Asymmetric Hydrogenation Research Articles

Asymmetric Hydrogenation of Acrylates by COF with Chiral Frustrated Lewis Pairs

Asymmetric Hydrogenation of Acrylates by COF with Chiral Frustrated Lewis Pairs

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor.

The chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine is the key core skeleton of potent Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5-a]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5-a]pyrimidines has been developed using substrate activation strategy, with up to 99% ee. The decagram scale synthesis further demonstrated the potential and promise of this procedure in the synthesis of Zanubrutinib. In addition, a mechanistic study indicated that the hydrogenation starts with 1,2-hydrogenation.

Spiro-Josiphos Ligands for the Ir-Catalyzed Asymmetric Synthesis of Chiral Amines under Hydrogenation Conditions.

Transition metal-catalyzed asymmetric hydrogenation possesses unparalleled advantages to prepare chiral amines. Here we reported a novel ligand that combined Josiphos and a spirobiindane scaffold and simultaneously investigated its application in Ir-catalyzed asymmetric hydrogenation for the synthesis of chiral amines. Excellent catalytic activity (5000 TON), high enantioselectivity (up to 99% ee), and broad substrate scope (different C═N substrates) make it highly promising for both academic research and industrial applications.

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.

Rhodium-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3-Dipolar Nitrones.

Owing to their distinctive 1,3-dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N-O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN-derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine), the reaction proceeds via a novel 7-membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram-scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity.

Rhodium‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3‐Dipolar Nitrones

AbstractOwing to their distinctive 1,3‐dipolar structure, the catalytic asymmetric hydrogenation of nitrones to hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol and susceptibility to N−O bond cleavage. In this study, the asymmetric hydrogenation and transfer hydrogenation of nitrones were accomplished with a tethered TsDPEN‐derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p‐toluenesulfonyl‐1,2‐diphenylethylene‐1,2‐diamine), the reaction proceeds via a novel 7‐membered cyclic transition state, producing chiral hydroxylamines with up to 99 % yield and >99 % ee. The practical viability of this methodology was underscored by gram‐scale catalytic reactions and subsequent transformations. Furthermore, mechanistic investigations and DFT calculations were also conducted to elucidate the origin of enantioselectivity.

Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation

Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation

Catalytic performance of Noyori–Ikariya-type ruthenium complex with tethered syn-ULTAM ligand for the asymmetric transfer hydrogenation of ketones

The ruthenium complex of the tethered syn-ULTAM ligand, i.e. syn-3-(α-aminobenzyl)-benzo-γ-sultam, has been evaluated for the asymmetric transfer hydrogenation (ATH) of a variety of ketones in formic acid/triethylamine mixture. Its performance was similar to the established Noyori–Ikariya-type catalysts for the reduction of benzo-fused cyclic ketones, but the enantioselectivity for the reduction of acetophenone was only moderate. The syn-ULTAM-based catalyst was particularly efficient and enantioselective for ATH of the sterically demanding α,α-disubstituted ketones. Moreover, we report a divergent ATH of 2-phenyl-1,3-indandione to either cis-2-phenyl-1-indanol, or cis,trans-2-phenyl-1,3-indandiol.

Stereocontrol via Propeller Chirality in FLP-Catalyzed Asymmetric Hydrogenation.

Utilization of chiral frustrated Lewis pairs as catalysts in enantioselective hydrogenation of unsaturated molecules represents a promising approach in asymmetric synthesis. In our effort to improve our current understanding of the factors governing the stereoselectivity in these catalytic processes, herein we examined the mechanism of direct hydrogenation of aromatic enamines catalyzed by a binaphthyl-based chiral amino-borane. Our computational analysis reveals that only one particular conformer of the key borohydride reaction intermediate can be regarded as a reactive form of this species. This borohydride conformer has a well-defined chiral propeller shape, which induces facial selectivity in the hydride transfer to pro-chiral iminium intermediates. The propeller chirality of the reactive borohydride conformer is generated by the axially chiral binaphthyl scaffold of the amino-borane catalyst through stabilizing π-π stacking interactions. This new computational insight can be readily used to interpret the high degree of stereoinduction observed for these reactions. We expect that the concept of chirality relay could be further exploited in catalyst design endeavors.

Frontispiece: Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones

Frontispiece: Unlocking the Asymmetric Hydrogenation of Tetrasubstituted Acyclic Enones

Design and Synthesis of Diphosphine Ligands Based on the Chiral Biindolyl Scaffold and Their Application in Transition-Metal Catalysis.

