Epoxide Ring-opening Reaction Research Articles

Origin of Chemoselectivity of Halohydrin Dehalogenase-Catalyzed Epoxide Ring-Opening Reactions.

By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2- has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2- is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.

Epoxide Ring-Opening Reactions for Abundant Production of Mugineic Acids and Nicotianamine Probes.

A succinct synthetic approach to mugineic acids and 2'-hydroxynicotianamine was established. Unlike all other synthetic methods, this approach utilized epoxide ring-opening reactions to form two C-N bonds and is characterized by the absence of redox reactions. Mugineic acid was synthesized from three readily available fragments on a gram scale in 6 steps. The protected 2'-hydroxynicotianamine was also synthesized in 4 steps, and the dansyl group, serving as a fluorophore, was introduced through a click reaction after propargylation of the 2'-hydroxy group. The dansyl-labeled nicotianamine (NA) iron complexes were internalized by oocytes overexpressing ZmYS1 (from maize) or PAT1 (from human) transporters, indicating successful transport of the synthesized NA-probe through these transporters.

Unveiling a Strategy for Ring Opening of Epoxides: Synthesis of 2-Hydroxyindolinylidenes Using α-Ester Sulfoxonium Ylides.

The untapped potential of α-carbonyl sulfoxonium ylides in epoxide ring-opening reactions has been a notable gap in current research, with such reactivity predominantly associated with the highly reactive dimethylsulfoxonium methylide. This study introduces an innovative approach wherein an epoxide indole, formed in situ from 2-hydroxyindoline-3-triethylammonium bromide, undergoes reaction with α-ester sulfoxonium ylides. The outcome is the efficient synthesis of a range of 2-hydroxyindolin-3-ylidenes, demonstrating favorable yields (41-81%) and Z/E ratios from 4:1 to those of exclusive Z isomers. Additionally, the photophysical properties of the synthesized indolinylidenes are explored, along with their derivatization using various nucleophiles under acid catalysis.

Deciphering the stereo-specific catalytic mechanisms of cis-epoxysuccinate hydrolases producing L(+)-tartaric acid

Microbial epoxide hydrolases, cis-Epoxysuccinate hydrolases (CESHs) have been utilized for commercial production of enantiomerically pure L(+)- and D(-)-tartaric acids for decades. However, the stereo-catalytic mechanism of CESH producing L(+)-tartaric acid (CESH[L]) remains unclear. Herein, the crystal structures of two CESH[L]s in ligand-free, product-complexed, and catalytic intermediate forms were determined. These structures revealed the unique specific binding mode for the mirror-symmetric substrate, an active catalytic triad consisting of Asp-His-Glu, and an arginine providing a proton to the oxirane oxygen to facilitate the epoxide ring-opening reaction, which has been pursued for decades. These results provide the structural basis for the rational engineering of these industrial biocatalysts.

Exploring the synthetic potential of epoxide ring opening reactions toward the synthesis of alkaloids and terpenoids: a review.

Epoxides are oxygen containing heterocycles which are significantly employed as crucial intermediates in various organic transformations. They are considered highly reactive three-membered heterocycles due to ring strain and they undergo epoxide ring opening reactions with diverse range of nucleophiles. Epoxide ring-opening reactions have gained prominence as flexible and effective means to obtain various functionalized molecules. These reactions have garnered substantial attention in organic synthesis, driven by the need to comprehend the synthesis of biologically and structurally important organic compounds. They have also found applications in the synthesis of complex natural products. In this review article, we have summarized the implementation of epoxide ring opening reactions in the synthesis of alkaloids and terpenoids based natural products reported within the last decade (2014-2023).

Non-enzymatic synthesis of C-methylated fluostatins: discovery and reaction mechanism.

