Asymmetric Hydrogenation Reactions 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.

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study.

Due to the unique effect of fluorine atoms, the efficient construction of high-value alkyl fluorides has attracted significant interest in modern drug development. However, enantioselective catalytic strategies for the efficient assembly of highly functionalized chiral C(sp3)-F scaffolds from simple starting materials have been underutilized. Herein, we demonstrate a nickel-catalyzed radical transfer strategy for the efficient, modular, asymmetric hydrogenation and hydroalkylation of alkenyl fluorides with primary, secondary, and tertiary alkyl halides under mild conditions. The transformation provides facile access to various structurally complex secondary and tertiary α-fluoro amide products from readily available starting materials with excellent substrate compatibility and distinct selectivity. Furthermore, the utility of this method is demonstrated by late-stage modifications and product derivatizations. Detailed mechanistic studies and DFT calculations have been conducted, showing that the rate-determining step for asymmetric hydrogenation reaction is NiH-HAT toward alkenyl fluorides and the stereo-determining step is alcohol coordination to Ni-enolates followed by a barrierless protonation. The mechanism for the asymmetric hydroalkylation reaction is also delivered in this investigation.

Efficient and Scalable Enantioselective Synthesis of a Key Intermediate for Rimegepant: An Oral CGRP Receptor Antagonist

Rimegepant is a calcitonin gene-related peptide antagonist used for acute treatment and prevention of migraine. We herein attempt to explore an efficient and practiced method for scale-up, regio- and enantioselective synthesis of (R)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (1), a key intermediate of rimegepant. In this work, a Ru-catalyzed asymmetric transfer hydrogenation (ATH) reaction was a key step. The optimization of the reaction conditions involved exploring the reaction parameters including catalysts, bases, and solvents. The results suggested that the Ru-catalyzed ATH process using formic acid as the hydrogen donor could be operated under mild conditions at a low catalyst loading (0.5 mol%), affording a high yield (92.1% yield with 99.8% purity) and gratifying enantioselectivity (99.9% ee) of the target product (1). This work first reported the Ru-catalyzed ATH process in the synthesis of key intermediates of rimegepant. The optimized ATH process was easy to implement and cost-effective, making it particularly suitable for manufacturing scale production.

Facile and practical access to chiral benzofused oxa-heterocycles via an asymmetric hydrogenation and intramolecular SNAr cascade

Herein, we report a tandem asymmetric hydrogenation and SNAr reaction, providing valuable six- and five-membered chiral benzofused cyclic ethers with high yields and enantioselectivities (up to 99% yield and up to 99% ee).

TADDOL-based P,S-bidentate diastereomeric ligands in asymmetric allylation and hydrogenation reactions

Diastereomeric P,S-bidentate phosphoramidite ligands with TADDOL core and (1R,2S)-1,2-diphenyl-2-(phenylthio)-ethan-1-amine residue were synthesized. These ligands provided up to 76% ee in the Pd-catalyzed alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate, up to 70% ee in the amination of this substrate with pyrrolidine, and 89–95% ee in the Rh-catalyzed asymmetric hydro- genation of dimethyl itaconate and methyl (Z)-2-acetamido-3-arylacrylates. The different contributions of diastereomeric chiral inducers to the catalytic outcome are discussed.

P-Stereogenic threonine derived Ir–P,N complexes. Reversible cyclometallation and asymmetric hydrogenation reactions

A threonine-derived phosphine-oxazoline iridium catalyst is reported, showcasing excellent selectivity in the hydrogenation of N-Boc-2,3-diarylallylamines. The reversible cyclometallation process between the square planar Ir(I) complex and the corresponding octahedral Ir(III) species is thoroughly investigated, while considering the influence of substitution at the phenyl group of the oxazoline on this equilibrium. X-Ray analysis reveals that the cyclometallated tridentate ligand adopts a fac coordination mode. Furthermore, the catalytic performance of these complexes in the asymmetric hydrogenation is evaluated and the utilization of Ir(III) pre-catalysts or Ir(I)/Ir(III) mixtures in hydrogenation reactions is proposed based on the observed equilibrium dynamics.

Meerwein Arylation of Aryl(alkyl)idenemalononitriles and Diazonium Salts for the Synthesis of 2-(Aryl(alkyl)/arylmethylene)malononitrile Derivatives.

A metal-free Meerwein arylation reaction from aryl(alkyl)idenemalononitriles and diazonium salts for the synthesis of 2-(aryl(alkyl)/arylmethylene)malononitrile derivatives under mild conditions was well developed. Different from the general addition reactions between alkenes and diazonium salts, this study performed the traditional coupling reaction for the formation of C(sp2)-C(sp2) bond arylation products. The radical reaction mechanism was well verified in the control experiments. The other advantages of the approach are broad-scope substrates and good group tolerance. Moreover, the obtained products can be readily converted into high-value asymmetric ketones and hydrogenation reactions.