An extremely concise, scalable, and stereoselective synthesis of a privileged chiral skeleton based on 2,2'-biindolyl and commercially available chiral building blocks has been developed. This novel skeleton allows for easy access to a range of bisphosphine ligands (decagram scale, up to 58% total yield, only three steps). The synthetic method is characterized by an efficient central-to-axial chirality transfer strategy. In particular, the superior performance of the ligands has been demonstrated in diverse reactions, including several asymmetric hydrogenations, asymmetric conjugate reductions, and cycloisomerization reactions, indicating a great potential for the application of the newly developed chiral backbones in further modifications and exploration of novel chiral ligands and catalysts.

Progress in Cobalt Complexes for Enabling Asymmetric Hydrogenation, H2 Production Catalysis and Alkene/Alkyne Hydro‐functionalization: A Review

AbstractThe use of hydrogen as an alternate clean fuel over conventional fuels, in addition to its role in chemical industries giving rise to useful products like hydrocarbons, has been the subject of research for many years. The need for hydrogen gas production methods has ever since been in demand. This review offers a comprehensive exploration of applications of cobalt complexes in asymmetric hydrogenation, H2 production catalysis and the hydro‐functionalization of alkenes and alkynes. Cobalt metal stands out, particularly due to its distinctive involvement in potential single‐electron processes. The main objective of this review is to provide an insight into the role of cobalt‐based coordination complexes as catalysts in hydrogenation reactions. It delves into models for enantio‐induction and extensively investigates the role of cobalt complexes in hydrogen evolution and associated reactions. Cobalt selection as the central metal is attributed to its beneficial (II)/(III) redox couple state, which proves valuable in hydride transfer reactions. While the review is structured based on substrate types, its core focus lies in the mechanism‐driven exploration of catalytic systems. These catalytic systems exhibit versatility in facilitating the hydrogenation and hydro‐functionalization of various types of double bonds through the utilization of tridentate ligands.

Asymmetric Transfer Hydrogenation of 2-Substituted Quinoxalines with Regenerable Dihydrophenanthridine.

The asymmetric hydrogenation of quinoxalines represents one of the most efficient approaches for the synthesis of optically active tetrahyroquinoxalines. In this paper, we demonstrate a metal-free asymmetric transfer hydrogenation of 2-substituted quinoxalines with regenerable dihydrophenanthridine under H2 using a combination of chiral phosphoric acid and achiral borane as catalysts. A wide range of optically active 2-substituted tetrahydroquinoxalines were produced in high yields with ≤98% ee.

Asymmetric Hydrogenation of Racemic 2-Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers.

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural β-amino acids via facile debenzylation and amino alcohol upon reduction.

Synthesis and Evaluation of (Bis)benzyltetrahydroisoquinoline Alkaloids as Antiparasitic Agents.

Visceral leishmaniasis and Chagas disease are neglected tropical diseases (NTDs) that severely impact the developing world. With current therapies suffering from poor efficacy and safety profiles as well as emerging resistance, new drug leads are direly needed. In this work, 26 alkaloids (9 natural and 17 synthetic) belonging to the benzyltetrahydroisoquinoline (BI) family were evaluated against both the pro/trypomastigote and amastigote forms of the parasites Leishmania infantum and Trypanosoma cruzi, the causative agents of these diseases. These alkaloids were synthesized via an efficient and modular enantioselective approach based on Bischler-Napieralski cyclization/Noyori asymmetric transfer hydrogenation to build the tetrahydroisoquinoline core. The bis-benzyltetrahydroisoquinoline (BBI) alkaloids were prepared using an Ullmann coupling of two BI units to form the biaryl ether linkage, which enabled a comprehensive survey of the influence of BI stereochemistry on bioactivity. Preliminary studies into the mechanism of action against Leishmania mexicana demonstrate that these compounds interfere with the cell cycle, potentially through inhibition of kinetoplast division, which may offer opportunities to identify a new target/mechanism of action. Three of the synthesized alkaloids showed promising druglike potential, meeting the Drugs for Neglected Disease initiative (DNDi) criteria for a hit against Chagas disease.

