Pinacol Ester Research Articles

Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET.

5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/μmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

One-Pot Dual C-C Bond-Forming Cascade Process via Suzuki Coupling and Intramolecular Cyclocondensation: An Access to Functionalized Naphthalenes.

Naphthyl ketones encompass a class of essential compounds of biological and industrial significance. The development of synthetic strategies to achieve naphthyl ketones in single-step reactions from readily available materials is highly desirable. Herein, domino one-pot synthesis of functionalized naphthyl ketones via intermolecular Suzuki-Miyaura coupling, followed by intramolecular distal aldol-type condensation with the γ-methyl/methylene groups is reported. The present strategy displayed a comprehensive substrate scope and good functional group tolerance and enabled access to a variety of substituted naphthyl ketones, including aromatic-aliphatic hybrid frameworks of interesting structural features starting from the easily accessible starting materials such as α-iodoenone and 2-formylphenylboronic acids as well as 2-formylphenylboronic acid pinacol esters.

Enhanced fungicidal activity and mechanism of pyraclostrobin nanoparticle with reactive oxygen species responsiveness against Rhizoctonia solani

The frequent application of pesticides has caused adverse effects on humans and the environment. Stimuli-responsive nanoparticles can enhance the control efficacy of pesticides to pest insects or fungus and reduce impacts on non-target organisms. In the present work, 4-(hydroxymethyl) phenylboronic acid pinacol ester (PBAP) groups were conjugated onto β-cyclodextrin (β-CD) to form a H2O2-eliminating material (Ox-bCD), and then the nanoparticiles (PYR@OxbCD) loaded pyraclostrobin (PYR) were successfully fabricated by a nanoprecipitation. The prepared PYR@OxbCD had excellent reactive oxygen species (ROS) release dependency, and significantly enhanced fungicidal activity against Rhizoctonia solani in vitro. PYR@OxbCD could accurately release PYR at infected rice plants, providing a better control efficacy than PYR suspension concentrate (SC). The contact angle of PYR@OxbCD on leaves was reduced, and the spreading and antiphotolysis properties were increased, which may lead to an increase of deposition and a lower dissipation rate. Furthermore, the released PYR from PYR@OxbCD enhanced the activity of peroxidase (POD) and catalase (CAT), and up-regulated the expression of defense genes including PAL, PR10, CHI, CAT, GluPOD and AsPOD. PYR@OxbCD exhibited a much weaker effect on microbial abundance in rice cropping systems. The study provides an idea for smart delivery of fungicides to prevent plant pathogens and offers a more comprehensive view about the resistance of R. solani-infected rice triggered by PYR@OxbCD in levels of phenotype, enzymatic activity, gene expression, and microbiome.

Pd-Catalyzed Homologation of Arylboronic Acids as a Platform for the Diversity-Oriented Synthesis of Benzylic C–X Bonds

AbstractWe report a synthetic platform for the formation of benzylic C–X bonds. Benzylboronic acid pinacol (Bpin) esters are useful synthetic intermediates but are commercially uncommon, leading to preparations that typically rely upon stoichiometric metalation. Pd-catalyzed formal homologation of arylboronic acids provides access to these compounds that, in turn, allow the formation of C–C, C–O, and C–N bonds from Pd- and Cu-mediated cross-coupling or oxidative processes. This affords a wide variety of benzylic alcohols, diarylmethanes, benzyl amines, and benzyl ethers. Limitations are disclosed, and the utility is further demonstrated by the generation of analogues of meclizine.

A dual-functional probe that allows cascade response to hydrogen peroxide oxidative stress-induced protein aggregation in live cells

The misfolding and aggregation of specific proteins induced by endogenous oxidation are closely related to some incurable diseases including cancers, diabetes and neurodegenerative diseases. Reactive oxygen species (ROS), as a common oxidizing substance in vivo would induce the oxidation of endogenous biomacromolecules like proteins. However, it remains a challenge to detect protein aggregation induced by specific ROS. Herein, we demonstrate that the developed probe (P2) with a dual function that can simultaneously detect hydrogen peroxide (H2O2) levels and protein aggregates formed by oxidative stress. In this probe, the boronic acid pinacol ester group was conjugated to fluorescent molecular rotor 4-hydroxybenzylidene-imidazolinone (HBI) and served as the H2O2 detection group. Experimental results show that the fluorescence of P2 can be activated by H2O2 and exhibited a positive correlation with the degree of protein aggregation. Moreover, combined with AggTag method P2 was successfully applied to dual-channel imaging of protein aggregation that is stressed by H2O2 in cellular. In general, this work not only provides a potential method to study protein aggregation that associates with oxidation in live cells but also can be generally applied to study other biological processes.

