Volume 84, Issue 11

The 14th International Meeting on Boron Chemistry (IMEBORON-XIV) was held in Niagara Falls, Canada in 2011 and was attended by 270 participants from 18 countries. The 19 articles in this month's Pure and Applied Chemistry ( PAC ) are derived from the research presented at the conference, which stimulated lively discussion and facilitated new collaborations. The conference was divided into three sections representing organic, inorganic, and medicinal boron chemistry. The participants enjoyed the three plenary lectures from Profs. Holger Braunschweig, Fred Hawthorne, and Varinder K. Aggarwal as well as 141 oral and 111 poster presentations. We would like to acknowledge the direction and support given by the Scientific Committee (Profs. Tom Baker, Rob Batey, Dennis Hall, Warren Piers, and Doug Stephan), as well as the members of the International Organizing Committee, who provided valuable contributions to the planning of the meeting. We appreciate the support of the conference sponsors, as well as IUPAC and the editorial staff of PAC . We also thank all of the attendees and participants for their contributions, and look forward to IMEBORON-XV, which will be held in the Czech Republic in 2014. John Valliant and Laura Harrington Conference Organizers

In our glucose-sensing system, a boronic acid-modified viologen molecule quenches the fluorescence of a separate dye molecule. When glucose or other monosaccharides are added and bind to the boronic acid, the quenching ability of the viologen is diminished and fluorescence increases. Thus, changes in the fluorescence of the dye can be correlated with changing glucose concentration. Quenching and sugar-sensing results are explained by an electrostatic interaction between dye and quencher. This modular system can be configured in a nearly unlimited number of ways through substitution and multiplexing of the two fundamental quencher and dye components. Significantly, fluorescent quantum dots (QDs) can also be used as the reporter component. The system can also be immobilized in a hydrogel polymer to provide real-time, reversible sugar sensing.

The chemistry of some reactive frustrated Lewis pairs (FLPs) is reported. This includes intramolecular P/B and N/B FLPs, some of which were used as catalysts for the hydrogenation of electron-rich olefin substrates. Some advanced intermolecular FLPs are reported, which includes systems derived from very bulky alkenyl boranes obtained from 1,1-carboboration reactions of 1-alkynes with tris(pentafluorophenyl)borane. Some such systems activate dihydrogen and transfer the resulting proton/hydride pair even to some electron-poor alkynes. Eventually, we report on the reaction of our intramolecular ethylene-bridged P/B FLP with nitric oxide (NO). N,B-addition of the P-Lewis base/B-Lewis acid combination is observed to form a new type of a persistent aminoxyl radical. Some of the chemistry of the new FLP-NO radicals is presented and discussed.

It has been demonstrated that the interaction of a simple Lewis base with tetraalkoxydiboranes generates an unusual nucleophilic character in one of the boryl moieties. The interaction of amines, N -heterocyclic carbenes (NHCs), and alkoxides with a diboron reagent results in the formation of a Lewis acid–base adduct, in which the formally intact sp 2 boryl moiety becomes nucleophilic. We describe in this work the application of this new type of nucleophilic boron synthon in the selective preparation of organoboranes through β-boration and diboration reactions.

Heterometallic cubane-type clusters were synthesized from the reaction of group 6 and 8 metallaboranes using transition-metal carbonyl compounds. Structural and spectroscopic study revealed the existence of novel “capped-cubane” geometry. In addition, the crystal structure of these clusters distinctly confirms the presence of boride unit as one of the vertices. These clusters possess 60 cluster valence electrons (cve) and six metal–metal bonds. A plausible pathway for the formation of ruthenium-capped cubane has been described.

