Boronic Acid Research Articles

Assessment of the Recovery of Erythritol Using Boronic Acid Polymers

Assessment of the Recovery of Erythritol Using Boronic Acid Polymers

Rapid and General Amination of Aryl Boronic Acids and Esters Using O-(Diphenylphosphinyl)hydroxylamine (DPPH).

O-(Diphenylphosphinyl)hydroxylamine (DPPH) is a general reagent for the conversion of (hetero)aryl boronic acids and esters to primary anilines. The transformation proceeds rapidly at rt and exhibits a broad substrate scope and exceptional functional-group tolerance. In terms of rate, the reaction is relatively insensitive to the electronic properties of the substrate, in contrast to similar reactions using electrophilic amination reagents such as hydroxylamine-O-sulfonic acid. Consequently, this protocol is particularly useful for accessing electron-deficient (hetero)aryl anilines, which had been challenging to prepare using prior methods.

Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.

Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (1). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2. We subsequently used structure-based drug design to further improve the potency of this series, ultimately achieving an inhibitor with an IC50 value of 12 nM. Many compounds in this series were designed to behave as prodrugs, releasing their payload with up to 4-fold improved oral exposure relative to the parent. Subtle stereochemical differences between these various inhibitors and prodrugs had substantial effects on potency and pharmacokinetics.

Nanotherapeutics-mediated restoration of pancreatic homeostasis and intestinal barrier for the treatment of severe acute pancreatitis.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas accompanied with intestinal injury, and effective therapeutic modalities are still highly lacking. Herein, a facile and effective nanotherapeutics (pHA@IBNCs) is developed to alleviate pancreatic inflammation and restore intestinal barrier for SAP treatment. Epigallocatechin gallate (EGCG, an anti-oxidant), interleukin-22 (IL-22, an anti-inflammatory and epithelial barrier-protecting cytokine), and bovine serum albumin (a framework protein), are assembled via non-covalent interactions to form nanocomplexes (IBNCs). Then, phenylboronic acid-modified hyaluronic acid (pHA) is synthesized and coated onto IBNCs via formation of the reversible boronate ester bonds to obtain pHA@IBNCs. Upon intravenous injection, pHA@IBNCs could efficiently accumulate at the lesion sites of sodium taurocholate (STC)-induced SAP mice, based on their prolonged blood circulation time and pHA-mediated targeting of activated intestinal epithelial cells and macrophages. Inside the inflammatory microenvironment, over-produced reactive oxygen species (ROS) trigger the shedding of the pHA layer and release of the drug payloads. Thereby, EGCG cooperates with IL-22 to attenuate pancreatitis and restore the intestinal barrier by scavenging ROS, suppressing pro-inflammatory cytokines secretion, and promoting the repair of intestinal epithelia. Such a nano-therapeutic approach targeting multiple pathological events may serve as a promising paradigm for the effective management of SAP.

Cu-Catalyzed Asymmetric Three-Component Radical Acylarylation of Vinylarenes with Aldehydes and Aryl Boronic Acids.

The direct use of readily available aldehydes as acyl radical precursors has facilitated diverse three-component acylative difunctionalization reactions of alkenes, offering a powerful route to synthesize β-branched ketones. However, asymmetric three-component acylative difunctionalization of alkenes with aldehydes still remains elusive. Here we report a copper-catalyzed asymmetric three-component radical acylarylation of vinylarenes with aldehydes and aryl boronic acids. This method begins with acyl radical formation from an aldehyde via hydrogen atom transfer. The acyl radical adds to the alkene, forming a new benzylic radical that then undergoes copper-catalyzed enantioselective arylation. A chiral binaphthyl-tethered bisoxazoline ligand is essential for achieving high stereocontrol. This strategy enables the direct synthesis of a range of synthetically valuable chiral β,β-diaryl ketones from aldehydes and vinylarenes.

A Covalent Organic Polymer Containing Dative Nitrogen→Boron Bonds: Preparation, Single‐Crystal Structure, and Photoresponse/Photocatalytic Performance

Design and realization of covalent organic polymers (COPs) with precise structure are challenging yet interesting. Herein, light‐yellow single crystals of a novel 1D COP (named as CityU‐32) containing the dative nitrogen→boron bonds through the assembly between trigonal‐planar boronic esters (derived from catechol and benzene‐1,3,5‐triyltriboronic acid) and 2,6‐di(pyridine‐4‐yl)naphthalene are prepared. The single‐crystal X‐ray diffraction analysis shows that CityU‐32 features a novel chain‐like zigzag structure with a multichain stacking feature, where the adjacent chains are stacked together and interlocked each other with a double hydrogen bonding interaction formed from the boronic ester units. Additionally, CityU‐32 has been demonstrated to show some potential applications in the field of hydrogen peroxide (H2O2) production.

