industrial scale.

Design and synthesis of novel 1,3-diene bridged chiral atropoisomeric diphosphine ligands for asymmetric hydrogenation of α-dehydro amino ketones

Design and synthesis of novel 1,3-diene bridged chiral atropoisomeric diphosphine ligands for asymmetric hydrogenation of α-dehydro amino ketones

Enantioselective Rhodium‐Catalyzed Pauson–Khand Reactions of 1,6‐Chloroenynes with 1,1‐Disubstituted Olefins

AbstractAn enantioselective rhodium(I)‐catalyzed Pauson–Khand reaction (PKR) using 1,6‐chloroenynes that contain challenging 1,1‐disubstituted olefins is described. In contrast to the previous studies with these types of substrates, which are only suitable for a single type of tether and alkyne substituent, the new approach results in a more expansive substrate scope, including carbon and heteroatom tethers with polar and non‐polar substituents on the alkene. DFT calculations provide critical insight into the role of the halide, which pre‐polarizes the alkyne to lower the barrier for metallacycle formation and provides the proper steric profile to promote a favorable enantiodetermining interaction between substrate and chiral diphosphine ligand. Hence, the chloroalkyne enables the efficient and enantioselective PKR with 1,6‐enynes that contain challenging 1,1‐disubstituted olefins, thereby representing a new paradigm for enantioselective reactions involving 1,6‐enynes.

Enantioselective Rhodium-Catalyzed Pauson-Khand Reactions of 1,6-Chloroenynes with 1,1-Disubstituted Olefins.

An enantioselective rhodium(I)-catalyzed Pauson-Khand reaction (PKR) using 1,6-chloroenynes that contain challenging 1,1-disubstituted olefins is described. In contrast to the previous studies with these types of substrates, which is only suitable for a single type of tether and alkyne substituent, the new approach results in a more expansive substrate scope, including carbon and heteroatom tethers with polar and non-polar substituents on the alkene. DFT calculations provide critical insight into the role of the halide, which pre-polarizes the alkyne to lower the barrier for the metallacycle formation and provides the proper steric profile to promote a favorable enantiodetermining interaction between substrate and chiral diphosphine ligand. Hence, the chloroalkyne enables the efficient and enantioselective PKR with 1,6-enynes that contain challenging 1,1-disubstituted olefins, which represents a new paradigm for enantioselective reactions involving 1,6-enynes.

Highly efficient and recyclable chiral phosphine-functionalized polyether ionic liquids for asymmetric hydrogenation of β-keto esters.

Herein, based on the concept of integration of phosphine ligands and ionic liquids (ILs), a class of chiral phosphine-functionalized polyether ionic liquids (CPF-PILs) were synthesized by ion-exchange reaction between polyether imidazolium ILs and a phenyl-sulfonated (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) chiral diphosphine ligand, and employed in the Ru-catalyzed homogeneous asymmetric hydrogenation of β-keto esters. The resulting CPF-PILs combined the dual functions of the chiral phosphine ligand and ILs, allowing efficient recovery and recycling of the chiral catalysts using only a catalytic amount of CPF-PILs. The effects of various factors, including the chiral catalyst structure, solvent properties, reaction temperature, hydrogen pressure, and hydrobromic acid dosage, on catalytic performance were thoroughly investigated, as well as the cycling stability and universality of the chiral catalysts were examined. The findings of the present study demonstrated that, under optimal reaction conditions, the model substrate methyl acetoacetate underwent quantitative conversion to methyl β-hydroxybutyrate with a 97% enantiomeric excess (ee). The chiral catalyst used in this process can be recycled up to 12 times and showed good applicability to structurally various β-keto esters. The present study presents a novel approach for using ILs in asymmetric hydrogenation reactions in an environmentally friendly manner.

Steric and dispersion effect of chiral diphosphine ligand on copper-catalyzed enantioselective incorporation of CO2with styrene: a computational study

The π-facial selectivity in 1,2-hydrocuopration step is mainly controlled by ligand–substrate steric repulsion, while stereoselectivity of CO2insertion into the Cu–C bond is primarily determined by ligand–CO2dispersion stabilizing interactions.

