Asymmetric Transfer Hydrogenation Research Articles

Stereoselective Access to β‐gem‐Difluorinated Alcohols Through Enzymatic Reduction

AbstractWe report here a mild process to access diversely functionalized enantioenriched β‐gem‐difluorinated (S)‐alcohols by using biocatalytic reduction in >99% yield and enantiomeric excesses ranging from 96% to >99%. This novel approach involves enzymatic reduction of α‐gem‐difluorinated heterocyclic and carbocyclic ketone derivatives as well as an acyclic gem‐difluorinated β‐ketosulfone and proceeds under mild conditions at 30 °C under aqueous conditions to produce a range of high added value enantioenriched difluorinated alcohols including 3,3‐difluorochromanol, 3,3‐difluorothiochromanol, 3,3‐difluoro‐dihydroquinolinol, and α‐difluorinated β‐hydroxysulfone derivatives. A comparative study between enzymatic reduction and metal‐catalyzed asymmetric transfer hydrogenation was carried out as well.

Asymmetric Transfer Hydrogenation of Stable NH Imines for the Synthesis of Enantiopure α‐Chiral Primary Amines

Asymmetric Transfer Hydrogenation of Stable <scp>NH</scp> Imines for the Synthesis of Enantiopure <scp>α‐Chiral</scp> Primary Amines

Polarizability matters in enantio-selection

The prevalence of chirality, or, handedness in biological world is a fundamental phenomenon and a characteristic hallmark of life. Thus, understanding the origin of enantio-selection, i.e., the sense and magnitude of asymmetric induction, has been a long-pursued goal in asymmetric catalysis. Herein, we demonstrated a polarizability-derived electronic effect that was shown to be capable of rationalizing a broad range of stereochemical observations made in the field of asymmetric catalysis. This effect provided a consistent enantio-control model for the prediction of major enantiomers formed in a ruthenium-catalyzed asymmetric transfer hydrogenations of ketones. Direct and quantitative linear free energy relationships between substrates’ local polarizabilities and observed enantio-selectivity were also revealed in three widely known asymmetric catalytic systems covering both reductions and oxidations. This broadly applicable polarizability-based electronic effect, in conjunction with conventional wisdom mainly leveraging on steric effect considerations, should aid rational design of enantio-selective processes for better production of chiral substances.

Synthesis of Chiral 1,2-Amino Alcohol-Containing Compounds Utilizing Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Unprotected α-Ketoamines.

Herein, we disclose a facile synthetic strategy to access an important class of drug molecules that contain chiral 1,2-amino alcohol functionality utilizing highly effective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-ketoamines. Recently, the COVID-19 pandemic has caused a crisis of shortage of many important drugs, especially norepinephrine and epinephrine, for the treatment of anaphylaxis and hypotension because of the increased demand. Unfortunately, the existing technologies are not fulfilling the worldwide requirement due to the existing lengthy synthetic protocols that require additional protection and deprotection steps. We identified a facile synthetic protocol via a highly enantioselective one-step process for epinephrine and a two-step process for norepinephrine starting from unprotected α-ketoamines 1b and 1a, respectively. This newly developed enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation was extended to the synthesis of many 1,2-amino alcohol-containing drug molecules such as phenylephrine, denopamine, norbudrine, and levisoprenaline, with enantioselectivities of >99% ee and high isolated yields.

α-Alkylation and Asymmetric Transfer Hydrogenation of Tetralone via Hydrogen Borrowing and Dynamic Kinetic Resolution Strategy Using a Single Iridium(III) Complex.

Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.

Organometallic Mn(I) Complexes in Asymmetric Catalytic (Transfer) Hydrogenation and Related Transformations

AbstractDirect asymmetric hydrogenation (AH) and asymmetric transfer hydrogenation (ATH) are among the most efficient approaches to produce chiral building blocks. Recently, these types of transformations have witnessed a shift towards the use of molecular catalysts based on earth‐abundant transition metals due to their ready availability, economic advantage, and novel properties. With particular regard to manganese, catalyst development has seen both the efficiency and substrate scope in AH and ATH greatly improved, with the emergence of a large number of well‐defined Mn‐complexes employed in this field. The reaction scope includes the AH and ATH of C=O bonds, asymmetric reduction of C=N bonds and the asymmetric reductive transformations of C=C bonds. Herein, our survey of the area focuses on the catalytic activity of such complexes, their versatility towards asymmetric transformations and the routes employed to convert substrates to their target molecules. We consider the collected findings of this article will be helpful to the reader by providing an insight into ligand design, thereby aiding future catalyst development. Moreover, this review is aimed at highlighting the remarkable progress made in the last seven years in the development of manganese complexes for enantioselective reduction.

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 &gt;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.

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.

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.

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.

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.

Regio- and Enantioselective Asymmetric Transfer Hydrogenation of One Carbonyl Group in a Diketone through Steric Hindrance.

On the basis of steric hindrance, one carbonyl group in a diketone can be reduced in a regioselective manner, with high enantioselectivity. The methodology can be extended to ketones with varied length of hydrocarbon chain spacing, and the products can be converted by oxidation to hydroxy esters or lactones without loss of enantiopurity.

