Synthesis of Partially Hydrogenated Cycloparaphenylenes with Bent and Fused Structures Bearing Armchair Carbon Nanotube-like Connections.

The Diels-Alder reactions between 2 equiv of (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene and 1,4-benzoquinone led to the formation of a key intermediate with all four 4-bromophenyl substituents cis to one another. The subsequent nickel-mediated homocoupling reactions then produced partially hydrogenated cycloparaphenylenes, including a molecule bearing two units of tetrahydro[6]cycloparaphenylene (4H[6]CPP) fused together through two 1,4-dimethoxybenzene units in an armchair (6,6)carbon nanotube-like connection. Similarly, two 6H[9]CPPs were connected through three 1,4-dimethoxybenzene units in an armchair (9,9)carbon nanotube-like arrangement. A bent 8H[12]CPP and a bent 12H[18]CPP, which were fused intramolecularly with two and three 1,4-dimethoxybenzene units, respectively, to create the bent structures, were likewise synthesized. A molecule containing a bent 8H[12]CPP fused to a 4H[6]CPP was likewise constructed. The structures of these partially hydrogenated CPPs were established by X-ray structure analysis, NMR spectroscopy, and additional independent synthetic pathways.

Synthesis and Characterization of Functionalized [12]Cycloparaphenylenes Containing Four Alternating Biphenyl and Naphthyl Units.

Functionalized [12]cycloparaphenylenes ([12]CPPs) containing four alternating biphenyl and naphthyl units were synthesized. A macrocyclic furan-containing CPP precursor was used for the Diels-Alder reaction with the parent benzyne or 3,6-dimethoxybenzyne to form the corresponding macrocyclic carbon frameworks. The subsequent reductive deoxygenation of the Diels-Alder adducts with Fe2(CO)9 followed by oxidative aromatization with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone produced the functionalized [12]CPPs. The effect of macrocyclic ring size on the reaction rate of oxidative aromatization was investigated.

Synthesis of Cycloparaphenylenes Bearing Furan-2,5-diyl or 2,2'-Bifuran-5,5'-diyl Units in the Macrocyclic Structures.

Synthetic pathways to furan-containing cycloparaphenylenes (CPPs) as molecular nanohoops bearing 10, 12, and 15 aromatic units including furan-2,5-diyl or 2,2'-bifuran-5,5'-diyl units have been developed. The X-ray structures of a partially hydrogenated bifuran-containing CPP precursor and the corresponding fully aromatized bifuran-containing CPP were obtained to allow the determination of their conformational arrangements in the crystal lattice. The optical and electrochemical properties of the furan-containing CPPs were investigated.

Hybrid organic-inorganic inhibitors of a PDZ interaction that regulates the endocytic fate of CFTR.

Together strong: Cooperative binding of organic (see picture, red) and inorganic fragments provides a strategy for the potent inhibition of protein-protein interactions. By targeting specific Lewis basic side chains in peripheral regions of the binding site for coordination to a rhodium(II) center, the affinity of otherwise weak ligands is improved.

Synthesis of a Borylated Ibuprofen Derivative through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of boron functionalized NSAIDs (bora-NSAIDs) was synthesized under mild conditions via the copper-catalyzed regioselective boracarboxylation of vinyl arenes using carbon dioxide (CO2 balloon) and a diboron reductant at room temperature. This original method was performed primarily in a glovebox or with a vacuum gas manifold (Schlenk line) under rigorous air-free and moisture-free conditions, which often led to irreproducible reaction outcomes due to trace impurities. The present protocol describes a simpler and more convenient benchtop method for synthesizing a representative bora-NSAID, bora-ibuprofen. A Suzuki-Miyaura cross-coupling reaction between 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester produces 4-isobutylstyrene. The styrene is subsequently boracarboxylated regioselectively to provide bora-ibuprofen, an α-aryl-ß-boryl-propionic acid, with good yield on a multi-gram scale. This procedure allows for the broader utilization of copper-catalyzed boracarboxylation in synthetic laboratories, enabling further research on bora-NSAIDs and other unique boron-functionalized drug-like molecules.

Reaction of O2 with [(-)-sparteine]Pd(H)Cl: evidence for an intramolecular [H-L]+ "reductive elimination" pathway.

