A druggable copper-signalling pathway that drives inflammation.

Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

Chiral Sulfoximine Mediated Cobalt-Catalyzed Atropselective C-H Annulation of Ynamides.

An achiral Cp*Co(III)-catalyzed enantioselective C-H activation/annulation of chiral sulfoximine-enabled thioamides with ynamides is presented herein. This method successfully synthesizes axially chiral five-membered 2-amidoindenones with good enantiocontrol. Interestingly, the annulation with chiral oxazolidone-containing ynamides could provide a separable mixture of diastereomers (up to ~10:1 dr). Moreover, enantiopure sulfoximines could be recovered with ~99% purity, making this method practical. DFT studies show valuable insight into the mechanism and origin of asymmetric induction.

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters.

Synthetic application of asymmetric catalysis relies on strategic alignment of bond construction to creation of chirality of a target molecule. Remote desymmetrization offers distinctive advantages of spatial decoupling of catalytic transformation and generation of a stereogenic element. However, such spatial separation presents substantial difficulties for the chiral catalyst to discriminate distant enantiotopic sites through a reaction three or more bonds away from a prochirality center. Here, we report a strategy that establishes acyclic quaternary carbon stereocenters through cross-coupling reactions at distal positions of aryl substituents. The new class of amino acid-derived ionic chiral catalysts enables desymmetrizing (enantiotopic-group-selective) Suzuki-Miyaura reaction, Sonogashira reaction, and Buchwald-Hartwig amination between diverse diarylmethane scaffolds and aryl, alkynyl, and amino coupling partners, providing rapid access to enantioenriched molecules that project substituents to widely spaced positions in the three-dimensional space. Experimental and computational investigations reveal electrostatic steering of substrates by the C-terminus of chiral ligands through ionic interactions. Cooperative ion-dipole interactions between the catalyst's amide group and potassium cation aid in the preorganization that transmits asymmetry to the product. This study demonstrates that it is practical to achieve precise long-range stereocontrol through engineering the spatial arrangements of the ionic catalysts' substrate-recognizing groups and metal centers.

Gold-Catalyzed Heck Reaction.

Herein, we report a gold-catalyzed Heck reaction facilitated by the ligand-enabled Au(I)/Au(III) redox catalysis. The elementary organometallic steps such as migratory insertion and ß-hydride elimination have been realized in the catalytic fashion for the first time in gold chemistry. The present methodology not only overcomes the limitations of previously known transition metal-catalyzed Heck reactions such as the requirement of specialized substrates and formation of a mixture of regioisomeric products as a result of the undesirable chain-walking process but also offers complementary regioselectivity as compared to other transition metal catalysis.

Enantioselective and Regiodivergent Synthesis of Dihydro-1,2-oxazines from Triene-Carbamates via Chiral Phosphoric Acid-Catalysis.

Conjugated trienes are fascinating building blocks for the rapid construction of complex polycyclic compounds. However, limited success has been achieved due to the challenging regioselectivity control. Herein, we report an enantio- and diastereoselective process allowing to regioselectively control the functionalization of NH-triene-carbamates. Synthesis of chiral cis-3,6-dihydro-2H-1,2-oxazines is achieved by a chiral phosphoric acid catalyzed Nitroso-Diels-Alder cycloaddition involving [(1E,3E,5E)-hexa-1,3,5-trien-1-yl]carbamates. Moreover, modular access to three different regioisomers with excellent diastereoselectivities and high to excellent enantioselectivities is obtained by a careful choice of the reaction conditions. A computational study reveals that the regioselectivity is influenced by the steric demand of the substituents at the 6-position of the triene, as well as noncovalent interactions between the two cycloaddition partners. Utility of each regioisomeric cycloadduct is highlighted by a variety of synthetic transformations.

Unlocking the Chain-Walking Process in Gold Catalysis.

The successful realization of gold-catalyzed chain-walking reactions, facilitated by ligand-enabled Au(I)/Au(III) redox catalysis, has been reported for the first time. This breakthrough has led to the development of gold-catalyzed annulation reaction of alkenes with iodoarenes by leveraging the interplay of chain-walking and π-activation reactivity mode. The reaction mechanism has been elucidated through comprehensive experimental and computational studies.

A Three-Component Arene Difunctionalization: Merger of C(sp3 )/(sp2 )-H Bond Addition.

A tandem three-component C-H bond addition involving the activation of an inert C(sp3 )-H bond is reported. The process enables the direct regioselective synthesis of 1,2-difunctionalized arenes with the formation of C(sp3 )- and C(sp2 )-C(arene) bonds. 2-Iodobenzoic acid derivatives behave as masked bifunctional reagent (BFR) and react with 2-pyridyl-methyl sulfoximine (MPyS) protected aliphatic acids bearing α,α-disubstituted groups, and alkenes to produce ß-aryl-δ-alkenyl amide derivatives in a single operation. The transformation involves Pd(II)/Pd(IV) and Pd(II)/Pd(0) catalytic systems. Detailed mechanistic studies, including density functional theory (DFT) calculations, reveal the formation of large T-shaped palladacycles and the onset of a 1,2-palladium migration via decarboxylation.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

Experimental and Theoretical Investigation of an Azaoxyallyl Cation-Templated Intramolecular Aryl Amination Leading to Oxindole Derivatives.

