Visible light-promoted C(sp3)-H α-carbamoylation of cyclic ethers with isocyanides.

A protocol exploiting isocyanides as carbamoylating agents for the α-C(sp3)-H functionalization of cyclic ethers has been optimized via a combined visible light-driven hydrogen atom transfer/Lewis acid-catalyzed approach. The isocyanide substrate scope revealed an exquisite functional group compatibility (18 examples, with yields up to 99%). Both radical and polar trapping, kinetic isotopic effect and real-time NMR studies support the mechanistic hypothesis and provide insightful details for the design of new chemical processes involving the generation of oxocarbenium ions.

Site-Selective Radical Aromatic C-H Functionalization of Alloxazine and Flavin through Ground-State Single Electron Transfer.

Flavins and their alloxazine isomers are key chemical scaffolds for bioinspired electron transfer strategies. Their properties can be fine-tuned by functional groups, which must be introduced at an early stage of the synthesis as their aromatic ring is inert towards post-functionalization. We show that the introduction of a remote metal-binding redox site on alloxazine and flavin activates their aromatic ring towards direct C-H functionalization. Mechanistic studies are consistent with a synthetic sequence involving ground-state single electron transfer (SET) with an electrophilic source followed by radical-radical coupling. This unprecedented reactivity opens new opportunities in molecular editing of flavins by direct aromatic post-functionalization and the utility of the method is demonstrated with the site-selective C6 functionalization of alloxazine and flavin with a CF3 group, Br or Cl, that can be further elaborated into OH and aryl for chemical diversification.

Activation of lysosomal iron triggers ferroptosis in cancer.

Iron catalyses the oxidation of lipids in biological membranes and promotes a form of cell death referred to as ferroptosis1-3. Identifying where this chemistry takes place in the cell can inform the design of drugs capable of inducing or inhibiting ferroptosis in various disease-relevant settings. Whereas genetic approaches have revealed underlying mechanisms of lipid peroxide detoxification1,4,5, small molecules can provide unparalleled spatiotemporal control of the chemistry at work6. Here, we show that the ferroptosis inhibitor liproxstatin-1 (Lip-1) exerts a protective activity by inactivating iron in lysosomes. Based on this, we designed the bifunctional compound fentomycin that targets phospholipids at the plasma membrane and activates iron in lysosomes upon endocytosis, promoting oxidative degradation of phospholipids and ferroptosis. Fentomycin effectively kills primary sarcoma and pancreatic ductal adenocarcinoma cells. It acts as a lipolysis-targeting chimera (LIPTAC), preferentially targeting iron-rich CD44high cell-subpopulations7,8 associated with the metastatic disease and drug resistance9,10. Furthermore, we demonstrate that fentomycin also depletes CD44high cells in vivo and reduces intranodal tumour growth in an immunocompetent murine model of breast cancer metastasis. These data demonstrate that lysosomal iron triggers ferroptosis and that lysosomal iron redox chemistry can be exploited for therapeutic benefits.

Tsuji-Trost Based Cascades: From Passerini Adducts of Cinnamaldehyde to Allylated Oxazolones.

The Passerini coupling of cinnamaldehyde derivatives affords allylic esters that may behave as both electrophiles and nucleophiles in Tsuji-Trost reactions. We present herein the interaction of the latter with methylallylcarbonate, leading to the formation of oxazolidine-diones. The efficiency of the process relies on the building up of a CO2 overpressure in the medium. A reaction mechanism highlighting the reversibility of the Tsuji-Trost reaction is proposed for the process.

Regime Switch in the Dual-Catalyzed Coupling of Alkyl Silicates with Aryl Bromides.