(Sp)PdCl(2) [Sp = (-)-sparteine] catalyzes a number of different aerobic oxidation reactions, and reaction of O(2) with a Pd(II)-hydride intermediate, (Sp)Pd(H)Cl (1), is a key step in the proposed catalytic mechanism. Previous computational studies suggest that O(2) inserts into the Pd(II)-H bond, initiated by abstraction of the hydrogen atom by O(2). Experimental and computational results obtained in the present study challenge this conclusion. Oxygenation of in-situ-generated (Sp)Pd(H)Cl exhibits a zero-order dependence on [O(2)]. This result is inconsistent with a bimolecular H-atom-abstraction pathway, and DFT computational studies identify a novel "reductive elimination" mechanism, in which the chelating nitrogen ligand undergoes intramolecular deprotonation of the Pd(II)-hydride. The relevance of this mechanism to other Pd(II) oxidation catalysts with chelating nitrogen ligands is evaluated.

Mechanistic studies of Wacker-type intramolecular aerobic oxidative amination of alkenes catalyzed by Pd(OAc)2/pyridine.

Wacker-type oxidative cyclization reactions have been the subject of extensive research for several decades, but few systematic mechanistic studies of these reactions have been reported. The present study features experimental and DFT computational studies of Pd(OAc)(2)/pyridine-catalyzed intramolecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism that consists of (1) steady-state formation of a Pd(II)-amidate-alkene chelate with release of 1 equiv of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible ß-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of palladium(0) to regenerate the active trans-Pd(OAc)(2)(py)(2) catalyst. Evidence is obtained for two energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a pyridine-dissociated Pd(II) species. Analysis of natural charges and bond lengths of the alkene-insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic attack of the amidate ligand on the coordinated alkene.

Benzannulation and Hydrocarboxylation Methods for the Synthesis of a Neopentylene-Fused Analogue of Ibuprofen.

Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as "neoprofen". The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.

Structure-selective modification of aromatic side chains with dirhodium metallopeptide catalysts.

The combination of peptide molecular recognition and residue-selective dirhodium catalysis allows modification of aromatic side chains that is selective for coil structures. A rate enhancement of >10(3) relative to nonselective dirhodium modification was observed. The increased reactivity of this approach creates the first selective chemical modification of the phenylalanine residue.

Helix induction by dirhodium: access to biocompatible metallopeptides with defined secondary structure.

The use of carboxylate side chains to induce peptide helicity upon binding to dirhodium centers is examined through experimental and computational approaches. Dirhodium binding efficiently stabilizes alpha helicity or induces alpha helicity in otherwise unstructured peptides for peptides that contain carboxylate side chains with i, i+4 spacing. Helix induction is furthermore possible for sequences with i, i+3 carboxylate spacing, though in this case the length of the side chains is crucial: ligating to longer glutamate side chains is strongly helix inducing, whereas ligating the shorter aspartate side chains destabilizes the helical structure. Further studies demonstrate that a dirhodium metallopeptide complex persists for hours in cellular media and exhibits low toxicity toward mammalian cells, enabling exploitation of these metallopeptides for biological applications.

Electronic structural comparison of the reactions of dioxygen and alkenes with nitrogen-chelated palladium(0).

The reaction of molecular oxygen with palladium(0) centers is a key step in Pd-catalyzed aerobic oxidation reactions. The present study provides a density functional theory (DFT) computational analysis of the mechanism and electronic structural features of the reversible, associative exchange between O(2) and ethylene at an ethylenediamine (en)-coordinated palladium(0) center. Salient features of the mechanism include: (1) the near thermoneutrality of the O(2)-alkene exchange reaction, consistent with experimentally observed reversible exchange between O(2) and alkenes at well-defined Pd centers, (2) end-on activation of triplet O(2) at an apical site of the trigonal Pd(0) center, resulting in formation of a Pd(I)(η(1)-superoxide) species, (3) rearrangement of the Pd(I)(η(1)-superoxide) species into a pseudo-octahedral (en)Pd(η(2)-O(2))(η(2)-C(2)H(4)) species with concomitant crossing from the triplet to singlet energy surfaces, and (4) release of alkene from an axial face of (en)Pd(II)(η(2)-peroxo) with a geometry in which the alkene leaves with an end-on trajectory (involving an interaction of the Pd d(z(2)) and alkene π* orbitals). This study highlights the similar reactivity and reaction pathways of alkenes and O(2) with an electron-rich metal center, despite the different ground-state electronic configurations of these molecules (closed-shell singlet and open-shell triplet, respectively).

