Asymmetric Hydrogenation Research Articles

Heterogeneous Asymmetric Hydrogenation of C=C and C=O Double Bonds

Nowadays, heterogeneous catalysts play a crucial role in the field of asymmetric catalysis to produce enantiopure compounds for various applications. The unique properties of heterogeneous systems, such as high stability, reusability, or ease of separation, allow effective catalysis of asymmetric transformations and their further implementation in industrial processes. In this mini review, we address the recent trend in the synthesis of chiral heterogeneous catalysts and their subsequent application in asymmetric hydrogenation reactions. We focus on current advances in asymmetric hydrogenation reactions of C=O and C=C bonds due to their high relevance in the fine chemicals industry. Our main aim is to provide a short overview of this expanding field, its current challenges, and future perspectives.

Enantioselective Synthesis of Chiral 1,5-Benzodiazepin-2-ones by Pd-Catalyzed Asymmetric Hydrogenation and Reductive Amination.

The enantioselective synthesis of chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones via asymmetric hydrogenation catalyzed by the Pd/f-spiroPhos complex in the presence of hydrochloric acid as an additive has been developed, achieving excellent enantioselectivities and high turnover numbers, up to 99% ee and TON = 4600. More significantly, the asymmetric reductive amination of β-keto esters with 1,2-phenylenediamine has also been successfully realized to afford chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones with comparable enantioselectivities of up to 99% ee.

Asymmetric Transfer Hydrogenation of gem-Difluorocyclopropenyl Ketones: The Synthesis and Functionalization of Enantioenriched cis gem-Difluorocyclopropyl Ketones.

The asymmetric transfer hydrogenation of gem-difluorocyclopropenyl ketones, catalyzed by a Noyori-Ikariya ruthenium complex, was developed to access substituted optically enriched cis-disubstituted gem-difluorocyclopropyl ketones, and the value of these latter building blocks was illustrated by the synthesis of heterocycles fused to the difluorocyclopropyl moiety.

Asymmetric Hydrogenation of Naphthalenes with Molybdenum Catalysts: Ligand Design Improves Chemoselectivity

Asymmetric Hydrogenation of Naphthalenes with Molybdenum Catalysts: Ligand Design Improves Chemoselectivity

Asymmetric hydrogenation of tetrasubstituted β-phosphorylated α,β-unsaturated esters catalyzed by nickel complexes of chiral phosphinooxazolines

Asymmetric hydrogenation of tetrasubstituted β-phosphorylated α,β-unsaturated esters catalyzed by nickel complexes of chiral phosphinooxazolines

Design and Synthesis of Sulfur-Containing Tetradentate Ligands for Ir-Catalyzed Asymmetric Hydrogenation of Ketones.

Developing highly active and enantioselective ligands for the asymmetric hydrogenation of ketones has consistently attracted significant attention from scientists. A series of novel tetradentate sulfur-containing ligands, termed as f-thiophamidol, were successfully designed and synthesized which exhibited excellent performance in the asymmetric hydrogenation of simple ketones (up to 99% yield, 99% ee) and α-substituted β-keto sulfonamides (up to 99% yield, 99% ee, 99:1 dr). The subsequent successful gram-scale experiments with high TON demonstrated the immense potential application value of this system in synthesizing drug molecules.

Chiral Polymeric Diamine Ligands for Iridium-Catalyzed Asymmetric Transfer Hydrogenation.

A series of polymeric chiral diamine ligands are developed by diboron-templated asymmetric reductive couplings, and their iridium complexes Ir-polydiamines are efficient and recyclable catalysts for asymmetric transfer hydrogenation (ATH) of functionalized ketones, affording a series of optically active secondary alcohols in excellent enantioselectivities (up to 99% ee) and unprecedentedly high total TONs (12,000, six cycles). Ir-polydiamine catalysts with longer chains offered higher reactivities, providing a plausible deactivation mechanism and practical solutions of ATH for vitamin B5 and phenylephrine.

Electrochemically Driven Asymmetric Hydrogenation of Aromatic Ketones by Noyori–Ikariya Catalyst

ABSTRACTThe electrochemically driven asymmetric hydrogenation of 2,2,2‐trifluoroacetophenone was performed using a Noyori–Ikariya catalyst, yielding a 97% product yield and a 47% enantiomeric excess (ee) with a charge input of only 0.5 F/mol. In comparison, the ethoxylate anion generated by the electroreduction of the solvent, EtOH, can efficiently drive the transfer hydrogenation of Ru catalysts more effectively than organic bases. After optimizing the electrolysis conditions, this method has been successfully extended to other aromatic ketones, including heterocyclic aromatic ketones and the base‐sensitive substrate ethyl benzoylformate, with yields ranging from 71% to 97% and ee values ranging from 55% to 82%. A possible reaction mechanism was proposed.

