Β-amino Alcohols Research Articles

Enantioselective Friedel-Crafts Reaction of Heteroaromatic Compounds with Glyoxals Catalyzed by Chiral Oxazaborolidinium Ion Catalyst.

A catalytic enantioselective Friedel-Crafts reaction of various heteroaromatic compounds with glyoxals has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxyketones in high yield (up to 96%) with excellent enantioselectivity (up to >99% ee). The synthetic utility of this method was illustrated by conversion of the products to various derivatives such as 1,2-diol and β-amino alcohol.

Synthesis of β-amino alcohols from D-glucose and their molecular docking studies against β 1- and β 2- adrenoreceptors

A simple and convenient methodology has been developed for the synthesis of β-amino alcohols from native sugar D-glucose. First, D-glucose was converted into 2,6-anhydro-3,4,5,7-tetra-O-benzyl-heptitol which was then converted into its corresponding epoxide. Finally, the epoxide was reacted with variety of amines in the presence of samarium (III) trifluoromethanesulfonate to afford β-amino alcohols regioselectively in excellent yields of 90–95% followed by debenzylation to afford hydroxylated derivatives. Additionally, molecular docking studies of the synthesized compounds considering β 1- and β 2-adrenoreceptors as target structures were performed.

Analysis of the binding mechanism for a water-soluble Pd(II) complex containing β-amino alcohols with HSA applying experimental and computational methods

In the study ahead, the binding interactions of the [Pd (HEAC) Cl2] complex with human serum albumin (HSA) protein have been assayed in vitro (pH= 7.40) utilizing computational and experimental procedures. The mentioned complex was synthesized as a water-soluble complex from {2-((2-((2-hydroxyethyl)amino)ethyl)amino) cyclohexanol} ligand = HEAC. The results of electronic absorption and circular dichroism investigations illustrated that the hydrophobicity of the Tryptophan microenvironment in HSA undergoes the changes by binding to the Pd(II) complex without substantial perturbations on the protein secondary structure. The fluorescence emission spectroscopy analysis revealed that with rising temperature, the quenching constant (K sv) in the Stern–Volmer’s relation decreases; so, it can be said that the interaction process is along with a static quenching mechanism. The values of 2.88 × 105 M−1, and 1.26 represent the binding constant (K b) and the number of the binding sites (n), respectively. The Job graph showed the maximum point at χ = 0.5, which means organizing a new set with 1:1 stoichiometry. Thermodynamic profile (ΔH < 0, ΔS < 0, and ΔG < 0) has affirmed that van der Waals forces and hydrogen bonds have a basic function in the Pd(II) complex-albumin bindings. The ligand-competitive displacement studies utilizing warfarin and ibuprofen have represented that Pd(II) complex interacts with albumin by site II (subdomain IIIA). The computational molecular docking theory approved the results of the site-competitive tests; also, it indicated the existence of hydrogen bonds and van der Waals forces in Pd(II) complex-albumin interactions. Communicated by Ramaswamy H. Sarma

Highly stable Lewis acidic trifloaluminate ionic liquid supported on silica and metallosilicates as an efficient catalyst for continuous flow aminolysis of epoxides

In this work heterogeneous catalysts based on hybrid materials consisted of calcium and/or magnesium silicates and modern task-specific ionic liquids (supported ionic liquid phase material) dedicated particularly for continuous flow synthesis of fine chemicals with liquid reagents were designed. Pure SiO2 (as a reference sample), as well as magnesium (MgO-SiO2) or calcium (CaO-SiO2) silicates were used as supports for Lewis acidic trifloaluminate ionic liquids immobilized via chemical bound. The lowest ionic liquid loading was determined for SiO2 (15.58 wt%) and the highest for CaO-SiO2 (23.70 wt%). Resulted catalysts were used for the optimization of process parameters of the synthesis of β-amino alcohols in batch reactor (molar ratio aniline: styrene oxide 1.1:1; 1 mol% of catalyst, 60 °C). Not only the most active (conversion of styrene oxide 100.0% and selectivity to main product 98.7%) but also stable in 3 cycles of the process was the catalyst based on MgO-SiO2. The activity of poorly recyclable precursor of ionic liquid used as an active phase Al(OTf)3 was also lower (conversion 87.3% and selectivity 94.6%). Substrate scope confirmed the versatility of this method. The key achievement of the research was the confirmation of activity and stability of the most active catalyst in batch process for the aminolysis of epoxide in the presence of heterogeneous catalyst based on MgO-SiO2 in flow system through 72 h (conversion 81.1%, selectivity 95.9%). The proof of concept for the design of this catalytic system for production of selected fine chemicals is shown in this study.