Two C-methylated fluostatins (FSTs) B3 (1) and B4 (2) were synthesized from flavin-mediated nonenzymatic epoxide ring-opening reactions of FST C. The structures of 1 and 2 were elucidated by HRESIMS, NMR, and ECD spectroscopic analyses. A subsequent 13C labeling study demonstrated that the C-methyl groups of 1 and 2 were derived from DMSO and enabled the mechanistic proposal of a nonenzymatic C-methylation.

Synthesis, spectroscopic characterizations, DFT calculations and molecular docking studies of new quinoline-oxirane/piperidine/morpholine hybrids from quinoline gem‑dicyanoepoxide

We report in this paper a combined experimental and theoretical study of new 2-quinolone-piperidine (5a) and -morpholine (5b-c) hybrids from3-(2-chloroquinolin-3-yl) oxirane-2,2-dicarbonitrile (3) via an epoxide ring opening reaction using appropriate synthetic routes. In a parallel approach, a tandem consecutive process was carried out, without isolation of the brominated intermediate for the synthesis of 2-quinolone-morpholine (5c). The prepared compounds were fully characterized by conventional analytical techniques, and single-crystal X-ray diffraction for compound 5c was also reported. To increase the accuracy of experimental results, DFT and TD-DFT calculations were performed including molecular structure optimization, NMR, optical and electronic data, frontier molecular orbitals and molecular descriptors. In addition, a molecular docking calculation was carried out to estimate the affinity between compounds 3, 5a, 5b and 5c and Acetylcholinesterase (AChE)/ Butyrylcholinesterase (BuChE). Theoretical results are in agreement with the experimental.

Chemical Tailoring of β-Cyclodextrin-Graphene Oxide for Enhanced Per- and Polyfluoroalkyl Substances (PFAS) Adsorption from Drinking Water.

We report on the synthesis of β-cyclodextrin (βCD) modified graphene oxide (GO) nanosheets, having different sized alkyl linkers (GO-Cn -βCD) and their exploitation as sorbent of per- and polyfluoroalkyl substances (PFAS) from drinking water. βCD were functionalized with a pending amino group, and the resulting precursors grafted to GO nanosheets by epoxide ring opening reaction. Loading of βCD units in the range 12 %-36 % was estimated by combined XPS and elemental analysis. Adsorption tests on perfluorobutanoic acid (PFBA), a particularly persistent PFAS selected as case study, revealed a strong influence of the alkyl linker length on the adsorption efficiency, with the hexyl linker derivative GO-C6 -βCD outperforming both pristine GO and granular activated carbon (GAC), the standard sorbent benchmark. Molecular dynamic simulations ascribed this evidence to the favorable orientation of the βCD unit on the surface of GO which enables a strong contaminant molecules retention.

In vitro cytotoxic effect of stigmasterol derivatives against breast cancer cells