Si anodes via dual strategies of coating Si with a rigid polymer and employing a polymer binder with improved mechanical properties

Si undergoes significant volume change over cycles which degrades the structural integrity and stability of the electrode. This volume change is the primary barrier to the commercialization of Si anodes, and it is more pronounced for Si particle sizes over 150 nm. In this study, a crosslinked polymer binder is developed using poly(acrylic acid-co-acrylamide) (PAAM) with enhanced elasticity compared to the widely used poly(acrylic acid). PAAM is further grafted with boronic acid and dopamine, yielding PAAM-B-D, a binder with improved adhesion due to its 3D crosslinked network. Additionally, 350-nm Si is coated with cyclized polyacrylonitrile (cPAN) and heat-treated to form a conjugated structure. The cPAN-coated Si (cSi) exhibits enhanced conductivity and mechanical stiffness and is used as an active material. The developed Si anode effectively combines cPAN-coated Si with the crosslinked network formed in the PAAM-B-D polymer for enhanced adhesion. The cSi@PAAM-B-D electrode sufficiently maintains its structural integrity and mitigates the Si volume change even with the large-sized 350-nm Si. The cSi@PAAM-B-D exhibits a high initial Coulombic efficiency of 86.5 %, at a Si mass loading of 2 mg cm−2. It also shows a capacity retention of 83.6 % and a high areal capacity of 3 mAh cm−2 after 50 cycles.

Poly(vinyl alcohol) potentiating an inert D-amino acid-based drug for boron neutron capture therapy.

Since the discovery of D-amino acids, they have been considered inactive and have not been used as potent drugs. Here, we report that simple mixing with poly(vinyl alcohol) (PVA) unleashed latent potentials of D-amino acids in boron neutron capture therapy (BNCT). PVA formed boronate esters with seemingly useless boronated D-amino acids and induced tumor-associated amino acid transporter-superselective internalization and prolonged intracellular retention, accomplishing complete cure of tumors. The superselective internalization was achieved by switching the internalization pathway from ineffective pass through the transporter to the transporter-mediated endocytosis. The acidic environment in the endo-/lysosome dissociated the boronate esters and elicited the stealthiness of the drugs, preventing their externalization and prolonging intracellular retention time. In a subcutaneous tumor model, this system accomplished surprisingly high tumor-selective accumulation that could not be achieved by conventional approaches and induced drastic BNCT effects. PVA may be a unique material to unlock potentials of seemingly inert molecules.

Aryl Radicals Generated from Aryl Pinacol Boronates Modify Peptides and Proteins

We report here a distinct reaction, which generates aryl radicals from aryl pinacol boronates under mild aqueous conditions and can be used for peptide and protein modifications. The strategy leverages the versatile reactivity of aryl pinacol boronates to form aryl radicals in presence of ammonium persulfate (APS). The formed aryl radicals insert readily into peptide disulfide bonds while tolerating other functionalities. On the protein level, the reactivity extends beyond the disulfide bonds. The methodology benefits from the accessibility of starting aryl pinacol boronates, as well as biocompatible conditions. In contrast to conventional methods used for aryl radical generation, the strategy is metal‐free, does not require photoinduction and can be readily performed under aqueous conditions. The mechanism of the reactions was investigated by radical‐trapping experiments, spectroscopic analysis and oxygen scavenging. The presented approach broadens the application of aryl pinacol boronate esters in radical reactions.

Copper-Catalyzed Sonogashira-Type Coupling Reaction of Vinylacetylene ortho-Carborane with Boronic Acid in the Synthesis of Luminophores with Phosphorescent Emission

Copper-Catalyzed Sonogashira-Type Coupling Reaction of Vinylacetylene ortho-Carborane with Boronic Acid in the Synthesis of Luminophores with Phosphorescent Emission

Platinum‐Catalyzed Regio‐ and Enantioselective Diboration of Unactivated Alkenes with (pin)B−B(dan)

