Catalytic enantioselective allene–anhydride approach to β,γ-unsaturated enones bearing an α-all-carbon-quarternary center

A protocol of highly regio- and enantioselective copper-catalyzed hydroacylation of the non-terminal C C bond in 1,1-disubstituted terminal allenes with anhydrides has been developed. Both aromatic and aliphatic carboxylic anhydrides are applicable to the efficient construction of all carbon quarternary centers connected with a versatile C C bond and a useful ketone functionality. The synthetic potentials of the enantioenriched products have also been demonstrated. Density functional theory (DFT) calculations were performed to explain the steric outcome of the products: the hydroacylation proceeds through a six-membered transition state and the ligand-substrate steric interactions account for the observed enantioselectivity although the chiral ligand is far away from the to-be-genetated chiral center.

A protocol of highly regio- and enantioselective copper-catalyzed hydroacylation of the non-terminal C C bond in 1,1-disubstituted terminal allenes with anhydrides has been developed.     

Trityl Cation-Catalyzed Hosomi-Sakurai Reaction of Allylsilane with β,γ-Unsaturated α-Ketoester to Form γ,γ-Disubstituted α-Ketoesters

(Ph₃C)[BPh(^F)₄]-catalyzed Hosomi-Sakurai allylation of allylsilanes with β,γ-unsaturated α-ketoesters has been developed to give γ,γ-disubstituted α-ketoesters in high yields with excellent chemoselectivity. Preliminary mechanistic studies suggest that trityl cation dominates the catalysis, while the silyl cation plays a minor role.     

Determinants for α4β2 vs. α3β4 Subtype Selectivity of Pyrrolidine-Based nAChRs Ligands: A Computational Perspective with Focus on Recent cryo-EM Receptor Structures

The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4β2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4β2 agonist N-methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion. Indeed, the direct or water mediated interaction with hydrophilic residues of the relatively narrower β2 minus side through the elements decorating the aromatic ring and the stabilization of the latter by facing to the not conserved β2-Phe119 result as key distinctive features for the α4β2 affinity. Consistently, these compounds show, despite the structural similarity, very different α4β2 vs. α3β4 selectivities, from modest to very high, which relate to rigidity/extensibility degree of the portion containing the aromatic ring and to substitutions at the latter. Furthermore, the structural rationalization of the rat vs. human differences of α4β2 vs. α3β4 selectivity ratios is here proposed.     

The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ

14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer’s and Parkinson’s diseases, respectively, a process that is intimately linked to the diseases’ progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ₄₀) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of ¹⁵N-labeled Aβ₄₀ and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ₄₀ (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ₄₀ and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy.     

Design and Synthesis of New α-hydroxy β-fluoro/β-trifluoromethyl and Unsaturated Phosphonates from Carbohydrate-Derived Building Blocks via Pudovik and Horner–Wadsworth–Emmons Reactions

Herein, we present the application of fluorinated carbohydrate-derived building blocks for α-hydroxy β-fluoro/β-trifluoromethyl and unsaturated phosphonates synthesis. Pudovik and Horner–Wadsworth–Emmons reactions were applied to achieve this goal. The proposed pathway of the key reactions is supported by the experimental results, as well as quantum chemical calculations. The structure of the products was established by spectroscopic (1D, 2D NMR) and spectrometric (MS) techniques. Based on our data received, we claim that the progress of the Pudovik and HWE reactions is significantly influenced by the acidic protons present in the molecules as assessed by pK_a values of the reagent.     

