Ruthenium-Catalyzed E-Selective Alkyne Semihydrogenation with Alcohols as Hydrogen Donors.

Selective direct ruthenium-catalyzed semihydrogenation of diaryl alkynes to the corresponding E-alkenes has been achieved using alcohols as the hydrogen source. The method employs a simple ruthenium catalyst, does not require external ligands, and affords the desired products in > 99% NMR yield in most cases (up to 93% isolated yield). Best results were obtained using benzyl alcohol as the hydrogen donor, although biorenewable alcohols such as furfuryl alcohol could also be applied. In addition, tandem semihydrogenation-alkylation reactions were demonstrated, with potential applications in the synthesis of resveratrol derivatives.

Azulene Functionalization by Iron-Mediated Addition to a Cyclohexadiene Scaffold.

The functionalization of azulenes via reaction with cationic η5-iron carbonyl diene complexes under mild reaction conditions is demonstrated. A range of azulenes, including derivatives of naturally occurring guaiazulene, were investigated in reactions with three electrophilic iron complexes of varying electronic properties, affording the desired coupling products in 43-98% yield. The products were examined with UV-vis/fluorescence spectroscopy and showed interesting halochromic properties. Decomplexation and further derivatization of the products provide access to several different classes of 1-substituted azulenes, including a conjugated ketone and a fused tetracycle.

Chiral 1,5-disubstituted 1,2,3-triazoles - versatile tools for foldamers and peptidomimetic applications.

1,4- and 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- and Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono- or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology.

Release of Terminal Alkynes via Tandem Photodeprotection and Decarboxylation of o-Nitrobenzyl Arylpropiolates in a Flow Microchannel Reactor.

Photocleavable protecting groups (PPGs) offer a complementary protection paradigm compared to traditional protection groups. Herein, an o-nitrobenzyl (NB) PPG was employed to protect a variety of arylpropiolic acids. Upon a cascade of light-triggered photodeprotection in a microchannel reactor (residence times of 100-500 s), followed by Cu-catalyzed decarboxylation at 60 °C, the NB-protected arylpropiolic acid afforded a terminal alkyne. This terminal alkyne was further reacted in situ with an azide via click chemistry to yield a 1,2,3-triazole in a one-pot reaction. Furthermore, the effect of different substituents (methyl, vinyl, allyl, and phenyl) at the benzylic position on the rate of photodeprotection was studied. The quantum yields of photolysis for the benzylic-substituted esters were determined to be as high as 0.45 compared to the unsubstituted ester with a 0.08 quantum yield of photolysis.

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications.

The ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) affords 1,5-disubstituted 1,2,3-triazoles in one step and complements the more established copper-catalyzed reaction providing the 1,4-isomer. The RuAAC reaction has quickly found its way into the organic chemistry toolbox and found applications in many different areas, such as medicinal chemistry, polymer synthesis, organocatalysis, supramolecular chemistry, and the construction of electronic devices. This Review discusses the mechanism, scope, and applications of the RuAAC reaction, covering the literature from the last 10 years.

Turn-off mode fluorescent norbornadiene-based photoswitches.

Single-molecule fluorescence emission of certain positive photochromic systems such as diarylethenes have been exploited for biological imaging and optical memory storage applications. However, there is a lack of understanding if negative photochromic systems can be used for such type of applications. Hence, to explore the potential of negative photochromic molecules for possible optical memory storage applications, we have here synthesized and studied a series of four norbornadiene-quadricyclane (NBD-QC) photoswitching molecules. These molecules feature either linearly conjugated or cross-conjugated pi-electron systems. Upon photoisomerization, the UV-vis absorption spectra of the molecules revealed a strong blue shift in the QC-form, with a photoisomerization quantum yield close to 80% for the cross-conjugated systems. In contrast, a strong intrinsic emission (up to Φf = 49%) for the linearly conjugated compounds in the NBD form was observed. Upon light-induced isomerization, the emission was completely turned off in the QC-form in all the compounds studied. Further, the robustness of the system was evaluated by performing several switching cycles. Under nitrogen, the emission can be turned off and recovered with almost no loss of emission. We also show that the QC-form can be photochemically triggered to convert back to the NBD-form using a low energy UV light (340 nm), allowing an all optical conversion to both species. The demonstrated properties can make the NBD-QC system attractive for potential applications such as optical memory storage devices.

Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

Conformational properties of 1,4- and 1,5-substituted 1,2,3-triazole amino acids ­ building units for peptidic foldamers.