A synthesis of the first double-decker sandwich ion [(1',2'-C 2 B 9 H 11 )-3,3'-Co-(1,2-C 2 B 8 H 10 )-6,3"-Co-(1",2"-C 2 B 9 H 11 )] 2– ( DD 2– ) derivatives is described, having been developed in connection with our search for biologically active substances. A series of B-substituted hydroxyl derivatives was prepared by direct hydroxylation of the ion using aqueous sulfuric acid. Two isomers of monohydroxy derivatives were isolated. The main product was substituted at the central “canastide” ion fragment, whereas the substitution site for the minor isomer corresponded to a B(8) atom of one of the terminal 11-vertex dicarbollide parts. Similarly, the disubstitution occurred slightly more preferentially on the “canastide” fragment providing the main isomeric derivative with a symmetric structure. The cesium salt of this ion was characterized by X-ray diffraction. Two other isomeric species have one substituent sitting on the “canastide” ion and the second present on the dicarbollide ligand in apart or syn -geometric arrangement. A new zwitterion anion [(1',2'-C 2 B 9 H 11 )-3',3-Co-(8-(CH 2 ) 4 O-1,2-C 2 B 8 H 9 )-6,3"-Co-(1",2"-C 2 B 9 H 11 )-] 1– was prepared by the reaction of the parent ion with tetrahydrofuran (THF), activated by BF 3 ·OEt 2 . This new compound serves as a versatile building block for constructing organic derivatives, as exemplified by the ring cleavage by various amines or phenolate ions and the synthesis of a basic series of compounds of general formulation [(1',2'-C 2 B 9 H 11 )-3',3-Co-(8-X-(CH 2 ) 4 O-1,2-C 2 B 8 H 9 )-6,3"-Co-(1",2"-C 2 B 9 H 11 )] n – where the organic end-groups X adjacent to the “canastide” moiety via a B-oxatetramethylene spacer corresponds to C 4 H 9 NH 2 , NC 5 H 5 , N(C 2 H 5 ) 3 , (C 6 H 5 ) 3 P ( n = 1), or (4- t-Bu -C 6 H 4 -1-O) – and (2-CH 3 O-C 6 H 4 O) – ( n = 2). We show that dicluster compounds with two identical DD 2– anion units or asymmetric molecules containing two different clusters, the cobalt bis(dicarbollide) and the DD 2– anion, are accessible using this building block. All compounds were characterized by high-resolution NMR ( 1 H, 13 C, and 11 B) and mass spectrometry. Some of the compounds were tested by in vitro assay for their ability to inhibit the HIV-protease (HIV-PR) enzyme. The majority of the tested species proved substantially high activity toward the HIV-PR, exhibiting on the other hand a noncompetitive mechanism of the inhibition.

Organoboronic acid derivatives are well-established intermediates for the preparation of alcohols and amines, and in the formation of C–C bonds via different reactions, including homologations, carbonyl allylboration, or transition-metal-catalyzed cross-coupling chemistry. In the past decade, there has been great interest in the development of catalytic enantioselective methods for the preparation of chiral, optically enriched organoboronates as precursors of enantioenriched compounds. While the mainstream strategy remains the late-stage borylation of organic functional groups, our group has focused on an alternate strategy focused on modification of boron-containing substrates. In this way, acyclic and cyclic secondary alkyl- and allyl-boronates were prepared through catalytic enantioselective processes such as [4 + 2] cycloadditions, isomerizations, allylic substitutions, and conjugate additions. The resulting optically enriched boronates have been successfully utilized in the syntheses of complex natural products and drugs. One remaining challenge in the chemistry of secondary alkylboronate derivatives is their cross-coupling, especially with control of stereoselectivity. In this regard, our recent approach featured the conjugate asymmetric borylation of β-boronyl acrylates, providing the first enantioselective preparation of highly optically enriched 1,1-diboronyl derivatives. The chirality of these geminal diboron compounds is conferred through the use of two distinct boronate adducts, which can be coupled chemo- and stereoselectively with a variety of aryl and alkenyl halides under palladium catalysis.

Compounds with polyhedral borane moieties have demonstrated numerous unique properties for a variety of applications, including nanoelectronics, drug delivery vehicles, and live cell imaging. Polyhedral boranes are good pharmacophore analogs of carbocycles because polyhedral boranes are inherently insensitive to many undesirable enzymatic metabolic transformations typical for a majority of aromatic compounds. The defined shape, low molecular volume, and high 3D symmetry of the surface are useful for the application of the polyhedral borane scaffolds as universal and convenient spacers for the modular assembly approach with a controllable predisposition of peripheral groups.

In medicinal chemistry, carbaboranes can be employed either as boron carriers for boron neutron capture therapy (BNCT) or as scaffolds for radiodiagnostic or therapeutic agents. We have developed a suitable synthesis employing the phosphoramidite method to connect meta -carbaboranyl bis-phosphonites with the 6'-OH group of isopropylidene-protected galactose, followed by oxidation or sulfurization to give the corresponding bis-phosphonates. Deprotection yielded water-soluble compounds. The corresponding disodium salts exhibit especially low cytotoxicity. Preliminary results on the in vivo toxicity and biodistribution of two compounds in mice indicated a lack of selectivity for the cotton rat lung (CRL) tumor chosen for the experiment. For the incorporation of carbaboranes into breast tumor-selective modified neuropeptide Y, [F 7 , P 34 ]-NPY, a synthesis of a carbaborane-modified lysine derivative was developed. Linkage of the lysine to the boron cluster was achieved by using a propionic acid spacer. Incorporation of the amino acid derivatives into NPY and [F 7 , P 34 ]-NPY by solid-phase peptide synthesis was successful. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained. Asborin, the carbaborane analogue of aspirin, is a rather weak inhibitor of cyclooxygenase-1 (COX-1) and COX-2, but a highly potent aldo/keto reductase 1A1 (AKR1A1) inhibitor. Modification either at the carboxyl group or at the chlorophenyl ring in indomethacin with ortho - and meta -carbaboranyl derivatives gave active derivatives only for the ortho -carbaborane directly attached to the carboxyl group, while the corresponding adamantyl and meta -carbaboranyl derivatives were inactive.