Advanced MOF/MXene heterostructure with carbon aerogel to boosts the ions movement in asymmetric supercapacitors and hydrogen production

Supercapacitors represent a promising avenue for advanced energy storage solutions. However, achieving devices that simultaneously possess all the ideal properties, such as high capacitance, fast charge-discharge rates, and excellent cyclability, remains a significant challenge. Herein, a facile approach for fabricating carbon aerogel-induced chromium metal-organic framework (CA@MIL-101) integrated with titanium carbide MXene (CA@MIL-101-(Cr)/Ti3C2Tx) nanocomposites was demonstrated via hydrothermal method. The CA@MIL-101-(Cr)/Ti3C2Tx nanocomposites offer numerous divalent ion active sites and significantly improve charge transfer kinetics, attributed to their interconnected porous structure. This novel anode exhibits an outstanding specific capacity of 1632 Cg-1 with a PVDF binder-based electrode and a high rate of performance. Moreover, a full-cell supercapacitor was developed with carbon aerogel as the cathode and CA@MIL-101 (Cr)/Ti3C2Tx as the anode. With its hierarchical pore structure and functional groups, the CA@MIL-101 (Cr)/Ti3C2Tx anode achieves an energy density of 38 Wh-kg−1, a high-power density of 1280 W-kg−1, and robust anti-self-discharge behavior. The CA@MIL-101 (Cr)/Ti3C2Tx//CA supercapattery uses both adsorption/desorption processes and faradaic reactions for charge storage. The synthesized materials also perform exceptionally well electro-catalytically. This research advances high-performance CA@MIL-101 (Cr)/Ti3C2Tx electrodes, enhances understanding of supercapacitor charge storage, and paves the way for next-generation energy storage technologies.

Reduction of Tertiary Carbon Radicals via Asymmetric Hydrogen Atom Transfer (AHAT)†

Comprehensive SummaryIn the past two decades, the development of asymmetric radical reactions has achieved tremendous progress, which has emerged as a powerful tool for the synthesis of chiral molecules in synthetic chemistry. Among the diverse array of radical processes, the transfer of hydrogen atoms to tertiary carbon radicals offers the potential for constructing chiral tertiary carbon centers in a stereoselective fashion. Notwithstanding the challenges associated with the reactive and evanescent nature of radical species, the use of chiral reagents or mediators has enabled the stereocontrol of the asymmetric hydrogen atom transfer (AHAT), which provides novel avenues for advancing the field of asymmetric synthesis. Key Scientists

Cobalt-Catalyzed Asymmetric Hydrogenation of Ketones Enabled by the Synergism of an N-H Functionality and a Redox-Active Ligand.

The transition metal-catalyzed asymmetric hydrogenation (AH) of ketones to produce enantioenriched alcohols is an important reaction in organic chemistry with applications in the pharmaceutical and agrochemical fields. Using earth-abundant, biorelevant cobalt as the central metal in the catalyst has a high potential to improve sustainability and achieve hydrogenation reactions that are scalable. However, due to the high d-electron count, designing cobalt catalysts that exhibit turnover numbers (TONs, ≥1000) and enantioselectivities (≥90%) sufficient for synthetic utility and practical scalability (≥1 kg scale) remains a challenge. In this work, an efficient catalyst design strategy utilizing an amino(imino)diphosphine Co(II) bromide precatalyst is presented to achieve this goal. The quantitative production of a wide range of secondary chiral alcohols with TONs of up to 150,000 and an enantiomeric excess (e.e.) of up to 99% at a scale of up to 1.35 kg was achieved, indicating that the proposed cobalt catalyst is highly promising for AH and scale-up reactions. A mechanistic study revealed that the synergism of an N-H functionality and a redox-active ligand endows the cobalt catalyst with a high productivity and excellent enantioselectivity.

Cinchona alkaloids-derived chiral ligands for Mn-catalyzed ATH of ketones: Improvement of enantioselectivity through π-π stacking-induced hydrogen bond

Inexpensive and readily available manganese metals combined with novel chiral ligands derived from cinchona alkaloids catalyzed the asymmetric transfer hydrogenation of aromatic ketones. All tested aromatic ketones were highly enantioselectively converted to the corresponding chiral alcohols, obtaining up to 99.4% ee. Based on control experiments and density functional theory (DFT) calculations, a plausible mechanism was discussed. During catalysis, π-π stacking in the catalyst promoted the formation of hydrogen bonds between the substrate and the catalyst, and the stronger the stacking, the stronger the hydrogen bonds, while stronger hydrogen bonds were more favourable for achieving high enantioselectivity in manganese-catalyzed asymmetric transfer hydrogenation.

Enantiopure P-Chiral Secondary Phosphines (P*HRR') from the Catalytic Asymmetric Hydrogenation of P═C Bonds.

We report the first bottleable enantiopure P-chiral secondary phosphines from the rhodium-catalyzed asymmetric hydrogenation of phosphaalkenes. Catalytic asymmetric hydrogenation, a reaction of broad academic and industrial importance for C═C, N═C, and O═C bonds, has not previously been reported for the P═C bond. The hydrogenation of ArP═CR2 (Ar = Mes, m-Xyl and TMOP; R = Ph, 4-C6H4F) affords four unprecedented P-stereogenic secondary phosphines in 76%-90% isolated yields with 91%-97% enantiomeric excess (ee). These isolable P-chiral secondary phosphines are configurationally stable indefinitely in the solid state and show only modest loss in ee when kept in solution for over a month at room temperature.

