Correction to "De Novo Engineering of Pd-Metalloproteins and Their Use as Intracellular Catalysts".

[This corrects the article DOI: 10.1021/jacsau.4c00379.

Assembly of 2-Substituted Tetrahydroquinolines from -Methylbenzenesulfamides and Dienes, Using a C(sp)-H Activation/Annulation Sequence.

1,2,3,4-Tetrahydroquinolines (THQs) are essential structural cores in many natural products and pharmaceutical drugs. Especially relevant are those presenting substitutions at position 2, yet practical methods for their one-step assembly from acyclic precursors are very scarce. Herein, we present a straightforward approach to assembling these skeletons from -methylanilines using a palladium-catalyzed C(sp)-H activation/formal cycloaddition sequence.

Bioorthogonal Synthetic Chemistry Enabled by Visible-Light Photocatalysis.

The field of bioorthogonal chemistry has revolutionized our ability to interrogate and manipulate biological systems at the molecular level. However, the range of chemical reactions that can operate efficiently in biological environments without interfering with the native cellular machinery, remains limited. In this context, the rapidly growing area of photocatalysis offers a promising avenue for developing new type of bioorthogonal tools.

Cobalt-Catalyzed (3 + 2) Cycloaddition of Cyclopropene-Tethered Alkynes: Versatile Access to Bicyclic Cyclopentadienyl Systems and Their CpM Complexes.

Low-valent cobalt complexes can promote intramolecular (3 + 2) cycloadditions of alkyne-tethered cyclopropenes to provide bicyclic systems containing highly substituted cyclopentadienyl moieties with electronically diverse functional groups. The adducts can be easily transformed into new types of CpRh(III) and CpIr(III) complexes, which show catalytic activity in several relevant transformations. Preliminary computational (DFT) and experimental studies provide relevant information on the mechanistic peculiarities of the cobalt-catalyzed process and allow us to rationalize its advantages over the homologous rhodium-promoted reaction.

De Novo Engineering of Pd-Metalloproteins and Their Use as Intracellular Catalysts.

The development of transition metal-based catalytic platforms that promote bioorthogonal reactions inside living cells remains a major challenge in chemical biology. This is particularly true for palladium-based catalysts, which are very powerful in organic synthesis but perform poorly in the cellular environment, mainly due to their rapid deactivation. We now demonstrate that grafting Pd(II) complexes into engineered β-sheets of a model WW domain results in cell-compatible palladominiproteins that effectively catalyze depropargylation reactions inside HeLa cells.

Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained.

Gold(III) Auracycles Featuring C(sp)-Au-C(sp) Bonds: Synthesis and Mechanistic Insights into the Cycloauration Step.

The direct auration of arenes is a key step in numerous gold-catalyzed reactions. Although reported more than 100 years ago, understanding of its underlying mechanism has been hampered by the difficulties in the isolation of relevant intermediates given the propensity of gold(III) species to undergo reductive elimination. Here, we report the synthesis and isolation of a new family of intriguing zwitterionic [C(sp)^C(sp)]-auracyclopentanes, as well as of their alkyl-gold(III) precursors and demonstrate their value as mechanistic probes to study the C(sp)-Au bond-forming event.

Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

Background: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking.

Methods: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs).

Intracellular Synthesis of Indoles Enabled by Visible-Light Photocatalysis.

Performing abiotic synthetic transformations in live cell environments represents a new, promising approach to interrogate and manipulate biology and to uncover new types of biomedical tools. We now found that photocatalytic bond-forming reactions can be added to the toolbox of bioorthogonal synthetic chemistry. Specifically, we demonstrate that exogenous styryl aryl azides can be converted into indoles inside living mammalian cells under photocatalytic conditions.

Cobalt(I)-Catalyzed (3 + 2 + 2) Cycloaddition between Alkylidenecyclopropanes, Alkynes, and Alkenes.

Cobalt(I) catalysts equipped with bisphosphine ligands can be used to promote formal (3 + 2 + 2) intramolecular cycloadditions of enynylidenecyclopropanes of type . The method provides synthetically appealing 5,7,5-fused tricyclic systems in good yields and with complete diastereo- and chemoselectivity. Interestingly, its scope differs from that of previously reported annulations based on precious metal catalysts, specifically rhodium and palladium.

Axially Chiral 2-Hydroxybiaryls by Palladium-Catalyzed Enantioselective C-H Activation.

This article describes the discovery and development of a palladium-catalyzed asymmetric C-H olefination of 2-hydroxybiaryls. The strategy allows a direct assembly of optically active, axially chiral 2-substituted-2'-hydroxybiaryls from readily available precursors and demonstrates that the native hydroxy unit of the substrates can work as an efficient directing group for the C-H activation. This represents a substantial advantage over other approaches that require the preinstallation of metal coordinating units.

Molecular dynamics modelling of the interaction of a synthetic zinc-finger miniprotein with DNA.

We report the modelling of the DNA complex of an artificial miniprotein composed of two zinc finger modules and an AT-hook linking peptide. The computational study provides for the first time a structural view of these types of complexes, dissecting interactions that are key to modulate their stability. The relevance of these interactions was validated experimentally.

Ruthenium-catalyzed intermolecular alkene-alkyne couplings in biologically relevant media.

Cationic cyclopentadienyl Ru(ii) catalysts can efficiently promote mild intermolecular alkyne-alkene couplings in aqueous media, even in the presence of different biomolecular components, and in complex media like DMEM. The method can also be used for the derivatization of amino acids and peptides, therefore proposing a new way to label biomolecules with external tags. This C-C bond-forming reaction, based on simple alkene and alkyne reactants, can now be added to the toolbox of bioorthogonal reactions promoted by transition metal catalysts.

Controlling oncogenic KRAS signaling pathways with a Palladium-responsive peptide.