Metallaphotoredox catalyzed cross-coupling of an arylbromide (Ar-Br) with an alkyl bis(catecholato)silicate (R-Si⊖ ) has been analyzed in depth using a continuum of analytical techniques (EPR, fluorine NMR, electrochemistry, photophysics) and modeling (micro-kinetics and DFT calculations). These studies converged on the impact of four control parameters consisting in the initial concentrations of the iridium photocatalyst ([Ir]0 ), nickel precatalyst ([Ni]0 ) and silicate ([R-Si⊖ ]0 ) as well as light intensity I0 for an efficient reaction between Ar-Br and R-Si⊖ . More precisely, two regimes were found to be possibly at play. The first one relies on an equimolar consumption of Ar-Br with R-Si⊖ smoothly leading to Ar-R, with no side-product from R-Si⊖ and a second one in which R-Si⊖ is simultaneously coupled to Ar-Br and degraded to R-H. This integrative approach could serve as a case study for the investigation of other metallaphotoredox catalysis manifolds of synthetic significance.

Assessing the Extent of Potential Inversion by Cyclic Voltammetry: Theory, Pitfalls, and Application to a Nickel Complex with Redox-Active Iminosemiquinone Ligands.

Potential inversion refers to the situation where a protein cofactor or a synthetic molecule can be oxidized or reduced twice in a cooperative manner; that is, the second electron transfer is easier than the first. This property is very important regarding the catalytic mechanism of enzymes that bifurcate electrons and the properties of bidirectional redox molecular catalysts that function in either direction of the reaction with no overpotential. Cyclic voltammetry is the most common technique for characterizing the thermodynamics and kinetics of electron transfer to or from these molecules. However, a gap in the literature is the absence of analytical predictions to help interpret the values of the voltammetric peak potentials when potential inversion occurs; the cyclic voltammograms are therefore often analyzed by simulating the data, with no discussion of the possibility of overfitting and often no estimation of the error on the determined parameters. Here we formulate the theory for the voltammetry of freely diffusing or surface-confined two-electron redox species in the experimentally relevant irreversible limit where the peak separation depends on the scan rate. We explain why the model is intrinsically underdetermined, and we illustrate this conclusion by analysis of the voltammetry of a nickel complex with redox-active iminosemiquinone ligands. Being able to characterize the thermodynamics of two-electron electron-transfer reactions will be crucial for designing more efficient catalysts.

Copper-Catalyzed Homocoupling of Boronic Acids: A Focus on B-to-Cu and Cu-to-Cu Transmetalations.

Controlling and understanding the Cu-catalyzed homocoupling reaction is crucial to prompt the development of efficient Cu-catalyzed cross-coupling reactions. The presence of a coordinating base (hydroxide and methoxide) enables the B-to-Cu(II) transmetalation from aryl boronic acid to CuIICl2 in methanol, through the formation of mixed Cu-(µ-OH)-B intermediates. A second B-to-Cu transmetalation to form bis-aryl Cu(II) complexes is disfavored. Instead, organocopper(II) dimers undergo a coupled transmetalation-electron transfer (TET) allowing the formation of bis-organocopper(III) complexes readily promoting reductive elimination. Based on this mechanism some guidelines are suggested to control the undesired formation of homocoupling product in Cu-catalyzed cross-coupling reactions.

Machine Learning Yield Prediction from NiCOlit, a Small-Size Literature Data Set of Nickel Catalyzed C-O Couplings.

Synthetic yield prediction using machine learning is intensively studied. Previous work has focused on two categories of data sets: high-throughput experimentation data, as an ideal case study, and data sets extracted from proprietary databases, which are known to have a strong reporting bias toward high yields. However, predicting yields using published reaction data remains elusive. To fill the gap, we built a data set on nickel-catalyzed cross-couplings extracted from organic reaction publications, including scope and optimization information. We demonstrate the importance of including optimization data as a source of failed experiments and emphasize how publication constraints shape the exploration of the chemical space by the synthetic community. While machine learning models still fail to perform out-of-sample predictions, this work shows that adding chemical knowledge enables fair predictions in a low-data regime. Eventually, we hope that this unique public database will foster further improvements of machine learning methods for reaction yield prediction in a more realistic context.

A Single Bioinspired Hexameric Nickel Catechol-Alloxazine Catalyst Combines Metal and Radical Mechanisms for Alkene Hydrosilylation.

