Showing papers in "Helvetica Chimica Acta in 2021"

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

Abstract: Thiol-mediated uptake is emerging as method of choice to penetrate cells. This study focuses on irreversible covalent inhibitors of thiol-mediated uptake. High-content high-throughput screening of the so far largest collection of hypervalent iodine reagents affords inhibitors that are more than 250 times more active than Ellman’s reagent and rival the best dynamic covalent inhibitors. Comparison with other irreversible reagents reveals that inhibition within one series follows reactivity, whereas inhibition across series deviates from reactivity. These trends support that molecular recognition, besides dynamic covalent exchange, contributes significantly to thiol-mediated uptake. The most powerful inhibitors besides the best hypervalent iodine reagents were Fukuyama’s nosyl protecting group and super-cinnamaldehydes that have been introduced as irreversible activators of the pain receptor TRPA1. Considering that several viruses use different forms of thiol-mediated uptake to enter cells, the identification of new irreversible inhibitors of thiol-mediated uptake is of general interest for the discovery of new antivirals.

Development and Molecular Understanding of a Pd-catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis

Abstract: A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic Ncyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand σ–donation, π–acidity and sterics are key drivers that govern yield. Categorization into three ligand groups – monophosphines, bisphosphines and miscellaneous – was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong σ–donating, weak π–accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts.

Design of Chiral NHC-Carboxylates as Potential Ligands for Pd-Catalyzed Enantioselective C−H Activation

Abstract: Despite numerous efforts, the synthesis of scalemic carbo- and heterocycles through Pd0-catalyzed C(sp3)-H activation employing chiral ancillary ligands or chiral bases is still limited Inspired by the recently reported outstanding performance of IBiox-type NHC ligands and bifunctional ligands in similar transformations, a new class of bifunctional NHC-ligands bearing a pendant carboxylate group was designed A library of 10 imidazolium-carboxylic acids was obtained in five to six steps from enantiopure L-tert-leucinol In addition, four well-defined Pd(DMBPA)-NHC palladacycles were synthesized in good to excellent yields from the corresponding imidazolium precursors These complexes were tested in a prototypical C(sp3)-H arylation reaction, and the most active one afforded the indoline product in low yield but significant enantioselectivity These new bifunctional NHCs could find broader applications in catalytic enantioselective transformations occurring under milder conditions

Halogen Bonding of N-Halosuccinimides with Amines and Effects of Brønsted Acids in Quinuclidine-Catalyzed Halocyclizations

Abstract: An arguable expectation in halogen chemistry is that an amine will react oxidatively with an Nhalosuccinimide (NXS) to form an N-halogenated species bearing a covalent N