Recent advances in ß-l-rhamnosylation.

l-Rhamnose forms the key components of important antigenic oligo- and polysaccharides of a variety of pathogens. Obtaining 1,2-cis stereoselectivity in the glycosylation of l-rhamnoside is quite challenging due to the unavailability of neighboring group participation and disfavoring of the anomeric effect and stereoelectronic effect of the substituents on the C-2 axial position. Nevertheless, various methodologies have been developed exploiting diverse pathways for obtaining ß-stereoselectivity in the glycosylation of l-rhamnose. This review describes the recent advances in ß-l-rhamnosylation and its applications in the total synthesis of ß-l-rhamnose-containing biologically important oligosaccharides.

Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-ß-lactamases.

Despite major advances in the ß-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a ß-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.

Injectable Self-Healing Hydrogels Based on Boronate Ester Formation between Hyaluronic Acid Partners Modified with Benzoxaborin Derivatives and Saccharides.

We demonstrate here, for the first time, formation of injectable dynamic covalent hydrogels at physiological pH using benzoxaborin-saccharide complexation as a reversible cross-linking method. The gels were prepared by simply mixing hyaluronic acid modified with an original boronic acid derivative, 3,4-dihydro-2H-benzo[e][1,2]oxaborinin-2-ol (1,2-ABORIN), and HA functionalized with 1-amino-1-deoxy-d-fructose. Dynamic rheological experiments confirmed the gel-like behavior (storage modulus (G') > loss modulus (G″) in the frequency window explored) for the designed HA-1,2-ABORIN/HA-fructose network. Furthermore, this hydrogel exhibited excellent self-healing and injectability behaviors in aqueous conditions and was found to be responsive to pH. Additionally, fibroblast cells encapsulated in the HA network showed high viability (>80% after 7 days of cell culture), as monitored by Live/Dead staining. Taken together, this new class of boronate ester cross-linked hydrogel provides promising future for diverse biomedical applications.

Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-ß-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections.

A major resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent ß-lactamases can now confer resistance to other ß-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of ß-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-ß-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum ß-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of ß-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum ß-lactamase inhibitor to enter clinical development.

Novel 1,2-cis-stereoselective glycosylations utilizing organoboron reagents and their application to natural products and complex oligosaccharide synthesis.

In this mini-review article, 1,2-cis-stereoselective glycosylation methods utilizing organoboron reagents and 1,2-anhydroglycosyl donors that were developed in our laboratory, including regio- and 1,2-cis-stereoselective glycosylations using glycosyl-acceptor-derived boronic ester catalysts and 1,2-cis-stereoselective glycosylations using glycosyl-acceptor-derived borinic ester catalysts, are recounted. Representative applications of these methods to the synthesis of biologically active natural products and a complex oligosaccharide are also described.

Chemoselective Alteration of Fluorophore Scaffolds as a Strategy for the Development of Ratiometric Chemodosimeters.

Ratiometric sensors generally couple binding events or chemical reactions at a distal site to changes in the fluorescence of a core fluorophore scaffold. However, such approaches are often hindered by spectral overlap of the product and reactant species. We provide a strategy to design ratiometric sensors that display dramatic spectral shifts by leveraging the chemoselective reactivity of novel functional groups inserted within fluorophore scaffolds. As a proof-of-principle, fluorophores containing a borinate (RF620 ) or silanediol (SiOH2R) functionality at the bridging position of the xanthene ring system are developed as endogenous H2 O2 sensors. Both these fluorophores display far-red to near-infrared excitation and emission prior to reaction. Upon oxidation by H2 O2 both sensors are chemically converted to tetramethylrhodamine, producing significant (≥66 nm) blue-shifts in excitation and emission maxima. This work provides a new concept for the development of ratiometric probes.

Borinic Acid Polymer: Simplified Synthesis and Enzymatic Biofuel Cell Application.

A simplified one-pot and less harmful method has been introduced for the synthesis of borinic acid monomer. The corresponding borinic acid polymer (PBA) has been prepared by reversible addition-fragmentation chain transfer polymerization. Property investigations confirm the characteristics of PBA as a new type of "smart material" in the field of thermo-responsive polymer. The potential application of PBA in the field of enzymatic biofuel cell has been illustrated with a wide open circuit potential of 0.92 V.

Fast Diazaborine Formation of Semicarbazide Enables Facile Labeling of Bacterial Pathogens.

