Boronic Groups Research Articles

Hydrogen Peroxide Induced Activation of Gene Expression in Mammalian Cells using Boronate Estrone Derivatives

Keeping the boron out of the ER: A genetic switch was engineered that activates gene expression in the presence of H(2)O(2). The use of a boronate group on an estrone molecule allows for activation of gene expression through binding of the estrogen receptor only when the boron group is oxidized by H(2)O(2). This sensor is highly sensitive and specific for H(2)O(2).

Methyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-nitrobenzoate

The six-membered boronate ester ring of the title compound, C13H16BNO6, adopts an envelope conformation with the C atom bearing the dimethyl substituents at the flap. The O—B—C—C torsion angles between the boronate group and the benzene ring are 72.5 (2) and 81.0 (2)°. The 4-nitro­benzoate unit adopts a slightly twisted conformation, with dihedral angles between the benzene ring and the nitrate and methyl ester groups of 17.5 (2) and 14.4 (3)°, respectively. In the crystal, inversion-related pairs of mol­ecules show weak π–π stacking inter­actions [centroid–centroid distance = 4.0585 (9) Å and inter­planar spacing = 3.6254 (7) Å].

A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding

Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis-hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5-(2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe3+ and shows only weak affinity for Cu2+ or Zn2+, in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties.

Regiocontrolled CuI-Catalyzed Borylation of Propargylic-Functionalized Internal Alkynes

Good to excellent reactivity and regiocontrol have been achieved in the Cu(I)-catalyzed borylation of dialkyl internal alkynes with bis(pinacolato)diboron. The presence of a propargylic polar group (OH, OR, SAr, SO(2)Ar, or NHTs), in combination with PCy(3) as ligand, allowed maximizing the reactivity and site-selectivity (β to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high β-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO(2)Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes.

On the Directing Effect of Boronate Groups in the Lithiation of Boronated Thiophenes

AbstractAn investigation of thiophene boronates has revealed the usefulness of a metalation reaction in the synthesis of various lithiated thiophene boronates, which were further converted to functionalized thiopheneboronic derivatives. The lithiation of 2‐ and 3‐thienylboronic N‐butyldiethanolamine (BDEA) esters with lithium diisopropylamide and lithium 2,2,6,6‐tetramethylpiperidide showed that both boronated thiophenes were readily deprotonated. In the latter case, lithiation at the 2‐position adjacent both to sulfur and the borocanyl group is thermodynamically favoured due to the significant stabilizing effect of the borocanyl group. Further derivatization with a range of electrophiles followed by hydrolysis afforded various 2‐substituted 3‐thiopheneboronic acids. Lithiation of the corresponding thiopheneboronic “ate” complexes of the type [ThB(OR)3]Li revealed that the 2‐thienyl derivatives could not be effectively deprotonated, whereas the “ate” complex, [3‐ThB(OEt)3]Li, was selectively lithiated with nBuLi at C‐2. This points to a directing effect of the anionic boronate moiety. The resulting bimetallic species, [(2‐Li‐3‐Th)B(OEt)3]Li, underwent ring‐closing dimerization upon heating to give, after subsequent hydrolysis, 4,8‐dihydro‐4,8‐dihydroxy‐p‐diborino[2,3‐b:5,6‐b′]dithiophene ― a cyclic diborinic acid. A computational study of the lithiation of boronated thiophenes and furans proved that boronation decreases ring‐proton acidity. This effect is much stronger for the boronic “ate” complexes than for the corresponding neutral BDEA esters. Calculations of the transition states have shown that the specific directing effect of boronate groups in 3‐thienyl derivatives is due to intramolecular oxygen–lithium coordination.

Transition‐Metal‐Free Synthesis of Pinacol Alkylboronates from Tosylhydrazones

Highly efficient: Pinacol alkylboronates were synthesized by the reaction of tosylhydrazones with bis(pinacolato)diboron or pinacolborane under transition-metal-free conditions. This reaction represents an expeditious conversion of carbonyl functionality into a boronate group.