Correction to “Double Asymmetric Hydrogenation of α-Iminoketones: Facile Synthesis of Enantiopure Vicinal Amino Alcohols”

Correction to “Double Asymmetric Hydrogenation of α-Iminoketones: Facile Synthesis of Enantiopure Vicinal Amino Alcohols”

Copper-Catalyzed Asymmetric Hydrogenation of Unsymmetrical ortho-Br Substituted Benzophenones.

The asymmetric hydrogenation of benzophenones, catalyzed by low-activity earth-abundant metal copper, has hitherto remained a challenge due to the substrates equipped with two indistinguishably similar aryl groups. In this study, we demonstrated that the prochiral carbon of the ortho-bromine substrate exhibits the highest electrophilicity and high reactivity among the ortho-halogen substituted benzophenones, as determined by the Fukui function (f+) analysis and hydrogenation reaction. Considering that the enantiodirecting functional bromine group can be easily derivatized and removed in the products, we successfully achieved a green copper-catalyzed asymmetric hydrogenation of ortho-bromine substituted benzophenones. This method yielded a series of chiral benzhydrols with excellent results. The utility of this protocol has been validated through a gram-scale reaction and subsequent product transformations. Hirshfeld partition (IGMH) and energy decomposition analysis (EDA) indicate that the CH···HC multiple attractive dispersion interactions (MADI) effect between the catalyst and substrate enhances the catalyst's activity.

Asymmetric Transfer Hydrogenation of Ketones Improved by PNN-Manganese Complexes.

Chiral manganese(I) complexes that contain carbocyclic-fused 8-amino-5,6,7,8-tetrahydroquinolinyl groups that are appended with distinct para-R substituents have proven to be effective catalysts in the asymmetric transfer hydrogenation (ATH) of a wide range of ketones (48 examples). Notably, Mn2 proved to be the most productive catalyst, allowing an outstanding turnover number of 8300 with catalyst loadings as low as 0.01 mol %. Furthermore, this catalytic protocol shows considerable promise for applications in the synthesis of chiral drugs such as Lusutrombopag.

Data-Driven Insights into the Transition-Metal-Catalyzed Asymmetric Hydrogenation of Olefins.

The transition-metal-catalyzed asymmetric hydrogenation of olefins is one of the key transformations with great utility in various industrial applications. The field has been dominated by the use of noble metal catalysts, such as iridium and rhodium. The reactions with the earth-abundant cobalt metal have increased only in recent years. In this work, we analyze the large amount of literature data available on iridium- and rhodium-catalyzed asymmetric hydrogenation. The limited data on reactions using Co catalysts are then examined in the context of Ir and Rh to obtain a better understanding of the reactivity pattern. A detailed data-driven study of the types of olefins, ligands, and reaction conditions such as solvent, temperature, and pressure is carried out. Our analysis provides an understanding of the literature trends and demonstrates that only a few olefin-ligand combinations or reaction conditions are frequently used. The knowledge of this bias in the literature data toward a certain group of substrates or reaction conditions can be useful for practitioners to design new reaction data sets that are suitable to obtain meaningful predictions from machine-learning models.

Ir-Catalyzed Asymmetric Hydrogenation of N-Fused Heteroarenes with High Nitrogen Density: An Access to Chiral 2,5-Disubstituted 5,6-Dihydropyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines.

A highly enantioselective Ir-catalyzed asymmetric hydrogenation of 2,5-disubstituted pyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines containing four nitrogen atoms has been first realized. Under additive-free conditions, a variety of chiral 2,5-disubstituted 5,6-dihydropyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazines can be afforded in high yields (86-98%) with excellent enantioselectivities of up to 99% ee. This method provides a straightforward strategy for the efficient synthesis of chiral multinitrogen polyheterocyclic compounds.

Ru-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated γ-Lactams.

A highly efficient Ru-catalyzed asymmetric hydrogenation of α,β-unsaturated γ-lactams has been developed by using a C2-symmetric ruthenocenyl phosphine-oxazoline as the chiral ligand. This method achieves the enantioselective synthesis of chiral β-substituted γ-lactams in high yields and with excellent enantioselectivities (up to 99% yield with 99% ee). Mechanistic studies based on detailed control experiments and computational investigation revealed that the cationic Ru-complex acts as the active catalytic species; the protonation process of the oxa-π-allyl-Ru complex, which is formed by the migratory insertion of the C=C double bond to the Ru-H bond (the stereocontrolling step) followed by an isomerization process, is the rate-determining step, and the existence of PPh3 is crucial for the highly efficient catalytic behavior. The protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs and bioactive compounds, particularly for the 150 kg-scale industrial production of Brivaracetam, an antiepileptic drug that shows 13-fold more potent binding to the synaptic vesicle protein 2A compared with the well-known Levetiracetam.

Asymmetric hydrogenation of ketimines with minimally different alkyl groups by anionic manganese catalysts.

Asymmetric hydrogenation of ketimines with minimally different alkyl groups by anionic manganese catalysts.