BackgroundStigmasterol is an unsaturated phytosterol that belong to the class of tetracyclic steroids abundant in Rhoicissus tridentata. Stigmasterol is an important constituent since it has shown impressive pharmacological effects such as anti-osteoarthritis, anticancer, anti-diabetic, anti-inflammatory, antiparasitic, immunomodulatory, antifungal, antioxidant, antibacterial, and neuroprotective activities. Furthermore, due to the presence of π system and hydroxyl group, stigmasterol is readily derivatized through substitution and addition reactions, allowing for the synthesis of a wide variety of stigmasterol derivatives.MethodsStigmasterol (1) isolated from Rhoicissus tridentata was used as starting material to yield eight bio-active derivatives (2–9) through acetylation, epoxidation, epoxide ring opening, oxidation, and dihydroxylation reactions. The structures of all the compounds were established using spectroscopic techniques, NMR, IR, MS, and melting points. The synthesized stigmasterol derivatives were screened for cytotoxicity against the hormone receptor-positive breast cancer (MCF-7), triple-negative breast cancer (HCC70), and non-tumorigenic mammary epithelial (MCF-12 A) cell lines using the resazurin assay.ResultsEight stigmasterol derivatives were successfully synthesized namely; Stigmasterol acetate (2), Stigmasta-5,22-dien-3,7-dione (3), 5,6-Epoxystigmast-22-en-3β-ol (4), 5,6-Epoxystigmasta-3β,22,23-triol (5), Stigmastane-3β,5,6,22,23-pentol (6), Stigmasta-5-en-3,7-dion-22,23-diol (7), Stigmasta-3,7-dion-5,6,22,23-ol (8) and Stigmast-5-ene-3β,22,23-triol (9). This is the first report of Stigmasta-5-en-3,7-dion-22,23-diol (7) and Stigmasta-3,7-dion-5,6,22,23-ol (8). The synthesized stigmasterol analogues showed improved cytotoxic activity overall compared to the stigmasterol (1), which was not toxic to the three cell lines tested (EC50 ˃ 250 µM). In particular, 5,6-Epoxystigmast-22-en-3β-ol (4) and stigmast-5-ene-3β,22,23-triol (9) displayed improved cytotoxicity and selectivity against MCF-7 breast cancer cells (EC50 values of 21.92 and 22.94 µM, respectively), while stigmastane-3β,5,6,22,23-pentol (6) showed improved cytotoxic activity against the HCC70 cell line (EC50: 16.82 µM).ConclusionNatural products from Rhoicissus tridentata and their derivatives exhibit a wide range of pharmacological activities, including anticancer activity. The results obtained from this study indicate that molecular modification of stigmasterol functional groups can generate structural analogues with improved anticancer activity. Stigmasterol derivatives have potential as candidates for novel anticancer drugs.

“Tai Chi” philosophy driven dual-network ionogel membrane comprised of ionic guests in a multifunctional host for propylene/propane separation

Facilitated transport ionogel membranes have shown great prospects in propylene/propane separation due to the stability of carrier media, no leakage, and promising thermal/physical properties. In the present study, inspired by the Tai Chi philosophy of adjusting inorganic and organic features, a dual-network ionogel was made of multi-functional organosilane, [EMIM][TFSI] ionic liquid, AgBF4, and catalysts. An effective strategy, including solvent-free solvolytic sol-gel and epoxide ring-opening reaction, was proposed to keep the inorganic/organic balance and obtain ionogel films with high IL loading (up to 82%) and self-standing. The ionogels were characterized by a phase diagram, formation mechanism, FTIR, N2 adsorption-desorption isotherms, TGA, SEM, mechanical properties, and transport properties. The Multifunctional host induced the breaking of bondage between the components of IL electrolyte (AgBF4 and IL); thereby more free Ag+ ions become available for facilitating the olefin transport. A computational molecular approach was applied to better understand the possible interactions between the ionic guest and multifunctional host. Results indicate that the optimized ionogel not only has excellent transport properties (C3H6 permeability of 243.1 Barrer and C3H6/C3H8 selectivity of 20.2) but also has desirable mechanical and thermal properties. The synthesis of ionogel based on Tai Chi philosophy opens a new window for facilitated transport of gas separation membranes.

Selective Synthesis of Monofluorinated Compounds Applying Amine/HF Reagents.

For nucleophilic monofluorination, amine/HF reagents such as Et3 N⋅3HF, Pyr⋅9HF (Olah's reagent) and similar combinations belong to the most frequently used fluoride sources, whereupon the selectivity of these reagents can be very different depending of its acidity, the nucleophilicity of the fluoride equivalent, and the structure of the particular substrate. These reagents can be used safely in ordinary chemistry laboratories for nucleophilic substitution reactions by fluoride at sp3 -hybridized carbon centers. For ring opening reactions of epoxides, the regio- and stereoselectivity is very much depending of the nature of the epoxide and the acidity of the HF reagent favoring either SN 1 or SN 2 type reactions. Similarly, the outcome of halofluorination and similar reactions with sulfur or seleno electrophiles can be controlled by the particular combination of the electrophile and the fluoride source. Examples for the application of these reaction types for the synthesis of fluorine-containing analogues of natural products or biologically relevant compounds are in the focus of this personal account.