Clathrochelate Complexes Containing Axial Cymantrene and Tromancenium Moieties.

New clathrochelate complexes of manganese, iron and cobalt containing peripheral organometallic manganese moieties cymantrene or tromancenium were synthesized via self-assembly from di/tri-topic dioximes, metal templates and cymantrene/tromancenium boronic acid pinacol esters. These air-stable, highly colored, oligometallic complexes are composed of various combinations of MnIFeIIMnI, MnICoIIMnI, MnIMnIIMnIIMnI and MnICoIICoIIMnI metal assemblies with corresponding complicated magnetic and electrochemical properties. Full spectroscopic and structural characterization by 1H/11B/13C NMR, HRMS, IR, UV-vis, single crystal XRD and CV (cyclic voltammetry) is provided. Tetrametallic complexes containing tromanceniumyl substituents with two CoII or MnII central metals exhibit promising anticancer properties against different tumor cell lines.

A Golgi-targeted fluorescent probe for imaging H2O2 and releasing H2S during Golgi stress

Golgi stress was the major stress response in the Golgi apparatus, which might be induced the disruption of redox balance and relate to a variety of diseases. As an important reactive oxygen species (ROS), hydrogen peroxide (H2O2) played an essential role in the Golgi apparatus, the abnormal concentration of H2O2 might cause oxidative damage. In contrast, hydrogen sulfide (H2S) acted as a protector for the Golgi apparatus to relieve Golgi stress. Combined thiocarbamates as H2S donor group activated by oxidizing phenylboronic acid pinacol ester to hydroxyl by H2O2, a Golgi-targeted fluorescent probe Golnap-H2O2 had been developed based on a reported Golgi-targeted fluorophore. Golnap-H2O2 showed the selectivity to H2O2 and the ability to release H2S in the existence of carbonic anhydrase. Besides, Golnap-H2O2 exhibited the targeting ability to Golgi apparatus and was qualified for imaging H2O2. According to our study results, Golnap-H2O2 could not only be used as a satisfactory imaging tool for detecting H2O2 in Golgi apparatus to explore the complex physiological functions, but also be used as a potential H2S donor for cytoprotection.

Synthesis and Palladium-Catalyzed Cross-Coupling of an Alkyl-Substituted Alkenylboronic Acid Pinacol Ester with Aryl Bromides

The palladium-catalyzed cross-coupling reaction of alkyl-substituted alkenylboron reagents with aryl halides is a versatile method to introduce a hydrophobic hydrocarbon chain onto organic compounds of interest. The application of the cross-coupling reaction is enabled by synthetic methods for the preparation of alkenylboron reagents. The geometrically pure, alkyl-substituted alkenylboron reagent, (E)-octenylboronic acid pinacol ester, was prepared by 9-BBN-catalyzed hydroboration reaction of 1-octene with pinacolborane in refluxing 1 M THF solution. This reagent was then evaluated in palladium-catalyzed cross-coupling reactions with aryl bromides. The highest yield of the (E)-1-phenyloctene was obtained when SPhos was used as the ligand, K2CO3 was used as the base, and DMF was used as the reaction solvent. Other electron-rich, electron-poor, sterically hindered, and heteroaromatic substrates produced the corresponding (E)-1-phenyloctene derivatives in moderate to good yield. KEYWORDS: Organic synthesis; Aryl alkene synthesis; Palladium-catalyzed cross-coupling; Suzuki-Miyaura reaction; Stereocontrolled alkene preparation; Hydroboration; 9-Borobicyclo[3.3.1]nonane; Reaction optimization

Cyclic RGD-Functionalized pH/ROS Dual-Responsive Nanoparticle for Targeted Breast Cancer Therapy.