Syntheses Based on 3,4α-Epoxy-1,5,7α,6β(H)-guai-10(14),11(13)-dien-6,12-olide

The sesquiterpene γ-lactone estafiatin 1, the molecule of which has a structure of 3,4α-epoxy-1,5,7α,6β(H)-guai-10(14),11(13)-dien-6,12-olide, is characteristic of plants of the genera Achillea L. and Artemisia L. of the Asteraceae family. This article presents the results of chemical modification for three reaction centers of the estafiatin molecule 1: epoxy cycle, exomethylene group conjugated with γ-lactone carbonyl, and exomethylene group in position C10=C14; and at the same time 33 new derivatives were synthesized, the structures of which were established based on physicochemical constants, spectral data (IR-, PMR-, ¹³C-NMR), and X-ray diffraction analysis. The stereo- and regiospecificity, as well as the chemoselectivity of the reaction based on estafiatin molecule 1, are discussed. The reactivity of the substrate is significantly influenced by the stereochemistry of its molecule, the nature of the reagent, and the reaction medium. Based on the results of in silico screening, derivatives of estafiatin with high binding energies for both DNA-topoisomerase I and DNA-topoisomerase II were identified. The values of the inhibitory dose of IC₅₀ for estafiatin 1 and its derivatives were determined on cell lines of eight types of tumors. in vivo experiments of the samples made it possible to establish that estafiatin 1 and its derivatives have pronounced antitumor activity against Pliss lymphosarcoma, Walker’s carcinosarcoma, sarcoma 45, sarcoma-180, alveolar liver cancer PC-1, leukemia P-388 and L-1210, and sarcoma-45 resistant to 5-fluorouracil.     

Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUC_last values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t_1/2 > 1 h) and serum (t_1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.     

Identification of β-strand mediated protein–protein interaction inhibitors using ligand-directed fragment ligation

β-Strand mediated protein–protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. β-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the presence of the protein as template and in situ screening using a fluorescence anisotropy (FA) assay identified peptide hybrid hits with comparable affinity to the GKAP peptide binding sequence. Identified hits were validated using FA, ITC, NMR and X-ray crystallography to confirm selective inhibition of the target PDZ-mediated PPI and mode of binding. These analyses together with molecular dynamics simulations demonstrated the ligands make transient interactions with an unoccupied basic patch through electrostatic interactions, establishing proof-of-concept that this unbiased approach to ligand discovery represents a powerful addition to the armory of tools that can be used to identify PPI modulators.

Dynamic ligation screening is used to identify acylhydrazone-linked peptide-fragment hybrids which bind to the SHANK1 PDZ domain with comparable affinity to the native GKAP peptide as shown by biophysical and structural analyses.     

Pharmacophore Mapping Combined with dbCICA Reveal New Structural Features for the Development of Novel Ligands Targeting α4β2 and α7 Nicotinic Acetylcholine Receptors

The neuronal nicotinic acetylcholine receptors (nAChRs) belong to the ligand-gated ion channel (GLIC) group, presenting a crucial role in several biological processes and neuronal disorders. The α4β2 and α7 nAChRs are the most abundant in the central nervous system (CNS), being involved in challenging diseases such as epilepsy, Alzheimer’s disease, schizophrenia, and anxiety disorder, as well as alcohol and nicotine dependencies. In addition, in silico-based strategies may contribute to revealing new insights into drug design and virtual screening to find new drug candidates to treat CNS disorders. In this context, the pharmacophore maps were constructed and validated for the orthosteric sites of α4β2 and α7 nAChRs, through a docking-based Comparative Intermolecular Contacts Analysis (dbCICA). In this sense, bioactive ligands were retrieved from the literature for each receptor. A molecular docking protocol was developed for all ligands in both receptors by using GOLD software, considering GoldScore, ChemScore, ASP, and ChemPLP scoring functions. Output GOLD results were post-processed through dbCICA to identify critical contacts involved in protein-ligand interactions. Moreover, Crossminer software was used to construct a pharmacophoric map based on the most well-behaved ligands and negative contacts from the dbCICA model for each receptor. Both pharmacophore maps were validated by using a ROC curve. The results revealed important features for the ligands, such as the presence of hydrophobic regions, a planar ring, and hydrogen bond donor and acceptor atoms for α4β2. Parallelly, a non-planar ring region was identified for α7. These results can enable fragment-based drug design (FBDD) strategies, such as fragment growing, linking, and merging, allowing an increase in the activity of known fragments. Thus, our results can contribute to a further understanding of structural subunits presenting the potential for key ligand-receptor interactions, favoring the search in molecular databases and the design of novel ligands.     

Alterations in β-Cell Sphingolipid Profile Associated with ER Stress and iPLA2β: Another Contributor to β-Cell Apoptosis in Type 1 Diabetes

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca²⁺-independent phospholipase A₂ beta (iPLA₂β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA₂β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA₂β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA₂β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA₂β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA₂β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA₂β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.     

