Boronic Acid Research Articles

Phenylboronic Acid-Functionalized Micelles Dual-Targeting Boronic Acid Transporter and Polysaccharides for siRNA Delivery into Brown Algae.

Brown algae play essential roles ecologically, practically, and evolutionarily because they maintain coastal areas, capture carbon dioxide, and produce valuable chemicals such as therapeutic drugs. To unlock their full potential, understanding the unique molecular biology of brown algae is imperative. Genetic engineering tools that regulate homeostasis in brown algae are essential for determining their biological mechanisms in detail. However, few methodologies have been developed to control gene expression due to the robust structural barriers of brown algae. To address this issue, we designed peptide-based, small interfering RNA (siRNA)-loaded micelles decorated with phenylboronic acid (PBA) ligands. The PBA ligands facilitated the cellular uptake of the micelles into a model brown alga, Ectocarpus siliculosus (E. Siliculosus), through chemical interaction with polysaccharides in the cell wall and biological recognition by boronic acid transporters on the plasma membrane. The micelles, featuring "kill two birds with one stone" ligands, effectively induced gene silencing related to auxin biosynthesis. As a result, the growth of E. siliculosus was temporarily inhibited without persistent genome editing. This study demonstrated the potential for exploring the characteristics of brown algae through a simple yet effective approach and presented a feasible system for delivering siRNA in brown algae.

Evaluation of hemilabile Pd(II) NNS and NNSe non-symmetric pincers in Suzuki–Miyaura cross-coupling: Unexpected selective nitrile hydration of 4-bromonitrobenzene in mild conditions

In this work, four non-symmetric NNS and NNSe Pd(II) pincer complexes (1–4) supported by tridentate iminophosphorane ligands bearing both the indole heterocycle and a varying chalcogenoether pending arm [XR = SPh (1), SePh (2), SMe (3), SeMe (4)], were tested in the Suzuki–Miyaura cross coupling reaction between phenyl boronic acid and aryl bromides. The modest catalytic activity of complex 3 under conventional heating (110 °C), was boosted under microwave irradiation, leading to excellent yields of coupling under remarkably mild conditions: 5 min of reaction time at 70 °C under aerobic conditions. The complexes supported by NNS ligands proved to be more robust and superior catalysts than those supported by NNSe ligands, which tended to decompose under catalytic conditions. Among the four complexes, pincer 3 also demonstrated the best catalytic performance and was tested in the coupling of a variety of p-substituted bromobenzenes. Notably, the catalytic performance of complex 3 was unaffected by the mercury drop test, and with most substrates in the series, the percentage of conversion reflected the aryl bromides’ Hammett parameter. However, little to no coupling occurred with p-bromobenzonitrile and the reaction with p-nitrobenzene resulted in only limited conversion yields. In fact, when activated using microwave irradiation, complex 3 unexpectedly catalyzed the nitrile hydration of p-bromobenzonitrile, yielding p-bromobenzamide under remarkably mild Suzuki–Miyaura coupling conditions.

Late-stage guanine C8–H alkylation of nucleosides, nucleotides, and oligonucleotides via photo-mediated Minisci reaction

Chemically modified nucleosi(ti)des and functional oligonucleotides (ONs, including therapeutic oligonucleotides, aptamer, nuclease, etc.) have been identified playing an essential role in the areas of medicinal chemistry, chemical biology, biotechnology, and nanotechnology. Introduction of functional groups into the nucleobases of ONs mostly relies on the laborious de novo chemical synthesis. Due to the importance of nucleosides modification and aforementioned limitations of functionalizing ONs, herein, we describe a highly efficient site-selective alkylation at the C8-position of guanines in guanosine (together with its analogues), GMP, GDP, and GTP, as well as late-stage functionalization of dinucleotides and single-strand ONs (including ssDNA and RNA) through photo-mediated Minisci reaction. Addition of catechol to assist the formation of alkyl radicals via in situ generated boronic acid catechol ester derivatives (BACED) markedly enhances the yields especially for the reaction of less stable primary alkyl radicals, and is the key to success for the post-synthetic alkylation of ONs. This method features excellent chemoselectivity, no necessity for pre-protection, wide range of substrate scope, various free radical precursors, and little strand lesion. Downstream applications in disease treatment and diagnosis, or as biochemical probes to study biological processes after linking with suitable fluorescent compounds are expected.