One-Pot Synthesis of Chiral 1-Aryl-2-Aminoethanols via Ir-Catalyzed Asymmetric Hydrogenation.

A straightforward synthesis approach to chiral 1-aryl-2-aminoethanols via the one-pot asymmetric hydrogenation catalyzed by Ir catalyst was developed. This tandem process involves the in situ generation of α-amino ketones via the nucleophilic substitution of α-bromoketones with amines and the Ir-catalyzed asymmetric hydrogenation of ketone intermediates to provide diverse enantiomerically enriched β-amino alcohols. The excellent yields and enantioselectivities (up to 96% yield and up to >99% ee) with a wide substrate scope in this one-pot strategy were obtained.

O-Allylhydroxyamine: A Bifunctional Olefin for Construction of Axially and Centrally Chiral Amino Alcohols via Asymmetric Carboamidation.

Difunctionalization of olefins offers an attractive approach to access complex chiral structures. Reported herein is the design of N-protected O-allylhydroxyamines as bifunctional olefins that undergo catalytic asymmetric 1,2-carboamidation with three classes of (hetero)arenes to afford chiral amino alcohols via C-H activation. The C═C bond in O-allylhydroxyamine is activated by the intramolecular electrophilic amidating moiety as well as a migrating directing group. The asymmetric carboamidation reaction pattern depends on the nature of the (hetero)arene reagent. Simple achiral (hetero)arenes reacted to give centrally chiral β-amino alcohols in excellent enantioselectivity. The employment of axially prochiral or axially racemic heteroarenes afforded amino alcohols with both axial and central chirality in excellent enantio- and diastereoselectivity. In the case of axially racemic heteroarenes, the coupling follows a kinetic resolution pattern with an s-factor of up to >600. A nitrene-based reaction mechanism has been suggested based on experimental studies, and a unique mode of induction of enantio- and diastereoselectivity has been proposed. Applications of the amino alcohol products have been demonstrated.

Asymmetric Hydrogenation of α-Amino Esters into Optically Active β-Amino Alcohols through Dynamic Kinetic Resolution Catalyzed by Ruthenabicyclic Complexes.

Racemic α-substituted α-amino esters were hydrogenated into enantioenriched β-amino alcohols through dynamic kinetic resolution with chiral ruthenabicyclic complexes. The reaction was carried out with a substrate/catalyst molar ratio of 200-1000 under 15 atm of H2 at 25 °C to afford a variety of β-substituted β-aminoethanols in up to 96% ee (24 examples). The mechanistic studies including deuteration experiments suggested that the reaction proceeds with 1,2-hydride migration of the α-amino acetalate intermediate into the α-hydroxy imine followed by the continuous reduction of the imino compound, affording the amino alcohol product.

Ni4 complex encapsulated hybrid Na–Y catalyst: Structural investigation and enhanced Catalysis

In this present work, synthesized tetranuclear Ni complex is anchored on thiol functionalized Na–Y zeolite. Structure, phase integrity, shape, thermal stability and the existence of functional groups are identified by using different analytical techniques like powder XRD, N2 adsorption-desorption, Fourier transformed infrared spectroscopy (FT-IR), Nuclear magnetic resolution (29Si MAS NMR and 13C CP MAS NMR), scanning electron microscope (SEM-EDX), thermogravimetric analysis etc. The prepared hybrid catalyst Na–Y–S–Ni4 shows remarkable catalytic property by promoting the formation of high-yield products like β-amino alcohol by electrophilic ring opening reaction. 89% and 90% conversion of pyrrolidine and piperidine with high selectivity of the desired product are observed in ring breaking of cyclohexene oxide.

Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone.

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (-)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.

Electroreductive Hydroxymethylation of Imines with Ketones To Access β-Amino Alcohols.

In this article, an electrochemical method for the direct synthesis of β-amino alcohols from imines and ketones is described. Mechanistic studies, including a radical trapping experiment, electron paramagnetic resonance, cyclic voltammetry, and divided-cell electrolysis experiment, support the radical-involved reductive cross coupling of imines with ketones at the cathode. The use of abundant and easily prepared starting materials, high atom- and step-economy, and insensitivity to air and moisture make this synthetic strategy more efficient for the construction of various β-amino alcohol derivatives.

