Isoxazolidine Derivatives Research Articles

Understanding the regio-and diastereoselective synthesis of a potent antinociceptive isoxazolidine from C-(pyridin-3-yl)-N-phenylnitrone in the light of molecular electron density theory

[3+2] cycloaddition reaction of C-(pyridin-3-yl)-N-phenylnitrone and 2-propen-1-ol yields stereochemically defined potent antinociceptive isoxazolidine derivative. Computational quantum calculations (CQC) are performed for this synthesis to predict the polar character, mechanism and selectivity within the framework of molecular electron density theory (MEDT). Topological analysis of the electron localization function (ELF) classifies the nitrone as a zwitter-ionic(zw-) type three atom component (TAC) showing absence of any pseudoradical or carbenoid centre. Four reaction channels corresponding to the possible regio- and stereoselective pathways are studied at DFT/ /B3LYP/6-311G(d,p) level of theory. The reaction follows one-step mechanism with asynchronous transition states and the computed activation energies agree well with experimental data. The reaction can be differentiated into nine ELF topological phases, with faster C?C bond formation. Global electron density theory (GEDT) at the favoured transition state and conceptual density functional theory (CDFT) indices at the ground state of the reagents indicate non-polar character. Non-covalent interactions are predicted by atoms-in-molecules (AIM) analysis and non-covalent interaction (NCI) plots at the transition states.

Quantum chemical studies on the mechanistic aspects of tandem sequential cycloaddition reactions of cyclooctatetraene with ester and nitrones

The mechanisms of the tandem sequential [4 + 2]/[3 + 2] and [3 + 2]/[4 + 2] cycloaddition sequences involving an ester, cyclooctatetraene (COTE), and cyclic and acyclic nitrones for the formation of a diverse range of isoxazolidine derivatives and other synthetic precursors are reported. A thorough exploration of the PES has characterized several regio-, stereo- and enantio-selective mechanistic channels involved in these reactions. A perturbation molecular orbital (PMO) analysis been employed to rationalize the results. It has also been found that the initial electrocyclic ring closure of the COTE is the rate-determining step in the tandem sequential [4 + 2]/[3 + 2] addition sequence. The thermolytic breakdown of the tandem adducts to subsequent monocyclic, bicyclic and tricyclic adducts occurs generally with very high activation barriers making it an inconvenient synthetic approach. The different reactivity of all the three double bonds present in the dipolarophile is reported. Finally, the mechanistic possibilities of [3 + 2]/[4 + 2] addition sequences involving the same reaction components in the case of cyclic and acyclic nitrones are explored extensively. The results suggest a novel and convenient routes for obtaining products of high selectivity with less energetic requirements. In some instances, new cycloadducts hitherto unreported are obtained.

Synthesis and Antimicrobial Evaluation of Some Isoxazolidine Derivatives

Synthesis and Antimicrobial Evaluation of Some Isoxazolidine Derivatives

Asymmetric 1,3‐Dipolar Cycloaddition Reactions of Enones by Primary Amine Catalysis

AbstractWe report herein a 1,3‐dipolar cycloaddition between enones and nitrones with good to excellent distereo‐ and enantioselectivities by a chiral primary amine catalyst, which furnishes an operationally simple synthetic protocol for the fused bicyclic isoxazolidine derivatives with multiple stereogenic centers.

Biological Activities Evaluation of Enantiopure Isoxazolidine Derivatives: In Vitro, In Vivo and In Silico Studies.

A series of enantiopure isoxazolidines (3a-c) were synthesized by 1,3-dipolar cycloaddition between a (-)-menthone-derived nitrone and various terminal alkenes. The screened compounds were evaluated for their antioxidant activity by two in vitro antioxidant assays, including β-carotene/linoleic acid bleaching, and inhibition of lipid peroxidation (thiobarbituric acid reactive species, TBARS). The results revealed that compound 3b (EC50 = 0.55 ± 0.09mM) was the most potent antioxidant as compared to the standard drug (EC50 = 2.73 ± 0.07mM) using the TBARS assay. Furthermore, the antimicrobial activity was assessed using disc diffusion and microdilution methods. Among the synthesized compounds, 3c was found to be the most potent antimicrobial agent as compared to the standard drug. Subsequently, the acute toxicity study has also been carried out for the newly synthesized compounds and the experimental studies revealed that all compounds were safe up to 500mg/kg and no death of animals were recorded. The cytotoxicity of these compounds was assessed by the MTT cell proliferation assay against the continuous human cell lines HeLa and compound 3c (GI50 = 46.2 ± 1.2μM) appeared to be more active than compound 3a (GI50 = 200 ± 2.8μM) and 3b (GI50 = 1400 ± 7.8μM). Interestingly, all tested compounds displayed a good α-amylase inhibitory activity in competitive manner with IC50 values ranging between 23.7 and 64.35μM when compared to the standard drug acarbose (IC50 = 282.12μM). In addition, molecular docking studies were performed to understand the possible binding and the interaction of the most active compounds to the α-amylase pocket.

