Β-amino Alcohols Research Articles

Design of chiral ferrocenylphosphine-spiro phosphonamidite ligands for ruthenium-catalyzed highly enantioselective coupling of 1,2-diols with amines

A series of chiral ferrocene-backbone phosphines-spiro phosphonamidite ligands was developed for ruthenium-catalyzed enantioselective access to a broad range of β-amino alcohols from 1,2-diols and amines via the borrowing-hydrogen prciniple.

Catalytic enantioselective synthesis of β-amino alcohols by nitrene insertion

Chiral β-amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral ligands and chiral organocatalysts. The catalytic asymmetric β-amination of alcohols offers a direct strategy to access this class of molecules. Herein, we report a general intramolecular C(sp3)–H nitrene insertion method for the synthesis of chiral oxazolidin-2-ones as precursors of chiral β-amino alcohols. Specifically, the ring-closing C(sp3)–H amination of N -benzoyloxycarbamates with 2 mol% of a chiral ruthenium catalyst provides cyclic carbamates in up to 99% yield and with up to 99% ee. The method is applicable to benzylic, allylic, and propargylic C–H bonds and can even be applied to completely non-activated C(sp3)–H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently be hydrolyzed to obtain chiral β-amino alcohols. The method is very practical as the catalyst can be easily synthesized on a gram scale and can be recycled after the reaction for further use. The synthetic value of the new method is demonstrated with the asymmetric synthesis of a chiral oxazolidin-2-one as intermediate for the synthesis of the natural product aurantioclavine and chiral β-amino alcohols that are intermediates for the synthesis of chiral amino acids, indane-derived chiral Box-ligands, and the natural products dihydrohamacanthin A and dragmacidin A.

Cascade Biocatalysis for Regio- and Stereoselective Aminohydroxylation of Styrenyl Olefins to Enantiopure Arylglycinols

Chiral β-amino alcohols are privileged scaffolds frequently found in pharmaceutically active molecules and natural products. Aminohydroxylation of olefins is one of the most powerful strategies to access chiral vicinal amino alcohols. However, the direct regio- and stereoselective aminohydroxylation of olefins to unprotected enantioenriched β-amino alcohols remains a long-standing challenge. Herein, we report that a novel one-pot four-enzyme [styrene monooxygenase (SMO)/epoxide hydrolase (EH)/alcohol dehydrogenase (ADH)/ω-transaminase (TA)] biocatalytic cascade efficiently catalyzes the direct transformation of readily available styrenyl olefins into unprotected 2-amino-2-phenyl ethanols in good yields and excellent enantioselectivity. In vitro cascade biocatalysis aminohydroxylation of styrenyl olefins was first investigated by the combined four enzymes (SMO/EH/ADH/TA) with a trace amount of NADH (0.02 mM) and pyridoxal-5′-phosphate (0.1 mM), affording both enantiomers of β-amino alcohols 5a–j in 13.9–98.7% conversions and 86–99% ee. Whole-cell-based cascade biocatalysis was achieved by using the constructed recombinant Escherichia coli pairwise combinations and single tailor-made whole-cell biocatalyst without an additional NADH cofactor; (R)- and (S)-β-amino alcohols 5a–j could be obtained in 14.6–99.7% conversions and 86–99% ee. Moreover, the preparative experiments of this new cascade biocatalysis were demonstrated by the single tailor-made whole-cell biocatalyst [E. coli (CGS-DEM) and E. coli (CGS-DEB)] with the substrates 1a–b and 1h in an aqueous-organic two-phase system, affording chiral β-amino alcohols [(R)- or (S)-5a–b, h] in good yields (50.9–64.3%) and excellent ee (>99%).

Ring-Opening of Epoxides with Amines for Synthesis of β-Amino Alcohols in a Continuous-Flow Biocatalysis System

An efficient method for the preparation of β-amino alcohols catalyzed by lipase TL IM from Thermomyces lanuginosus in a continuous-flow reactor was developed. The eco-friendly biocatalyst combined with continuous-flow reaction technology displayed high efficiency in the synthesis of β-amino alcohols. The benign reaction conditions (35 °C) and short residence time (20 min), together with the use of low cost and readily available starting materials, make this synthetic approach a promising alternative to current β-amino alcohol synthesis.