Soy Isoflavones Inhibit Both GPIb-IX Signaling and αIIbβ3 Outside-In Signaling via 14-3-3ζ in Platelet

Soy diet is thought to help prevent cardiovascular diseases in humans. Isoflavone, which is abundant in soybean and other legumes, has been reported to possess antiplatelet activity and potential antithrombotic effect. Our study aims to elucidate the potential target of soy isoflavone in platelet. The anti-thrombosis formation effect of genistein and daidzein was evaluated in ex vivo perfusion chamber model under low (300 s⁻¹) and high (1800 s⁻¹) shear forces. The effect of genistein and daidzein on platelet aggregation and spreading was evaluated with platelets from both wildtype and GPIbα deficient mice. The interaction of these soy isoflavone with 14-3-3ζ was detected by surface plasmon resonance (SPR) and co-immunoprecipitation, and the effect of αIIbβ3-mediated outside-in signaling transduction was evaluated by western blot. We found both genistein and daidzein showed inhibitory effect on thrombosis formation in perfusion chamber, especially under high shear force (1800 s⁻¹). These soy isoflavone interact with 14-3-3ζ and inhibited both GPIb-IX and αIIbβ3-mediated platelet aggregation, integrin-mediated platelet spreading and outside-in signaling transduction. Our findings indicate that 14-3-3ζ is a novel target of genistein and daidzein. 14-3-3ζ, an adaptor protein that regulates both GPIb-IX and αIIbβ3-mediated platelet activation is involved in soy isoflavone mediated platelet inhibition.     

Inhibition of (dppf)nickel-catalysed Suzuki–Miyaura cross-coupling reactions by α-halo-N-heterocycles

A nickel/dppf catalyst system was found to successfully achieve the Suzuki–Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki–Miyaura cross-coupling reactions. However, the corresponding Kumada–Tamao–Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.

Nickel complexes with a dppf ligand can form inactive dinickel(ii) complexes during Suzuki–Miyaura cross-coupling reactions. However, these complexes can react with Grignard reagents in Kumada–Tamao–Corriu cross-coupling reactions.     

Solvent directed chemically divergent synthesis of β-lactams and α-amino acid derivatives with chiral isothiourea

A protocol for the chemically divergent synthesis of β-lactams and α-amino acid derivatives with isothiourea (ITU) catalysis by switching solvents was developed. The stereospecific Mannich reaction occurring between imine and C(1)-ammonium enolate generated zwitterionic intermediates, which underwent intramolecular lactamization and afforded β-lactam derivatives when DCM and CH₃CN were used as solvents. However, when EtOH was used as the solvent, the intermediates underwent an intermolecular esterification reaction, and α-amino acid derivatives were produced. Detailed mechanistic experiments were conducted to prove that these two kinds of products came from the same intermediates. Furthermore, chemically diversified transformations of β-lactam and α-amino acid derivatives were achieved.

A protocol for the solvent directed chemically divergent synthesis of β-lactam and α-amino acid derivatives with chiral isothiourea was reported.     

Regioselective catalytic carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones

A new Pd/Cu-catalyzed carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones with complete regioselectivity has been developed. This transformation shows broad substrate scope and excellent functional-group tolerance. Moreover, the obtained 1,2-carbonylboration products provide substantial opportunities for further transformations which cannot be obtained by known carbonylation procedures. Preliminary mechanistic studies indicate that the three hydrogen atoms of the products originated from ethyl acetate.

A multi-component procedure on the carbonylative and hydroborative synthesis of β-boryl ketones has been developed with alkynes, B₂pin₂ and aryldiazonium salts as the substrates and using ethyl acetate as the reagent and solvent.

