Nickel-Catalyzed Enantio- and Diastereoselective Synthesis of Fluorine-Containing Vicinal Stereogenic Centers.

The construction of fluorinated architectures has been a topic of interest to medicinal chemists due to their unique ability to improve the pharmacokinetic properties of bioactive compounds. However, the stereoselective synthesis of fluoro-organic compounds with vicinal stereogenic centers is a challenge. Herein, we present a directing-groupfree nickel-hydride catalyzed hydroalkylation of fluoroalkenes to afford fluorinated motifs with two adjacent chiral centers in excellent yields and stereoselectivities. Our method provides expedient access to biologically relevant, highly enantioenriched organofluorine compounds. Furthermore, the strategy can be used for the diastereo- and enantioselective synthesis of vicinal difluorides, which have recently gained attention in the fields of organocatalysis and peptide mimics.

Copper-Catalyzed Benzylic Functionalization of Lignin-Derived Monomers.

Within the field of lignin biorefining, significant research effort has been dedicated to the advancement of catalytic methods for lignocellulose depolymerization. However, another key challenge in lignin valorization is the conversion of the obtained monomers into higher value-added products. To address this challenge, new catalytic methods that can fully embrace the inherent complexity of their target substrates are needed. Here, we describe copper-catalyzed reactions for benzylic functionalization of lignin-derived phenolics via intermediate formation of hexafluoroisopropoxy-masked para-quinone methides (p-QMs). By controlling the rates of copper catalyst turnover and p-QM release, we have developed copper-catalyzed allylation and alkynylation reactions of lignin-derived monomers to install various unsaturated fragments amenable to further synthetic applications.

Photocatalytic Decarboxylative Coupling of Aliphatic N-hydroxyphthalimide Esters with Polyfluoroaryl Nucleophiles.

Polyfluoroarenes are an important class of compounds in medical and material chemistry. The synthesis of alkylated polyfluoroarenes remains challenging. Here we describe a decarboxylative coupling reaction of N-hydroxyphthalimide esters of aliphatic carboxylic acids with polyfluoroaryl zinc reagents (Zn-ArF ) via synergetic photoredox and copper catalysis. This method readily converts primary and secondary alkyl carboxylic acids into the corresponding polyfluoroaryl compounds, which could have a wide range of F-content (2F-5F) and variable F-substitution patterns on the aryl groups. Broad scope and good functional group compatibility were achieved, including on substrates derived from natural products and pharmaceuticals. Mechanistic study revealed that a [Cu-(ArF )2 ] species could be responsible for the transfer of polyfluoroaryl groups to the alkyl radicals.

Tetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylates as inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

The reactions between 5-substituted pyrazolidine-3-ones, aldehydes, and methyl methacrylate provided tetrahydropyrazolo[1,2-a]pyrazole-1-carboxylates as mixtures of syn- and anti-diastereomers. Testing for inhibition of dihydroorotate dehydrogenase of Plasmodium falciparum (PfDHODH) revealed high activity of some anti-isomers of the methyl esters, while the corresponding carboxylic acids and carboxamides were not active. The most active representative, methyl (1S*,3S*,5R*)-1,5-dimethyl-7-oxo-3-phenyltetrahydro-1H,5H-pyrazolo[1,2-a]pyrazole-1-carboxylate (IC50 = 2.9 ±â€¯0.3 µM), also exhibited very high selectivity of the parasite enzyme vs. the human enzyme, PfDHODH/HsDHODH > 350. According to the molecular docking score, this high activity is explainable by synergic interactions of the methyl, phenyl and the CO2Me substituent with the hydrophobic pockets in the active site of the enzyme. The carboxylic acid and carboxamides derived from this compound did not inhibit PfDHODH.