Mechanism of Pd(OAc)2/pyridine catalyst reoxidation by O2: influence of labile monodentate ligands and identification of a biomimetic mechanism for O2 activation.

The mechanism of catalyst oxidation by O(2) in Pd-catalyzed aerobic oxidation reactions has been the subject of considerable debate, particularly with respect to the reactivity of Pd(II)-hydride species. Here, we describe the use of unrestricted DFT computational methods to investigate the mechanism of catalyst reoxidation with the Pd(OAc)(2)/pyridine catalyst system, one of the most widely used catalysts. These studies probe four different pathways for the formation of a Pd(II)-hydroperoxide species from the reaction of O(2) from the corresponding Pd(II)-hydride [(py)(n)Pd(II)(H)OAc]: 1) a homolytic pathway involving hydrogen-atom abstraction by O(2); 2) AcOH reductive elimination to yield a Pd(0) species that subsequently reacts with O(2); 3) migratory insertion of O(2) into a Pd-H bond; and 4) oxidative addition of O(2) to Pd(II) to yield a Pd(IV)(eta(2)-peroxo) species. In contrast to previous studies of reactions between O(2) and Pd-hydride species, the reductive-elimination pathway (mechanism 2) is significantly more favorable than any of the other pathways. This outcome is traced to the presence of labile ligands (pyridine) that can readily dissociate from Pd to enable the hydride and acetate ligands to occupy cis-coordination sites. These results strongly support the involvement of Pd(0) as an intermediate in the catalytic cycle. Investigations of the mechanism of the reaction of O(2) with the Pd(0) intermediate revealed a novel, previously unrecognized mechanism that yields a Pd-OOH product without proceeding through the intermediacy of a Pd(II)(eta(2)-peroxo) species. This mechanism resembles pathways commonly observed in biological O(2) activation and suggests that noble-metal and biological oxidation mechanisms may be more similar than previously appreciated.

Rapid nickel(ii)-promoted cysteine S-arylation with arylboronic acids.

S-Arylation of cysteine residues is an increasingly powerful tool for site-specific modification of proteins, providing novel structure and electronic perturbation. The present work demonstrates an operationally-simple cysteine arylation reaction 2-nitro-substituted arylboronic acids, promoted by a simple nickel(ii) salt. The process exhibits strikingly fast reaction rates under physiological conditions in purely aqueous media with excellent selectivity toward cysteine residues. Cysteine arylation of natural proteins and peptides allows attachment of useful reactive handles for stapling, imaging, or further conjugation.

Access to a pair of ambiphilic phosphine-borane regioisomers by rhodium-catalyzed hydroboration.

Lewis basic substrates, such as vinylphosphines and enamines, can be problematic for transition-metal catalysed hydrofunctionalization reactions due to their propensity to ligate and deactivate transition-metal catalysts as well as form direct Lewis adducts with reaction partners. While exploring rhodium-catalyzed hydroboration of diphenylvinylphosphine with pinacolborane, we found that a high degree of regiocontrol could be achieved without the need to diminish the Lewis basicity of the phosphine by oxidation or prior-protection. At slightly elevated temperature, a high yield of the previously unreported branched regioisomer, 1-pinacolatoborono-1-diphenylphosphinoethane, was achieved with regioselectivity greater than 10 : 1 using [Rh(COD)Cl]2 as the catalyst and AgOTf as a catalytic additive. Inversion of regioselectivity occurred at low temperature and high yield of the linear regioisomer was observed. Subsequent functionalization of the new branched phosphine-boronic ester and its coordination to rhodium were also investigated.

Synthesis and Properties of Conjugated Macrocycles Containing 2,7-Bis(2-thienyl)-9H-fluoren-9-one Units.

