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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.

The first example of Pd(ii)-catalyzed anomeric C(sp3)–H arylation of 3-aminosugars by using a transient directing group approach is reported. The free amine was then exploited in a CuAAC reaction to access to a variety of C3-triazolo C-glycosides in good yields.

An unconventional approach for the regioselective synthesis of polyaromatic biaryls via site-selective Ag-catalyzed twofold electrophilic cycloisomerization followed by Au-catalyzed double C-H activation is described. The developed process allows the synthesis of highly decorated biaryls with excellent regioselectivity. As revealed by DFT computations, the reaction represents a rare example of C1-C5

Unraveled herein is a Ru(II)-catalyzed two-fold C-H functionalization of arenes that combines an asymmetric intramolecular hydroarylation and a functionalization/annulation using alkynes, isocyanates, or alkenes. This process constructs complex heterocycles such as dihydrobenzofuran- or indoline-fused isoquinolinones or isoindolidinones having a tertiary or a qua-ternary stereocenter, with good yields and enantioselectivities (up to 97:3 er). The enantiopure rigid aryl-methyl-sulfoximine directing groups provides high asymmetric induction. In particular, the chiral sulfoxide (~99% ee) precursor used in the synthesis of the enantiopure sulfoximines is spontaneously eliminated during the reaction. It can be recovered without loss of enantiopurity and reused. Finally, density functional theory calculations show that the interaction between the p-cymene ligand attached to the Ru-species and the enantiopure sulfoximine moiety controls the facial selectivity in the migratory CH insertion of the olefin.

A cationic palladium-catalyzed arylalkenylation of ynamides is presented. The putative keteniminium arylpalladium intermediate likely dictates the regioselective carbopalladation of the ynamide to form a vinylpalladium species. The capture of this complex by the olefin yields linear conjugated β-alkenyl aminodienes (especially with

An overlooked pericyclic reaction between allyl alcohols and alkenes to form carbonyl compounds is analyzed. It combines the characteristic features of the Alder-ene reaction and of the oxy-Cope rearrangement. This oxy-ene reaction could be involved in biosynthetic pathways.

A gold(i)-catalyzed synthesis of highly functionalized nitrogen-containing polycyclic scaffolds was developed (up to 92% yield and 93% ee).

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.

The first example of Pd(II)-catalyzed anomeric arylation of 3-aminosugars is reported by using an L,X-type transient directing groups (TDG) approach combined with an external 2-pyridone ligand. The released free amine was in situ transformed into an azide function, which was then exploited in a CuAAC to increase the molecular complexity and prepare a variety of complex substituted C3-triazolo C-glycosides in good yields.

The first synthesis of various N-metallocenyl ynamides has been developed and two strategies for the oxidative cyclization of N-ferrocenyl ynamide into ansa[3]-ferrocenylamide are also reported. The mechanism for the iodine(III)-triggered transfor-mation has been studied by means of DFT calculations, showing that it proceeds through a Concerted Iodination Deprotona-tion step.

Difluoromethylene-skipped enones have been readily obtained from arylvinyltriflates and aryldifluoroenoxysilanes. While these useful compounds are difficult to synthesize by the classical aldol/dehydration approach, the use of a squaramide/Li

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.

Illustrated herein is a Pd(II) catalyzed one-pot direct difunc-tionalization of two distinct C(sp3)-H bonds [gem-ʹ-di-Me groups bearing aliphatic carboxylic acid] with bifunctional reagent (BFR) 2-iodo benzoic acid. The methyl 2-pyridyl sul-foximine (MPyS) bidentate directing group (DG), 2-chloro-5-trifluoromethyl ligand, and NaBrO3 co-oxidant combination helps the concerted metalation deprotonation (CMD) of inert C(sp3)-H bond as well reductive elimination steps; density functional theory (DFT) studies validate such insights. This process makes two [CC and CO] bonds of gem-ʹ-di-Me groups of DG-enabled aliphatic carboxylic acids in a single operation offering access to unusual benzo-fused peripheral substituted ω-membered lactones. This concept is uncovered for the first time. The transformation tolerates labile functional groups featuring broad scope with the construction of wide range of novel molecules of structural diversity. Ki-netic and control experiments study reveal the participation of monomeric-Pd-species on the catalytic cycle. Synthetic versatility of the complex molecular entities is also presented.

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)

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.

An unconventional cobalt(iii)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o′-C–H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse ‘S’ coordination over a more conventional ‘N’ coordination of thioamides to the Co-catalyst specifically regulates the formation of four [C–C and C–S at first and then C–N and C–C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, the late-stage annulation of biologically relevant motifs and drug candidates is disclosed (17 examples). The preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6π-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation process., A Co-catalyzed one-pot double annulation of sulfoximine bearing thioamides with alkynes for the synthesis of [6,6]-fused thiopyrano-isoquinolines is disclosed. The annulation involves a 6π-electrocyclization of 7-membered S-chelated cobaltacycle.

