Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation Research Articles

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.

Asymmetric Transfer Hydrogenation of 2,3-Disubstituted Flavanones through Dynamic Kinetic Resolution Enabled by Retro-Oxa-Michael Addition: Construction of Three Contiguous Stereogenic Centers.

A ruthenium-catalyzed asymmetric transfer hydrogenation of 2,3-disubstituted flavanones was developed for the construction of three contiguous stereocenters under basic conditions through a combination of dynamic kinetic resolution and retro-oxa-Michael addition, giving chiral flavanols with excellent enantioselectivities and diastereoselectivities. The reaction proceeded via a base-catalyzed retro-oxa-Michael addition to racemize two stereogenic centers simultaneously in concert with a highly enantioselective ketone transfer hydrogenation step. The asymmetric transfer hydrogenation could be achieved at gram scale without loss of the activity and enantioselectivity.

Total synthesis of resolvin D3.

Resolvin D3 was synthesized by the Suzuki-Miyaura cross-coupling reaction of C1-C8 borane with C9-C22 iodoolefin as the key reaction. The latter intermediate was obtained by the sequential Wittig reactions of C9-C13 phosphonium salt with C14-C19 aldehyde and then C9-C19 aldehyde with propyltriphenylphosphonium bromide. The stereogenic centers at C4, C11, and C17 were constructed by the ruthenium-catalyzed asymmetric transfer hydrogenation with high stereoselectivity.

Total Synthesis of Resolvin T4

AbstractA total synthesis of resolvin T4 was achieved by connecting three intermediates by Wittig reactions. The enal in the C1–C10 part was constructed through reduction of a propargylic alcohol with Red-Al followed by oxidation. The enal moiety in the C11–C16 part was synthesized by a ring-opening reaction of a silyl epoxide followed by a Peterson elimination. The chiral centers at C7 and C13 were constructed by ruthenium-catalyzed asymmetric transfer hydrogenation.

Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of β-Substituted α-Oxobutyrolactones.

A concise and effective ruthenium-catalyzed asymmetric transfer hydrogenation of β-substituted α-oxobutyrolactones has been developed, delivering a series of cis-β-substituted α-hydroxybutyrolactone derivatives with excellent yields, enantioselectivities, and diastereoselectivities. Two consecutive stereogenic centers were constructed in one step through dynamic kinetic resolution under basic conditions. The reaction could be conducted on a gram scale without loss of activity and enantioselectivity. The reductive products could be easily transformed into useful building blocks.

Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of 3-Fluorochromanone Derivatives to Access Enantioenriched cis-3-Fluorochroman-4-ols through Dynamic Kinetic Resolution.

Enantioenriched cis-3-fluoro-chroman-4-ol derivatives were conveniently prepared by the ruthenium-catalyzed asymmetric transfer hydrogenation of a new family of 3-fluoro-chromanones through a dynamic kinetic resolution process. The reaction proceeded under mild conditions using a low catalyst loading and HCO2H/Et3N (1:1) as the hydrogen source, affording the reduced fluorinated alcohols in good yields (80-96%), high diastereomeric ratios (up to 99:1 dr), and excellent enantioselectivities (up to >99% ee).

Room-Temperature Asymmetric Transfer Hydrogenation of Biomass-Derived Levulinic Acid to Optically Pure γ-Valerolactone Using a Ruthenium Catalyst.

This study presents a first report on ruthenium-catalyzed asymmetric transfer hydrogenation (ATH) of levulinic acid (LA) to chiral γ-valerolactone (GVL). ATH of LA has been explored with Noyori’s chiral catalyst (Ru–TsDPEN) in methanol solvent. Efficacy of ATH reaction of LA was investigated under different reactions conditions such as temperature, catalyst, and hydrogen donor concentration. The effect of various organic tertiary bases along with formic acid (FA) as a hydrogen donor was studied, and N-methylpiperidine with FA (1:1 molar ratio) was revealed as an efficient hydrogen donor for ATH of LA to GVL furnishing chiral GVL with complete conversion and 93% enantiomeric excess (ee). This operationally simple and mild ATH protocol was tested for practical applicability of ATH of LA obtained from biomass waste (rice husk and wheat straw) and furnished chiral GVL with 82% ee.

Enantioselective Synthesis of Homoisoflavanones by Asymmetric Transfer Hydrogenation and Their Biological Evaluation for Antiangiogenic Activity.

Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel antiangiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases. We have previously reported the therapeutic potential of anti-angiogenic homoisoflavanone derivatives with efficacy in retinal and choroidal neovascularization models, although these are racemic compounds due to the C3-stereogenic center in the molecules. This work presents asymmetric synthesis and structural determination of anti-angiogenic homoisoflavanones and pharmacological characterization of the stereoisomers. We describe an enantioselective synthesis of homoisoflavanones by virtue of ruthenium-catalyzed asymmetric transfer hydrogenation accompanying dynamic kinetic resolution, providing a basis for the further development of these compounds into novel experimental therapeutics for neovascular eye diseases.

Synthesis of Enantioenriched α,α-Dichloro- and α,α-Difluoro-β-Hydroxy Esters and Amides by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation

A mild and convenient approach was developed to prepare a series of α,α-dihalogeno β-hydroxy esters or amides by using commercially available Noyori's complex [RuCl( p-cymene)( R, R)-TsDPEN] as a catalyst (S/C = 100-200) in the asymmetric transfer hydrogenation of the corresponding ketones. Moderate to high yields (up to 99%) and excellent enantioselectivities (up to >99% ee) were achieved for a series of variously substituted dichloro and difluoro β-hydroxy esters and amides.

Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of Chiral Sulfinylimines

Key words ruthenium catalysis - transfer hydrogenation - butylsulfinylimines - allylic amines

Chiral C2-symmetric η6-p-cymene-Ru(II)-phosphinite complexes: Synthesis and catalytic activity in asymmetric reduction of aromatic, methyl alkyl and alkyl/aryl ketones

Abstract Chiral C2-symmetric bis(phosphinite) ligands and their binuclear ruthenium(II) complexes have been synthesized and used as catalysts in the ruthenium-catalyzed asymmetric transfer hydrogenation of aromatic, methyl alkyl and alkyl/aryl ketones using 2-propanol as both the hydrogen source and solvent in the presence of KOH. Under optimized conditions, all complexes showed high catalytic activity as catalysts in the reduction of various ketones to corresponding chiral secondary alcohols. Products were obtained with high conversions (99%) and moderate to good enantioselectivities (82% ee). Furthermore, C2-symmetric bis(phosphinite) ligands and their binuclear ruthenium(II) complexes were characterized by multinuclear NMR spectroscopy, FT-IR spectroscopy, LC/MS-MS and elemental analysis.

Enantioselective Synthesis of Isoflavanones by Catalytic Dynamic Kinetic Resolution.

A ruthenium-catalyzed asymmetric transfer hydrogenation of racemic isoflavanones with dynamic kinetic resolution yields virtually enantiopure isoflavanols as single diastereomers. Subsequent oxidation gives rise to isoflavanones in high enantiomeric purities.

Ruthenium-Catalyzed Dynamic Kinetic Resolution Asymmetric Transfer Hydrogenation of β-Chromanones by an Elimination-Induced Racemization Mechanism

Chiral chroman derivatives are important pharmacophores in natural and synthetic bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these compounds is an important goal. Ruthenium-catalyzed asymmetric transfer hydrogenation under strongly basic conditions has been found to induce dynamic kinetic resolution of β-substituted chromanones, producing valuable chromanols in high yields and with high levels of stereocontrol. The reaction proceeds by base-catalyzed racemization of the β-stereocenter through a conjugate elimination/conjugate addition pathway in concert with a highly selective ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and transition state structures has revealed the driving interactions for diastereoselectivity as well as unexpected CH–O stabilizing interactions between the catalyst sulfonamide and the reacting substrate.

Kinetic Resolution Driven Diastereo- and Enantioselective Synthesis of cis-β-Heteroaryl Amino Cycloalkanols by Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation.

The utility of tethered Ru-TsDPEN catalyst has been demonstrated for the asymmetric transfer hydrogenation of rac-α-heteroaryl amino cycloalkanones to construct biologically important cis-β-heteroaryl amino cycloalkanols with two contiguous chiral centers via dynamic kinetic resolution. The stated (R,R)-Teth-TsDPEN-Ru-catalyzed transformation is carried out under mild conditions using formic acid/triethylamine as a hydrogen source with excellent diastereo- and enantioselectivities. Further, this methodology has been applied for the synthesis of an antileishmanial agent and chiral ionic liquid.