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)2, as the catalytically active intermediate, which can decay to a dimeric species (κ3-PCNOx)IrH(μ-H)2IrH(κ2-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

Biological assays, electrochemical behavior, and theoretical DFT calculations of Ru(II) complexes of chiral phosphinite based based on β-amino alcohols: Transfer hyrogenation of ketones using a HCOOH/Et3N mixture

Synthesis of two phosphinite ligands based on β-amino alcohols, in high yields has been demonstrated. When we treated [Ru(arene)(μ-Cl)Cl]2 {arene:p-cymene,benzene} with chelating phosphinite ligands, we obtained neutral Ru(II)-complexes possessing the general formula [Ru(arene)phosphiniteCl2]. The structure of the ligands and complexes was confirmed using analytical and spectroscopic techniques. The quantum chemical calculations were carried out for the ruthenium complexes at the DFT/CAM-B3LYP level of theory in gas phase. The phosphinite complexes were subjected to cyclic voltammetry studies in order to determine the energies of HOMO and LUMO levels and to estimate their electrochemical and some electronic properties. Organic complex-based memory substrates were immobilized using TiO2-modified ITO electrodes, and the memory functions of phosphinite-based organic complexes were verified by chronoamperometry (CA) and open-circuit potential amperometry (OCPA). In the present study, the antioxidant potentials of ruthenium-based p-cymene and benzene complexes through DPPH radical scavenging, metal chelating, and reducing power activities were also determined. In addition, DNA binding abilities and antimicrobial activities of these complexes against pathogenic bacteria were studied. Finally, the ruthenium complex, (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenyl phosphinitobis[dichloro(η6-benzene)ruthenium(II)] also catalyzed asymmetric transfer hydrogenation of acetophenone with high conversion (up to 99%) and good enantioselectivity (ee up to 89 %), in the existence of formic acid and triethylamine in dichloromethane medium under air atmosphere.

Access to Enantioenriched β‐Hydroxy gem‐Difluorinated Heterocyclic and Acyclic Derivatives through Rh(III)‐Catalyzed Asymmetric Transfer Hydrogenation

AbstractWe report a process to access a variety of enantioenriched α‐gem‐difluorinated alcohols. A Rh(III)‐catalyzed asymmetric transfer hydrogenation method was developed in 85–98% yields and enantiomeric excesses ranging from 52% to &gt;99%. The reduction proceeds under mild conditions with a range of difluorinated molecules including 3,3‐difluorochromanone, 3,3‐difluorothiochromanone, 3,3‐difluoro‐dihydroquinolinone and α‐difluorinated β‐ketosulfone derivatives to provide the desired enantioenriched difluorinated alcohols which are valuable fluorinated building blocks.

Bridging the incompatibility gap in dual asymmetric catalysis over a thermoresponsive hydrogel-supported catalyst

The integration of dual asymmetric catalysis is highly beneficial for the synthesis of organic molecules with multiple stereocenters. However, two major issues that need to be addressed are the intrinsic deactivation of dual-species and the extrinsic conflict of reaction conditions. To overcome these concerns, we have utilized the compartmental and thermoresponsive properties of poly(N-isopropylacrylamide) (PNIPAM) to develop a cross-linked PNIPAM-hydrogel-supported bifunctional catalyst. This catalyst is designed with Rh(diene) species situated on the outer surface and Ru(diamine) species positioned within the interior of the hydrogel. The compartmental function of PNIPAM in the middle overcomes intrinsic mutual deactivations between the dual-species. The thermoresponsive nature of PNIPAM allows for precise control of catalytic pathways in resolving external conflicts by controlling the reaction switching between an Rh-catalyzed enantioselective 1,4-addition at 50°C and a Ru-catalyzed asymmetric transfer hydrogenation (ATH) at 25°C. As we envisioned, this sequential 1,4-addition/reduction dual enantioselective cascade reaction achieves a transformation from incompatibility to compatibility, resulting in direct access to γ-substituted cyclic alcohols with dual stereocenters in high yields and enantio/diastereoselectivities. Mechanistic investigation reveals a reversible temperature transition between 50°C and 25°C, ensuring a cascade process comprising a 1,4-addition followed by the ATH process.

Asymmetric transfer hydrogenation of 2,3-diphenylpropenoic acids over heterogeneous palladium catalysts modified by cinchona alkaloids

Asymmetric catalytic methods are among the convenient syntheses procedures of optically pure organic compounds, many of which are valuable pharmaceutical intermediates. Applying heterogeneous catalysts may contribute to their economic and environmentally benign synthesis. Among the easiest and often used methods of introducing chiral centres in molecules are the reduction of prochiral unsaturated compounds. Although, several heterogeneous catalytic systems are known in which in situ chirally-modified metals are used, such catalysts have never been applied in asymmetric transfer hydrogenations. Here we report the enantioselective transfer hydrogenations of (E)-2,3-diphenylpropenoic acids over supported palladium catalysts modified by dihydrocinchonidine carried out in ordinary laboratory glassware using easily available, cheap hydrogen donor, i.e. potassium formate. High conversions and good enantioselectivities were obtained in transfer hydrogenations of various acids substituted on phenyl rings. Results obtained with various acid derivatives and with few cinchona alkaloid modifiers indicated that the transfer hydrogenations occur through a similar surface intermediate as the enantioselective hydrogenations with molecular hydrogen. A deuterium tracer study showed low deuterium incorporation in the product possibly due to dissociation of formate and exchange with the surface mobile hydrogens, however, these processes are strongly influenced by the donor cation. The asymmetric transfer hydrogenation may be carried out at over 2 g scale, thus may be used as an advantageous laboratory synthetic procedure without applying special precautions characteristic of gaseous reactants.

A hybrid Au/Ru catalyst for sequential alkyne hydration/asymmetric transfer hydrogenation reactions

A hybrid catalytic system was developed for sequential alkyne hydration/asymmetric transfer hydrogenation reactions through the confinement of an amphiphilic polymer supported ruthenium and gold catalysts within core/shell silica gel.