Metal Node Control of Brønsted Acidity in Heterobimetallic Titanium-Organic Frameworks.

Compared to indirect framework modification, synthetic control of cluster composition can be used to gain direct access to catalytic activities exclusive of specific metal combinations. We demonstrate this concept by testing the aminolysis of epoxides with a family of isostructural mesoporous frameworks featuring five combinations of homometallic and heterobimetallic metal-oxo trimers (Fe3, Ti3, TiFe2, TiCo2, and TiNi2). Only TiFe2 nodes display activities comparable to benchmark catalysts based on grafting of strong acids, which here originate from the combination of Lewis Ti4+ and Brønsted Fe3+-OH acid sites. The applicability of MUV-101(Fe) to the synthesis of β-amino alcohols is demonstrated with a scope that also includes the gram scale synthesis of propranolol, a natural β-blocker listed as an essential medicine by the World Health Organization, with excellent yield and selectivity.

Visible light-mediated three-component functionalization of olefins with sulfoxyimidoylsulfonium salt for the synthesis of β-amino alcohols and amino ethers.

A new strategy involving three-component functionalization of olefins with sulfoxyimidoylsulfonium salt and a nucleophilic reagent for the synthesis of β-amino alcohols and β-amino ethers by photoredox catalysis was developed. The sulfoxyimidoylsulfonium salt is important and serves as the N-centred radical precursor. β-Amino alcohols and β-amino ethers bearing various functional groups are synthesized in good yields under mild conditions. Furthermore, the advantages of this strategy are greater safety, no additives, and easy to obtain raw materials.

Expeditious preparation of β-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis.

An economical route providing quick access to chiral β-amino alcohols bearing one β-sec-alkyl group was developed. This protocol starts with commercially available and cheap chiral sources such as derivatives of L-serine and L-threonine. A series of vicinal amino alcohols with high optical purity were prepared in good yields through 4 or 6 operationally simple steps. Two different strategies (three routes) were designed for the synthesis of amino alcohols bearing β-sec-alkyl groups with various steric hindrance.

Parallel kinetic resolution of aziridines via chiral phosphoric acid-catalyzed apparent hydrolytic ring-opening

An intriguing chiral phosphoric acid-catalyzed asymmetric hydrolytic ring-opening of racemic aziridines via regiodivergent PKR is presented, providing an efficient approach for the construction of chiral β-amino alcohols.

Photoredox-Catalyzed Synthesis of β-Amino Alcohols: Hydroxymethylation of Imines with α-Silyl Ether as Hydroxymethyl Radical Precursor.

Carbon-carbon bond formation is an efficient approach for the synthesis of amino alcohols using two simple starting materials. Herein, we present a novel method for a divergent synthesis of β-amino ethers and β-amino alcohols in a sequential one-pot protocol under high-efficiency, mild, and metal- or metal-free conditions. Especially, TMSCH2OPMP was developed as a synthetic equivalent of α-hydroxymethyl radical in an in situ photocatalyzed oxidative PMP group deprotection strategy under air. A preliminary mechanistic investigation provides evidence for reaction mechanism involving a photoinduced α-alkoxy methyl radical and superoxide.

Biocatalytic aminohydroxylation of styrenes for efficient synthesis of enantiopure β-amino alcohols

A general biocatalytic process of intermolecular aminohydroxylation of styrenes with aniline has been achieved for efficient one-pot preparation of enantiopure β-amino alcohols. The reaction involves first asymmetric epoxidation of alkene substrates by a heme-dependent monooxygenase (P450) or the FAD-dependent styrene monooxygenase, followed by the aminolysis of nascent epoxide intermediates with aniline in water solution. Hybrid cluster-continuum (HCC) model calculations reveal the mechanism of the aminolysis of epoxide with aniline as well as the critical role of the water in mediating such a reaction. In addition, the combined experiments with simulations demonstrate that the chirality of amino alcohol is determined by the absolute configuration of the epoxide formed in the enzymatic reaction. In conclusion, the developed biocatalytic process provides an efficient, environmentally friendly approach for production of high value-added enantiopure β-amino alcohols, starting from cheap and readily available alkenes.