The chemistry and reactivity of carborane-appended magnetic nanoparticles and boron-based nanomaterials are briefly reviewed with an emphasis on our contribution to this field. The carborane-appended magnetic nanoparticles exhibited great potential to be useful in boron neutron capture therapy (BNCT). A facile route to synthesize boron nanorods (BNRs) and boron nitride nanotubes (BNNTs) is also demonstrated. While functionalized BNRs and BNNTs have been successfully prepared, the derivatives of BNNTs were investigated as potential carriers for BNCT.

Isotopes have played an important role in chemistry, biology, and medicine. For the last three decades, we have focused on the use of organoboron compounds as precursors to isotopically labeled physiologically active reagents. During that period, we have successfully developed methods for incorporating short- and long-lived isotopes of carbon, nitrogen, oxygen, and the halogens using a variety of reactive organoboron precursors. In addition, labeling strategies employing polymer-supported organoboron derivatives were developed. In this report, we present a short overview focused on the evolution of radiolabeling techniques based on boron chemistry.

The ferrocenylboranes (BOhfip 2 )Fc and 1,1'-(BOhfip 2 ) 2 Fc were prepared (Fc = ferrocenyl, Ohfip = (CF 3 ) 2 CH-O); 1,1'-(BOhfip 2 ) 2 Fc was further oxidized giving [1,1'-(BOhfip 2 ) 2 Fc] + [Al(OR F ) 4 ] – by oxidation of 1,1'-(BOhfip 2 ) 2 Fc with Ag + [Al(OR F ) 4 ] – (R F = C(CF 3 ) 3 ). Their X-ray crystal structures were determined and give further information on the Fe–B interaction through the dip angles α *. In [1,1'-(BOhfip 2 ) 2 Fc] + [Al(OR F ) 4 ] – , this Fe–B interaction is enfeebled: the dip angles α * (0.3º and 5.4º) are significantly smaller than in (BOhfip 2 )Fc (7.8º) and 1,1'-(BOhfip 2 ) 2 Fc (8.0º), and the hexafluoroisopropoxy moieties are twisted out of the Cp plane by up to 66.1º. NMR and vibrational spectra support the crystal structure assignments.

The hypoxia-inducible factor (HIF) takes part in transcriptional activation of hypoxia-responsive genes such as vascular endothelial growth factor (VEGF), insulin-like growth factor, and inducible nitric oxide synthase. Since VEGF plays an important role in pathological angiogenesis such as tumor growth and ischemic diseases, the inhibition of VEGF inducer HIF is an attractive approach for the inhibition of pathological angiogenesis. Recently, we have reported that the introduction of boronic acid and a carborane moiety into phenoxyacetanilide induced a potent inhibitory effect on HIF-1α activation under hypoxic conditions. In the present study, to clarify the mechanism of action of carboranylphenoxyacetanilide GN26361 against HIF inhibition, we designed and synthesized molecular probes of GN26361 substituted with benzophenone to induce covalent binding with the target protein by UV (photoaffinity labeling) and an acetylenic moiety to conjugate with the green-fluorescent Alexa Fluor 488-azide by click reaction. In-gel fluorescent imaging of target protein bound with the probe was identified as heat shock protein 60 (HSP60). Moreover, direct binding in gel fluorescent imaging was observed by photoaffinity labeling and click reaction of the probe with recombinant HSP60. These results indicate that HSP60 is the target protein of GN26361 and might be a new molecular target for HIF inhibition.

Tartrate-derived (2 R ,3 R )-1,4-dimethoxy-1,1,4,4-tetraphenylbutane-2,3-diol has found diverse applications in asymmetric organic synthesis. Among these, its utilization as a protecting group for boronic acids has been investigated extensively. Besides being extraordinarily stable and thus allowing a plethora of transformations, it enables access to various diastereo- and enantiomerically pure organoboron reagents and versatile intermediates in asymmetric synthesis.

Allylic and allenyl boronates or boranes were uncovered as suitable pronucleophiles in catalytic C–C bond formations with C(sp 3 ) electrophiles such as O , O -acetals and N , O -aminals or ethers and carbohydrates. These transformations were most efficiently catalyzed by In(I) triflate. Importantly, chiral counteranion-directed, catalytic asymmetric allylation and allenylation of N , O -aminals was developed by employing a catalyst system composed of In(I) chloride and a chiral silver 2,2'-dihydroxy-1,1'-binaphthalene (BINOL)-phosphate.