Synthesis of Bone Meal-derived 4-Carboxyphenylboronic Acid Functionalized Sulfur and Nitrogen Co-doped Graphene Quantum Dots Nanoprobe for Sialic Acid Sensing

Detection of sialic acid using advanced sensors in milk-based products is essential in the food industry. Therefore, the present work reports the sulfur and nitrogen-doped graphene quantum dots from bone meal functionalized with boronic acid (Boro-S/N-dGQDs) nanoprobe for sialic acid sensing applications. Briefly, S/N-dGQDs were functionalized with 4-carboxyphenylboronic acid to improve performance of fluorescent sensors toward the detection of sialic acid. Here, boronic acid surface decoration on S/N-dGQD was confirmed by several spectral characterizations. The addition of different quantities of sialic acid results in a directly proportionate correlation to fluorescence quenching. It gives a broad linear range of 50 ng/mL to 1000 ng/mL and a limit of detection of 6.04 ng/mL. Also, it displayed remarkable selectivity, likely due to interaction of sialic acid-containing 1,2-diol with hydroxyl group of Boro-S/N-dGQDs nanoprobe. Designed sensor demonstrated good stability and reproducibility. Real-time analysis of sialic acid in different milk-based products confirmed practicability of Boro-S/N-dGQDs.

Catalytic and Base-free Suzuki-type α-Arylation of Cyclic 1,3-Dicarbonyls via a Cyclic Iodonium Ylide Strategy.

To date, it remains challenging to achieve a general and catalytic α-arylation of cyclic 1,3-dicarbonyls, particularly ubiquitous heteroaromatic ones. In most cases, the preparation of their medically significant arylated derivatives requires multistep synthetic sequences. Herein, we introduce a new, convenient strategy involving the conversion of cyclic 1,3-dicarbonyls to cyclic iodonium ylides (CIYs), followed by rhodium-catalyzed α-arylation with arylboronic reagents via carbene coupling. This approach is mild, operationally simple, base-free, biocompatible, and exhibits broad substrate scope (>100 examples), especially with respect to various heteroaromatic 1,3-dicarbonyls and ortho-substituted or base-sensitive arylboronic acids. Importantly, owing to the excellent compatibility with various arylboronic acids or boronate esters (ArBpin, ArBneop, or ArBF3K), this method allows the late-stage installation of heterocyclic 1,3-dicarbonyl motifs in highly complex settings. The utility of this transformation is further demonstrated through significantly simplifying the synthesis of several bioactive molecules and natural products.

Catalytic and Base‐free Suzuki‐type α‐Arylation of Cyclic 1,3‐Dicarbonyls via a Cyclic Iodonium Ylide Strategy

AbstractTo date, it remains challenging to achieve a general and catalytic α‐arylation of cyclic 1,3‐dicarbonyls, particularly ubiquitous heteroaromatic ones. In most cases, the preparation of their medically significant arylated derivatives requires multistep synthetic sequences. Herein, we introduce a new, convenient strategy involving the conversion of cyclic 1,3‐dicarbonyls to cyclic iodonium ylides (CIYs), followed by rhodium‐catalyzed α‐arylation with arylboronic reagents via carbene coupling. This approach is mild, operationally simple, base‐free, biocompatible, and exhibits broad substrate scope (>100 examples), especially with respect to various heteroaromatic 1,3‐dicarbonyls and ortho‐substituted or base‐sensitive arylboronic acids. Importantly, owing to the excellent compatibility with various arylboronic acids or boronate esters (ArBpin, ArBneop, or ArBF3K), this method allows the late‐stage installation of heterocyclic 1,3‐dicarbonyl motifs in highly complex settings. The utility of this transformation is further demonstrated through significantly simplifying the synthesis of several bioactive molecules and natural products.

Evolution of the Manufacturing Route towards a Key Benzothiophen‐2‐yl‐Boronic Acid Building Block of Rogaratinib

AbstractThe evolution of the synthesis of a benzothiophene‐2‐yl‐boronic acid ‐ a key building block for the anti‐cancer agent Rogaratinib ‐ is reported from multi‐gram scale to industrialization. The pitfalls and learnings during process development are outlined, describing the optimization of the initial research synthesis route, investigation of an alternative approach based on a palladium‐catalyzed Newman‐Kwart rearrangement and finally changing the synthetic strategy from thiophene‐construction to benzene‐ring formation. Although the initial route was utilized to deliver material on kg‐scale, the requirements for market‐supply triggered the decision to pursue a new synthetic route. Catalyst costs, high purity‐requirements, and not the least technical practicality caused the change to a synthesis with indeed higher step‐count. However, this could be mitigated by repeated application of a telescoping approach. The free boronic acid was finally selected and manufactured as a stable isolated intermediate after challenges like proto‐deboronation and trimerization to boroxine upon drying could be solved by an optimized crystallization procedure.

