Aluminum-Catalyzed Intramolecular Vinylation of Arenes by Vinyl Cations.

This study addresses the challenges associated with vinyl cation generation, a process that traditionally requires quite specific counterions. Described herein is a novel intramolecular vinylation of arenes catalyzed by aluminum(III) chloride, utilizing practical conditions and readily available vinyl triflates derived from 2-aceto-3-arylpropionates. Comprehensive experimental data support diverse carbocycle synthesis, exemplified by indenes and higher analogues. Control experiments verify the applicability of the vinylation protocol, and synthetic applications showcase a potent tubulin polymerization inhibitor with anticancer properties. Density functional theory computations reveal a Lewis-acid-driven mechanism involving triflate moiety abstraction to generate a reactive vinyl cation.

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.

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.

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.

Probing Chiral Sulfoximine Auxiliaries in Ru(II)-Catalyzed One-Pot Asymmetric C-H Hydroarylation and Annulations with Alkynes.

Developed herein is a chiral sulfoximine-enabled Ru(II)-catalyzed asymmetric C-H activation/functionalization involving intramolecular hydroarylation and functionalization/annulation of alkynes. This process constructs dihydrobenzofuran- or indoline-fused isoquinolinones having a tertiary or quaternary stereocenter with good yields and enantioselectivities (up to 97:3 enantiomeric ratio). The chiral sulfoxide precursor used in synthesizing the enantiopure sulfoximines is spontaneously eliminated during the reaction. It can be recovered without losing enantiopurity (∼99% enantiomeric excess) and reused.

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.

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.

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.

Transient imine as a directing group for the Pd-catalyzed anomeric C(sp3)-H arylation of 3-aminosugars.

The first example of Pd(II)-catalyzed anomeric arylation of 3-aminosugars is reported by using an L,X-type transient directing group (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.

N-Metallocenyl Ynamides: Preparation, Reactivity, and Synthesis of ansa[3]-Ferrocenylamides.

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 transformation has been studied by means of DFT calculations, showing that it proceeds through a concerted iodination deprotonation step.

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.

Squaramide/Li+-Catalyzed Direct SN1-Type Reaction of Vinyl Triflates with Difluoroenoxysilanes through Vinyl Cations.

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+ catalyst allows their direct formation via a vinyl carbocation paired with a weakly coordinating perfluorinated alkoxyaluminate. This strategy makes possible a reaction between a typically weak electrophile and a weak nucleophile. Control experiments and DFT computations shed light on the mechanism of this transformation.

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.

Expedient Access to Polyaromatic Biaryls by Unconventional Ag-Catalyzed Cycloaromatization of Alkynylthiophenes and Au-Catalyzed Double C-H Activation.

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 endo-exo and C1-C6 endo-endo cycloaromatization. The formation of the 6-membered ring is predicted to be the fruit of an uncommon SEAr on a vinyl carbocation.

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.

A cyclic divalent N(I) species isoelectronic to carbodiphosphoranes.

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.

Transition structures for the oxy-ene reaction.

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.

Cationic-palladium catalyzed regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes.

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.

Palladium-Catalyzed Regioselective Arylalkenylation of Ynamides.

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 ß-alkenyl aminodienes (especially with trans selectivity). The transformation features a broad scope with labile functional group tolerance and makes 42 unusual molecular scaffolds with structural diversity. DFT studies provide valuable insights into the reaction mechanism.