Isoxazolidine Derivatives of Lappaconitine and Talatisamine

Isoxazolidine derivatives of lappaconitine and talatisamine were prepared by [3 + 2]-cycloaddition of lappaconitine and talatisamine nitrones to allyl alcohol.

Design, synthesis, molecular properties and in vitro antioxidant and antibacterial potential of novel enantiopure isoxazolidine derivatives

A novel series of enantiopure isoxazolidines have been synthesized in good yields and with high stereoselectivity by 1,3-dipolar cycloaddition between a (–)-menthone-derived nitrone as a glycine equivalent and various terminal alkenes. The structures and the stereochemistry of the obtained cycloadducts have been determined by spectroscopic methods. Almost all the compounds were predicted to exhibit various degrees of antioxidant and antibacterial potentiality. Finally, the drug likeness and bioactivity were calculated using Molinspiration software. The results indicated that all compounds are in accordance with Lipinski’s rule of five showing good drug likeness and bioactivity score for drug targets with no violations.

Synthesis of Some Novel Class of Regioselective Spiro Isoxazolidine Derivatives via 1,3‐Dipolar Cycloaddition Reaction of N‐Benzyl‐C‐fluoro‐substituted Phenyl Nitrones in Ionic Liquid

Synthesis of some new class of regioselective spiro isoxazolidine derivatives have been described using N‐benzyl‐C‐fluoro substituted‐phenyl nitrones with new dipolarophiles via 1,3‐dipolar cycloaddition reaction in ionic liquid. The novel spiro cycloadducts found to exhibit good synthetic potentiality as they could be converted into synthetically more important spiro 1,3‐amino alcohols. Simple reaction methodology, noninvolvent of catalysts, good to excellent yields, and greener approaches are the important features noticed in this syntheses.

Synthesis of Some New Scaffolds of Amino Isoxazolidines and Their Further Functionalization into New Class of Peptides: A New Approach

Some new class of amino isoxazolidine derivatives have been synthesized from α‐amino nitrones in water with good to excellent yields. The new isoxazolidines are further functionalized into new scaffolds of peptides with good synthetic potentiality. Simple reaction methodology, greener approaches, atom efficiency, noninvolvement of catalysts, faster reaction conditions, excellent yields, and a new approach in peptide synthesis are the attractions in these syntheses.

Isoxazolidine derivatives as corrosion inhibitors for low carbon steel in HCl solution: experimental, theoretical and effect of KI studies.

Two isoxazolidine derivatives namely 5-(benzo[d][1,3]dioxol-5-ylmethyl)-2-tetradecyl isoxazolidine (BDMTI) and 5-(4-hydroxy-3-methoxybenzyl)-2-tetradecyl isoxazolidine (HMBTI) were synthesized and characterized using FTIR, C-NMR, H-NMR, and elemental analysis. The synthesized compounds were evaluated as corrosion inhibitors for API 5L X60 steel in 1 M HCl in the temperature range of 25–60 °C using gravimetric and electrochemical (Electrochemical Impedance Spectroscopy (EIS), Potentiodynamic Polarization (PDP) and Linear Polarization Resistance (LPR)) techniques. The effect of addition of a small amount of iodide ions on the corrosion inhibition performance of the compounds was also assessed. In addition, quantum chemical calculations and Monte Carlo simulations were employed to correlate the electronic properties of the compounds with the corrosion inhibition effect as well as to evaluate the adsorption/binding of the inhibitor molecules on the steel surface. Experimental results show that the two compounds inhibited the corrosion of carbon steel in an acid environment with HMBTI showing superior performance. The corrosion inhibition effect was found to be dependent on the inhibitors' concentration and temperature. Addition of iodide ions improves the inhibition efficiency considerably due to co-adsorption of the iodide ions and the inhibitors on the steel surface which was competitive in nature as confirmed from the synergistic parameter (S1) which was less than unity at higher temperature. Experimental and theoretical results are in good agreement.

Cycloaddition of Benzyne with Alkoxy-Substituted Pyrroline-N-oxides­: Unexpected Rearrangement to an N-Phenylpyrrole

Reaction of enantiopure 3,4-dialkoxy-pyrroline N-oxides with benzyne affords the expected tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazoles along with an unexpected 2,3-disubstitued-N-phenyl-pyrrole derived from an unprecedented rearrangement of the adduct of nitrone with two molecules of benzyne. A mechanism for the unusual rearrangement is proposed. The benzo[d]isoxazolidine derivatives are conveniently converted into 2-(2-hydroxyphenyl)-3,4-dialkoxypyrrolidines by reductive opening of the N–O bond.