Ratiometric fluorescence detection of dopamine based on copper nanoclusters and carbon dots

Nanoclusters for fluorescence detection are generally comprised of rare and expensive noble metals, and the nanoclusters based on more affordable transition metal have attracted increasing attention. This study designed a ratiometric fluorescent probe to detect dopamine (DA), an important neurotransmitter. With carbon dots encapsulated within silica (CDs@SiO2) as the reference, the emitted reference signal was almost unchanged due to the protection of inert silicon shell. Meanwhile, copper nanoclusters modified with 3-aminophenyl boronic acid (APBA-GSH-CuNCs) provided the sensing signal, in which the phenylboric acid could specifically recognize the cis-diol structure of DA, and caused the fluorescence quenching by photoinduced electron transfer. This dual emission ratiometric fluorescent probe exhibited high sensitivity and anti-interference, and was able to selectively responded to DA with a linear range of 0–1.4 mM, the detection limit of 5.6 nM, and the sensitivity of 815 mM−1. Furthermore, the probe successfully detected DA in human serum samples, yielding recoveries ranging from 92.5% to 102.7%. Overall, this study highlights the promising potential of this ratiometric probe for detecting DA.

Selective Anticervical Cancer Injectable and Self-Healable Hydrogel Platforms Constructed of Drug-Loaded Cross-Linkable Unimolecular Micelles in a Single and Combination Therapy.

In the face of severe side effects of systemic chemotherapy used in cervical cancer, topical selective drug carriers with long-lasting effects are being sought. Hydrogels are suitable platforms, but their use is problematic in the case of delivery of hydrophobic drugs with anticancer activity. Herein, hydrogels constructed of unimolecular micelles displaying enhanced solubilization of aromatic lipophilic bioactive compounds are presented. Star-shaped poly(benzyl glycidyl ether)-block-poly(glycidyl glycerol ether) with an aryl-enriched core show high encapsulation capacity of poor water-soluble nifuratel and clotrimazole. Nifuratel attained selectivity against cervical cancer cells, whereas clotrimazole preserved its original selectivity. The combination of unimolecular micelles loaded with both drugs provided synergism; however, they were still selective against cervical cancer cells. The cross-linking of drug-loaded unimolecular micelles via dynamic boronic esters provided injectable and self-healable hydrogel drug carriers also displaying synergistic anticancer activity, suitable for intravaginal administration and assuring the effective coverage of the afflicted tissue area and efficient tissue permeability with hydrophobic bioactive compounds. Here, we show that the combination of star-shaped polyether amphiphiles and boronic ester cross-linking chemistry provides a new strategy for obtaining hydrogel platforms suitable for efficient hydrophobic drug delivery.

Fast-relaxing hydrogels with reversibly tunable mechanics for dynamic cancer cell culture

The mechanics of the tumor microenvironment (TME) significantly impact disease progression and the efficacy of anti-cancer therapeutics. While it is recognized that advanced in vitro cancer models will benefit cancer research, none of the current engineered extracellular matrices (ECM) adequately recapitulate the highly dynamic TME. Through integrating reversible boronate-ester bonding and dithiolane ring-opening polymerization, we fabricated synthetic polymer hydrogels with tumor-mimetic fast relaxation and reversibly tunable elastic moduli. Importantly, the crosslinking and dynamic stiffening of matrix mechanics were achieved in the absence of a photoinitiator, often the source of cytotoxicity. Central to this strategy was Poly(PEGA-co-LAA-co-AAPBA) (PELA), a highly defined polymer synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. PELA contains dithiolane for initiator-free gel crosslinking, stiffening, and softening, as well as boronic acid for complexation with diol-containing polymers to give rise to tunable viscoelasticity. PELA hydrogels were highly cytocompatible for dynamic culture of patient-derived pancreatic cancer cells. It was found that the fast-relaxing matrix induced mesenchymal phenotype of cancer cells, and dynamic matrix stiffening restricted tumor spheroid growth. Moreover, this new dynamic viscoelastic hydrogel system permitted sequential stiffening and softening to mimic the physical changes of TME.

Rapid, Homogenous, B-Alkyl Suzuki-Miyaura Cross-Coupling of Boronic Esters.

A rapid, anhydrous Suzuki-Miyaura cross-coupling of alkylboronic esters with aryl halides is described. Parallel experimentation revealed that the combination of AntPhos, an oxaphosphole ligand, neopentyldiol alkylboronic esters, and potassium trimethylsilanolate (TMSOK) enables successful cross-coupling. In general, reactions proceed in under 1 h with good yields and high linear/branched (l/b) selectivities. Crucially, two literature examples which previously took >20 h to reach completion were accomplished in a fraction of the time with the method described herein. Mechanistic studies revealed that the reaction proceeds through a stereoretentive pathway and identified the boronic ester skeleton as a predominant pathway for deleterious protodehalogenation.