Synthesis and corrosion inhibitory effect of a novel β-amino alcohol compound

To develop high efficiency organic pickling inhibitor, a new β-amino alcohol compound named 1,16-(5,12-dihydroxy-7,10-dioxa-3,14-diazahexadecane) di-p-benzenesulfonamide (TDB) was well designed and synthesized. The corrosion inhibition performances of TDB for mild steel in 0.5 M H2SO4 solution were investigated by weight-loss, electrochemical impedance spectroscopy and potentiodynamic methods. It has been found that the inhibition efficiency of TDB derived from potentiodynamic method was 90.7 % at a low concentration of 10 mg/L at 25 °C. Effect of temperature indicated that the inhibition efficiency was still above 89 % even at 45 °C in the presence of 100 mg/L of TDB in 0.5 M H2SO4 solution. XPS analyses showed that TDB prevented the attack of the corrosive medium by adsorbing on the surface of the mild steel. Theoretical calculations indicated that the structure of TDB is conducive to form an adsorption layer on the mild steel surface.

Metal-Free β-Amino Alcohol Synthesis: A Two-step Smiles Rearrangement.

A novel method for the synthesis of β-amino alcohols has been demonstrated under mild reaction conditions with a broad scope via a two-step Smiles rearrangement. What is more, theoretical calculations have been performed to confirm the rationality of the mechanism. The method has been proved to be notably effective for N-arylated amino alcohols, which are difficult to synthesize by traditional methods.

Enantioselective Diels–Alder Reaction of 3-Nitrocoumarins Promoted by Chiral Organoammonium Salt Catalysts

AbstractAn enantioselective Diels–Alder reaction of 3-nitrocoumarins has been developed. A tryptophan-derived C 1-symmetric organoammonium thiourea catalyst promoted the reaction of 3-nitrocoumarins with Danishefsky’s diene to give the corresponding adducts with good enantioselectivity (up to 94% ee). One of the resulting adducts was converted into a chiral carbocyclic quaternary β-amino alcohol.

Molecular docking studies, drug-likeness and in-silico ADMET prediction of some novel β-Amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles derivatives as elevators of p53 protein levels

Malaria is a killer disease caused by Plasmodium falciparum and is responsible for over a million death annually. Chloroquine, quinine, pyrimethamine, proguanil, artemisinin, atovaquone, and mefloquine are different kinds of drugs employed to treat the disease, but due to increased drug resistance to these drugs, their use becomes less effective. Hence, the need for new antimalarial drugs with better activities and a new mechanism of action along different pathways against a new target. As well as the knowledge of their interactions, the drug-likeness of antimalarial drugs is necessary. Twenty-four derivatives of β-Amino alcohol grafted 1,4,5-trisubstituted 1,2,3-triazoles were docked against a p53 protein, as well as predicting their drug-likeness and ADMET properties. From the docking analysis, compound 10, {1-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-(4-bromophenyl)-2-((3,4-dimethylphenyl)amino)ethanol} was found to be the most stable compound with Re-rank docking score -100.295KJmol−1 against p53 protein. The “drug-likeness” and ADMET prediction performed nearly showed compliance with the Lipinski rule, and the compounds were found to have good absorption, distribution, metabolism, and excretion generally. The results of the study can be used for future optimization of derivatives of {1-(1-benzyl-5-phenyl-1H-1,2,3-triazol-4-yl)-1-(4-bromophenyl)-2-((3,4-dimethylphenyl)amino)ethanol}for better molecular interactions with p53 protein, and effective Plasmodium falciparum inhibition.

Enantioselective Cascade Biocatalysis for Deracemization of Racemic β-Amino Alcohols to Enantiopure (S)-β-Amino Alcohols by Employing Cyclohexylamine Oxidase and ω-Transaminase.

Optically active β-amino alcohols are very useful chiral intermediates frequently used in the preparation of pharmaceutically active substances. Here, a novel cyclohexylamine oxidase (ArCHAO) was identified from the genome sequence of Arthrobacter sp. TYUT010-15 with the R-stereoselective deamination activity of β-amino alcohol. ArCHAO was cloned and successfully expressed in E. coli BL21, purified and characterized. Substrate-specific analysis revealed that ArCHAO has high activity (4.15 to 6.34 U mg-1 protein) and excellent enantioselectivity toward the tested β-amino alcohols. By using purified ArCHAO, a wide range of racemic β-amino alcohols were resolved, (S)-β-amino alcohols were obtained in >99 % ee. Deracemization of racemic β-amino alcohols was conducted by ArCHAO-catalyzed enantioselective deamination and transaminase-catalyzed enantioselective amination to afford (S)-β-amino alcohols in excellent conversion (78-94 %) and enantiomeric excess (>99 %). Preparative-scale deracemization was carried out with 50 mM (6.859 g L-1 ) racemic 2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol was obtained in 75 % isolated yield and >99 % ee.