Structure and Circularly Polarized Luminescence of Copper(I) Complexes Bearing Bipyridine and Chiral Diphosphine Ligands

Copper(I) (Cu(I)) complexes bearing chiral phosphine and diimine ligands were prepared, and their chiroptical properties studied. The complex with a twisted diimine ligand and a diphosphine ligand showed moderate-intensity emission and circularly polarized luminescence (CPL) with considerable dissymmetry factor, gem. The signs and intensities in the CPL spectra were found to reflect the dihedral angles of the two pyridine rings in the diimine ligand.

Rhodium-Catalyzed Asymmetric Hydrogenation of All-Carbon Aromatic Rings.

Compared with heteroarenes, homogeneous asymmetric hydrogenation of all-carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine-catalyzed asymmetric hydrogenation of all-carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central-chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron-donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Rhodium‐Catalyzed Asymmetric Hydrogenation of All‐Carbon Aromatic Rings

AbstractCompared with heteroarenes, homogeneous asymmetric hydrogenation of all‐carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine‐catalyzed asymmetric hydrogenation of all‐carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central‐chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group. The key to success is the introduction of chiral diphosphine ligands with steric hindrance and strong electron‐donating properties. The axially chiral monophosphine ligands could be obtained by simple conversion of the hydrogenation products bearing the phosphine atom.

Inherently Chiral 6,7-Diphenyldibenzo[ e,g ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Inherently Chiral 6,7-Diphenyldibenzo[ <i>e,g</i> ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Insight into the Effects of Chiral Diphosphine Ligands on the Structure and Optical Properties of the Au24Cd2 Nanocluster.

Introduction of chiral ligands has been regarded as an effective strategy to obtain nanoclusters with optical purity. However, how the chiral ligands work is still unclear due to the lack of structural comparison between racemic nanoclusters and the corresponding optically active ones. In this work, three structurally related Au24Cd2 nanoclusters, including one racemic and two homochiral nanoclusters, were synthesized, and their crystal structures were characterized using single-crystal X-ray crystallography (SC-XRD). Based on their crystal structures, the origin of the chirality in Au24Cd2 was found to be the twist of the kernel and the chiral arrangement of the metal-ligand surface. Au24Cd2 protected with chiral ligands exhibits a more twisted kernel than the racemic one. Therefore, the chirality of chiral diphosphine was found to transfer from the ligands to the metal-ligand interface and then to the metal core, inducing its distortion to produce enhanced chirality. In addition, the optical properties including optical absorption and circular dichroism of these structurally related Au24Cd2 nanoclusters were compared.

Development of C2-Symmetric Chiral Diphosphine Ligands for Highly Enantioselective Hydrogenation Assisted by Ion Pairing.

A new series of C2-symmetrical chiral ferrocene-based diphosphino-ethane ligands termed as f-DPE were developed. Assisted by the ion pairing interaction with the ligand, a wide scope of 2-substituted acrylic acids was hydrogenated to obtain chiral propanoic acids with high yields and enantioselectivities. The well-known anti-inflammatory drugs ibuprofen, naproxen, and flurbiprofen could be synthesized efficiently. In addition, the synthetic utilities of the current method were demonstrated by gram-scale experiments.

Ir-Catalyzed cyclization of α,ω-dienes with an N-methyl group via two C-H activation steps.

Iridium-catalyzed sp3 C-H alkylation of an N-methyl group with 1,5- and 1,6-dienes proceeded to give five- and six-membered carbocyclic compounds, respectively, in high yields. The reaction involves intermolecular alkylation of the N-methyl group with a vinyl moiety and subsequent intramolecular cyclization at the β-position of the initially formed alkylated intermediate. The reaction using a chiral bidentate phosphine ligand enabled the asymmetric synthesis of the cyclic compounds.