Breast cancer is the most common malignant tumor in women and is a big challenge to clinical treatment due to the high morbidity and mortality. The pH/ROS dual-responsive nanoplatforms may be an effective way to significantly improve the therapeutic efficacy of breast cancer. Herein, we report a docetaxel (DTX)-loaded pH/ROS-responsive NP that could achieve active targeting of cancer cells and selective and complete drug release for effective drug delivery. The pH/ROS-responsive NPs were fabricated using nanocarriers that consist of an ROS-responsive moiety (4-hydroxymethylphenylboronic acid pinacol ester, HPAP), cinnamaldehyde (CA, an aldehyde organic compound with anticancer activities) and cyclodextrin (α-CD). The NPs were loaded with DTX, modified with a tumor-penetration peptide (circular RGD, cRGD) and named DTX/RGD NPs. The cRGD could promote DTX/RGD NPs penetration into deep tumor tissue and specifically target cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, the pH-responsive acetal was cleaved to release CA in the lysosomal acidic environment. Meanwhile, the high ROS in tumor cells induced the disassembly of NPs with complete release of DTX. In vitro cellular assays verified that DTX/RGD NPs could be effectively internalized by 4T1 cells, obviously inducing apoptosis, blocking the cell cycle of 4T1 cells and consequently, killing tumor cells. In vivo animal experiments demonstrated that the NPs could target to the tumor sites and significantly inhibit the tumor growth in 4T1 breast cancer mice. Both in vitro and in vivo investigations demonstrated that DTX/RGD NPs could significantly improve the antitumor effect compared to free DTX. Thus, the DTX/RGD NPs provide a promising strategy for enhancing drug delivery and cancer therapy.

Cold Physical Plasma-Mediated Fenretinide Prodrug Activation Confers Additive Cytotoxicity in Epithelial Cells.

Cold physical plasma is a partially ionized gas operated at body temperature and utilized for heat-sensitive technical and medical purposes. Physical plasma is a multi-component system consisting of, e.g., reactive species, ions and electrons, electric fields, and UV light. Therefore, cold plasma technology is an interesting tool for introducing biomolecule oxidative modifications. This concept can be extended to anticancer drugs, including prodrugs, which could be activated in situ to enhance local anticancer effects. To this end, we performed a proof-of-concept study on the oxidative prodrug activation of a tailor-made boronic pinacol ester fenretinide treated with the atmospheric pressure argon plasma jet kINPen operated with either argon, argon-hydrogen, or argon-oxygen feed gas. Fenretinide release from the prodrug was triggered via Baeyer-Villiger-type oxidation of the boron-carbon bond based on hydrogen peroxide and peroxynitrite, which were generated by plasma processes and chemical addition using mass spectrometry. Fenretinide activation led to additive cytotoxic effects in three epithelial cell lines in vitro compared to the effects of cold plasma treatment alone regarding metabolic activity reduction and an increase in terminal cell death, suggesting that cold physical plasma-mediated prodrug activation is a new direction for combination cancer treatment studies.

Ratiometric SERS imaging for indication of peroxynitrite fluctuations in diabetic wound healing process

Peroxynitrite (ONOO−) involves in diabetic wounds and its concentration is fluctuated in different pathological stages during the wound healing process. Thus, ONOO− may be utilized as a powerful biomarker to indicate the healing process of diabetic wound. However, the pathological roles of ONOO− can’t be fully understood yet. Herein, inspired by the mechanism that phenylboronic pinacol ester can react with ONOO− specifically, we report a new kind of SERS nanoprobes to monitor ONOO− fluctuation during diabetic wound healing process. The gold-silver (Au@Ag) core-ultrathin shell nanoparticles were utilized as active substrate and conjugated with phenylboronic pinacol ester molecules on the surface of Ag shell to simultaneously act as Raman reporter molecules and recognition moiety of ONOO−. In addition, functional polyethylene glycol (HS-PEG) and bovine serum albumin layers were sequentially immobilized on the surface of Ag shell to improve the stability of the nanoprobes. In the presence of ONOO−, phenylboronic pinacol ester could be converted into the corresponding phenol, inducing the SERS signal changes. The concentration fluctuation of ONOO− could be quantitatively detected through the SERS signal intensity ratio (1076 cm−1/998 cm−1) changes of typical peaks. The nanoprobes exhibited a wide response range from 0 to 75 μM with 0.12 μM as the detection limit. In the diabetic wound skin models, ONOO− concentration fluctuations during the wound healing process before and after drug treatment could be obtained by SERS imaging. We expect the proposed SERS imaging assay could be a noninvasive and powerful tool to monitor the diabetic wound healing.

Light-Driven Four-Component Reaction with Boronic Acid Derivatives as Alkylating Agents: An Amine/Imine-Mediated Activation Approach.

Herein, we describe a one-pot aminoalkylation of styrene derivatives with boronic acids (BAs) and boronic acid pinacol esters as radical precursors for the synthesis of complex secondary amines in moderate to high yields through a mild and easily accessible organophotoredox-catalytic four-component reaction. Additionally, we report for the first time in a photoredox process the activation of alkyl boronic acid derivatives by imines, which play a dual role in the reaction as both substrate and Lewis base activator. The protocol applicability was greatly enhanced by its successful adaptation to photoflow reactors.

Controlled Synthesis, Chiral Assembly, and Circularly Polarized Luminescence of Poly(Phenyl Isocyanide)-Block-Polyfluorene Copolymers.

