α-Aminophosphonate inhibitors of metallo-ß-lactamases NDM-1 and VIM-2.

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-ß-lactamases is of particular concern as these enzymes degrade ß-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-ß-lactamases could allow the continued use of existing ß-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities (IC50 4.1-506 µM) of a series of novel non-cytotoxic α-aminophosphonate-based inhibitor candidates are presented herein. We disclose the solution NMR spectroscopic and computational investigation of their NDM-1 and VIM-2 binding sites and binding modes. Whereas the binding modes of the inhibitors are similar, VIM-2 showed a somewhat higher conformational flexibility, and complexed a larger number of inhibitor candidates in more varying binding modes than NDM-1. Phosphonate-type inhibitors may be potential candidates for development into therapeutics to combat metallo-ß-lactamase resistant bacteria.

Charge-controlled Pd catalysis enables the meta-C-H activation and olefination of arenes.

The regioselective C-H activation of arenes remains one of the most promising techniques for accessing highly important functionalized motifs. Such functionalizations can generally be achieved through directed and non-directed processes. The directed approach requires a covalently attached directing group (DG) on the substrate to induce reactivity and selectivity and therefore intrinsically leaves a functional group at the point of attachment within the molecule, even after the tailored DG has been removed. Conversely, non-directed methods typically suffer from regioselectivity issues, especially for unbiased substrates. Herein, we report a unique approach that employs weak charge-charge and charge-dipole interactions to enable the meta-selective activation and olefination of arenes to address these challenges in Pd catalysis. The charged moiety can easily be converted to uncharged simple arenes by hydrogenation or cross-coupling. In-depth mechanistic studies prove that the charge is responsible for the observed selectivity. We expect our studies to be generalizable and thereby enable further regioselective transformations.

Palladium-Catalyzed Nondirected Late-Stage C-H Deuteration of Arenes.

We describe a palladium-catalyzed nondirected late-stage deuteration of arenes. Key aspects include the use of D2O as a convenient and easily available deuterium source and the discovery of highly active N,N-bidentate ligands containing an N-acylsulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labeling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, among other applications, will prove useful as a tool in drug development processes and for mechanistic studies.

Rhodium(i) complexes derived from tris(isopropyl)-azaphosphatrane-controlling the metal-ligand interplay.

Proazaphosphatranes are intriguing ligand architectures comprising a bicyclic cage of flexible nature. They can undergo structural deformations due to transannulation while displaying modular electronic and steric properties. Herein, we report the synthesis and coordination chemistry of rhodium(i) complexes bearing a tris(isopropyl)-azaphosphatrane (TiPrAP) ligand. The molecular structure of the primary complex (1) revealed the insertion of the metal center into a P-N bond of the ligand. The addition of a Lewis acid, i.e., lithium chloride, promoted the dynamic behavior of the complex in the solution, which was studied by state-of-the-art NMR spectroscopy. Substituting the cyclooctadiene ligand at the metal center with triphenylphosphine or 2-pyridyldiphenylphosphine unveiled the adaptive nature of the TiPrAP backbone capable of switching its axial nitrogen from interacting with the phosphorus atom to coordinate the rhodium center. This led the entire ligand edifice to change its binding to rhodium from a bidentate to tridentate coordination. Altogether, our study shows that introducing a TiPrAP ligand allows for unique molecular control of the immediate environment of the metal center, opening perspectives in controlled bond activation and catalysis.