Herein, development and detailed investigation of a SN '-type intramolecular aromatic substitution reaction involving α-arylazaoxyallyl cation intermediate, is disclosed. The study showcased that while α-aryl-α-chlorohydroxamate could be activated by a combination of base and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) into the corresponding azaoxyallyl cations, it could further emerge into a π-extended species involving the adjacent α-aryl moiety, and this transition is contingent on electronic effects of the aromatic ring as well as on α-substituents. An effective activation of the α-aromatic ring could pave the path for intramolecular Ar(Csp2 )-N bond formation towards oxindoles. Control experiments and DFT calculations suggested that a non-pericyclic nucleophilic amination pathway is most likely operative and precluded the possibility of concerted or electrophilic amination mechanism. HFIP as the reaction solvent plays pivotal roles in the transformation.

Leveraging the Domino Skeletal Expansion of Thia-/Selenazolidinones via Nitrogen-Atom Transfer in Hexafluoroisopropanol: Room Temperature Access to Six-Membered S/Se,N-Heterocycles.

Herein, a highly regioselective domino skeletal-expansion process that transforms 2-aminothiazolidinone into six-membered S,N-heterocycle is developed with the aid of TMS-azide in hexafluoroisopropanol (HFIP) at ambient temperature. Functioning of the C2 tertiary amine as latent reactive group on thiazolidinone moiety was the key to this development, which allowed relay substitution with azide and imparted subsequent ring-expansion under metal/acid free-conditions. The reaction also underscored an intermolecular nitrogen-atom transfer process from TMS-azide leading to final products, where any intermediary azidothiazolidinone was absent. The strategy was extendable to analogous synthesis of Se,N-heterocycles, and furthermore, late-stage drug-modification and follow-up transformations were also performed. Density functional theory calculations and control experiments provided important mechanistic insights and highlighted potential roles of HFIP in the transformation.

Acid-Promoted Iso-Nazarov Cyclization of Conjugated trans-Dienones and Dienals for the Synthesis of 2-Cyclopentenones.

The acid-promoted cyclization of all-trans linearly conjugated dienones and dienals constitutes a synthetic strategy for the construction of 2-cyclopentenones.

Unbiased C3-Electrophilic Indoles: Triflic Acid Mediated C3-Regioselective Hydroarylation of N-H Indoles.

The direct dearomative addition of arenes to the C3 position of unprotected indoles is reported under operationally simple conditions, using triflic acid at room temperature. The present regioselective hydroarylation is a straightforward manner to generate an electrophilic indole at the C3 position from unbiased indoles in sharp contrast to previous strategies. This atom-economical method delivers biologically relevant 3-arylindolines and 3,3-spiroindolines in high yields and regioselectivities from both intra- and intermolecular processes. DFT computations suggest the stabilization of cationic or dicationic intermediates with H-bonded (TfOH)n clusters.

Palladium-Catalyzed Silylcyanation of Ynamides: Regio- and Stereoselective Access to Tetrasubstituted 3-Silyl-2-Aminoacrylonitriles.

The palladium-catalyzed silylcyanation of ynamides is described. This reaction is fully regioselective, delivering tetrasubstituted 2-aminoacrylonitriles derivatives exclusively. Unexpectedly, the nature (aryl or alkyl) of the substituent located at the ß-position of the ynamide directly controls the stereoselectivity. The reaction tolerates a number of functional groups and can be considered as the first general access to fully substituted 2-aminoacrylonitriles. Given the singular reactivity observed, a computational study was performed to shed light on the mechanism of this intriguing transformation. Relying on the specific reactivity of the newly installed vinylsilane functionality, the scope of 2-aminoacrylonitriles has been enlarged by postfunctionalization.

Enantioselective and Diastereodivergent Synthesis of Spiroindolenines via Chiral Phosphoric Acid-Catalyzed Cycloaddition.

A diastereodivergent and enantioselective synthesis of chiral spirocyclohexyl-indolenines with four contiguous stereogenic centers is achieved by a chiral phosphoric acid-catalyzed cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-dienecarbamates. Modular access to two different diastereoisomers with high enantioselectivities was obtained by careful choice of reaction conditions. Their functional group manipulation provides an efficient access to enantioenriched spirocyclohexyl-indolines and -oxindoles. The origins of this stereocontrol have been identified using DFT calculations, which reveal an unexpected mechanism compared to our previous work dealing with enecarbamates.

Concerted vs Nonconcerted Metalation-Deprotonation in Orthogonal Direct C-H Arylation of Heterocycles with Halides: A Computational Study.