AbstractAsymmetric diboration of terminal alkenes is well established, and subsequent selective functionalization of the less hindered primary boronic ester is commonly achieved. Conversely, selective functionalization of the sterically less accessible secondary boronic ester remains challenging. An alternative way to control chemoselective functionalization of bis(boron) compounds is by engendering different Lewis acidity to the two boryl moieties, since reactivity would then be dictated by Lewis acidity instead of sterics. We report herein the regio‐ and enantioselective Pt‐catalyzed diboration of unactivated alkenes with (pin)B−B(dan). A broad range of terminal and cyclic alkenes undergo diboration to furnish the differentiable 1,2‐bis(boron) compounds with high levels of regio‐ and enantiocontrol, giving access to a wide variety of novel building blocks from a common intermediate. The reaction places the less Lewis acidic B(dan) group at the less hindered position and the resulting 1,2‐bisboryl alkanes undergo selective transformations of the B(pin) group located at the more hindered position. The regioselectivity of the diboration has been studied by DFT calculations and is believed to originate from the trans influence, which lowers the activation barrier for formation of the regioisomer that places the weaker electron donor [B(pin) vs B(dan)] opposite the strong electron donor (alkyl group) in the platinum complex.

Boosting mRNA-Engineered Monocytes via Prodrug-Like Microspheres forBone Microenvironment Multi-Phase Remodeling.

Monocytes, as progenitors of macrophages and osteoclasts, play critical roles in various stages of bone repair, necessitating phase-specific regulatory mechanisms. Here, icariin (ICA) prodrug-like microspheres (ICA@GM) are developed, as lipid nanoparticle (LNP) transfection boosters, to construct mRNA-engineered monocytes for remodeling the bone microenvironment across multiple stages, including the acute inflammatory and repair phases. Initially, ICA@GM is prepared from ICA-conjugated gelatin methacryloyl via a microfluidics system. Then, monocyte-targeting IL-4 mRNA-LNPs are then prepared and integrated into injectable microspheres (mRNA-ICA@GM) via electrostatic and hydrogen bond interactions. After bone-defect injection, LNPs are controlled released from mRNA-ICA@GM within 3 days, rapidly transfecting monocytes for monocyte IL-4 mRNA-engineering, which effectively suppressed acute inflammatory responses via polarization programming and paracrine signaling. Afterwards, ICA is sustainably released as well via cleavable boronate esters across multiple stages, cooperatively boosting the mRNA-engineered monocytes to inhibit coenocytic fusion and osteoclastic function. Both in vitro and in vivo data indicated that mRNA-ICA@GM can not only reverse the inflammatory environment but also suppress monocyte-derived osteoclast formation to accelerate bone repair. In summary, mRNA-engineered monocytes and ICA prodrug-like microspheres are combined to achieve long-lasting multi-stage bone microenvironment regulation, offering a promising repair strategy.

A Precise Route to Tetrasubstituted Allyl Amines via Regioselective Dicarbofunctionalization of Masked Propargyl Amines.

Allyl amines are vital components in various biologically important molecules and play a significant role in their function. Presently, most methods are geared toward the preparation of di- and trisubstituted allyl amines, leaving a gap for the development of more versatile approaches. We herein describe an approach to yield tetrasubstituted allyl amines through palladium (Pd)-catalyzed regioselective dicarbofunctionalization of masked N-phthalimide-protected propargyl amines. The cationic Pd-intermediate in conjunction with the masked amine exerts collective control for the reaction regioselectivity. This method accommodates a wide range of alkynes, aryl boronic acids, and aryl diazonium salts offering direct access to a wide range of unusual tetrasubstituted allyl amines.

Co-Catalyzed Suzuki-Miyaura Coupling of Organoboronic Acids and Alkynyl Chlorides Using Potassium Bicarbonate as Base.

Organoboronic acids, some of the most common and widely used organoboron compounds, have not yet been used in the cobalt-catalyzed cross coupling reactions, despite cobalt demonstrating good reactivity with zinc reagents, Grignard reagents, and metal organoborates that are formed by n-butyl lithium or alkaline metal alkoxide salts and organoboron esters. Herein, a highly efficient and practical cobalt-catalyzed coupling reaction of aryl/alkenyl boronic acids and alkynyl chloride under mild reaction conditions is reported. The advantages of the organoboronic acids, along with a broad functional group compatibility and the reaction's tolerance to moisture and air, enable this reaction to be a synthetically useful protocol for the construction of a C(sp2)-C(sp) bond. Lastly, the synthesis of two natural products and a key intermediate of roxadustat was effectively accomplished using the methodology to construct the critical alkynyl-aryl bond.