Synthesis, Absolute Configuration, Antibacterial, and Antifungal Activities of Novel Benzofuryl β-Amino Alcohols.

A series of new benzofuryl α-azole ketones was synthesized and reduced by asymmetric transfer hydrogenation (ATH). Novel benzofuryl β-amino alcohols bearing an imidazolyl and triazolyl substituents were obtained with excellent enantioselectivity (96–99%). The absolute configuration (R) of the products was confirmed by means of electronic circular dichroism (ECD) spectroscopy supported by theoretical calculations. Selected benzofuryl α-azole ketones were also successfully asymmetrically bioreduced by fungi of Saccharomyces cerevisiae and Aureobasidium pullulans species. Racemic and chiral β-amino alcohols, as well as benzofuryl α-amino and α-bromo ketones were evaluated for their antibacterial and antifungal activities. From among the synthesized β-amino alcohols, the highest antimicrobial activity was found for (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-imidazol-1-yl)ethan-1-ol against S. aureus ATCC 25923 (MIC = 64, MBC = 96 μg mL−1) and (R)-1-(3,5-dimethylbenzofuran-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethan-1-ol against yeasts of M. furfur DSM 6170 (MIC = MBC = 64 μg mL−1). In turn, from among the tested ketones, 1-(benzofuran-2-yl)-2-bromoethanones (1–4) were found to be the most active against M. furfur DSM 6170 (MIC = MBC = 1.5 μg mL−1) (MIC—minimal inhibitory concentration, MBC—minimal biocidal concentration).

Synthesis of β-Amino Alcohols by Visible-Light-Assisted Intramolecular Copper-Catalyzed C–H Amination

Synthesis of β-Amino Alcohols by Visible-Light-Assisted Intramolecular Copper-Catalyzed C–H Amination

Synthesis of Monomeric and Dimeric Siloxanes Derived of β-Aminoalcohols

The preparation and structural characterization of dimeric and monomeric siloxanes are described. The silicon complexes were obtained from β-amino alcohols and dichlorodimethylsilane, bisdi- methylaminodimethylsilane and diphenyldichlorosilane. The com- plexes were characterized by 1H, 13C and 29Si NMR spectroscopy and mass spectrometry. The X-ray crystallography study for one com- pound confirmed the formation of a sixteen-membered heterocycle.

Enantioselective 1,2-Addition of α-Aminoalkyl Radical to Aldehydes via Visible-Light Photoredox Initiated Chiral Oxazaborolidinium Ion Catalysis

Enantioselective 1,2-addition reaction of α-aminoalkyl radical to α,β-unsaturated or aromatic aldehydes to synthesize highly optically active β-amino alcohols has been developed. In the presence of...

M-Type SrFe12O19 Ferrite: An Efficient Catalyst for the Synthesis of Amino Alcohols under Solvent-Free Conditions

Magnetically separable strontium hexaferrite SrFe12O19 was prepared using the chemical coprecipitation method, and the nanostructured material was characterized by X-ray diffraction, scanning electron microscopy (SEM), energy-dispersive spectrometry (EDS), and BET analysis. The SEM images showed the homogeneity of the chemical composition of SrFe12O19 and uniform distribution of size and morphology. The pore size of the nanomaterial and its specific area were determined by BET measurements. Strontium hexaferrite SrFe12O19 exhibited a strong magnetic field, which is highly suitable in the heterogeneous catalysis as it can be efficiently separated from the reaction. The magnetic nanocatalyst showed high activity and environmentally benign heterogeneous catalysts for the epoxide ring-opening with amines affording β-amino alcohols under solvent-free conditions. When unsymmetrical epoxides were treated in the presence of aromatics amines, the regioselectivity was influenced by the electronic and steric factors. Total regioselectivity was observed for the reactions performed with aliphatic amines. The magnetically SrFe12O19 nanocatalyst showed excellent recyclability with continuously good catalytic activities after four cycles.

Enantioselective radical C-H amination for the synthesis of β-amino alcohols.

Asymmetric, radical C–H functionalizations are rare, yet powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regio-selective C–H amination of alcohols to access medicinally valuable, chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol is transiently converted to an imidate radical that undergoes intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C–H amination enables broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl, and propargyl C–H bonds. Mechanistic experiments reveal triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity – enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C–H amination.