ChemInform Abstract: Ru‐Catalyzed Asymmetric Transfer Hydrogenation of α‐Trifluoromethylimines.

Enantioselective transformation of strong electron-withdrawing acyclic α-trifluoromethylimines to α-trifluoromethylamines through a ruthenium-catalyzed asymmetric transfer hydrogenation has been developed. The method described here is a facile catalytic process with sodium formate as a hydrogen resource and water–dimethylformamide as a cosolvent. The benefit of this enantioselective transformation affords a series of chiral α-trifluoromethylamines with high yields and excellent enantioselectivities (93–99% ee) under mild reaction conditions.

Ru-Catalyzed asymmetric transfer hydrogenation of α-trifluoromethylimines.

Enantioselective transformation of strong electron-withdrawing acyclic α-trifluoromethylimines to α-trifluoromethylamines through a ruthenium-catalyzed asymmetric transfer hydrogenation has been developed. The method described here is a facile catalytic process with sodium formate as a hydrogen resource and water-dimethylformamide as a cosolvent. The benefit of this enantioselective transformation affords a series of chiral α-trifluoromethylamines with high yields and excellent enantioselectivities (93-99% ee) under mild reaction conditions.

ChemInform Abstract: New Chiral Ruthenium(II)‐Phosphinite Complexes Containing a Ferrocenyl Group in Enantioselective Transfer Hydrogenations of Aromatic Ketones.

Abstract A new and versatile class of unsymmetrical ferrocenyl-phosphinite ligands possessing a stereogenic center has been prepared from commercially available, inexpensive aminoacids such as, d -, l -phenylglycine and d -, l -phenylalanine, through a concise synthetic procedure. These ligands are not very sensitive to air and moisture, and display good enantioselectivities in the ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives, in which up to 91% ee was obtained. A comparison of the catalytic properties of amino alcohols and other analogues based on a ferrocenyl backbone is also discussed briefly. The structures of these ligands and their corresponding complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis.

Ruthenium-Catalysed Efficient Asymmetric Transfer Hydrogenation of Aromatic Ketones using Cinchona Alkaloids as Chiral Ligands

Cinchona alkaloid derivatives were applied in asymmetric transfer hydrogenation of aromatic ketones in a ruthenium catalytic system using i-PrOH as the hydrogen source. A series of aromatic ketones...

New chiral ruthenium(II)–phosphinite complexes containing a ferrocenyl group in enantioselective transfer hydrogenations of aromatic ketones

A new and versatile class of unsymmetrical ferrocenyl-phosphinite ligands possessing a stereogenic center has been prepared from commercially available, inexpensive aminoacids such as, d-, l-phenylglycine and d-, l-phenylalanine, through a concise synthetic procedure. These ligands are not very sensitive to air and moisture, and display good enantioselectivities in the ruthenium-catalyzed asymmetric transfer hydrogenation of acetophenone derivatives, in which up to 91% ee was obtained. A comparison of the catalytic properties of amino alcohols and other analogues based on a ferrocenyl backbone is also discussed briefly. The structures of these ligands and their corresponding complexes have been elucidated by a combination of multinuclear NMR spectroscopy, IR spectroscopy, and elemental analysis.

Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation

This thesis covers the development of two new methods for the asymmetric reduction of ketones and ketone intermediates. The protocols developed are based on the use of a ruthenium pseudo-dipeptide catalyst that previously has been shown to be efficient and selective in the asymmetric reduction of carbonyl compounds.The first part of this thesis describes the development of an efficient protocol for sequential isomerization and asymmetric reduction of allylic alcohols into saturated chiral alcohols in a one-pot procedure. This transformation has previously been reported at high temperature and with long reaction times, yielding the products in poor enantioselectivity. In the current project, the same transformation was investigated, however, with a significally more active catalyst. As a result we were able to use milder reaction conditions which yielded higher enantioselectivity in comparison to previously published protocols. The scope was investigated and the mechanism was briefly studied.The second part of this thesis describes the asymmetric reduction of sterically demanding ketones with the same metal complex as in the first part. It was found that longer reaction times in combination with the use of potassium tert-butoxide facilitate the reduction of sterically hindered ketones, to yield secondary alcohols with high enantioselectivity. The scope and the role of potassium were investigated, and a plausible new transition state was postulated.