Synthesis of 2-Amino-4-arylazulenes from 8-Aryl-2H-cyclohepta[b]furan-2-ones and Transformation into 6-Aryl-7H-naphth[3,2,1-cd]azulen-7-ones.

2-Amino-4-arylazulene derivatives were prepared from 8-aryl-2H-cyclohepta[b]furan-2-ones, which were converted into 6-aryl-7H-naphth[3,2,1-cd]azulen-7-ones through a several step process. The reaction of 8-aryl-2H-cyclohepta[b]furan-2-ones bearing an ester group at the 3-position with malononitrile in the presence of triethylamine afforded 2-amino-4-arylazulenes. The prepared 2-amino-4-arylazulenes were converted to the corresponding 2-chloro derivatives by the Sandmeyer reaction, which were subsequently transformed into 2,4-diarylazulenes by Suzuki-Miyaura coupling with various aryl boronic acids. 2,4-Diarylazulenes underwent intramolecular cyclization between aryl and cyano groups by Brønsted acid to give 6-aryl-7H-naphth[3,2,1-cd]azulen-7-ones. UV/vis spectral analysis revealed that 6-aryl-7H-naphth[3,2,1-cd]azulen-7-one with a N,N-dimethylaminophenyl group at the 6-position exhibited a broad and strong absorption band in the visible region due to intramolecular charge transfer. Furthermore, 6-aryl-7H-naphth[3,2,1-cd]azulen-7-ones exhibited halochromism in 30% CF3CO2H/CH2Cl2. Although fluorescence was not observed in solution, 8-aryl-2H-cyclohepta[b]furan-2-ones with an ester function were found to fluoresce in the solid state. 6-Aryl-7H-naphth[3,2,1-cd]azulen-7-ones also displayed spectral changes with good reversibility under the electrochemical redox conditions.

C-C Coupling in sterically demanding porphyrin environments.

Unlike their planar counterparts, classic synthetic protocols for C-C bond forming reactions on nonplanar porphyrins are underdeveloped. The development of C-C bond forming reactions on nonplanar porphyrins is critical in advancing this field of study for more complex porphyrin architectures, which could be used in supramolecular assemblies, catalysis, or sensing. In this work a library of arm-extended dodecasubstituted porphyrins was synthesized through the optimization of the classic Suzuki-Miyaura coupling of peripheral haloaryl substituents with a range of boronic acids. We report on palladium-catalyzed coupling attempts on the ortho-, meta-, and para-meso-phenyl position of sterically demanding dodecasubstituted saddle-shaped porphyrins. While para- and meta-substitutions could be achieved, ortho-functionalization in these systems remains elusive. Furthermore, borylation of a dodecasubstituted porphyrin's meso-phenyl position was explored and a subsequent C-C coupling showed the polarity of the reaction can be reversed resulting in higher yields. X-ray analysis of the target compounds revealed the formation of supramolecular assemblies, capable of accommodating substrates in their void.

Transition-metal-free nucleophilic substitution of alkenyl boronic acids with propargylic mesylates sp3-carbon electrophiles

We developed a highly versatile transition metal-free Suzuki type cross-coupling protocol. Alkenyl/aryl boronic acids could couple smoothly with propargylic mesylates Csp3 electrophiles in the presence of mild bases. The counterion in the base plays a crucial role for the reactivity. Our metal-free condition is orthogonal towards the classic transition metal catalysed Suzuki reactions.

Synthesis and structure-activity relationship of boronic acid bioisosteres of combretastatin A-4 as anticancer agents

The boronic acid group plays an important role in drug discovery. Following our discovery of a boronic acid analog of combretastatin A-4 (CA-4), a series of analogs featuring a boronic acid group on the C phenyl ring of CA-4 was synthesized and evaluated for cytotoxicity, as well as for their ability to inhibit tubulin polymerization, inhibit the binding of [3H]colchicine to tubulin and cause depolymerization of cellular microtubules. Modifications on the C ring of CA-4, either eliminating the methoxy group or replacing the C phenyl ring with a pyridine ring, resulted in a reduced potency for inhibiting tubulin polymerization, colchicine binding and cytotoxic activities as compared to CA-4. Replacing the phenol group with a boronic acid group on the C ring of phenstatin led to a slight increase in cytotoxic potency but a decreased potency for inhibition of tubulin assembly and colchicine binding. Moreover, there was a significant decrease in activity by replacing the C phenyl ring with a pyridine ring. Our results indicate the critical importance of the methoxy group on the C ring as well as the importance of the C phenyl ring compared to a pyridine ring, despite the latter providing a nitrogen atom as a hydrogen bond donor/acceptor, which was predicted by molecular modeling to enhance interaction with the target. The decreased activities of our modified CA-4 boronic analogs may be attributed to weakened hydrogen bonding in our docking model based on the crystal structure of colchicine bound to αβ-tubulin. Notably, even though their effectiveness in inhibiting tubulin polymerization and colchicine binding and causing microtubule depolymerization in cells, the majority of these boronic acid analogs exhibited substantial cytotoxicity. This suggests that they may have additional cellular targets that contribute to their cytotoxicity, and this warrants further evaluation of these unique boronic acid compounds as potential anticancer agents.