Asymmetric Synthesis of Chiral Seven-Membered NHCs, Their Transition-Metal Complexes and Application in Asymmetric ­Catalysis

AbstractA series of new chiral seven-membered NHCs were synthesized via Ru-catalyzed asymmetric hydrogenation reactions as the key step. Transition metal such as Rh, Ir and Au can coordinate to the developed NHCs. The crystal structures of the chiral seven-membered NHCs and their transition-metal complexes show a nonplanar framework with torsional twist. Furthermore, the chiral NHCs were applied in asymmetric hydrosilylation reactions, and the corresponding product was obtained with >95% yield and up to 83% ee.

Amido-ene(amido) Ni(II)-Catalyzed Highly Enantioselective Transfer Hydrogenations of Ketone: Dual Functions of the Ene(amido) Group

Catalytic asymmetric transfer hydrogenation (ATH) reactions of ketones have become an important tool for producing enantiomerically pure alcohols that are widely used in the syntheses of bioactive compounds. However, the high toxicities and low abundances of traditionally employed precious metals serving as catalyst centers have impeded widespread application of precious metal-based catalysts in asymmetric synthesis. Development of catalysts from abundant and less toxic 3d metals is highly desirable but still challenging. We report herein the development of structurally well-defined (R,R)-amido-ene(amido) nickel catalysts for ATH of ketone substrates, facilitating access to a wide range of secondary (S)-configuration alcohols, many of which are synthetic building blocks of biologically relevant molecules, with up to 95% enantiomeric excess (e.e.) and broad scope of functional group tolerance. Catalytic intermediate isolation and density functional theory calculation ascribed the catalytic activity to stabilization of the electron-rich nickel center with the ene(amido) group via a π-backdonation interaction within the catalytic intermediates, while the stereoinduction mainly arises from a catalyst–substrate π–π interaction in the transition state for enantioselective hydride transfer.

Construction of Monophosphine–Metal Complexes in Privileged Diphosphine-Based Covalent Organic Frameworks for Catalytic Asymmetric Hydrogenation

Privileged diphosphine ligands that chelate many transition metals to form stable chelation complexes are essential in a variety of catalytic processes. However, the exact identity of the catalytically active moieties remains ambiguous because the chelated metal catalysts may undergo rearrangement during catalysis to produce monophosphine-metal complexes, which are hard to isolate and evaluate the activities. By taking advantage of the isolation of two phosphorus atoms, we demonstrate here the successful construction of chiral monophosphine-Ir/Ru complexes of diphosphine ligands in covalent organic frameworks (COFs) for enantioselective hydrogenation. By condensation of the tetraaldehyde of enantiopure MeO-BIPHEP and linear aromatic diamines, we prepare two homochiral two-dimensional COFs with ABC stacking, in which the two P atoms of each diphosphine are separated and fixed far apart. Post-synthetic metalations of the COFs thus afford the single-site Ir/Ru-monophosphine catalysts, in contrast to the homogeneous chelated analogues, that demonstrated excellent catalytic and recyclable performance in the asymmetric hydrogenation of quinolines and β-ketoesters, affording up to 99.9% enantiomeric excess. Owing to the fact that the porous catalyst is capable of adsorbing and concentrating hydrogen, the catalytic reactions are promoted under ambient/medium pressure, which are typically performed under high pressure for homogeneous catalysis. This work not only shows that monophosphine-metal complexes of diphosphines can be catalytically active centers for asymmetric hydrogenation reactions but also provides a new strategy to prepare new types of privileged phosphine-based heterogeneous catalysts.

Asymmetric hydrogenation using a covalently immobilized Ru-BINOL-AP@MSNs catalyst

Ru-BINOL-AP@MSNs catalyst was synthesized using a state-of-the-art pathway without protecting or deprotecting groups. It achieved 84% conversion in an asymmetric hydrogenation reaction, with enantioselectivity >90% of the R-isomer.

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.

Dosage delivery of chiral ruthenium catalysts using non-ionic surfactants for asymmetric transfer hydrogenation reactions in aqueous media

Dosage delivery of asymmetric ruthenium catalysts for transfer hydrogenation reactions of ketones: nano-reactors in aqueous media.

Coinage Metal-Catalyzed Asymmetric Reactions of ortho-Alkynylaryl and Heteroaryl Aldehydes and Ketones.

Coinage metals have become the metal of choice due to their excellent catalytic activity in organic transformation processes. Combining various chiral ligands and coinage metals became a productive area of research and access to heterocyclic derivatives according to an efficient and sustainable manner. This review was devoted to the various recently developed coinage metal-catalyzed domino processes of ortho-alkynylaryl and heteroaryl aldehydes and ketones leading to functionalized heterocycles. Various gold chiral complexes were presented, and methods of preparations of chromenes along with indoles were covered. Ag-chiral complexes are also prone to interesting activities such as cyclization followed by reduction and functionalization with enolizable ketones or (diazomethyl)phosphonate. Asymmetric Cu-catalyzed domino cyclization and asymmetric transfer hydrogenation reactions efficiently led to functionalized chromenes. Some remarkable examples involving copper associated with ruthenium in the context of a cyclization and asymmetric hydrogenation process were also presented.