Designed Synthesis and Characterization of Novel Germanium Centered Porous Aromatic Frameworks (Ge-PAFs)

A novel series of germanium centered porous aromatic frameworks (Ge-PAFs) based on tetrakis(4-bromophenyl)germane as building units and 1,4-benzenediboronic acid or 4,4'-biphenyldiboronic acid as linkers were synthesized. These materials were characterized by Fourier transform infrared spectroscopy (FT-IR), C solid-state NMR, thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (TEM), and N2 gas sorption. FTIR spectroscopy is useful in probing the structure of Ge-PAFs networks. From the disappearance of the intense B—OH bands (at 3370 cm) and the C—Br bands (at 482 cm) in the FT-IR spectra, the formation of the product can be preliminarily confirmed. The solid-state C CP/MAS NMR spectra of Ge-PAFs indicate that a group of signals with a chemical shift in the range of δ 120—145 could be observed. They are related to aromatic carbon atoms in the framework-building phenylene groups. Both the FTIR and C CP/MAS NMR analyses show no obvious signals assigned to the halogen or boronic acid end groups, testifying that an almost complete coupling reaction has taken place. PXRD was carried out to investigate the crystallinity of Ge-PAFs, which indicate the amorphous texture. No long-range frameworks could be due to distortion and interpenetration of the phenyl rings. SEM images showed that Ge-PAF-1 and Ge-PAF-2 afforded a spherical morphology. Simultaneously, TEM revealed that both of Ge-PAFs possess a worm-like texture. The thermal stability of Ge-PAF-1 and Ge-PAF-2 was analyzed by TG analysis under air. These materials were stable up to 420 °C in air corresponding to 5% weight loss, which suggest that the Ge-PAFs exhibit high thermal stability. Moreover, Ge-PAF-1 and Ge-PAF-2 also show high chemical stability. It is also insoluble in common organic solvents such as methanol, ethanol, acetone, THF, CHCl3 and DMF. The N2 sorption isotherms were measured at 77 K to characterize the porosity of the Ge-PAFs networks. All networks give rise to type I nitrogen gas sorption isotherms with a distinct hysteresis for the whole range of relative pressure. This result confirms the mesoporous nature in networks which was also observed by previous reports, especially for non-ordered porous polymers. It is attributed to elastic deformations during the course of N2 sorption; that is, the network is swelling. This is in accordance with the low surface areas of Ge-PAFs. When the Brunauer-Emmett-Teller (BET) model of the adsorption is adopted, the apparent surface areas of Ge-PAF-1 and Ge-PAF-2 are 49 and 65 m•g respectively, which are lower when compared to other reported POFs. The pore size distribution calculated from non-local density functional theory (NL-DFT), indicated that the Ge-PAFs have a widespread pore size distribution between 0.5 and 5 nm, which also confirms the existence of mesopores in networks. What’s more, the introduction of germanium in Ge-PAFs might provide possibilities for applications in organic semiconductors.

Binding of mucin to water-soluble and surface-grafted boronate-containing polymers

The binding of mucin to water-soluble copolymers of N,N-dimethylacrylamide and N-acryloyl-m-aminophenylboronic acid grafted on the surface of glass is studied. Atomic force microscopy studies show that many graft copolymer islands 20-200 nm in diameter and 50 nm in height occur on the modified surface of flat glass. Owing to the presence of phenyl boronate groups, the copolymer behaves as a weak polyelectrolyte (pK(a) = 9.0) and, in the grafted state in an aqueous solution, experiences reversible transitions between states with higher and lower degrees of ionization. As evidenced by spectral correlation interferometry, this phenomenon brings about a change in the thickness of the grafted layer by approximately 0.5 nm. The ability of phenyl boronate groups to form cyclic esters with diol and polyol groups results in complexation of the soluble copolymer with mucin oligosaccharides and entails the appearance of slowly growing submicron particles formed by similarly charged polymers. The specificity of complexation is confirmed by dissolution of particles in the presence of fructose: a saccharide with a strong affinity for phenyl boronate groups. The binding of mucin to glass, which is chemically modified with the above copolymer, leads to formation of an adsorption layer with a thickness of 1.2-1.8 nm. Thus, boronate-containing copolymers are suitable for preparing carriers with controllable adsorption properties with respect to polyols, including mucinlike proteins of cellular glycocalyxes. (Less)