RAS oncoproteins are molecular switches associated with critical signaling pathways that regulate cell proliferation and differentiation. Mutations in the RAS family, mainly in the KRAS isoform, are responsible for some of the deadliest cancers, which has made this protein a major target in biomedical research. Here we demonstrate that a designed bis-histidine peptide derived from the αH helix of the cofactor SOS1 binds to KRAS with high affinity upon coordination to Pd(II).

Chiral Ligands Based on Binaphthyl Scaffolds for Pd-Catalyzed Enantioselective C-H Activation/Cycloaddition Reactions.

We report the first examples of the use of a new class of ligands (NOBINAc) for performing asymmetric C-H activations using palladium catalysts. These ligands combine the axial chirality of binaphthyl scaffolds with the bifunctional and bidentate coordination properties of mono-N-protected amino acids (MPAAs), which are well-known to favor Pd-promoted C-H activations via concerted metalation-deprotonation mechanisms. We demonstrate that our new ligands enable substantially higher enantioselectivities than MPAAs in the assembly of 2-benzazepines through formal (5 + 2) cycloadditions between homobenzyltriflamides or -methylbenzyltriflamides and allenes.

Exporting Homogeneous Transition Metal Catalysts to Biological Habitats.

The possibility of performing designed transition-metal catalyzed reactions in biological and living contexts can open unprecedented opportunities to interrogate and interfere with biology. However, the task is far from obvious, in part because of the presumed incompatibly between organometallic chemistry and complex aqueous environments. Nonetheless, in the past decade there has been a steady progress in this research area, and several transition-metal (TM)-catalyzed bioorthogonal and biocompatible reactions have been developed.

Organometallic catalysis in aqueous and biological environments: harnessing the power of metal carbenes.

Translating the power of transition metal catalysis to the native habitats of enzymes can significantly expand the possibilities of interrogating or manipulating natural biological systems, including living cells and organisms. This is especially relevant for organometallic reactions that have shown great potential in the field of organic synthesis, like the metal-catalyzed transfer of carbenes. While, at first sight, performing metal carbene chemistry in aqueous solvents, and especially in biologically relevant mixtures, does not seem obvious, in recent years there has been a growing number of reports demonstrating the feasibility of the task.

Selective recognition of A/T-rich DNA 3-way junctions with a three-fold symmetric tripeptide.

Non-canonical DNA structures, particularly 3-Way Junctions (3WJs) that are transiently formed during DNA replication, have recently emerged as promising chemotherapeutic targets. Here, we describe a new approach to target 3WJs that relies on the cooperative and sequence-selective recognition of A/T-rich duplex DNA branches by three AT-Hook peptides attached to a three-fold symmetric and fluorogenic 1,3,5-tristyrylbenzene core.

Deactivation of a dimeric DNA-binding peptide through a palladium-mediated self-immolative cleavage.

Herein, we describe an approach for the on-demand disassembly of dimeric peptides using a palladium-mediated cleavage of a designed self-immolative linker. The utility of the strategy is demonstrated for the case of dimeric basic regions of ZIP transcription factors. While the dimer binds designed DNA sequences with good affinities, the peptide-DNA complex can be readily dismounted by addition of palladium reagents that trigger the cleavage of the spacer, and the release of unfunctional monomeric peptides.

Palladium-Catalyzed Tandem Cycloisomerization/Cross-Coupling of Carbonyl- and Imine-Tethered Alkylidenecyclopropanes.

Pd catalysts featuring phosphorus-based monodentate ligands can detour the reactivity of carbonyl-tethered alkylidenecyclopropanes (ACPs) from standard (3+2) cycloadditions towards tandem cycloisomerization/cross-coupling processes. This new reactivity lies on the formation of key π-allyl oxapalladacyclic intermediates, which are subsequently trapped with external nucleophilic partners, instead of undergoing canonical C-O reductive eliminations. Importantly, the use of imine-tethered ACP's is also feasible.

Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp )-H Bonds.

The selective functionalization of C(sp )-H bonds using transition-metal catalysis is among the more attractive transformations of modern synthetic chemistry. In addition to its inherent atom economy, such reactions open unconventional retrosynthetic pathways that can streamline synthetic processes. However, the activation of intrinsically inert C(sp )-H bonds, and the selection among very similar C-H bonds, represent highly challenging goals.

Plasmonic-Assisted Thermocyclizations in Living Cells Using Metal-Organic Framework Based Nanoreactors.

We describe a microporous plasmonic nanoreactor to carry out designed near-infrared (NIR)-driven photothermal cyclizations inside living cells. As a proof of concept, we chose an intramolecular cyclization that is based on the nucleophilic attack of a pyridine onto an electrophilic carbon, a process that requires high activation energies and is typically achieved in bulk solution by heating at ∼90 °C. The core-shell nanoreactor (NR) has been designed to include a gold nanostar core, which is embedded within a metal-organic framework (MOF) based on a polymer-stabilized zeolitic imidazole framework-8 (ZIF-8).

Exporting Metal-Carbene Chemistry to Live Mammalian Cells: Copper-Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N-H Carbene Insertions.

Implementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells.

Assembly of Tetrahydroquinolines and 2-Benzazepines by Pd-Catalyzed Cycloadditions Involving the Activation of C(sp)-H Bonds.

Cycloaddition reactions are among the most practical strategies to assemble cyclic products; however, they usually require the presence of reactive functional groups in the reactants. Here, we report a palladium-catalyzed formal (4 + 2) cycloaddition that involves the activation of C(sp)-H bonds and provides a direct, unconventional entry to tetrahydroquinoline skeletons. The reaction utilizes amidotolyl precursors and allenes as annulation partners, and is catalyzed by Pd(II) precursors in combination with specific -acetylated amino acid ligands.