Peptidic foldamers have recently emerged as a novel class of artificial oligomers with properties and structural diversity similar to that of natural peptides, but possessing additional interesting features granting them great potential for applications in fields from nanotechnology to pharmaceuticals. Among these, foldamers containing 1,4- and 1,5-substitued triazole amino acids are easily prepared via the Cu- and Ru-catalyzed click reactions and may offer increased side chain variation, but their structural capabilities have not yet been widely explored. We here describe a systematic analysis of the conformational space of the two most important basic units, the 1,4-substitued (4Tzl) and the 1,5-substitued (5Tzl) 1,2,3-triazole amino acids, using quantum chemical calculations and NMR spectroscopy. Possible conformations of the two triazoles were scanned and their potential minima were located using several theoretical approaches (B3LYP/6-311++G(2d,2p), ωB97X-D/6-311++G(2d,2p), M06-2X/6-311++G(2d,2p) and MP2/6-311++G(2d,2p)) in different solvents. BOC-protected versions of 4Tzl and 5Tzl were also prepared via one step transformations and analyzed by 2D NOESY NMR. Theoretical results show 9 conformers for 5Tzl derivatives with relative energies lying close to each other, which may lead to a great structural diversity. NMR analysis also indicates that conformers preferring turn, helix and zig-zag secondary structures may coexist in solution. In contrast, 4Tzl has a much lower number of conformers, only 4, and these lack strong intraresidual interactions. This is again supported by NMR suggesting the presence of both extended and bent conformers. The structural information provided on these building units could be employed in future design of triazole foldamers.

Cu(I) stabilizing crosslinked polyethyleneimine.

Polyethyleneimine (PEI) is known for its metal-coordinating properties and in its crosslinked form has applications in different areas ranging from drug delivery to waste water treatment and recovery of trace metals. With the aim to regulate the coordination environment of Cu(I) and Cu(II) ions in marine coatings, we have prepared a triazole cross-linking agent with 'soft' coordination that can crosslink PEI via indirect reductive amination. We have shown that this triazole crosslinker not only increases the Cu(II) absorption capacity of the crosslinked PEI in comparison to the traditionally used glutaraldehyde-crosslinked PEI (PEI-GA), but also allows the crosslinked polymer network to stabilize the Cu(I) oxidation state more effectively. The Cu(II) uptake and Cu(I) stabilization of the polymer have been determined by elemental analysis and UV-vis spectroscopy. It was found that the triazole-crosslinked polymer (PEI-TA) could coordinate up to 12 wt% of Cu(II) before and 6 wt% Cu(II) after imine reduction.

Bridging ligand length controls at selectivity and enantioselectivity of binuclear ruthenium threading intercalators.

The slow dissociation of DNA threading intercalators makes them interesting as model compounds in the search for new DNA targeting drugs, as there appears to be a correlation between slow dissociation and biological activity. Thus, it would be of great value to understand the mechanisms controlling threading intercalation, and for this purpose we have investigated how the length of the bridging ligand of binuclear ruthenium threading intercalators affects their DNA binding properties. We have synthesised a new binuclear ruthenium threading intercalator with slower dissociation kinetics from ct-DNA than has ever been observed for any ruthenium complex with any type of DNA, a property that we attribute to the increased distance between the ruthenium centres of the new complex. By comparison with previously studied ruthenium complexes, we further conclude that elongation of the bridging ligand reduces the sensitivity of the threading interaction to DNA flexibility, resulting in a decreased AT selectivity for the new complex. We also find that the length of the bridging ligand affects the enantioselectivity with increasing preference for the ΔΔ enantiomer as the bridging ligand becomes longer.

Synthesis, characterization and computational evaluation of bicyclooctadienes towards molecular solar thermal energy storage.

Molecular solar-thermal energy storage (MOST) systems are based on photoswitches that reversibly convert solar energy into chemical energy. In this context, bicyclooctadienes (BODs) undergo a photoinduced transformation to the corresponding higher energy tetracyclooctanes (TCOs), but the photoswitch system has not until now been evaluated for MOST application, due to the short half-life of the TCO form and limited available synthetic methods. The BOD system degrades at higher temperature via a retro-Diels-Alder reaction, which complicates the synthesis of the compounds. We here report a cross-coupling reaction strategy that enables an efficient synthesis of a series of 4 new BOD compounds. We show that the BODs were able to switch to the corresponding tetracyclooctanes (TCOs) in a reversible way and can be cycled 645 times with only 0.01% degradation. Half-lives of the TCOs were measured, and we illustrate how the half-life could be engineered from seconds to minutes by molecular structure design. A density functional theory (DFT) based modelling framework was developed to access absorption spectra, thermal half-lives, and storage energies which were calculated to be 143-153 kJ mol-1 (0.47-0.51 MJ kg-1), up to 76% higher than for the corresponding norbornadiene. The combined computational and experimental findings provide a reliable way of designing future BOD/TCO systems with tailored properties.