In this work, π-conjugated block copolymers consisting of poly(phenyl isocyanide) (PPI) and polyfluorene (PF) segments are facilely prepared by one-pot sequential polymerization of phenyl isocyanide (monomer 1) and 7-bromo-9,9-dioctylfluorene-2-boronic acid pinacol ester (monomer 2). The Pd(II)-terminated PPI is first prepared via polymerizing monomer 1catalyzed with phenyl alkyne-Pd(II) complex and then utilized to initiate the controlled Suzuki cross-coupling polymerization of monomer 2, yielding various PPI-b-PF copolymers possessing controlled molar mass and narrow dispersity. Owing to the helical conformation of PPI segment and π-conjugated structure of PF segment, PPI-b-PF copolymers present distinctive optical property and fascinating chiral self-assembly behavior. During the self-assembly process, chirality transfer from helical PPI block to the supramolecular aggregates of helical nanofibers occurs to afford optically active helical nanofibers with high optical activity. Furthermore, the self-assembled helical nanofibers exhibit excellent circularly polarized luminescence performance.

Synthesis of hydrothermally derived boron and sulfur-incorporated reduced graphene oxide sheets for supercapacitor applications

The combination of boron and sulfur incorporated reduced graphene oxide (B/S-rGO) was synthesized by a simple hydrothermal technique using a novel and single source of thiophene-2 boronic acid pinacol ester. Structural and functional groups of the synthesized materials were analyzed by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy analysis. The Raman analysis revealed the defective structure after incorporating sulfur and boron elements into rGO. The morphological and the presence of elements in the synthesized material were analyzed by scanning electron microscopy, transmission electron microscopy and elemental mapping analysis. The chemical states and chemical composition of B/S-rGO were observed by X-ray photoelectron spectroscopy (XPS) analysis. The electrochemical performance of the prepared material was studied using cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) and electrochemical impedance analysis. GCD studies were performed for B/S-rGO electrode material in an aqueous 1 M H2SO4 electrolyte. The prepared material showed a high specific capacitance of 345 Fg−1 at 1 Ag−1 in a three-electrode configuration. B/S-rGO based device exhibited 97 Fg−1 of specific capacitance at 1 Ag−1 in a symmetric two-electrode configuration. B/S-rGO based symmetric device showed a high energy density of 13.4 Whkg−1 at 249 Wkg−1 and more than 96% capacity retention after 5000 cycles.

Pd-Catalyzed Organometallic-Free Homologation of Arylboronic Acids Enabled by Chemoselective Transmetalation.

A Pd-catalyzed homologation of arylboronic acids is reported. Halomethylboronic acid pinacol esters (Bpin) undergo a remarkably facile, yet rare, oxidative addition enabled by an α-boryl effect. Simultaneous chemoselective transmetalation allows use of these metalloid reagents for formal C1 insertion to deliver benzyl Bpin products without the requirement for stoichiometric organometallic reagents. The utility of the process is demonstrated by stepwise C(sp3)-C(sp2) cross-coupling of the boronic ester products into diarylmethane pharmacophores and electrophile/nucleophile chemoselective cross-coupling. Control experiments that demonstrate the reactivity enhancement provided by the α-boryl effect are provided, along with a description of the limitations of the formal homologation process.

Rhenium(I) bromo tricarbonyl complexes from anthracenyl derivatized ligands

The ligand 2-(1H-pyrazol-1-yl)pyrazine (pypyr) was prepared by reaction of 2-bromopyrazine with N-lithium pyrazolate with 92.5% yield, while the anthracenyl derivatives 2-(anthracen-9-yl)-5-(1H-pyrazol-1-yl)pyrazine (pypyr-anthra) and 9,10-bis(5-(1H-pyrazol-1-yl)pyrazin-2-yl)anthracene (pypyr-anthra-pypyr) were prepared by reaction of the 9-anthraceneboronic or bis-boronic acid pinacol ester with 2-bromo-5-(1H-pyrazol-1-yl)pyrazine with medium yields (49.6 and 31.5 % respectively). The respective ReI(CO)3Br complexes: [(pypyr)Re(CO)3Br], [(pypyr-anthra)Re(CO)3Br] and [Br(CO)3Re(pypyr-anthra-pypyr)Re(CO)3Br] were prepared in high yields (94, 84 and 78 % respectively) by reaction with bromotricarbonyl(tetrahydrofuran)rhenium(I) dimer. DFT modelling suggests the anthracenyl moiety is not coplanar with the pyrazolyl-pyrazine fragment, defining a dihedral angle of 65° and 67° for [(pypyr-anthra)Re(CO)3Br] and [Br(CO)3Re(pypyr-anthra-pypyr)Re(CO)3Br] respectively. Each one of the three rhenium(I) molecules shows a quasi-reversible reduction wave around − 1.10 V, assigned by comparison with the uncoordinated ligand, the pypyr fragment, while additional reductions waves related to this core or the anthryl arms are present. UV–Vis spectra show absorption bands and/or shoulders around 400–450 nm for the series of compounds in solution. The respective extinction coefficients (∼4 × 103 M−1cm−1), the sensitivity to solvent polarity and DFT modelling suggest they corresponds to MLCT Redπ → π(pyr)* transitions. Despite their high emissivity, the uncoordinated ligands completely lose their emission upon coordinated to ReI(CO)3Br. The rhenium(I) complexes emit around 650 nm upon excitation, although [(pypyr)Re(CO)3Br] is a moderate emissive molecule, while [(pypyr-anthra)Re(CO)3Br] and [Br(CO)3Re(pypyr-anthra-pypyr)Re(CO)3Br] are very weak ones. In contrast these two last molecules showed a remarkably high yield as singlet oxygen sensitizers.