Boronic acids can serve as organic soluble substitutes for water molecules in the metal-catalyzed hydration of alkynes. The Au-catalyzed addition of boronic acids to alkynes provides an alternative method for enolate generation, which proceeds under exceptionally mild conditions. The resulting enolates can be trapped by aldehydes present in the reaction mixture, giving aldol products that can be isolated as cyclic borate esters. These compounds are versatile synthetic intermediates that can be elaborated into a variety of products by transformation of the boron moiety. The Au-catalyzed reaction of boronic acids with propargylic alcohols results in efficient Meyer–Schuster rearrangement to the corresponding enones. The rearrangement of tertiary alcohols gives ( E )-enones with moderate to good selectivity, and the addition of a boronic acid to the reaction appears to enhance the level of geometrical control. The rearrangement of primary alcohols to terminal enones also occurs readily in the presence of catalytic Au(I) and a boronic acid, and the resulting terminal enones can be reacted with nucleophiles in one-pot procedures to give a variety of β-substituted ketones.

Red-shifted and near-infrared (NIR)-active rhodamine analogs and their boronic acid derivatives were synthesized and studied. These latter compounds function as fluorogenic NIR active substrates for sugar sensing. The effects of benzannulation and boronic acid functionalization on fluorophore optical and sensing properties are described.

Boron and carbon, either in elemental form or when combined, are structurally very different. They are indeed complementary, and the weaknesses of one can be complemented by the strengths of the other, and vice versa. The structural complementarity can be readily observed in the shape of [X n H n ] y – (X = C or B) compounds. One visualization of this complementarity can be found by comparing the most popular carbon and boron organometallic sandwich molecules, [Fe(C 5 H 5 ) 2 ] and [3,3'-Co(1,2-C 2 B 9 H 11 ) 2 ] – . Both obey the 18e – rule, and in both the metal is η 5 coordinated by two pentagonal faces. However, for [Fe(C 5 H 5 ) 2 ], the first ring of atoms outside the pentagonal face is coplanar with the coordinating face, whereas for [3,3'-Co(1,2-C 2 B 9 H 11 ) 2 ] – the substituents are out of the coordinating face featuring a canopy shading the metal. Taking advantage of this feature, [3,3'-Co(1,2-C 2 B 9 H 11 ) 2 ] – can be a well-performing molecular clutch electrochemically driven. When it is engaged, the beams of the upper [7,8-C 2 B 9 H 11 ] 2– ligand in [3,3'-Co(1,2-C 2 B 9 H 11 ) 2 ] – mesh the beams of the lower [7,8-C 2 B 9 H 11 ] 2– . This occurs when the molecular friction disk, the Co, is as Co 3+ . When Co 3+ is reduced to Co 2+ , its radius is elongated, and both sets of beams are unmeshed allowing for a more free rotation, or molecular clutch disengagement.

Protein–protein interactions (PPIs) play a central role in all biological processes and have been the focus of intense investigations from structural molecular biology to cell biology for the majority of the last two decades and, more recently, are emerging as important targets for pharmaceuticals. A common motif found at the interface of PPIs is the α-helix, and apart from the peptidic structures, numerous nonpeptidic small molecules have been developed to mimic α-helices. The first-generation terphenyl scaffold is able to successfully mimic key helix residues and disrupt relevant interactions, including Bcl-xL-Bak interactions that are implicated in apoptosis mechanism. These scaffolds were designed and evaluated in silico. Analysis revealed that substituents on aromatic scaffolds can efficiently mimic side-chain surfaces. Unfortunately, the literature describes a long and difficult procedure to access these aromatic-based scaffolds. The search for new simpler methodology is the aim of the research of our medicinal chemistry team. On the basis of structural requirements, we developed a program concerning the synthesis of new oligo(het)aryl scaffolds produced by iterative couplings of boronic species ( garlanding ) in which substituents on rings project functionality in spatial orientations that mimic residues of an α-helix.

Carbohydrate biomarkers play very important roles in a wide range of biological and pathological processes. Compounds that can specifically recognize a carbohydrate biomarker are useful for targeted delivery of imaging agents and for development of new diagnostics. Furthermore, such compounds could also be candidates for the development of therapeutic agents. A tremendous amount of active work on synthetic lectin mimics has been reported in recent years. Amongst all the synthetic lectins, boronic-acid-based lectins (boronolectins) have shown great promise. Along this line, four classes of boronolectins including peptide-, nucleic-acid-, polymer-, and small-molecule-based ones are discussed with a focus on the design principles and recent advances. We hope that by presenting the potentials of this field, this review will stimulate more research in this area.