Sequential one-pot ruthenium-catalyzed azide-alkyne cycloaddition from primary alkyl halides and sodium azide.

An experimentally simple sequential one-pot RuAAC reaction, affording 1,5-disubstituted 1H-1,2,3-triazoles in good to excellent yields starting from an alkyl halide, sodium azide, and an alkyne, is reported. The organic azide is formed in situ by treating the primary alkyl halide with sodium azide in DMA under microwave heating. Subsequent addition of [RuClCp*(PPh(3))(2)] and the alkyne yielded the desired cycloaddition product after further microwave irradiation.

Palladium-catalyzed stereoselective domino arylation-acylation: an entry to chiral tetrahydrofluorenone scaffolds.

A palladium-catalyzed domino arylation-cyclization of biocatalytically derived cyclic 1,3-dienes is demonstrated. The reaction introduces a high degree of structural complexity in a single step, giving access to tricyclic tetrahydrofluorenones with full regio- and stereoselectivity. The transformation proceeds through a novel acylation-terminated Heck-type sequence, and quantum chemical calculations indicate that C-H activation is involved in the terminating acylation step.

Recent applications of polymer supported organometallic catalysts in organic synthesis.

Recent developments concerning the application of polymer supported organometallic reagents in solid phase synthesis are reviewed, with a special focus on methodology for carbon-carbon formation. Examples of reactions that are covered include the classical Suzuki, Sonogashira and Heck coupings, but also aryl amination, epoxide opening, rearrangements, metathesis and cyclopropanation. Applications in the field of asymmetric synthesis are also discussed.

Palladium Catalyzed Stereoselective Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism.

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a Pd-catalyzed Heck reaction effects a regio- and stereoselective arylation of the cyclohexadiene ring, with 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations explain the selectivity both by a kinetic preference for the observed arylation position and by reversible carbopalladation in competing positions. Further product transformation allowed the formation of a tricyclic ketone possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from planar nonchiral benzoic acid in just a few steps.

Carbohydrate functionalization using cationic iron carbonyl complexes.

Cationic iron carbonyl cyclohexadiene complexes were employed in the derivatization of the 3-OH position of unprotected and protected methyl beta-D-galactopyranosides using two different approaches, giving access to galactopyranosides with an aromatic or cyclohexadienoic functionality in this position.

An iron carbonyl approach to the influenza neuraminidase inhibitor oseltamivir.

A novel synthetic route towards oseltamivir, an influenza neuraminidase inhibitor, has been achieved employing a cationic iron carbonyl complex, providing an alternate pathway with the potential to access diverse analogues.

Carbon-carbon and carbon-heteroatom bond formation on solid phase using cationic iron carbonyl complexes.

Iron-mediated methodology for the formation of carbon-carbon and carbon-heteroatom sp(3) bonds on solid phase has been developed. Treatment of a polymer-bound cationic iron cyclohexadienyl complex with carbon, oxygen, nitrogen, and phosphorus nucleophiles, followed by cleavage with amines and subsequent decomplexation, yielded 18 different cyclohexadienoic acid amides of high purity. [reaction: see text]

A biocatalytic route to P-chirogenic compounds by lipase-catalyzed desymmetrization of a prochiral phosphine-borane.

[reaction: see text] Available methods for synthesis of P-chirogenic compounds are limited. We set out to find biocatalytical means to introduce asymmetry in a phosphine-borane. After screening different lipases, Candida antarctica lipase B was found to give excellent results in the desymmetrization of prochiral phosphine-boranes. Both enantiomers can be obtained in up to >98% optical purity via acetylation or hydrolysis in processes that allow recycling of the substrates.

Synthesis and Characterization of New Binuclear Co(0) Complexes with Diphosphinoamine Ligands. A Potential Approach for Asymmetric Pauson-Khand Reactions.

The synthesis of P-N-P bidentate ligands and the evaluation, based on IR and X-ray data, of their pi-acceptor properties in the complexes derived from phenylacetylene-dicobalt hexacarbonyl have been carried out. In addition, the reactivity of these complexes in the Pauson-Khand reaction has been examined.