Deuteration of Arenes via Pd-Catalyzed C–H Activation – A Lesson in Nondirected C–H Activation, Isotopic Labelling and NMR Characterization

Isotopic labelling is an important tool in medicinal research, metabolomics, and for understanding reaction mechanisms. In this context, transition metal catalyzed C–H activation has emerged as a key technology for deuterium incorporation via hydrogen isotope exchange. A detailed and easy-to-implement experimental procedure for a nondirected arene deuteration has been developed that exclusively uses commercial equipment and chemicals. The protocol is ideally suited for students and other prospective applicants who are not experts in catalysis. The degree of deuterium incorporation was analyzed via different means like mass spectrometry, 1H and 2H NMR. A hands-on understanding of quantitative NMR as well as the influence of H/D exchange on experimental spectra was conveyed by comparative NMR spin simulations. Students were measurably familiarized with the concepts of C H activation, isotope effects, and basics in experimental catalysis

Catalytic Formal Carbyne Transformation of Phosphorus Ylides

The selective functionalization of unreactive C–H bonds over reactive polar functionalities paves the way for the efficient synthesis of complex molecular frameworks. Here, we report a consecutive C–H alkylation and Wittig-type reaction of phosphorus ylides, enabling the conversion of inert C–H and C=P bonds into C–C and C=C bonds, respectively. Under blue-light irradiation and with the aid of an appropriate photoredox catalyst, a mixture encompassing phosphorus ylides, electron-rich olefins, and unsaturated carbonyl compounds adeptly undergoes a previously elusive three-component cycloaddition. This transformation allows for the rapid construction of the synthetically versatile functionalized six-membered carbocycles from readily available substrates

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

We describe a palladium catalyzed non-directed 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-acyl sulfonamide group. The reported protocol enables high degrees of deuterium incorporation via a reversible C-H activation step and features an extraordinary functional group tolerance, allowing for the deuteration of complex substrates. This is exemplified by the late-stage isotopic labelling of various pharmaceutically relevant motifs and related scaffolds. We expect that this method, amongst other applications, will prove useful as a tool in drug development processes and for mechanistic studies

Charge-Controlled Pd-Catalysis Enables the Meta-C–H Activation/ Olefination of Arenes

The regioselective C–H activation of arenes remains one of the most promising techniques to access 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 to address these challenges in palladium catalysis that employs weak charge-charge and charge-dipole interactions to enable the meta-selective activation/olefination of arenes. The charged moiety could 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 thereby enabling further regioselective transformations

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

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-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-β-lactamase resistant bacteria.peerReviewe

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

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-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-β-lactamase resistant bacteria