Enantioselective Addition of Diethylzinc to Aromatic Aldehydes Using Novel Thiophene-Based Chiral Ligands

Chiral norephedrine-derived β-amino alcohols with a thiophene moiety were synthesized from thiophene carbaldehydes (methyl- or ethyl-substituted) and chiral amino alcohols, such as both enantiomers of norephedrine and 2-aminopropanol. The synthesized ligands were applied to the catalytic asymmetric addition of diethylzinc to aldehydes to obtain optically active alcohols with a high conversion (92%) and excellent enantioselectivities (ee up to 99%). The highest enantioselectivity (ee 99%) was obtained with p-trifluorobenzaldehyde as the substrate containing the strongly electron-acceptor CF3 group.

Advances in Henry Reaction: A Versatile Method in Organic Synthesis

: Henry reaction is an important reaction employing carbonyls which furnishes β-nitro alcohol, nitroalkene, α-nitro ketones, β-amino alcohol as products and byproducts that may be transfigured as building blocks for other synthetic reactions. This paper focuses on various synthetic routes for Henry reaction, a versatile reaction of high significance in organic synthesis. The paper discusses the chemistry and plausible products of the reaction, along with the various available synthetic routes for the same, ranging from classical conventional methods to modern methods of green chemistry trends. Use of various catalysts as rate enhancer as well as use of various catalysts as enantioselective frontman for stereoselective reactions, have been described in this work.

Stereodivergent Asymmetric Synthesis of α,β-Disubstituted β-Aminoalkylboronic Acid Derivatives via Group-Selective Protodeboronation Enabling Access to the Elusive Anti Isomer.

Chiral β-aminoalkylboronates generate growing interest as versatile synthetic building blocks to access β-aminoalcohols and other useful compounds, and also as bioisosteres of β-amino acids in drug discovery. In this study, the lack of methodology to access both syn and anti diastereomers of optically enriched, acyclic α,β-disubstituted β-aminoalkylboronates is addressed with the development of a divergent, diastereoselective strategy for the monoprotodeboration of β-amino gem-bis(boronate) precursors. To this end, new reaction conditions were successfully optimized to provide the elusive anti diastereomer by inverting a sequence of desulfinylation and protodeboronation. The desired syn or anti isomers are isolated independently in good yields and excellent diastereoselectivity (up to >20:1 dr) for a wide scope of substituents. The diastereotopic group selectivity of the new conditions yielding the anti isomer is rationalized by invoking a reactive rotamer featuring two ammonium-boronate hydrogen bonds, which enables phosphate coordination to boron with a concomitant, stereoretentive protonation of the least sterically hindered C-B bond. The accessibility and utility of both diastereomers of these α,β-disubstituted β-aminoalkylboronates is exemplified with the functionalization of the amino group, stereospecific oxidation to β-amino alcohols and C-C bond transformations of the secondary alkylboronate, and the preparation of free boronic acids and hemiboronic heterocycles.

High throughput solid-phase screening of bacteria with cyclic amino alcohol deamination activity for enantioselective synthesis of chiral cyclic β-amino alcohols.

To screening of bacteria with cyclic amino alcohol deamination activity for enantioselective synthesis of chiral cyclic β-amino alcohols. A new strain named Arthrobacter sp. TYUT010-15 with the (R)-selective deamination activity of cyclic β-amino alcohol has been isolated from nature via a high throughput solid-phase screening method. The reaction conditions of TYUT010-15 were optimized. Using the resting cell of TYUT010-15 as the catalyst, kinetic resolution of trans-2-aminocyclopentanol, trans-2-aminocyclohexanol and cis-1-amino-2-indanol was carried out to afford (1S, 2S)-trans-2-aminocyclopentanol, (1S, 2S)-trans-2-aminocyclohexanol and (1R, 2S)-cis-1-amino-2-indanol in > 99% ee and 49.6-50% conversion. Four aromatic β-amino alcohols and two amines were also resolved, (S)-β-amino alcohols and (R)-amines were obtained in > 99% ee. Preparation experiment was conducted with 200mM (23.2g L-1) racemic trans-2-aminocyclohexanol, yielding the desired (1S, 2S)-trans-2-aminocyclohexanol in 40% isolated yield, > 99% ee and 5.8g L-1 d-1 space time yields. This study provides a high throughput solid-phase method for screening of bacteria with cyclic amino alcohol deamination activity and a first example for practical preparation of chiral cyclic β-amino alcohol by Arthrobacter sp. TYUT010-15.

Asymmetric aldol reaction of isatins with acetone in the presence of terpene amino alcohols

Asymmetric aldol reactions of isatin and 4,6-dibromoisatin with acetone are efficiently catalyzed by β-amino alcohols derived from α-pinene and 3-carene. The target compounds can be isolated by crystallization from toluene, which eliminates the need for using chromatography and makes the asymmetric synthesis of (R)-convolutamydine A (up to 94% ee and yield 75%) simple and convenient.