Differentiating enantiomers by directional rotation of ions in a mass spectrometer

Conventional mass spectrometry does not distinguish between enantiomers, or mirror-image isomers. Here we report a technique to break the chiral symmetry and to differentiate enantiomers by inducing directional rotation of chiral gas-phase ions. Dual alternating current excitations were applied to manipulate the motions of trapped ions, including the rotation around the center of mass and macro movement around the center of the trap. Differences in collision cross section were induced, which could be measured by ion cloud profiling at high resolutions above 10,000. High-field ion mobility and tandem mass spectrometry analyses of the enantiomers were combined and implemented by using a miniature ion trap mass spectrometer. The effectiveness of the developed method was demonstrated with a variety of organic compounds including amino acids, sugars, and several drug molecules, as well as a proof-of-principle ligand optimization study for asymmetric hydrogenation.

Asymmetric Transfer Hydrogenation of Cyclobutenediones.

Four-membered carbocycles are fundamental substructures in bioactive molecules and approved drugs and serve as irreplaceable building blocks in organic synthesis. However, developing efficient protocols furnishing diversified four-membered ring compounds in a highly regio-, diastereo-, and enantioselective fashion remains challenging but very desirable. Here, we report the unprecedented asymmetric transfer hydrogenation of cyclobutenediones. The reaction can selectively afford three types of four-membered products in high yields with high stereoselectivities, and the highly functionalized products enable a series of further transformations to form more diversified four-membered compounds. Asymmetric synthesis of di-, tri-, and tetrasubstituted bioactive molecules has also been achieved. Systematic mechanistic studies and theoretical calculations have revealed the origin of the regioselectivity, the key hydrogenation transition state models, and the sequence of the double and triple hydrogenation processes. The work provides a new choice for the catalytic asymmetric synthesis of cyclobutanes and related structures and demonstrates the robustness of asymmetric transfer hydrogenation in the accurate selectivity control of highly functionalized substrates.

Continuous‐Flow Asymmetric Hydrogenation for the Synthesis of an (S)‐Metolachlor Intermediate Using Catalysts Immobilized on a Core/Shell‐Type Support

AbstractHere we show continuous‐flow synthesis of a key inter‐mediate of (S)‐Metolachlor, which is a widely used agrochemical that is in huge demand, with asymmetric hydrogenation using a heterogeneous catalyst immobilized on a core/shell‐type support. We have immobilized a homogeneous catalyst onto a core/shell‐type heterogeneous support that was developed in our laboratory, which showed high turnover frequency and turnover number over a long period (over 120 h) when used in a solvent‐free continuous‐flow manner. This result demonstrates the feasibility of continuous‐flow production of chiral agrochemicals with packed‐bed heterogeneous catalysts. Moreover, the heterogenization protocol was shown to be applicable to elaborate practical catalysts used in industry, especially the group of phosphine ligands.

Ruthenium complexes of new chiral phosphine‐amine‐ether ligands (Ru‐PNO) for asymmetric hydrogenation – the role of backbone chirality in pincer ligand design

New chiral phosphine‐amine‐ether (PNO) ligands of the general formula Ph2PCH(R1)(CH2)nCH(R1)N(R2)CH(R3)CH2OMe, where R1, R2, and R3 = H or Me, n = 0 or 1, and their ruthenium complexes of the type [RuCl2(PPh3)(PNO)] have been synthesized. The coordination compounds were characterized by 1D and 2D NMR spectroscopy, modeled by DFT calculations, and in one case analyzed by X‐ray crystallography. The combined spectroscopic and theoretical investigations revealed that the relative configuration of the stereogenic elements in the P–N and N–O backbone represents a crucial factor in determining the conformation of the pincer‐type chelates and may also affect the configuration of the coordinated stereogenic nitrogen in the NH subunit, an essential element of stereochemical communication in outer sphere bifunctional catalysis. The new complexes were applied in the asymmetric hydrogenation of fused ring bicyclic ketones (i.e., 1‐tetralone and 4‐chromanone derivatives), a challenging substrate class, where enantioselectivities up to 97% could be obtained. Based on the spectroscopic and theoretical studies and catalytic experiments, structural features affecting the stereochemistry of the coordination could be identified and a qualitative enantioinduction model has been proposed.

Cinchona-Alkaloid-Derived NNP Ligand for Iridium-Catalyzed Asymmetric Hydrogenation of β-Keto Ester.

The Ir-catalyzed asymmetric hydrogenation of β-keto esters with Cinchona-alkaloid-derived NNP ligands has been developed. β-Hydroxy esters of opposite configuration were afforded smoothly with 91.5-99.1 and 81.6-99.3% ee, respectively, using NNP L2 and L7 derived from quinidine and quinine separately even on the gram scale. The protocol for the preparation of β-hydroxy esters of opposite configuration by the simple conversion of ligand configurations offered further opportunities for the synthesis of biologically active molecules and drugs.