Construction of boro-containing organic molecules remains an important and hot research field due to their wide applications in materials science,¹ pharmaceuticals² and organic chemistry.³ A multitude of methods have been developed for the synthesis of organoboron compounds over the past decades.⁴ Among these methods, transition-metal-catalyzed borofunctionalization of alkynes is a powerful synthetic strategy due to its high selectivity and efficiency.⁵ For example, the use of copper as a precatalyst for the borylation of alkynes has generated renewed interest in the area. The β-borylalkenylcopper intermediates obtained via syn addition of borylcopper to alkynes can electrophilically trap various electrophiles to form different alkenylboronates (Scheme 1, 1). The classical approach of this type of transformation is alkyne hydroboration (Scheme 1, 1a).⁶ Subsequently, with vinylcopper species as the proposed key intermediates, their further reactions with halogen substitutes (Scheme 1, 1b),⁷ CO₂ (Scheme 1, 1c),⁸ allyl phosphates (Scheme 1, 1d),⁹ and tin alkoxides (Scheme 1, 1e)¹⁰ to give the corresponding alkenylboronates were reported. More recently, Mankad and Cheng reported their achievements on the direct efficient synthesis of tetrasubstituted β-borylenones using a copper-catalyzed four-component coupling reaction of simple chemical feedstocks: internal alkynes, alkyl halides, bis(pinacolato)diboron (B₂pin₂) and CO (Scheme 1, 1f).¹¹ Inspired by their achievements and considering the advantage of a multicomponent borocarbonylation reaction, we developed a new Pd/Cu-catalyzed multi-component carbonylation and borylation reaction of alkynes, aryldiazonium salts, B₂Pin₂, ethyl acetate and CO to obtain saturated β-boryl ketones (Scheme 1, ​,3).3). In addition, this new catalyst system can catalyze the regioselective functionalization of alkynes to obtain 2,1-carbonylboration products that are different from the 1,2-products by known transition-metal-catalyzed borylacylation (Scheme 1, ​,2a)2a) and borocarbonylation (Scheme 1, ​,2b)2b) of alkenes.¹² Nevertheless, the carbonylative and hydroborative coupling of alkynes with aryldiazonium salts to obtain saturated β-boryl ketones is still a challenge and has never been reported.Open in a separate windowScheme 1Strategies for borofunctionalization.Open in a separate windowScheme 2Scope of alkynes. Reaction conditions: 1 (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2a (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Open in a separate windowScheme 3Scope of aryldiazonium salts. Reaction conditions: 1a (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2 (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Initially, we tested various reaction conditions using phenyl acetylene (1a), 4-methoxybenzenediazonium tetrafluoroborate (2a) and bis(pinacolato)diboron as the reaction partners. To our delight, by using Pd(acac)₂ and CuI as the cooperative precatalyst, PPh₃ as the ligand, Na₂CO₃ as the base and ethyl acetate (EA) as the solvent at 110 °C under a CO atmosphere (20 bar) with 12 h reaction time, the desired borocarbonylative coupling product (3aa) was obtained in a good GC yield of 78% (

α,β-不饱和醛在Ni-Pt(111)面上吸附的理论研究

利用密度泛函理论研究了巴豆醛和肉桂醛分子在Pt-Ni-Pt(111)面的吸附构型以及相关电子性质. 吸附构型与吸附能结果表明, 巴豆醛和肉桂醛在覆盖度为1/25 ML的条件下, 以C=C和C=O双键协同吸附在Pt-Ni-Pt(111)面较为稳定, 且肉桂醛与Pt-Ni-Pt(111)面的吸附能远大于巴豆醛. 由Mulliken电荷布局和差分电荷密度可知, 在吸附过程中肉桂醛分子向Pt-Ni-Pt(111)面上转移的电荷数较巴豆醛更多, 相互作用更大. 由电子态密度分析结果可知, 不饱和醛与Pt-Ni-Pt(111)面的吸附作用主要是由于分子的p轨道电子与催化剂d轨道电子之间的相互作用. 由于苯基的存在使肉桂醛分子在Pt-Ni-Pt(111)面上的吸附更强, 且平行于催化剂表面.     