Bioorthogonal conjugation chemistry has enabled the development of tools for the interrogation of complex biological systems. Although a number of bioorthogonal reactions have been documented in literature, they are less ideal for one or several reasons including slow kinetics, low stability of the conjugated product, requirement of toxic catalysts, and side reactions with unintended biomolecules. Herein we report a fast (>103 M-1 s-1) and bioorthogonal conjugation reaction that joins semicarbazide to an aryl ketone or aldehyde with an ortho-boronic acid substituent. The boronic acid moiety greatly accelerates the initial formation of a semicarbazone conjugate, which rearranges into a stable diazaborine. The diazaborine formation can be performed in blood serum or cell lysates with minimal interference from biomolecules. We further demonstrate that application of this conjugation chemistry enables facile labeling of bacteria. A synthetic amino acid D-AB3, which presents a 2-acetylphenylboronic acid moiety as its side chain, was found to incorporate into several bacterial species through cell wall remodeling, with particularly high efficiency for Escherichia coli. Subsequent D-AB3 conjugation to a fluorophore-labeled semicarbazide allows robust detection of this bacterial pathogen in blood serum.

Borinic Acid Catalyzed Stereo- and Regioselective Couplings of Glycosyl Methanesulfonates.

In the presence of a diarylborinic acid catalyst, glycosyl methanesulfonates engage in regio- and stereoselective couplings with partially protected pyranoside and furanoside acceptors. The methanesulfonate donors are prepared in situ from glycosyl hemiacetals, and are coupled under mild, operationally simple conditions (amine base, organoboron catalyst, room temperature). The borinic acid catalyst not only influences site-selectivity via activation of 1,2- or 1,3-diol motifs, but also has a pronounced effect on the stereochemical outcome: 1,2-trans-linked disaccharides are obtained selectively in the absence of neighboring group participation. Reaction progress kinetic analysis was used to obtain insight into the mechanism of glycosylation, both in the presence of catalyst and in its absence, while rates of interconversion of methanesulfonate anomers were determined by NMR exchange spectroscopy (EXSY). Together, the results suggest that although the uncatalyzed and catalyzed reactions give rise to opposite stereochemical outcomes, both proceed by associative mechanisms.

Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions.

A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Brønsted acidity of acetic acid.

Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example.

Two benzazaborinine analogues of propranolol were synthesized and extensively profiled in vitro and in vivo. These analogues showed potency and physicochemical and in vitro ADME-tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs.

Borinic acid catalysed peptide synthesis.

The catalytic synthesis of peptides is a major challenge in the modern organic chemistry hindered by the well-established use of stoichiometric coupling reagents. Herein, we describe for the first time that borinic acid is able to catalyse this reaction under mild conditions with an improved activity compared to our recently developed thiophene-based boronic acid. This catalyst is particularly efficient for peptide bond synthesis affording dipeptides in good yields without detectable racemization.

Thermo-responsive behavior of borinic acid polymers: experimental and molecular dynamics studies.

The thermo-responsive properties of borinic acid polymers were investigated by experimental and molecular dynamics simulation studies. The homopolymer poly(styrylphenyl(tri-iso-propylphenyl)borinic acid) (PBA) exhibits an upper critical solution temperature (UCST) in polar organic solvents that is tunable over a wide temperature range by addition of small amounts of H2O. The UCST of a 1 mg mL(-1) PBA solution in DMSO can be adjusted from 20 to 100 °C by varying the H2O content from ∼0-2.5%, in DMF from 0 to 100 °C (∼3-17% H2O content), and in THF from 0 to 60 °C (∼4-19% H2O). The UCST increases almost linearly from the freezing point of the solvent with higher freezing point to the boiling point of the solvent with the lower boiling point. The mechanistic aspects of this process were investigated by molecular dynamics simulations. The latter indicate rapid and strong hydrogen-bond formation between BOH moieties and H2O molecules, which serve as crosslinkers to form an insoluble network. Our results suggest that borinic acid-containing polymers are promising as new "smart" materials, which display thermo-responsive properties that are tunable over a wide temperature range.

A borinic acid polymer with fluoride ion- and thermo-responsive properties that are tunable over a wide temperature range.

A new type of smart borinic acid polymer with luminescence and multiple stimuli-responsive properties is reported. In DMSO with small amounts of water, the homopolymer PBA shows a tunable upper critical solution temperature (UCST). As the amount of water increases from 0 to 2.5 % (v/v), the UCST rises linearly from 20 °C to 100 °C (boiling point of water). Thus, the thermal responsive behavior can be tuned over a wide temperature range. Furthermore, polymer solutions in DMSO show a reversible response to fluoride ions, which can be correlated to the presence of the Lewis acidic borinic acid groups. Upon addition of fluoride, the polymer becomes soluble because the functional R2BOH groups are converted into ionic [R2BF2](-) groups, but turns insoluble again upon addition of H2O, which reverses this process.

Organoboron-catalyzed regio- and stereoselective formation of ß-2-deoxyglycosidic linkages.

A borinic acid derived catalyst enables regioselective and ß-selective reactions of 2-deoxy- and 2,6-dideoxyglycosyl chloride donors with pyranoside-derived acceptors having unprotected cis-1,2- and 1,3-diol groups. The use of catalysis to promote a ß-selective pathway by enhancement of acceptor nucleophilicity constitutes a distinct approach from previous work, which has been aimed at modulating donor reactivity by variation of protective and/or leaving groups.