Phenylboronic Ester- and Phenylboronic Acid-Terminated Alkanethiols on Gold Surfaces

In this work, it is shown that a well-organized monolayer of phenylboronic ester-terminated thiol (BOR-capped) on gold surfaces can be prepared. Our results also show that the BOR-capped molecular system can be cleaved directly on the surface, resulting in an unprotected BOR-uncapped monolayer with the boronic acid functional groups available for coordination to diol molecules in the ambient media. The monolayers of BOR-capped and BOR-uncapped were characterized using infrared spectroscopy, near edge X-ray absorption fine structure spectroscopy, X-ray photoelectron spectroscopy, ellipsometry, and contact angle goniometry. The X-ray photoelectron spectroscopy results showed that both BOR-capped and BOR-uncapped are chemically linked to the gold substrate. According to the infrared spectroscopy results, the main component of the C═O vibrational mode present in the amide moiety is perpendicular oriented relative to the gold surface normal for the BOR-capped molecular system. The near edge X-ray absorption fi...

Iridium-Catalyzed Allylic Amination Route to α-Aminoboronates: Illustration of the Decisive Role of Boron Substituents.

The development of a new route to α-aminoboronates using an iridium-catalyzed allylic amination on boronated substrates is described. Unlike the boronate group, the trifluoroborato substituent was found to govern the regioselectivity exclusively in favor of branched products. The transformation of an allylic substitution product into an α-aminoboronic ester in an efficient way validated the implementation of this approach.

Boron‐ and Silicon‐Substituted [3]‐1‐Heterodendralenes as Versatile Building Blocks for the Rapid Construction of Polycyclic Architectures

B and Si, additional assets: Skeletally diverse polycyclic compounds with up to six stereocenters were assembled with excellent stereoselectivity from simple 2-vinyl α,β-unsaturated aldehydes possessing a trimethylsilyl or a boronate group at position 3 (see scheme). The pre-encoded skeletal information was ensured by the initial choice of the positions of the heteroatoms (O, Si or B).

Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks

Efficient access to chiral C(sp3) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp3) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp3-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp3) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.

Selective Sulfoxidation of Thioethers and Thioaryl Boranes with Nitrate, Promoted by a Molybdenum–Copper Catalytic System

The catalytic reduction of nitrate by molybdo-enzymes plays a central role in the global biological cycle of nitrogen. However, the use of nitrates as oxidants in synthetic organic chemistry is very limited and typically requires very strong acidic and other extreme reaction conditions. We have developed a highly chemoselective and efficient catalytic process for the sulfoxidation of thioethers and arylthioethers containing boronic acid or boronic ester functional groups, using nitrate salts as oxidants. This homogeneous catalytic reaction was carried out in acetonitrile, where the MoO(2)Cl(2)(OPPh(3))(2) complex 1 or a mixture of complex 1 with Cu(NO(3))(2) were used as catalysts. We examined the reaction mechanism using (1)H, (15)N, and (31)P NMR techniques and (18)O-labeled sodium nitrate (NaN(18)O(3)) and show that the thioethers are oxidized by nitrate, generating nitrite. Our work adds to the existing chemical transformations available for organoboron compounds, providing straightforward accessibility to a variety of new substrates that could be suitable for Suzuki cross-coupling chemistry.

Hydrogen Bond Ring Patterns of the Hydrated Molecular Salt of 4-Carboxybenzeneboronate with Cyclopentylammonium

