Nina Kann

Transition-Metal-Catalyzed Propargylic Substitution

(Chemical Equation Presented) Keen for a share in the glory: Until recently, the title reaction stood in the shadows, its famous sister, catalytic allylic substitution, in the limelight. Catalytic propargylic substitution has now emerged as an efficient transformation that can be catalyzed by a variety of transition metals (see picture). Among the recent developments are copper-catalyzed asymmetric propargylic amination reactions. Nu = nucleophile

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.

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.

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.

Modular Asymmetric Synthesis of P-Chirogenic β-Amino Phosphine Boranes

A short concise route to beta-aminophosphine boranes is presented via the desymmetrization of prochiral phosphine boranes, forming P-chirogenic aldehydes that are rapidly transformed to the target compounds employing reductive amination under microwave irradiation. This sequence provides a modular route to P-chirogenic P,N ligands, and in addition, the intermediate aldehydes are versatile P-chiral building blocks for ligand design in general. An alternative pathway via the corresponding alpha-carboxyphosphines is also described. The ligands were subsequently evalutated in the asymmetric conjugate addition of diethylzinc to trans-beta-nitrostyrene.

Two novel fusion inhibitors of human respiratory syncytial virus.

To search for novel drugs against human respiratory syncytial virus (RSV), we have screened a diversity collection of 16,671 compounds for anti-RSV activity in cultures of HEp-2 cells. Two of the hit compounds, i.e., the N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (designated as P13) and the 1,4-bis(3-methyl-4-pyridinyl)-1,4-diazepane (designated as C15), reduced the virus infectivity with IC₅₀ values of 0.11 and 0.13μM respectively. The concentration of P13 and C15 that reduced the viability of HEp-2 cells by 50% was 310 and 75μM respectively. Both P13 and C15 exhibited no direct virucidal activity or inhibitory effects on the virus attachment to cells. However, to inhibit formation of RSV-induced syncytial plaques P13 and C15 had to be present during the virus entry into the cells and the cell-to-cell transmission of the virus. The RSV multiplication in HEp-2 cells in the presence of P13 or C15 resulted in rapid selection of viral variants that were ∼1000 times less sensitive to these drugs than original virus. Sequencing of resistant viruses revealed presence of amino acid substitutions in the F protein of RSV, i.e., the D489G for C15-selected, and the T400I and N197T (some clones) for the P13-selected virus variants. In conclusion, we have identified two novel fusion inhibitors of RSV, and the detailed understanding of their mode of antiviral activity including selection for the drug resistant viral variants may help to develop selective and efficient anti-RSV drugs.

Applications of the Nicholas Reaction in the Synthesis of Natural Products

The Nicholas reaction involves the treatment of a cobalt carbonyl-stabilized propargylic cation with a variety of nucleophiles to form a new carbon-carbon or carbon-heteroatom bond. Several features of this reaction make it especially well suited for applications in natural product synthesis, in particular when cyclic and polycyclic target molecules are involved. This review summarizes the results in this area from the last ten years, including approaches towards terpenes, alkaloids and marine natural products.

Solid phase organometallic chemistry

This review covers recent results in the area of solid phase organometallic chemistry during the period 2000–2006. The focus is on carbon–carbon bond formation, but other aspects of organometallic reactions are also discussed. This includes the use of metal complexes as linkers, synthesis of biologically active compounds and complex natural product analogues, development of diversifying cleavage strategies, and testing the stability of new linkers and polymers under different reaction conditions. In many cases a direct comparison has been made between solid phase and solution phase chemistry. Thus, the advantages of performing reactions on polymer-supported substrates in terms of avoiding side reactions and facilitating product/metal separation are highlighted.

Parallel and Modular Synthesis of P-Chirogenic P,O-Ligands

A modular synthesis of P-chirogenic α-alkoxyphosphine ligands has been developed, allowing for the variation of two of the three groups on phosphorus. Oxidation and concomitant desymmetrization of a prochiral alkyl- or aryldimethylphosphine borane afforded α-hydroxyphosphines, which were subsequently deprotonated and alkylated in a parallel fashion. The choice of base and temperature for the alkylation step was found to be crucial for the outcome of the reaction. Selected ligands were subsequently screened in palladium catalyzed allylic substitution, affording product in good to excellent yield but moderate enantioselectivity, indicating that further optimization of the ligand structures is desirable to increase the stereoselectivity.

Solid phase synthesis using organometallic reagents

The scope of organometallic reactions on solid phase has lately expanded to include many new reactions. In this review, we summarise the recent developments in this area, covering reactions such as metathesis, carbene insertion, radical-mediated transformations, the use of organomagnesium, organozinc and organocopper reagents, applications of titanium alkylidenes for alkene synthesis, as well as the Pauson-Khand reaction, hydroformylation and other methods using metal carbonyl reagents. Palladium-catalysed reactions are not included as this area has been recently reviewed (vide infra).