Copper‐Catalyzed Highly Selective Protoboration of CF3‐Containing 1,3‐Dienes

AbstractThe copper‐catalyzed highly selective protoboration of CF3‐containing conjugated diene with proton source and B2Pin2 has been developed. This chemistry could suppress the well‐known defluorination and provide borated reagents with an intact CF3‐group. Further studies indicated that the functional group tolerance of this chemistry is very well, and the products could be used as versatile precursors for different types of transformations. Importantly, using chiral diphosphine ligand, we have developed the first example for using such starting material to synthesis allylic boron‐reagents which bearing a CF3‐containing chiral center. Notably, the reaction mechanism was intensively studied by DFT calculations, which could reveal the reason that defluorination was inhibited.

Copper-Catalyzed Highly Selective Protoboration of CF3 -Containing 1,3-Dienes.

The copper-catalyzed highly selective protoboration of CF3 -containing conjugated diene with proton source and B2 Pin2 has been developed. This chemistry could suppress the well-known defluorination and provide borated reagents with an intact CF3 -group. Further studies indicated that the functional group tolerance of this chemistry is very well, and the products could be used as versatile precursors for different types of transformations. Importantly, using chiral diphosphine ligand, we have developed the first example for using such starting material to synthesis allylic boron-reagents which bearing a CF3 -containing chiral center. Notably, the reaction mechanism was intensively studied by DFT calculations, which could reveal the reason that defluorination was inhibited.

Direct Observation of Diastereomeric α-C-Bound Enolates during Enantioselective α-Arylations: Synthesis, Characterization, and Reactivity of Arylpalladium Fluorooxindole Complexes.

The Pd-catalyzed asymmetric α-arylation of carbonyl compounds is a valuable strategy to form benzylic stereocenters. However, the origin of the stereoselectivity of these reactions is poorly understood, and little is known about the reactivity of the putative diastereomeric arylpalladium enolate intermediates. To this end, we report the synthesis and characterization of a series of diphosphine-ligated arylpalladium fluoroenolate complexes, including complexes bearing a metal-bound, stereogenic carbon and an enantioenriched chiral diphosphine ligand. These complexes reductively eliminate to form chiral α-aryl-α-fluorooxindoles with enantioselectivities and rates that are relevant to those of the catalytic process with SEGPHOS as the ancillary ligand. Kinetic studies showed that the rate of reductive elimination is slightly slower than the rate of epimerization of the intermediate, causing the reductive elimination step to impart the greatest influence on the enantioselectivity. DFT calculations of these processes are consistent with these experimental rates and suggest that the minor diastereomer forms the major enantiomer of the product. The rates of reductive elimination from complexes containing a variety of electronically varied aryl ligands revealed the unusual trend that complexes bearing more electron-rich aryl ligands react faster than those bearing more electron-poor aryl ligands. Noncovalent Interaction (NCI) and Natural Bond Orbital (NBO) analyses of the transition-state structures for reductive elimination from the SEGPHOS-ligated complexes revealed key donor-acceptor interactions between the Pd center and the fluoroenolate fragment. These interactions stabilize the pathway to the major product enantiomer more strongly than they stabilize that to the minor enantiomer.

Catalytic Asymmetric Synthesis of Silicon‐Stereogenic Dihydrodibenzosilines: Silicon Central‐to‐Axial Chirality Relay

AbstractA Rh‐catalyzed asymmetric synthesis of silicon‐stereogenic dihydrodibenzosilines featuring axially chiral 6‐membered bridged biaryls is demonstrated. In the presence of a RhI catalyst with a chiral diphosphine ligand, a wide range of dihydrodibenzosilines containing both silicon‐central and axial chiralities are conveniently constructed in excellent enantioselectivities via dehydrogenative C(sp3)−H silylation. Absolute configuration analysis by single‐crystal X‐ray structures revealed a novel silicon central‐to‐axial chirality relay phenomenon, which we believe will inspire further research in the field of asymmetric catalysis and chiroptical materials.