Synthesis of Boronates with a Protoilludane Skeleton

AbstractNaturally occurring sesquiterpenes with a protoilludane skeleton are frequently oxygenated at carbon atoms C4 and C8. Boronic acid pinacol esters (BPin) are potential precursors for hydroxy groups at these positions and synthetic methods have now been developed for their preparation. Introduction of a boronate in position C4 was achieved by Cu-catalyzed hydroboration of a photochemically generated cyclobutene precursor, which displayed the complete C15-carbon skeleton of protoilludanes. Introduction of BPin at carbon atom C8 was possible by starting with an alkenyl boronate as precursor in a photochemical transformation. A two-photon reaction cascade allowed for creation of the complete protoilludane skeleton with BPin selectively positioned at C8. Subsequent reactions were studied and the oxidative transformation of the boronates into the respective alcohols was shown.

Alkyl Radical Generation from Alkylboronic Pinacol Esters through Substitution with Aminyl Radicals.

Alkylboronic pinacol esters (APEs) are highly versatile reagents in organic synthesis. However, the direct generation of alkyl radicals from commonly used, bench-stable APEs has not been well explored. In this communication, alkyl radical generation from APEs through reaction with aminyl radicals is reported. The aminyl radicals are readily generated by visible-light-induced homolytic cleavage of the N-N bond in N-nitrosamines, and C radical generation occurs through nucleohomolytic substitution at boron. As an application, the highly efficient photochemical radical alkyloximation of alkenes with APEs and N-nitrosamines under mild conditions is presented. A wide range of primary, secondary, and tertiary APEs engage in this transformation that is easily scaled up.

Visible‐Light‐Promoted Reaction ofN‐Hydroxyphthalimide Esters with Vinyl Boronic Pinacol Ester

AbstractA novel and easy‐to‐execute light‐driven protocol for the preparation of alkyl boronic acid pinacol esters from vinyl boronate usingN‐hydroxyphthalimide esters as the potential precursor is described. In this photochemical protocol, theN‐hydroxyphthalimide ester's fragmentation generates C‐centered radicals, which undergo a radical Michael addition to vinyl boronic pinacol ester furnishing the desired products. A good substrate scope having various functionalities is presented and good to high yields are obtained.

Suzuki-Miyaura Coupling Polymerization: Synthesis, Characterization and Optical Properties

The new thiazole-based polymer was synthesized by the Suzuki-Miyaura crossing-coupling reaction of 5-bromo-N-(3-bromophenyl)thiazol-2-amine and 9,9-dioctyl-9H-fluorene-2,7-diboronic acid bis(pinacol) ester. The synthesized monomer and poly[N,N'(1,3-phenylene)bis(thiazol-2-amine)-co9,9’dioctylfluorene] (Poly[Tm]) were characterized by the Elemental analysis, Fourier Transform Infrared spectroscopy, Nuclear Magnetic Resonance spectroscopy, Thermogravimetric analysis and Gel Permission chromatography. Furthermore, the optical properties of the Poly[Tm] were studied at three concentrations of 0.625, 1.25 and 2.5 mM in solution. The absorption band edge values of Poly[Tm] decreased with the increasing concentration of the solutions. When the concentration of the Poly[Tm] solution was increased, transmittance values of the Poly[Tm] were increased, and its molar extinction coefficient was resulted in higher absorbance values. Synthesized Poly[Tm] could provide a novel concept for the design of transistors and photovoltaics.