Accessing α-Amino Ketyl Radicals from β-Amino Alcohols via Chemoselective Hydrogen Atom Transfer Catalysis

The selective activation of a given C–H bond in complex molecules possessing bonds of similar polarity and strength remains one of the foremost challenges in hydrogen atom transfer (HAT) catalysis. Herein, we present the combination of photoredox and HAT catalysis with an oxophilic boron-based catalyst to achieve the chemoselective abstraction of α-hydroxy C–H bonds in β-amino alcohols. This enables us to access α-amino ketyl radicals, which are exploited for the direct synthesis of γ-oxo-δ-amino esters─a prominent scaffold in biologically active molecules.

In vitro cytotoxic effects, in silico studies, some metabolic enzymes inhibition, and vibrational spectral analysis of novel β-amino alcohol compounds

In this study, an efficient single-step method for the preparation of β-amino alcohols (1–3) in aqueous media was applied. The aim was to investigate the cytotoxic activity of Compounds 1, 2 and 3 in neuroblastoma SH-SY5Y cell line and mouse fibroblast l-929 cell lines. Cytotoxic activities of compounds 1, 2 and 3 in this cell lines were also determined by MTT method. Cells were incubated with different concentrations of Compound 3 showed the highest cytotoxic activity in SHY5Y cells at an IC50 dose of 13.01±0.87 µM at 72 h compared to other compounds. Compound 3 was determined to have lower cytotoxic activity in l-929 cells. The chemical activities of the molecules against the B3LYP, HF, M062X level 3–21 g, 6–31 g, and SDD basis set with the Gaussian package program and biologically against the adenosine A(2A) receptor (PDB ID: 3PWH and 5NM4) proteins for neuroblastoma tumors cell with the Maestro Molecular modeling platform by Schrödinger were compared. Both experimental and theoretical NMR, UV–vis, and IR spectra of the studied molecules were compared. ADME/T analysis was performed to examine the drug properties of the molecules. Finally, these assayed for their activities against metabolic enzymes acetylcholinesterase and α-glucosidase. The most potent compounds against AChE were order compounds 3, 2 and 1 with Ki values of 35.88±6.61, 43.75±8.28, and 45.34±3.50 µM against AChE, respectively. The results indicated that all the synthesized compounds exhibited excellent inhibitory activities against mentioned enzymes as compared with standard inhibitors. These inhibitors may be candidates for drug design.

Pre-column Derivatization¸ Elution Order, Molecular Configuration and Green Chromatographic Separation of Diastereomeric Derivatives of β-Amino Alcohols

A green chromatographic method was developed for the indirect enantio-separation of racemic amino alcohols by introducing a micellar mobile phase for the HPLC. Here, cyanuric chloride-based activated chiral reagents were prepared, characterized, and used to derivatize racemic amino alcohols into diastereomeric derivatives. The chromatographic separation of the prepared diastereomeric derivatives was achieved on the C18 column of the RP-HPLC using a surfactant-based (Brij-35 + SDS) aqueous mobile phase (as an alternative to organic solvents). The impact of the varying concentration of surfactants in the mobile phase and pH of buffer on the chromatographic separation was optimized. Additionally, the DFT calculations were performed, and the absolute configurations and elution orders of the diastereomeric derivatives were investigated. Developed method’s robustness and selectivity was optimized by performing validation studies (LOD = 0.286 ng/mL; LOQ = 0.858 ng/mL). Also, the green assessment score was calculated for the developed method (84 scores; an excellent green method).

1,2-Amino oxygenation of alkenes with hydrogen evolution reaction

1,2-Amino oxygenation of alkenes has emerged as one of the most straightforward synthetic methods to produce β-amino alcohols, which are important organic building blocks. Thus, a practical synthetic strategy for 1,2-amino oxygenation is highly desirable. Here, we reported an electro-oxidative intermolecular 1,2-amino oxygenation of alkenes with hydrogen evolution, removing the requirement of extra-oxidant. Using commercial oxygen and nitrogen sources as starting materials, this method provides a cheap, scalable, and efficient route to a set of valuable β-amino alcohol derivatives. Moreover, the merit of this protocol has been exhibited by its broad substrate scope and good application in continuous-flow reactors. Furthermore, this method can be extended to other amino-functionalization of alkenes, thereby showing the potential to inspire advances in applications of electro-induced N-centered radicals (NCRs).