The discovery of new organometallic frameworks is of high interest for the field of bioorganometallic chemistry. In this work, to the best of our knowledge, we report the first synthesis of various N-metallocenyl ynamides and some of their reactivity. In particular, the use of hypervalent iodine(III) reagents triggered an unprecedented oxidative cyclization leading to ansa[3]-ferrocenyl compounds while the same reaction conditions with the ruthenocene analogues led to an acyclic acetoxy-adduct. The mechanism of the cyclization has been studied by means of DFT calculations, showing that it proceeds through a Concerted Iodination Deprotonation (CID) step. This study not only expands further the chemistry of ynamides but also opens up new avenues in bioorganometallic chemistry by providing an exclusive access to an original ferrocephane moiety to be employed in this research field.

The formation of a rare type of diphosphazenium cation is described. Its synthesis features a unique oxidative dealkylation of an iminophosphorane-phosphole by a silver(I) salt. DFT study of this compound reveals the low valent character of the N(I) center.

Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves specialized cells of the immune system able to clear sources of cell injury and damaged tissues to promote repair. Excessive inflammation can occur as a result of infections and is a hallmark of several diseases. The molecular basis underlying inflammatory responses are not fully understood. Here, we show that the cell surface marker CD44, which characterizes activated immune cells, acts as a metal transporter that promotes copper uptake. We identified a chemically reactive pool of copper(II) in mitochondria of inflammatory macrophages that catalyzes 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 a rationally-designed dimer of metformin triggers distinct metabolic and epigenetic states that oppose macrophage activation. This drug reduces inflammation in mouse models of bacterial and viral (SARS-CoV-2) infections, improves well-being and increases survival. Identifying mechanisms that regulate the plasticity of immune cells provides the means to develop next-generation medicine. Our work illuminates the central role of copper as a regulator of cell plasticity and unveils a new therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.

The direct dearomative addition of arenes to the C3-position of unprotected indoles is reported under operationally simple condi-tions, using triflic acid at room temperature. The present regioselective hydroarylation is a straightforward manner to generate an electrophilic indole at the C3-position without the need of a deactivating acetyl group at the indolic nitrogen as in previously reported 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.

International audience; 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.

A divergent and efficient one-pot sequence allowing direct access to 3-arylbenzofuran derivatives has been developed. The process, involving N-tosylhydrazones and bromophenols, proceeds via a palladium-catalyzed Barluenga-Valdes cross-coupling, followed by an aerobic, copper-catalyzed, radical cyclization to form Csp2-Csp2 and O-Csp2 bonds. 3-Arylated benzofurans bearing various substituents were obtained with good to excellent yields (up to 90%). Mechanistic investigation strongly supports a radical process for the cyclization step.

An efficient ortho-C-alkylation of unprotected anilines with a variety of styrenes and alkenes using a univalent cationic indium(I) catalyst is reported. Mechanistic studies revealed that the react...

The catalytic activity of cationic NHC-ZnII and NHC-AlIII (NHC=N-heterocyclic carbene) complexes in reactions that require the electrophilic activation of soft C-C π bonds has been studied. The former proved able to act as a soft π-Lewis acid in a variety of transformations. The benefit of the bulky IPr NHC ligand was demonstrated by comparison with simple ZnX2 salts. The tested NHC-AlIII catalyst is not able to activate C-C π bonds but simple AlX2 + ions were found potent in some cases.

International audience; We report an efficient synthesis of furopyrans through a gold(I)-catalyzed domino reaction. Starting from the same source, and by changing the solvent of the reaction, two classes of furopyrans are accessible. During this one-step process, which takes place in DMF, two bonds and two heterocycles are formed. DFT calculations furnish the mechanistic understanding of this transformation. The sequence includes a 5-endo-dig cyclization, a regioselective 8-endo-dig cyclization, a retro 8p and a 6p electro-cyclization.

International audience; The aza‐Piancatelli cyclization provides an expedient synthesis of 4‐aminocyclopentenone building blocks that may be converted into aminocyclopentitols, which are heavily represented motifs among natural products. However, its use as a key step in total synthesis was still unprecedented. Here, we disclose our in‐depth investigations regarding this reaction in order to access highly complex structures representing the core of some natural molecules. The applicability of the cyclization was highlighted by the 3‐step total synthesis of bruceolline D. Thus, we anticipate that this work will lay the ground for further applications in total synthesis

International audience; Hexafluoroisopropanol (HFIP) is a solvent with unique properties that has recently gained attention for promoting a wide range of challenging chemical reactions. It was initially believed that HFIP was almost exclusively involved in the stabilization of cationic intermediates, owing to its high polarity and low nucleophilicity. However, in many cases, the mechanism of action of HFIP appears to be more complex. Recent findings reveal that many Lewis and Brønsted acid-catalyzed transformations conducted in HFIP additionally involve cooperation between catalyst and HFIP hydrogen-bond clusters, akin to Lewis-or Brønsted acid-assisted-Brønsted acid catalysis. This feature article showcases the remarkable versatility of HFIP in Lewis and Brønsted acid-catalyzed reactions, with an emphasis on examples yielding mechanistic insight.