Mechanisms combining organic radicals and metallic intermediates hold strong potential in homogeneous catalysis. Such activation modes require careful optimization of two interconnected processes: one for the generation of radicals and one for their productive integration towards the final product. We report that a bioinspired polymetallic nickel complex can combine ligand- and metal-centered reactivities to perform fast hydrosilylation of alkenes under mild conditions through an unusual dual radical- and metal-based mechanism. This earth-abundant polymetallic complex incorporating a catechol-alloxazine motif as redox-active ligand operates at low catalyst loading (0.25 mol%) and generates silyl radicals and a nickel-hydride intermediate through a hydrogen atom transfer (HAT) step. Evidence of an isomerization sequence enabling terminal hydrosilylation of internal alkenes points towards the involvement of the nickel-hydride species in chain walking. This single catalyst promotes a hybrid pathway by combining synergistically ligand and metal participation in both inner- and outer- sphere processes.

Electrochemical Benzylic C-H Functionalization with Isocyanides.

We report the challenging direct carbamoylation or cyanation of benzylic C(sp3)-H bonds with an isocyanide via an electrochemical process giving rise to structures that are encountered in several biologically relevant compounds and drugs. This transformation proceeds under mild conditions without the need for any external oxidant and avoids the necessity to start from a prefunctionalized benzylic substrate or the deployment of the cation pool method. The anodic oxidation of the benzylic position and the subsequent addition of the isocyanide lead to the formation of a C-C bond and to a nitrilium cation that hydrolyzes to yield α-aryl acetamide derivatives, whereas the elimination of a t-butyl cation delivers α-aryl acetonitrile derivatives.

Metal-Free Deoxygenation of Amine N-Oxides: Synthetic and Mechanistic Studies.

We report herein an unprecedented combination of light and P(III)/P(V) redox cycling for the efficient deoxygenation of aromatic amine N-oxides. Moreover, we discovered that a large variety of aliphatic amine N-oxides can easily be deoxygenated by using only phenylsilane. These practically simple approaches proceed well under metal-free conditions, tolerate many functionalities and are highly chemoselective. Combined experimental and computational studies enabled a deep understanding of factors controlling the reactivity of both aromatic and aliphatic amine N-oxides.

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis, Structural Studies and Reactivity.

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.

Copper-catalyzed transformation of alkyl nitriles to N-arylacetamide using diaryliodonium salts.

This work reports a simple and efficient method for the copper-catalyzed redox-neutral transformation of alkyl nitriles using eco-friendly diaryliodonium salts and leading to N-arylacetamides. The method features high efficiency, broad substrate scope and good functional group tolerance.

Electrochemical TEMPO-Catalyzed Oxidative Ugi-Type Reaction.

Oxidative isocyanide-based multicomponent reactions (oxidative IMCRs) are very useful tools for the rapid construction of molecular diversity starting from readily available and stable substrates. Despite all their benefits, such multicomponent reactions are underdeveloped and strictly limited to 3-component processes. Indeed, in the presence of several reaction partners, the oxidation event needs to be rigorously chemoselective, which becomes incredibly more intricate as the number of reactive components increases. Nonetheless, we could overcome this significant pitfall and reach the first oxidative Ugi-type 4-IMCR by capitalizing on a very mild and green TEMPO-catalyzed electro-oxidation process. Employing alcohols as aldehyde surrogates and in the notable absence of any supporting electrolyte, this transformation proved to be extremely chemoselective in the presence of an amine and was compatible with a wide range of alcohols, amines, isocyanides, and carboxylic acids.

Reversing Reactivity: Stereoselective Desulfurative 1,2-trans-O-Glycosylation of Anomeric Thiosugars with Carboxylic Acids under Copper or Cobalt Catalysis.

We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene. Moreover, this protocol turned out to have a broad scope, allowing the preparation of a wide range of complex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of pharmaceuticals by this method was also demonstrated. To obtain a closer insight into the reaction mechanism, cyclic voltammetry was performed.

Copper Reactivity Can Be Tuned to Catalyze the Stereoselective Synthesis of 2-Deoxyglycosides from Glycals.

We demonstrate that tuning the reactivity of Cu by the choice of oxidation state and counterion leads to the activation of both "armed" and "disarmed" type glycals toward direct glycosylation leading to the α-stereoselective synthesis of deoxyglycosides in good to excellent yields. Mechanistic studies show that CuI is essential for effective catalysis and stereocontrol and that the reaction proceeds through dual activation of both the enol ether as well as the OH nucleophile.