Three-Dimensional Homochiral Covalent Organic Frameworks with Intrinsic Chiral qzd Topology.

Although a variety of chiral porous framework materials have been reported, there are few examples known to combine molecular chirality, helicity, and three-dimensional (3D) intrinsically chiral topology in one structure, which is beneficial for chirality transfer and amplification. Here, we report the synthesis of the first two 3D covalent organic frameworks (COFs) with an intrinsic chiral qzd topology, which exhibit unusual integration of various homochiral and homohelical features. By imine condensation of 4-connected porphyrin tetraamines and 2-connected enantiopure diene dialdehyde, we prepared two isostructural COFs with a noninterpenetrated qzd topology. The specific geometry and conformation flexibility of the V-shaped diene linker control the alignment of square-planar porphyrin units with rotational linkages and facilitate the creation of homochiral extended porous structures that feature a helical arrangement of porphyrins. Post-synthetic metalation of CCOF 23 with Rh(I) affords a heterogeneous catalyst for the asymmetric Michael addition reaction of aryl boronic acids to 2-cyclohexenone, which shows higher enantioselectivities compared to their homogeneous counterparts, presumably due to the confined effect of helical channels. This finding will provide an impetus to explore multichirality materials, offering new insights into the generation and control of helicity, homochirality, and enantioselectivity in the solid state.

Detailed Reaction Mechanism of Anthracene‐Bridged bis‐(3‐Pyridiniumboronic Acid) Chemosensor with D‐Glucose

AbstractDetailed reaction mechanisms of 4‐(N‐methyl)pyridinium boronic acid (1) and anthracene‐bridged bis(pyridinium boronic acid) compounds (diboronic acids 2 and 3) with D‐glucose were kinetically investigated in aqueous methanolic solutions. The crystal structure of diboronic acid 3 was determined using X‐ray crystallography. The pKa values of the two boronic acid moieties of diboronic acid (2 or 3) differed by one unit, indicating electronic interactions between the two boronic acid moieties. The kinetics of the reaction of boronic acid 1 with D‐glucose showed that both trigonal boronic acid and tetrahedral boronate ions were reactive with D‐glucose. UV‐Vis spectrophotometry and 1H NMR spectrometry of the reactions of phenylboronic acid with some model compounds of D‐glucose showed that the reactive moiety of α‐D‐glucofuranose towards phenylboronic acid was not the 1,2‐diol site, but the 3,5,6‐triol site. In the reactions of diboronic acids 2 and 3 with D‐glucose, the 3,5,6‐triol site of α‐D‐glucofuranose reacts first with one of the two equivalent boronic acid moieties of diboronic acid to form a 3,5‐bicoordinate intermediate as a rate‐determining step, followed by the reaction of the 1,2‐diol site of α‐D‐glucofuranose with another boronic acid moiety of diboronic acid to form the final 1,2 : 3,5‐tetracoordinate cyclic compound as a fast step.

Photoinduced Decarboxylative Borylation of N-Hydroxyphthalimide Esters with Hypoboric Acid.

We developed a visible-light-driven photochemical transformation in which activated primary, secondary, and tertiary alkylcarboxylic acids were converted into the corresponding boronic esters in the absence of catechol and any added photocatalyst. The procedure relies on the utilization of hypoboric acid and redox-active esters of alkylcarboxylic acids to ensure a simple and economic procedure. Quantum chemical calculations and mechanistic considerations provide deeper insights into the mechanism of photochemical borylation reactions.

Iminoboronate-based chiral dynamic covalent polymer for selective and sensitive fluoride recognition

The construction of chiral polymers using dynamic covalent chemistry is a convenient and straightforward strategy for obtaining functional materials. In this paper, we report the dynamic covalent polymers DCP1, DCP2, and DCP3 with dual dynamic covalent bonds of imine and boronic ester, and their recognition of fluoride ions. The three polymers are prepared from L-DOPA hexyl ester and 2-, 3-, and 4-formylphenylboronic acids, respectively. Iminoboronate, formed within repeated DCP1 units, results in the formation of a spirochiral structure centered at sp3-B and, consequently, the chiral twist or helix conformation of the polymer backbone. DCP1 exhibits distinctive chiroptical features that distinguish it from DCP2 and DCP3. Due to the strong competitive bonding of fluoride with boron, DCP1 has a low LOD (Limit of detection) for fluoride (0.018 mg/L). DCP1 also has good selectivity for fluoride via the responsive destruction of the spirochiral structure and the chiral conformation of the backbone. The construction of these chiral dynamic polymers provides a rapid and effective approach to designing functional polymers.