Phytochemical Profile,Antioxidant Capacity, α-Amylase and α-Glucosidase Inhibitory Potential of Wild Moroccan Inula viscosa (L.) Aiton Leaves

Medicinal plants offer imperative sources of innovative chemical substances with important potential therapeutic effects. Among them, the members of the genus Inula have been widely used in traditional medicine for the treatment of several diseases. The present study investigated the antioxidant (DPPH, ABTS and FRAP assays) and the in vitro anti-hyperglycemic potential of aerial parts of Inula viscosa (L.) Aiton (I. viscosa) extracts through the inhibition of digestive enzymes (α-amylase and α-glucosidase), responsible of the digestion of poly and oligosaccharides. The polyphenolic profile of the Inula viscosa (L.) Aiton EtOAc extract was also investigated using HPLC-DAD/ESI-MS analysis, whereas the volatile composition was elucidated by GC-MS. The chemical analysis resulted in the detection of twenty-one polyphenolic compounds, whereas the volatile profile highlighted the occurrence of forty-eight different compounds. Inula viscosa (L.) Aiton presented values as high as 87.2 ± 0.50 mg GAE/g and 78.6 ± 0.55mg CE/g, for gallic acid and catechin, respectively. The EtOAc extract exhibited the higher antioxidant activity compared to methanol and chloroform extracts in different tests with (IC₅₀ = 0.6 ± 0.03 µg/mL; IC₅₀ = 8.6 ± 0.08 µg/mL; 634.8 mg ± 1.45 AAE/g extract) in DPPH, ABTS and FRAP tests. Moreover, Inula viscosa (L.) Aiton leaves did show an important inhibitory effect against α-amylase and α-glucosidase. On the basis of the results achieved, such a species represents a promising traditional medicine, thanks to its remarkable content of functional bioactive compounds, thus opening new prospects for research and innovative phytopharmaceuticals developments.     

Bioactive Electrospun Fibers of Poly(ε-Caprolactone) Incorporating α-Tocopherol for Food Packaging Applications

Antioxidant activity is an important feature for food contact materials such as packaging, aiming to preserve freshness and retard food spoilage. Common bioactive agents are highly susceptible to various forms of degradation; therefore, protection is required to maintain functionality and bioavailability. Poly(ε-caprolactone) (PCL), a biodegradable GRAS labeled polymer, was used in this study for encapsulation of α-tocopherol antioxidant, a major component of vitamin E, in the form of electrospun fibers. Rheological properties of the fiber forming solutions, which determine the electrospinning behavior, were correlated with the properties of electrospun fibers, e.g., morphology and surface properties. Interactions through hydrogen bonds were evidenced between the two components. These have strong effect on structuration of macromolecular chains, especially at low α-tocopherol amounts, decreasing viscosity and elastic modulus. Intra-molecular interactions in PCL strengthen at high α-tocopherol amounts due to decreased solvation, allowing good structural recovery after cease of mechanical stress. Morphologically homogeneous electrospun fibers were obtained, with ~6 μm average diameter. The obtained fibers were highly hydrophobic, with fast release in 95% ethanol as alternative simulant for fatty foods. This induced good in vitro antioxidant activity and significant in vivo reduction of microbial growth on cheese, as determined by respirometry. Therefore, the electrospun fibers from PCL entrapping α-tocopherol as bioactive agent showed potential use in food packaging materials.     

Palladium-catalyzed synthesis of β-hydroxy compounds via a strained 6,4-palladacycle from directed C–H activation of anilines and C–O insertion of epoxides

A palladium-catalyzed C–H activation of acetylated anilines (acetanilides, 1,1-dimethyl-3-phenylurea, 1-phenylpyrrolidin-2-one, and 1-(indolin-1-yl)ethan-1-one) with epoxides using O-coordinating directing groups was accomplished. This C–H alkylation reaction proceeds via formation of a previously unknown 6,4-palladacycle intermediate and provides rapid access to regioselectively functionalized β-hydroxy products. Notably, this catalytic system is applicable for the gram scale mono-functionalization of acetanilide in good yields. The palladium-catalyzed coupling reaction of the ortho-C(sp²) atom of O-coordinating directing groups with a C(sp³) carbon of chiral epoxides offers diverse substrate scope in good to excellent yields. In addition, further transformations of the synthesized compound led to biologically important heterocycles. Density functional theory reveals that the 6,4-palladacycle leveraged in this work is significantly more strained (>10 kcal mol⁻¹) than the literature known 5,4 palladacycles.

The combined experimental and computational study on palladium-catalyzed regioselective C–H functionalization of O-coordinating directing groups with epoxides is described.