Formation of XPhos-Ligated Palladium(0) Complexes and Reactivity in Oxidative Additions.

Understanding the nature of the intermediate species operating within a palladium catalytic cycle is crucial for developing efficient cross-coupling reactions. Even though the XPhos/Pd(OAc)2 catalytic system has found numerous applications, the nature of the active catalytic species remains elusive. A Pd0 complex ligated to XPhos has been detected and characterized in situ for the first time using cyclic voltammetry and NMR techniques. In the presence of XPhos, Pd(OAc)2 initially associates with the ligand to form a complex in solution, which has been characterized as PdII (OAc)2 (XPhos). This PdII center is then reduced to the Pd0 (XPhos)2 species by an intramolecular process. This study also sheds light on the formation of PdI -PdI dimers. Finally, a kinetic study probes a dissociative mechanism for the oxidative addition with aryl halides involving Pd0 (XPhos) as the reactive species in equilibrium with the unreactive Pd0 (XPhos)2 . Remarkably, the reportedly poorly reactive PhCl reacts at room temperature in the oxidative addition, which confirms the crucial role of the XPhos ligand in the activation of aryl chlorides.

A Fluorescent False Neurotransmitter as a Dual Electrofluorescent Probe for Secretory Cell Models.

A dual electrofluorescent probe (FFN42) belonging to the fluorescent false neurotransmitter family was rationally designed for investigating cell secretion. This probe, which comprises a coumarin core with one amino and two hydroxy groups, is very promising due to its electroactive and fluorescent properties. The optimal excitation and emission wavelengths (380 nm and 470 nm respectively) make this probe adapted for use in fluorescence microscopy. FFN42 has a quantum yield of 0.18, a molar absorption coefficient of 12000 M-1 cm-1 and pKa values of 5.4 and 6.7 for the hydroxy groups. The electroactivity of FFN42 was evidenced on carbon fiber and ITO electrodes at relatively low oxidation potentials (0.24 V and 0.45 V vs Ag/AgCl respectively). Epifluorescence observations showed that FFN42 accumulated into secretory vesicles of PC12 and N13 cells. Toxicity tests further revealed that FFN42 had no lethal effect on these cells. Amperometric data obtained on carbon fiber electrodes proved that the probe is released by N13 cells.

Electroactive fluorescent false neurotransmitter FFN102 partially replaces dopamine in PC12 cell vesicles.

In the last decade, following fluorescent dyes and protein tags, pH sensitive false fluorescent neurotransmitters (FFN) were introduced and were valuable for labeling secretory vesicles and monitoring exocytosis at living cells. In particular, the synthetic analog of neurotransmitters FFN102 was shown to be an electroactive probe. Here, we show that FFN102 is suitable to be used as a bioanalytic probe at the widely used PC12 cell model. FFN102 was uptaken in the secretory vesicles of PC12 cells, partially replacing the endogenous dopamine stored in these vesicles. The different oxidation potentials of dopamine and FFN102 allowed to determine that ca. 12% of dopamine was replaced by FFN102. Moreover, the FFN102 was found to be over released through the initial fusion pore suggesting that it was mostly uptaken in fast diffusion compartment of the vesicles.

Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells.

The clinically approved drug metformin has been shown to selectively kill persister cancer cells through mechanisms that are not fully understood. To provide further mechanistic insights, we developed a drug surrogate that phenocopies metformin and can be labeled in situ by means of click chemistry. Firstly, we found this molecule to be more potent than metformin in several cancer cell models. Secondly, this technology enabled us to provide visual evidence of mitochondrial targeting with this class of drugs. A combination of fluorescence microscopy and cyclic voltammetry indicated that metformin targets mitochondrial copper, inducing the production of reactive oxygen species in this organelle, mitochondrial dysfunction and apoptosis. Importantly, this study revealed that mitochondrial copper is required for the maintenance of a mesenchymal state of human cancer cells, and that metformin can block the epithelial-to-mesenchymal transition, a biological process that normally accounts for the genesis of persister cancer cells, through direct copper targeting.