Synthesis, Characterization, and Catalytic Reactivities of Novel Dinuclear Cu(II) Complexes : Efficient Ring Opening Reaction of Epoxide

Synthesis, Characterization, and Catalytic Reactivities of Novel Dinuclear Cu(II) Complexes : Efficient Ring Opening Reaction of Epoxide

Vitamin B12 and hydrogen atom transfer cooperative catalysis as a hydride nucleophile mimic in epoxide ring opening

Epoxide ring-opening reactions have long been utilized to furnish alcohol products that are valuable in many subfields of chemistry. While many epoxide-opening reactions are known, the hydrogenative opening of epoxides via ionic means remains challenging because of harsh conditions and reactive hydride nucleophiles. Recent progress has shown that radical chemistry can achieve hydrogenative epoxide ring opening under relatively mild conditions; however, these methods invariably require oxophilic metal catalysts and sensitive reagents. In response to these challenges, we report a new approach to epoxide ring-opening hydrogenation using bio-inspired Earth-abundant vitamin B12 and thiol-centric hydrogen atom transfer (HAT) co-catalysis to produce Markovnikov alcohols under visible light irradiation. This powerful reaction system exhibits a broad substrate scope, including a number of electrophilic and reductively labile functionalities that would otherwise be susceptible to reduction or cleavage by hydride nucleophiles, and preliminary mechanistic experiments are consistent with a radical process.

Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated Derivatives from Epoxides toward the Synthesis of Aza Heterocycles.

A new method for directly synthesizing acylated and alkylated quinazoline derivatives by the epoxide ring-opening reaction in the presence of I2/DMSO with 2-aminobenzamide is described herein. The developed mild protocol is efficient and displays a wide variety of functional group tolerance and substrate-controlled high selectivity, and the application of a continuous flow technique allows for faster reaction time and higher yields. Moreover, the robustness of the method is applicable in gram-scale synthesis.

(1R,2R,6S)-2(4-(4-Isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol

Parkinson’s disease (PD) is a progressive neurodegenerative disorder mainly characterized by movement dysfunction. Earlier, it was found that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Prottremin) demonstrated antiparkinsonian activity in vivo on different animal models of PD. The paper presents synthesis of new Prottremin derivative, (1R,2R,6S)-2(4-(4-isopropylbenzyl)piperazin-1-yl)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-enol. The derivative was obtained by epoxide ring opening reaction with 1-(4-isopropylbenzyl)piperazine. The product yield was 48% after purification.

Theoretical Study of the Reaction Mechanism of Phenol–Epoxy Ring-Opening Reaction Using a Latent Hardening Accelerator and a Reactivity Evaluation by Substituents

The mechanism of the phenol-epoxide ring-opening reaction using tetraphenylphosphonium-tetraphenylborate (TPP-K) was investigated using the density functional theory (DFT) method. The reaction was initiated by breaking the P-B bond of TPP-K. The generated tetraphenylborate (TetraPB-) reacted with phenol to form a phenoxide ion, which combined with tetraphenylphosphonium (TPP+) to produce the active species, i.e., tetraphenylphosphonium phenolate (TPP-OPh). The phenoxide ion in TPP-OPh nucleophilically attacked the epoxide. Simultaneously, the H atom in the phenolic OH group moved to the O atom of the ring-opened epoxide. The formed phenoxide ion bound to TPP+ again, and TPP-OPh was regenerated. The rate-determining steps in the reaction were the cleavage of the P-B bond and the triphenylborane-forming reaction. The free energies of activation were calculated to be 36.3 and 36.1 kcal/mol, respectively. It is also suggested that these values in the rate-determining steps could be manipulated by substituents introduced on the Ph group of TetraPB-. Based on these results, it is possible to construct new design guidelines for latent hardening accelerators such as TPP-K.