A computational study on the base-assisted orthogonal C-H arylation of azoles with halides is reported. Although concerted metalation-deprotonation (CMD) is favored under acetate assistance at the C5 site that displays the best balance of nucleophilic and acidic character, the most acidic C2 site may be selectively targeted under carbonate assistance by taking advantage of a carbanionic-type (or non-concerted) metalation-deprotonation mechanism (nCMD). For the latter, several experimental probes including base, ligand, and solvent effects have been collected in favor of an outer-sphere deprotonation process after the formation of a [(Ln)(N1-heteroaryl)PdArX] complex. However, no computational analysis of this fundamental elementary step has been so far provided. We have carried out a series of density functional theory (DFT) calculations that delineate the structural and energetic aspects of the nCMD pathway. Starting with the oxa(thia)zole-4-carboxylates selected in our group to engineer the competitive C2 vs C5 arylation in azoles, we show that the energy barrier of the C2 anion generation is lying unexpectedly lower than the prior heterocycle coordination to Pd that is eventually identified as the rate-determining step. These calculations provide satisfactory explanations for the experimental observations of the divergence between nCMD and CMD reactivity, and notably a lower barrier at the C2 site for the nCMD process. On the other hand, the nCMD process is ineffective at the C5 site. Evaluation of various azoles reveals that the nCMD mechanism at C2 is viable from the most acidic (benzo)oxazoles to moderately acidic (benzo)thiazoles, as well as weakly acidic imidazoles. In all cases, in accordance with previously reported experimental data in orthogonal direct C-H arylation of azoles, the nCMD route is found energetically competitive to the CMD one at C5 for all azoles, except for imidazole which needs stronger basic conditions than simple carbonate assistance. Additionally, the acetate ligand, which is the base of choice for CMD, was found inefficient for nCMD and the comparative performance of acetate vs carbonate to assist CMD in the azole series reveals also considerable changes from electronically close but environmentally divergent C5-H vs C2-H bonds.

Reaction of Phosphines with 1-Azido-(2-halogenomethyl)benzene Giving Aminophosphonium-Substituted Indazoles.

The reaction between a 1-azido-(2-halogenomethyl)benzene and a phosphine gives different products depending on the nature of the halogen, the phosphine itself, and the solvent employed. While PPh3 (2 equiv) reacts with the chloro reagent in toluene to give the expected iminophosphorane-phosphonium adduct, trialkylphosphines (PCy3 and PEt3) surprisingly furnish an aminophosphonium substituted by a zwitterionic indazole. The bicyclic product can also form from PPh3 using the bromo reagent in acetonitrile. A mechanism is proposed for this cyclization based on DFT calculations.

DFT Analysis into the Calcium(II)-Catalyzed Coupling of Alcohols With Vinylboronic Acids: Cooperativity of Two Different Lewis Acids and Counterion Effects.

The mechanism of the calcium-catalyzed coupling of alcohols with vinylboronic acids has been analyzed by means of density functional theory computations. This study reveals that the calcium and boron Lewis acids associate to form a superelectrophile able to promote a pericyclic group transfer reaction with allyl alcohols. With other alcohols, the two Lewis acids act synergistically to activate the OH functionality and trigger a SNi reaction pathway. These two mechanisms are affected by the nature of the counterions, which has been rationalized by electronic and steric factors.

Zirconium-Catalyzed Hydroalumination of C═O Bonds: Site-Selective De-O-acetylation of Peracetylated Compounds and Mechanistic Insights.

An unprecedented hydroalumination of C ═ O bonds catalyzed by zirconocene dichloride is reported herein and applied to the site-selective deprotection of peracetylated functional substrates. A mixed metal hydride, with 1:1 zirconium/aluminum stoichiometry, is also shown to be the reductive species. A catalytic cycle is finally proposed for this transformation with no precedent in the field of zirconium catalysis.

Alkynophilicity of Group 13 MX3 Salts: A Theoretical Study.

The concept of alkynophilicity is revisited with group 13 MX3 metal salts (M = In, Ga, Al, B; X = Cl, OTf) using M06-2X/6-31+G(d,p) calculations. This study aims at answering why some of these salts show reactivity toward enynes that is similar to that observed with late-transition-metal complexes, notably Au(I) species, and why some of them are inactive. For this purpose, the mechanism of the skeletal reorganization of 1,6-enynes into 1-vinylcyclopentenes has been computed, including monomeric ("standard") and dimeric (superelectrophilic) activation. Those results are confronted with deactivation pathways based on the dissociation of the M-X bond. The role of the X ligand in the stabilization of the intermediate nonclassical carbocation is revealed, and the whole features required to make a good π-Lewis acid are discussed.

Hexafluoroisopropanol-Promoted Haloamidation and Halolactonization of Unactivated Alkenes.

Pyrrolidine and piperidine derivatives bearing halide functional groups are prevalent building blocks in drug discovery as halides can serve as an anchor for post-modifications. In principle, one of the simplest ways to build these frameworks is the haloamination of alkenes. While progress has been made in this field, notably with the development of enantioselective versions, this reaction is still fraught with limitations in terms of reactivity. Besides, a major question remaining is to understand the mechanism at work. The formation of a haliranium intermediate is typically mentioned, but limited mechanistic evidence supports it. Reported here is an efficient metal- and oxidant-free protocol to achieve the haloamidation of olefins, promoted by hexafluoroisopropanol, along with a DFT investigation of the mechanism. These findings should guide the future development of more complex transformations in the field of halofunctionalization.