Concave P-Stereogenic Phosphorodiamidite Ligands for Enantioselective Rh(I) Catalysis.

The development of a new class of concave P-stereogenic phosphorodiamidite ligands, derived from Tröger's bases (TBs), is explored. These ligands, characterized by their remarkable stability and unique structural geometry around the P atom, are used in asymmetric Rh(I)-catalyzed additions of boronic acids to NH-isatins resulting in excellent reactivities and reasonable enantioselectivity (er up to 92:8).

Rhodium(I)-Catalyzed Defluorinative Bisarylation of Monofluorodienes with Boronic Acids.

We herein describe a Rh(I)-catalyzed bisarylation reaction of monofluorodienes using arylboronic acids. Two aryl groups are installed in the trisubstituted (E)-alkene products in one step with excellent diastereoselectivities. An intriguing reaction sequence of Rh(I)-catalyzed 1,6-addition followed by defluorinative coupling is proposed for product formation.

Inhibition of atomic layer deposition of TiO2 by functionalizing silicon surface with 4-fluorophenylboronic acid

As the size of the components in electronic devices decreases, new approaches and chemical modification schemes are needed to produce nanometer-size features with bottom-up manufacturing. Organic monolayers can be used as effective resists to block the growth of materials on non-growth substrates in area-selective deposition methods. However, choosing the appropriate surface modification requires knowledge of the corresponding chemistry and also a detailed investigation of the behavior of the functionalized surface in realistic deposition schemes. This study aims to investigate the chemistry of boronic acids that can be used to prepare such non-growth areas on elemental semiconductors. 4-Fluorophenylboronic acid is used as a model to investigate the possibility to utilize the Si(100) surface functionalized with this compound as a non-growth substrate in a titanium dioxide (TiO2) deposition scheme based on sequential doses of tetrakis(dimethylamido)titanium and water. A combination of X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry allows for a better understanding of the process. The resulting surface is shown to be an effective non-growth area to TiO2 deposition when compared to currently used H-terminated silicon surfaces but to exhibit much higher stability in ambient conditions.

Ultrafast underwater self-healing piezo-ionic elastomer via dynamic hydrophobic-hydrolytic domains

The development of advanced materials capable of autonomous self-healing and mechanical stimulus sensing in aquatic environments holds great promise for applications in underwater soft electronics, underwater robotics, and water-resistant human-machine interfaces. However, achieving superior autonomous self-healing properties and effective sensing simultaneously in an aquatic environment is rarely feasible. Here, we present an ultrafast underwater molecularly engineered self-healing piezo-ionic elastomer inspired by the cephalopod’s suckers, which possess self-healing properties and mechanosensitive ion channels. Through strategic engineering of hydrophobic C–F groups, hydrolytic boronate ester bonds, and ions, the material achieves outstanding self-healing efficiencies, with speeds of 94.5% (9.1 µm/min) in air and 89.6% (13.3 µm/min) underwater, coupled with remarkable pressure sensitivity (18.1 kPa–1) for sensing performance. Furthermore, integration of this mechanosensitive device into an underwater submarine for signal transmission and light emitting diode modulation demonstrates its potential for underwater robotics and smarter human-machine interactions.

Dynamically bonded cellulose nanocrystal hydrogels: Structure, rheology and fire prevention performance

Flame retardant composite hydrogels offer many advantages over conventional flame retardants, such as high water-retention capacity, enhanced fire resistance, and mechanical tunability. Herein, we developed flame-retardant dynamic covalent hydrogels using wood-derived cellulose nanocrystals (CNCs) crosslinked with boronate ester bonds, addressing environmental and health issues associated with the presence of non-biodegradable synthetic polymer and/or inorganic nanoparticle components in the existing systems. Our rheological investigation shows a liquid-to-soft-solid transition of CNC dispersions with tunable network elasticity ranging between ≈ 0.2 kPa to 3.5 kPa and an immediate self-healing ability. Coating pine wood with these hydrogels delayed ignition by about 30 s compared to native wood, and achieved a remarkable limiting oxygen index of 64.5 %. Also, the increased borax content of the gels was found to decrease and delay the first peak of the heat release rate up to 40 s, causing an increase in the fire retardancy index by 277 %. We correlate the microstructure and rheological behavior with the fire prevention mechanisms for the rational design of sustainable fire-retardant materials, and the results showcased a circular use of plant-based dynamic gels to prevent wood fires, even after drying- a feature lacking in conventional hydrogels.