Sulfonic Acid-Grafted Hybrid Porous Polymer Based on Double-Decker Silsesquioxane as Highly Efficient Acidic Heterogeneous Catalysts for the Alcoholysis of Styrene Oxide.

β-Alkoxyalcohols generated from epoxide ring-opening reactions are significant due to their enormous value as pharmaceutical intermediates and fine chemicals. Using a phenyl-substituted double-decker-type silsesquioxane as the precursor, a hybrid porous material (PCS-DDSQ) was synthesized through a Scholl coupling reaction with an AlCl3 catalyst. Then, novel excellent Brønsted acid-derived silsesquioxane solid catalysts (PCS-DDSQ-SO3H-x) were successfully obtained through an electrophilic aromatic substitution reaction of chlorosulfonic acid on phenyl rings of PCS-DDSQ, fully characterized by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, powder X-ray diffraction, temperature-programmed desorption, water contact angle, Brunauer-Emmett-Teller model, thermogravimetric analysis, and solid-state 13C and 29Si nuclear magnetic resonance techniques. The catalytic behavior of the PCS-DDSQ-SO3H-x with different SO3H loadings for the methanolysis of styrene oxide was compared and evaluated. The presence of SO3H groups endows them with excellent catalytic abilities, achieving the highest values from PCS-DDSQ-SO3H-1 (the acid site of its catalyst is 1.84 mmol/g) as 99% conversion and 100% selectivity for the methanolysis of styrene oxide in 30 min, which shows superior catalytic properties of low dosage and high efficiency. Furthermore, the PCS-DDSQ-SO3H-1 catalyst can maintain high activity and selectivity after three cycles. This study provides a feasible method for the preparation of Brønsted solid acid catalysts with different acid loadings by introducing the sulfonic group into PCS-DDSQ.

Gilman reagent toward the synthesis of natural products.

With the ever-increasing scope of organocuprates, a well-established Gilman reagent has been considered as an unprecedented synthetic tool in modern organic chemistry. The broad research profile of the Gilman reagent (R2CuLi in THF or Et2O) is owing to its propensity to carry out three kinds of reactions, i.e., epoxide ring opening reactions, 1,4-conjugate addition reactions, and SN2 reactions in a regioselective manner. This review examines the applications of Gilman reagent in the total synthesis of both abundant and scarce natural products of remarkable synthetic pharmaceutical profile reported since 2011. The presented insights will be of a vital roadmap to general organic synthesis and it will contribute to the development of new natural products and their analogues in future drug discovery.

Post-synthetic modification of NH2-MIL88B(Fe) with sulfonic acid groups for acid-catalyzed epoxide ring-opening reaction

A new metal–organic framework-based solid acid catalyst was successfully prepared and exploited in the catalytic ring-opening of epoxides.

Tuning the Properties of Ester-Based Degradable Polymers by Inserting Epoxides into Poly(ϵ-caprolactone).

A series of ester-ether copolymers were obtained via the reaction between α,ω-dihydroxyl poly(ϵ-caprolactone) (PCL) and ethylene oxide (EO) or monosubstituted epoxides catalyzed by strong phosphazene bases. The two types of monomeric units were distributed in highly random manners due to the concurrence of epoxide ring-opening and fast transesterification reactions. The substituent of epoxide showed an interesting bidirectional effect on the enzymatic degradability of the copolymer. Compared with PCL, copolymers derived from EO exhibited enhanced hydrophilicity and decreased crystallinity which then resulted in higher degradability. For the copolymers derived from propylene oxide and 1,2-butylene oxide, the hydrophobic alkyl pendant groups also allowed lower crystallinity of the copolymers thus higher degradation rates. However, further enlarging the pendant groups by using styrene oxide or 2-ethylhexyl glycidyl ether caused a decrease in the degradation rate, which might be ascribed to the higher bulkiness hindering the contact of ester groups with lipase.