Enantiocontrolled Preparation of ϒ-Substituted Cyclohexenones: Synthesis and Kinase Activity Assays of Cyclopropyl-Fused Cyclohexane Nucleosides.

The enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives 1a,b was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.0]heptane scaffold is described. Nucleoside kinase activity assays with this cyclopropyl-fused cyclohexane nucleoside, together with other related nucleosides (2a–e), were performed, showing that thymine- and guanine- containing compounds have affinity for herpes simplex virus Type 1 (HSV-1) thymidine kinase (TK) but not for human cytosolic TK-1, thus pointing to their selectivity for herpetic TKs but not cellular TKs.

Highly efficient axially biscarboline ethers as catalysts used in 1,2- and 1,4-transfer hydrogenations of ketimines and β-enamino esters

A series of new axial chiral biscarboline ethers were synthesized using L-tryptophan aminoacid after dehydrogenation and oxidations using m-CPBA. These diastereoisomers can be obtained by column chromatography and used as catalysts in asymmetric hydrogenation reactions of β-enamine esters and ketimines. Chiral catalysts 6 and 7 exhibited very high enantioselectivity in the reactions. For example, high up to 98%ee was achieved in the enantioselective hydrogenations when only 1%mol of catalyst was used.

Self‐Assembly of a Chiral Bis‐phosphine Ligand Bearing Pyridyl Crown Ethers and Chiral Primary Ammoniums: Application to Catalytic Asymmetric Hydrogenation Reactions

AbstractA chiral bis‐hosphine ligand bearing two pyridyl crown ethers was complexed with primary ammonium salts of different absolute configuration to form supramolecular chiral catalysts, which were successfully applied in the Rh‐catalyzed asymmetric hydrogenation of α‐dehydroamino acid esters and Ir‐catalyzed asymmetric hydrogenation of quinoxalines. By comparison with the non‐assembled catalysts, the complexation between the chiral catalysts and primary ammoniums obviously improved enantioselectivities. Up to 11 % enhancement in ee values in asymmetric hydrogenation of α‐dehydroamino acid esters and 30 % enhancement in ee values in asymmetric hydrogenation of quinoxalines were achieved.

Review Study of Chiral N-Heterocyclic Carbene (NHC) Ligands in Stereoselective Metal-Catalyzed Reduction Reactions

Stereoselective metal-catalyzed reactions using N-heterocyclic carbene (NHC) ligands have shown significant recent advances, due to the ability of NHC ligands as strong σ-donor species to coordinate with a wide variety of transition metals. Therefore, the design of new ligands and the subsequent strategies for their synthesis enables new applications of their metal complexes in catalysis to be investigated. This study focuses on the applications of different classes of Ir-, Pd-, Au- and Rh-NHC ligand complexes as promising catalysts in the asymmetric hydrogenation, hydrosilylation and transfer hydrogenation reactions.

Manganese‐Catalyzed Asymmetric Hydrogenation of 3H‐Indoles

AbstractThe asymmetric hydrogenation (AH) of 3H‐indoles represents an ideal approach to the synthesis of useful chiral indoline scaffolds. However, very few catalytic systems based on precious metals have been developed to realize this challenging reaction. Herein, we report a Mn‐catalyzed AH of 3H‐indoles with excellent yields and enantioselectivities. The kinetic resolution of racemic 3H‐indoles by AH was also achieved with high s‐factors to construct quaternary stereocenters. Many acid‐sensitive functional groups, which cannot be tolerated when using a state‐of‐the‐art ruthenium catalyst, were compatible with manganese catalysis. This new process expands the scope of this transformation and highlights the uniqueness of earth‐abundant metal catalysis. The reaction could proceed with catalyst loadings at the parts per million (ppm) level with an exceptional turnover number of 72 350. This is the highest value yet reported for an earth‐abundant metal‐catalyzed AH reaction.

Manganese-Catalyzed Asymmetric Hydrogenation of 3H-Indoles.

The asymmetric hydrogenation (AH) of 3H-indoles represents an ideal approach to the synthesis of useful chiral indoline scaffolds. However, very few catalytic systems based on precious metals have been developed to realize this challenging reaction. Herein, we report a Mn-catalyzed AH of 3H-indoles with excellent yields and enantioselectivities. The kinetic resolution of racemic 3H-indoles by AH was also achieved with high s-factors to construct quaternary stereocenters. Many acid-sensitive functional groups, which cannot be tolerated when using a state-of-the-art ruthenium catalyst, were compatible with manganese catalysis. This new process expands the scope of this transformation and highlights the uniqueness of earth-abundant metal catalysis. The reaction could proceed with catalyst loadings at the parts per million (ppm) level with an exceptional turnover number of 72 350. This is the highest value yet reported for an earth-abundant metal-catalyzed AH reaction.