Synthetic pathways to conjugated macrocycles containing one, two, or three 2,7-bis(2-thienyl)-9H-fluoren-9-one (TFOT) units in the macrocyclic frameworks bearing 10, 16, or 24 aromatic units were developed. The Diels-Alder reaction between (E,E)-1-(5-bromo-2-thienyl)-4-(5-iodo-2-thienyl)-1,3-butadiene and dimethyl acetylenedicarboxylate produced the key Diels-Alder adduct for the subsequent macrocyclic ring formation. UV-vis and fluorescence spectra of the TFOT-containing molecules were recorded, and their electrochemical properties were investigated by cyclic and differential pulse voltammetry. Solvatofluorochromic properties were observed for the TFOT-containing molecules.

Synthesis and Structure of a Functionalized [9]Cycloparaphenylene Bearing Three Indeno[2,1-a]fluorene-11,12-dione-2,9-diyl Units.

A synthetic pathway to a functionalized [9]cycloparaphenylene bearing three indeno[2,1-a]fluorene-11,12-dione-2,9-diyl units in the macrocyclic ring structure ([3]CIFO) has been developed. The 1H and 13C NMR spectra show that only the anti rotamer (anti-[3]CIFO) is produced. DFT calculations indicate that the anti rotamer is thermodynamically more stable than the syn rotamer by 4.3 kcal/mol, and the rotational barrier from the anti to syn rotamer is estimated to be 23.3 kcal/mol. The UV-vis and fluorescence spectra and cyclic voltammogram of anti-[3]CIFO were investigated.

Syntheses and Structures of Functionalized [9]Cycloparaphenylenes as Carbon Nanohoops Bearing Carbomethoxy and N-Phenylphthalimido Groups.

Functionalized [9]cycloparaphenylenes ([9]CPPs) bearing nine aromatic units in the macrocyclic structures were synthesized. The macrocyclic structures were substituted with carbomethoxy or N-phenylphthalimido groups. The Diels-Alder reaction of (E,E)-1,4-bis(4-bromophenyl)-1,3-butadiene or a related diene with dimethyl acetylenedicarboxylate followed by the nickel-mediated homocoupling reactions and oxidative aromatization produced the functionalized [9]CPPs. Treatment of a resultant [9]CPP with aniline or 1,4-diaminobenzene gave the corresponding N-phenylphthalimides. The X-ray structure of a [9]CPP bearing six carbomethoxy groups was obtained.

Regioselective Copper-Catalyzed Boracarboxylation of Vinyl Arenes.

Regioselective copper-catalyzed boracarboxylation of vinyl arenes with bis(pinacolato)diboron and carbon dioxide has been achieved. New boron-functionalized α-aryl carboxylic acids, including nonsteroidal anti-inflammatory drugs (NSAIDs), are obtained in moderate to excellent yields. The synthetic utility of the transformation was shown through subsequent derivatization of the carbon-boron bond yielding formal hydroxy- and fluorocarboxylation products as well as anionic difluoroboralactones.

Potent and selective inhibition of SH3 domains with dirhodium metalloinhibitors.

Src-family kinases (SFKs) play important roles in human biology and are key drug targets as well. However, achieving selective inhibition of individual Src-family kinases is challenging due to the high similarity within the protein family. We describe rhodium(ii) conjugates that deliver both potent and selective inhibition of Src-family SH3 domains. Rhodium(ii) conjugates offer dramatic affinity enhancements due to interactions with specific and unique Lewis-basic histidine residues near the SH3 binding interface, allowing predictable, structure-guided inhibition of SH3 targets that are recalcitrant to traditional inhibitors. In one example, a simple metallopeptide binds the Lyn SH3 domain with 6 nM affinity and exhibits functional activation of Lyn kinase under biologically relevant concentrations (EC50 ∼ 200 nM).

Syntheses and Structures of Thiophene-Containing Cycloparaphenylenes and Related Carbon Nanohoops.

Thiophene-containing cycloparaphenylenes (CPPs) bearing 8, 10, and 16 aromatic and heteroaromatic units in the macrocyclic ring structures were synthesized. Specifically, two and four thiophene-2,5-diyl units were incorporated into functionalized [6]- and [12]CPP macrocyclic carbon frameworks, respectively. In addition, two 2,2'-bithiophene-5,5'-diyl units were inserted into a functionalized [6]CPP carbon framework. The cyclic and differential pulse voltammetry and the UV-vis and fluorescence spectra of the fully aromatized macrocycles and their precursors exhibited interesting electrochemical and optical properties.