Ruthenium-Catalyzed Asymmetric 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.

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.

Asymmetric Hydrogenative Coupling of Indoles with Unsaturated Ketones Enabled by Copper/Ruthenium Relay Catalysis

AbstractA relay catalytic system is developed for the asymmetric hydrogenative coupling of indoles with α,β-unsaturated ketones, affording enantioenriched chiral γ-indole alcohols with broad substrate scope and excellent enantioselectivities (32 examples, up to >99% ee). Mechanistic studies suggest that the relay catalytic system consists of copper-catalyzed alkylation and ruthenium-catalyzed asymmetric hydrogenation.

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.

Highly efficient ruthenium-catalyzed asymmetric hydrogenation of N-heteroaryl vinyl ethers

N-directing asymmetric hydrogenation of vinyl ether can afford excellent yield and ee without a coordinating group engagement.

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).

Asymmetric Hydrogenation of Racemic 6-Aryl 1,4-Dioxaspiro[4.5]decan-7-ones to Functionalized Chiral β-Aryl Cyclohexanols via a Dynamic Kinetic Resolution.

A ruthenium-catalyzed asymmetric hydrogenation method for the synthesis of functionalized β-aryl cyclohexanols is described. With chiral spiro ruthenium catalyst (Ra,S,S)-5c, a series of racemic α-aryl cyclohexanones bearing a β-monoethylene ketal group were hydrogenated to the corresponding functionalized β-aryl cyclohexanols in high yields with enantioselectivity of up to 99% ee via a dynamic kinetic resolution. This protocol can be conducted on a decagram scale and provide potential approaches for the synthesis of optically active and densely functionalized aryl cyclohexanols.

Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin

Alogliptin (1) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (10) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide (6) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.

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.

Progress in Ruthenium-Catalyzed Asymmetric Hydrogenation of β-Keto Esters

Progress in Ruthenium-Catalyzed Asymmetric Hydrogenation of <i>β</i>-Keto Esters

Ruthenium-Catalyzed Asymmetric Hydrogenation of β-Acetamidovinyl Sulfides

Key words rhodium catalysis - enantioselectivity - hydrogenation - acetamidovinyl sulfides - acetamidoalkyl sulfides

Ruthenium-Catalyzed Asymmetric Hydro-genation of Nitrogen-Containing Heterocycles

Ruthenium-Catalyzed Asymmetric Hydro-genation of Nitrogen-Containing Heterocycles

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.