Direct difunctionalization of chemically distinct ortho- and peri-C–H bonds of fused hetero(arenes) is illustrated through an unusual one-pot domino {[4 + 2] & [5 + 2]} double annulation with alkynes for the first time. This process is viable under Ru(II)-catalysis using a sulfoximine directing group and builds four bonds [(C–C)–(C–N) and (C–C)–(C–O)] in a single operation. Such synthetic manifestation offers access to uncommon [6,7]-fused oxepino-pyridine skeletons. DFT calculations provide mechanistic insight into this double annulation of naphthoic acid derivatives with alkynes and corroborate the participation of a ruthena-oxabicyclooctene intermediate, which is responsible for the rare 7-membered ring formation.

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 β-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.

The direct dearomative addition of arenes to the C3-position of unprotected indoles is reported under operationally simple conditions with triflic acid at room temperature. The present regioselective hydroarylation is a straightforward manner to gen-erate an electrophilic indole at the C3-position without the need to introduce a deactivating acetyl group on the indolic nitrogen as in previously reported strategies. This atom economy method delivers biologically relevant 3-aryl indolines and 3,3-spiroindolines in high yields and regioselectivities from both intra and intermolecular processes.

Herein we report for the first time that the thiosugar moiety can be used both as a directing group enabling the regioselective activation of a C–H bond of biaryl scaffolds and as a chiral source inducing axial chirality. Our approach enables the easy generation of complex thioglycoside atropoisomers, thus paving the way to new products of potential biological interest.

π-Extended tetrasubstituted olefins are widely found motifs in natural products, leading drugs, and agrochemicals. Thus, development of modular strategies for the synthesis of complex all-carbon-substituted olefins always draws attention. The difunctionalization of unsymmetrical alkynes is an attractive approach but it has remained faced with regioselectivity issues. Here we report the discovery of a regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes. A cationic Pd-catalyzed three-component coupling of aryl diazonium salts, aryl boronic acids (or olefins) and yne-acetates enables access to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance, building broad chemical space of structural diversity (94 molecules). The value of this synthetic method is demonstrated by the direct transformation of natural products and drug candidates containing yne-acetates, to enable highly substituted structurally complex allyl acetate analogues of biologically important compounds. Synthetic versatility of the carboxylate bearing highly substituted olefins is also presented. The reaction outcome is attributed to the in situ formation of stabilized cationic aryl-Pd species, which regulates regioselective aryl-palladation of unsymmetrical yne-acetates. Control experiments reveal the synergy between the carboxylate protecting group and the cationic Pd-intermediate in the regioselectivity and reaction productivity; density functional theory (DFT) studies rationalize the selectivity of the reaction.

International audience; The development of a novel stereoselective aza-Piancatelli reaction to access 4aminocyclopentenones is reported. This transformation relies on the use of chiral o-sulfinyl anilines as chiral inductors to afford the targeted products in good to excellent yields. Remarkably, the high value-added cyclopentenones could be obtained in excellent drs (up to > 95:5) depending upon the furan substitution pattern.

Reported is the discovery of an approach to regio- and stereoselective syn-1,2-dicarbofuctionalization of unsymmetrical alkynes. A cationic Pd-catalyzed three-component coupling of two distinct carbon-bearing functionalities aryl diazonium salts and aryl boronic acids/olefins with unsymmetrical alkynes enables accessing to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance building a novel chemical space of structural diversity (82 molecules) and is scalable. The cationic Pd species plays crucial; notably, density functional theory (DFT) studies establish this observation. Synthetic versatility of the modifiable carboxylate bearing highly-substituted olefins is also presented.

Reported herein is a syn-thioallylation of ynamides incorporating a sulfide moiety at the α-position and an allyl group at the β-position of the ynamide. The transformation is successful under ytterbium(III)-catalysis, providing access to highly substituted thioamino-skipped-dienes with broad substrate scope. Thus, tetrasubstituted olefins (with four different functional groups: amide, phenyl, thioaryl/alkyl, and allyl on the carbon centers) are made in a single step from readily accessible ynamides, preserving complete atom economy. The reaction can be extended to the synthesis of selenoamino dienes by ynamide syn-selenoallylation. DFT studies and control experiments provide insight into the reaction mechanism.

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.