A metal–organic frameworks-imprinted emulsion interface with dynamic size- and site-selective recognition for significantly enhanced flavoniods extraction

The boronic acid suspended Cr based MIL-100 (MIL-100-B) sorbents have been widely used to separation of cis-diol containing molecules. However, it’s still challenging in fabrication of high performance metal organic frameworks (MOFs) due to its irregular size and low content of functional groups. For improving identification efficiency, the emulsion microreactor were firstly designed to purify MIL-100-B prior to their use. Herein, a highly ordered MOFs-imprinted polymer microsphere was synthesized by O/W Pickering emulsion template, which can highly selective separation of MIL-100-B via the synergistic effect of boronic acid sites and imprinted cavities. The obtained purified H-MIL-100-B exhibited the uniform size and abundant boronic acid groups (B elements ratio up to 27.37 %). The emulsion imprinted microsphere (EIMs) showed the good selectivity towards MIL-100-B. Additionally, the obtained MOF-imprinted microsphere exhibited green, convenient, sustainable separation process towards the purification and recycle of MIL-100-B. The purified MOFs (H-MIL-100-B) were used to specific bind with cis-diol flavoniods naringin (NRG). Satisfactorily, H-MIL-100-B show high adsorption amount (43.69μmol/g at 308 K), fast capture kinetics (160 min), high selectivity and excellent regenerability (up to seven cycles). Remarkably, the purified NRG solutions displayed lasting antibacterial activity against Staphylococcus aureus (S. aureus) with inhibition zone of 13.47 mm. More importantly, the H-MIL-100-B could effectively promote the specific recognition ability of NRG by reducing matrix interference and improving purification efficiency (93.93 %) from complex natural extracts. A high score (0.75) was predicted via analytical GREEnness (AGREE) approaches, demonstrating environmentally friendly and greenness of separation process. The MOFs-imprinted emulsion microspheres possessed dynamic recognition properties towards target MOFs, thus opening new direction for the development of convenient and efficient microreactor for the purification of other functional MOFs.

Mechanically robust, self-healing and stretchable electromagnetic shielding materials based on multi-component dynamic bonded polyurethane elastomer

Stretchable self-healing electromagnetic interference (EMI) shielding materials can automatically restore their original performance after mechanical damage, and can still maintain over 20 dB EMI shielding effectiveness (EMI SE) under tensile state. In this work, a series of highly stretchable self-healing polyurethane elastomer PUBNS-X was prepared by introducing dynamic disulfide bonds, boronic ester bonds and boron-nitrogen coordination (B-N) on the polyurethane main chain. It was found that B-N coordination significantly increased the elongation at break and the tensile strength. The high dynamic reversibility of boronic ester, disulfide bond and B-N coordination bond synergistically endowed PUBNS-X with excellent temperature-triggered self-healing properties. The mechanical properties of PUBNS-X can be restored to more than 90 % at 60 °C. The pre-assembled silver nanowires (AgNWs) conductive network was then introduced into the polyurethane surface by taking advantage of the fluidity of the dynamically bonded polyurethane backbone to obtain a series of stretchable self-healing electromagnetic shielding composites (AgNWs/PUBNS-Y). The results showed that the EMI SE of AgNWs/PUBNS-Y can reach ∼55 dB, and the conductivity can be restored to 82 % of the original value after healing at 60 °C. The investigation of the electromagnetic interference shielding performance of composites under different strains showed that the EMI SE of AgNWs/PUBNS-3 can still maintain 20 dB under 90 % strain. These composites will have broad potential applications in the fields of flexible wearable electronic products, bionic intelligent materials and soft robots.