Visible-Light-Mediated Anti-Regioselective Nitrone 1,3-Dipolar Cycloaddition Reaction and Synthesis of Bisindolylmethanes.

The development of photoredox reactions of 1,3-dipolar cycloaddition of nitrones with alkenes is reported. It offers an efficient synthetic method to obtain isoxazolidine derivatives under mild conditions in synthetically useful yields. The nitrones are cyclized with oxidizable styrenes and aliphatic alkenes via a polar radical crossover cycloaddition reaction through photocatalytic reaction without additives. In addition, bis(indole)methanes can also be prepared through this method.

An Efficient Cascade Synthesis of Ethyl 3-Amino-5-oxoisoxazolidine-4-carboxylate Derivatives

An efficient cascade synthesis of ethyl 3-amino-5-oxoisoxa­zolidine-4-carboxylate derivatives from diethyl 2-(ethoxymethyl­ene)malonate, different hydroxylamines and various amines is developed. This approach tolerates a wide range of amines affording highly functionalized isoxazolidine derivatives, which are expected to be important in organic synthesis and medicinal chemistry.

Synthesis of novel d-glucose based anionic bolaamphiphiles and their catalytic application in 1,3-dipolar nitrone cycloaddition reactions

Three d-glucose based bolaamphiphiles have been synthesized by a simple and efficient synthetic methodology utilizing the free C-3 hydroxyl group of diisopropylidene glucose. The resulting bolaamphiphiles showed unique aggregation behavior in aqueous solution, e.g. transformation of vesicle to tubular morphology on aging. The chiral hydrophobic interior of these vesicles was utilized as tiny reaction vessels to carry out 1,3-dipolar nitrone cycloadditions in water. The corresponding isoxazolidine derivatives were formed with high diastereoselectivity in several cases. The bolaamphiphile with 12 carbon spacer (5c) showed better diastereoselectivity among the rest with just 2mol% of catalyst loading and can be reused.

Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

ABSTRACT1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO3 to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a–p in high yields via 1,3-dipolar cycloaddition reaction.

Lewis base-catalyzed diastereoselective [3 + 2] cycloaddition reaction of nitrones with electron-deficient alkenes: an access to isoxazolidine derivatives

A Lewis base-catalyzed [3 + 2] cycloaddition reaction of nitrones with electron-deficient alkenes has been achieved under mild reaction conditions, affording functionalized isoxazolidines as single diastereomers in moderate to excellent yields.

An intramolecular cycloaddition of nitrones with tethered olefins: a versatile synthesis of hexahydro-3H-xantheno[1,2-c]isoxazoles

A variety of isoxazolidine and isoxazoline derivatives have been prepared through a 1,3-dipolar cycloaddition of alkene-tethered chromene-3-carbaldehydes with hydroxyl amines. This is the first example of the preparation of highly diastereoselective isoxazolidine derivatives from alkene appended chromene-3-carboxaldehyde. This method is operationally simple and works with a diverse range of substrates.

Synthesis and Evaluation of New Isoxazolidine Derivatives of Aldehyde as Corrosion Inhibitors for Mild Steel Corrosion in Acidic and Saline Media

Synthesis and Evaluation of New Isoxazolidine Derivatives of Aldehyde as Corrosion Inhibitors for Mild Steel Corrosion in Acidic and Saline Media

Diastereoselective synthesis of novel tetra-and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives via intramolecular 1,3-dipolar cycloadditions

A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of is described.

3+2] Route to Quaternary Oxaprolinol Derivatives as Masked Precursors of Disubstituted β3,β3‐Amino Aldehyde

AbstractBicyclic isoxazolidines displaying one or two quaternary stereocenter(s) were formed starting from functional cyclic ketonitrones equipped with a phenyl glycinol chiral auxiliary. The products were engaged in stereocontrolled 1,3‐dipolar cycloaddition reactions with a range of electron‐rich and electron‐poor dipolarophiles. A new reductive removal of the phenyl glycinol chiral auxiliary was introduced and was shown to afford chemoselectively a quaternary isoxazolidine derivative (of oxaprolinol‐type) without cleaving the N–O isoxazolidine bond. Keeping the aldehyde function masked as a cyclic pseudo‐acetal, the liberated oxy‐amine function was shown to be available for a pseudo‐peptide coupling with various N‐protected amino acids. The isoxazolidine ring was opened by a reductive N–O bond cleavage, giving a pseudo‐dipeptide that was C‐terminated with an aldehyde function.