Carboxylic acid free novel isocyanide-based reactions.

In order to develop a practical method for the construction of drug-like and heterocyclic compounds, we have designed a novel Passerini- or Ugi-type reaction system where a compound (which we write in the general form as Z-X) composed of an electrophilic (Z) and a nucleophilic group (X) could essentially perform the same function as the carboxylic acid. Based on this concept, we have developed the O-silylative Passerini reaction and the borinic acid catalyzed α-addition of isocyanides to aldehydes and water. In addition, we have designed and demonstrated the addition reaction of isocyanides to nitrones in the presence of TMSCl to afford the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxyamides. Furthermore, a novel [5 + 1] cycloaddition of isocyanide was explored with C,N-cyclic N'-acyl azomethine imines as a "1,5-dipole" via a strategy involving intramolecular trapping of the isocyanide.

Synthesis of cardiac glycoside analogs by catalyst-controlled, regioselective glycosylation of digitoxin.

The cardiac glycoside natural product digitoxin was selectively glycosylated at one of its five hydroxyl groups using a borinic acid derived catalyst. This method provided access to the glycosylation pattern characteristic of a subclass of natural products from Digitalis purpurea. Variation of the glycosyl donor was tolerated, enabling the synthesis of novel cardiac glycoside analogs from readily available materials.

Cross-coupling of diarylborinic acids and anhydrides with arylhalides catalyzed by a phosphite/N-heterocyclic carbene co-supported palladium catalyst system.

A highly efficient cross-coupling of diarylborinic acids and anhydrides with aryl chlorides and bromides has been effected by using a palladium catalyst system co-supported by a strong σ-donor N-heterocyclic carbene (NHC), N,N'-bis(2,6-diisopropylphenyl) imidazol-2-ylidene, and a strong π-acceptor phosphite, triphenylphosphite, in tert-BuOH in the present of K(3)PO(4)·3H(2)O. Unsymmetrical biaryls with a variety of functional groups could be obtained in good to excellent yields using as low as 0.01, 0.2-0.5, and 1 mol % palladium loadings for aryl bromides and activated and deactivated aryl chlorides, respectively, under mild conditions. A ligand synergy between the σ-donor NHC and the π-acceptor phosphite in the Pd/NHC/P(OPh)(3) catalytic system has been proposed to be responsible for the high efficacy to arylchlorides in the cross-coupling. A scalable and economical process has therefore been developed for synthesis of Sartan biphenyl from the Pd/NHC/P(OPh)(3) catalyzed cross-coupling of di(4-methylphenyl)borinic acid with 2-chlorobenzonitrile.

Organoboron compounds as Lewis acid receptors of fluoride ions in polymeric membranes.

Newly synthesized organoboron compounds - 4-octyloxyphenylboronic acid (OPBA) and pinacol ester of 2,4,6-trifluorophenylboronic acid (PE-PBA) - were applied as Lewis acid receptors of fluoride anions. Despite enhanced selectivity, the polymer membrane electrodes containing the lipophilic receptor OPBA exhibited non-Nernstian slopes of the responses toward fluoride ions in acidic conditions. Such behavior was explained by the lability of the B-O bond in the boronic acids, and the OH(-)/F(-) exchange at higher fluoride content in the sample solution. In consequence, the stoichiometry of the OPBA-fluoride complexes in the membrane could vary during the calibration, changing the equilibrium concentration of the primary anion in membrane and providing super-Nernstian responses. The proposed mechanism was supported by (19)F NMR studies, which indicated that the fluoride complexation proceeds more effectively in acidic solution leading mainly to PhBF(3)(-) species. Finally, the performances of the membranes based on the phenylboronic acid pinacol ester, with a more stable B-O bond, were tested. As it was expected, Nernstian fluoride responses were recorded for such membranes with worsened fluoride selectivity.

Regioselective, borinic acid-catalyzed monoacylation, sulfonylation and alkylation of diols and carbohydrates: expansion of substrate scope and mechanistic studies.

Synthetic and mechanistic aspects of the diarylborinic acid-catalyzed regioselective monofunctionalization of 1,2- and 1,3-diols are presented. Diarylborinic acid catalysis is shown to be an efficient and general method for monotosylation of pyranoside derivatives bearing three secondary hydroxyl groups (7 examples, 88% average yield). In addition, the scope of the selective acylation, sulfonylation, and alkylation is extended to 1,2- and 1,3-diols not derived from carbohydrates (28 examples); the efficiency, generality, and operational simplicity of this method are competitive with those of state-of-the-art protocols including the broadly applied organotin-catalyzed or -mediated reactions. Mechanistic details of the organoboron-catalyzed processes are explored using competition experiments, kinetics, and catalyst structure-activity relationships. These experiments are consistent with a mechanism in which a tetracoordinate borinate complex reacts with the electrophilic species in the turnover-limiting step of the catalytic cycle.