The title molecular salt (cyclopentylammonium)·(4-carboxybenzeneboronate)·(H2O)3 was prepared by solution crystallization from 4-carboxybenzeneboronic acid and cyclopentylamine in a 1:1 stoichiometric ratio. The crystal belongs to the monoclinic space group Cc with a = 16.9273(5), b = 10.3387(3), c = 9.7475(3) A and β = 107.014(2)°. X-ray single crystal structure analysis reveals that a molecular salt formed, with H transfer from the carboxylic acid group of the starting 4-carboxybenzeneboronic acid to the amine cyclopentylamine. The boronic acid functional group hydrogen bonds to the carboxylate anion, while the ammonium cation on the cyclopentyl ring hydrogen bonds to two water molecules and the carboxylate anion. A total of 11 hydrogen bonds are formed, resulting in a 2-D network made up of five unique hydrogen bonded rings to ultimately produce an extended 3-D hydrogen bonded architecture. The title molecular salt is compared to related salts having the boronic acid functional group. The crystal structure of the molecular salt (cyclopentylammonium)·(4-carboxybenzeneboronate)·(H2O)3 (1) was determined and features five different hydrogen bonded rings to form a 3-D hydrogen bonded architecture. The boronic acid/carboxylate $$ \mathop R\nolimits_{2}^{2} (8) $$ dimer observed in 1 is compared to related structures in the Cambridge Structural Database.

Porous graphene oxide frameworks: Synthesis and gas sorption properties

We report detailed synthesis of a range of porous graphene oxide frameworks (GOFs) by expansion of graphene oxide (GO) sheets with various linear boronic acid pillaring units in a solvothermal reaction. The GOF structures develop through boronate-ester formation as a result of B–O bonding between boronic acids and oxygen functional groups on the GO layers. Synthesized GOFs exhibit periodic layered structures with largely expanded interlayer spacing as characterized by X-ray powder diffraction (XRD). The boronate-ester link formation is further evidenced by Fourier transform infrared (FTIR) and Raman spectroscopy. Furthermore, the strong boronate-ester bonds between GO layers results in improved thermal stability over the precursor GO. The solvent-free, evacuated frameworks provide highly increased accessible surface area for nitrogen adsorption compared to GO alone, which depends on the type and length of the boronic acid, indicating the importance of pillaring unit. Both isosteric heat of adsorption (Qst) and the adsorbed hydrogen capacity per surface area are twice as large as typical porous carbon materials and comparable to metal–organic frameworks (MOFs) with open metal centers. This enhanced Qst and adsorption capacity is attributed to optimum interlayer spacing between graphene planes such that hydrogen molecules interact with both surfaces. Finally, our systematic study reveals the profound effect of both synthesis and activation temperatures to obtain porous framework structures.

Colorimetric sensing of polyhydroxy compounds by an inclusion complex of boronic acid-modified amylose

A novel sensing method for polyhydroxy compounds has been established based on the stimuli-responsive inclusion complex of boronic acid-modified amylose with iodine. An aqueous solution containing the boronic acid-modified amylose and iodine was coloured bluish purple due to encapsulation of iodine within the helical cavity of amylose. When polyhydroxy compounds were added, the solution gradually lost its colour with increasing concentration of polyhydroxy compounds. This colour change was attributed to the dissociation of iodine from the amylose cavity in response to the polyhydroxy compounds. According to detailed examinations, it was concluded that the origin of the responsiveness is derived from an electrostatic repulsion between anionic boronate groups and iodine.

Synthesis and properties of MIDA boronate containing aromatic amino acids: New peptide building blocks

Herein, we report the synthesis of novel phenylalanine and tyrosine derivatives containing a N-methyliminodiacetic acid boronate group. These compounds can be prepared enantiomerically pure, they are stable to column chromatography and they can be stored in air for two months without degradation occurring. This new class of boronate containing aromatic amino acids has potential applications in both peptide chemistry and natural product synthesis.

Controlling Deposition and Release of Polyol-Stabilized Latex on Boronic Acid-Derivatized Cellulose

Poly(glycerol monomethacrylate)-stabilized polystyrene (PGMA-PS) latex particles undergo specific, pH-dependent adsorption onto regenerated cellulose film bearing surface phenylboronic acid groups (cellulose-PBA). Deposition occurs at pH 10 and is driven by the boronate ester formation with the polyol latex surface coating. In contrast, no deposition occurs at pH 4, and previously deposited particles can be readily desorbed at this lower pH. In control experiments, conventional anionic sulfate-stabilized polystyrene latex did not deposit onto the hydrophilic cellulose surface. The distribution of boronate groups in the cellulose was determined by exposure to Alizarin Red S dye, which forms a fluorescent complex with phenylboronic acid; confocal microscopy was used to determine a surface density of 3 nm(2) per boronic acid group on the cellulose surface. Although the boronic acid binding constant with PGMA is relatively low (5.4 L/mol), the cooperative interactions between multiple PBA surface sites and the many PGMA chains per latex particle are sufficient to induce specific latex adsorption, providing a convenient new tool for controlling nanoparticle deposition on surfaces.

5 × 5 CMOS capacitive sensor array for detection of the neurotransmitter dopamine

This work presents miniaturized CMOS (complementary metal oxide semiconductor) capacitive sensors for detection of the neurotransmitter dopamine (DA) down to the sub-fM range. Sensing resolution is significantly enhanced by monolithic sensor integration to reduce the parasitic effect and the use of sub-μm interdigitated microelectrodes as the sensing interface. The 5 × 5 sensor array contains five designs of different electrode sizes and each design has five sensors. The positive charges produced from protonation of boronate and amino group after immobilization of 4-carboxyphenylboronic acid (CPBA) result in an increase of the electrode-analyte capacitance. Then the negative charges produced after binding of CPBA and DA molecules decrease the electrode-analyte capacitance. Signal transduction is achieved through a CMOS readout circuit whose output frequency is inversely proportional to the capacitance. Experimental results showed the ratios of average percentage capacitance changes of the experiment groups over those of the control groups were all larger than one for the five designs at DA concentration of 0.1 fM. Selectivity against the non-analyte species, such as tyramine, has also been demonstrated.

Methods for detection and measurement of hydrogen peroxide inside and outside of cells.

Hydrogen peroxide (H(2)O(2)) is an incompletely reduced metabolite of oxygen that has a diverse array of physiological and pathological effects within living cells depending on the extent, timing, and location of its production. Characterization of the cellular functions of H(2)O(2) requires measurement of its concentration selectively in the presence of other oxygen metabolites and with spatial and temporal fidelity in live cells. For the measurement of H(2)O(2) in biological fluids, several sensitive methods based on horseradish peroxidase and artificial substrates (such as Amplex Red and 3,5,3'5'-tetramethylbenzidine) or on ferrous oxidation in the presence of xylenol orange (FOX) have been developed. For measurement of intracellular H(2)O(2), methods based on dihydro compounds such as 2',7'-dichlorodihydrofluorescein that fluoresce on oxidation are used widely because of their sensitivity and simplicity. However, such probes react with a variety of cellular oxidants including nitric oxide, peroxynitrite, and hypochloride in addition to H(2)O(2). Deprotection reaction-based probes (PG1 and PC1) that fluoresce on H(2)O(2)-specific removal of a boronate group rather than on nonspecific oxidation have recently been developed for selective measurement of H(2)O(2) in cells. Furthermore, a new class of organelle-targetable fluorescent probes has been devised by joining PG1 to a substrate of SNAP-tag. Given that SNAP-tag can be genetically targeted to various subcellular organelles, localized accumulation of H(2)O(2) can be monitored with the use of SNAP-tag bioconjugation chemistry. However, given that both dihydro- and deprotection-based probes react irreversibly with H(2)O(2), they cannot be used to monitor transient changes in H(2)O(2) concentration. This drawback has been overcome with the development of redox-sensitive green fluorescent protein (roGFP) probes, which are prepared by the introduction of two redox-sensitive cysteine residues into green fluorescent protein; the oxidation of these residues to form a disulfide results in a conformational change of the protein and altered fluorogenic properties. Such genetically encoded probes react reversibly with H(2)O(2) and can be targeted to various compartments of the cell, but they are not selective for H(2)O(2) because disulfide formation in roGFP is promoted by various cellular oxidants. A new type of H(2)O(2)-selective, genetically encoded, and reversible fluorescent probe, named HyPer, was recently prepared by insertion of a circularly permuted yellow fluorescent protein (cpYFP) into the bacterial peroxide sensor protein OxyR.