Gold Meets Selenium: Dual Activation of Selenium-Containing Propargyl Alcohols Towards the Synthesis of 2H-Chromenes and Mechanistic Insights.

Herein, we report the synthesis of seleno-substituted chromenes from selenoalkynes and phenols. In this cascade reaction, the applied gold catalyst not only functions as a p-acid, but also as a Lewis acid, enabling the propargylic substitution in the first step to connect the oxygen carbon bond. Under the optimal reaction condition a total of 26 chromenes were accessible by this modular access. During scale up experiments, the hydrolysis of the vinylselenium substructure to the corresponding chromenones was observed. By revisiting the electron-rich starting materials, four chromenones were produced following a one-pot reaction using a single gold catalyst. To better understand the interaction of gold and selenium, a series of nuclear magnetic resonance studies and high-resolution mass spectrometry studies were performed, which led to the proposal of a mechanism for this transformation.

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers.

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via ß-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold-sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5-sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation-oxidation protocols for regioselective access to oxazole sulfoxides and sulfones.

Recent Advances in the Synthesis of Peptidomimetics via Ugi Reactions.

Peptidomimetics have been extensively explored in many area due to their ability to improve pharmacological qualities and interesting biological activities. Cycles could be incorporated in peptides to reduce their flexibility, often enhancing the affinity for a certain receptor. Many efforts have been made to synthesize various peptidomimetics. Among them, the Ugi reaction is a popular way for the synthesis of peptidomimetics because it provides peptide-like products. The Ugi reaction consists of the condensation of an aldehyde or ketone, a carboxylic acid, an amine, and an isocyanide usually giving a linear peptidomimetic. In order to obtain other linear, cyclic or polycyclic peptidomimetics, the acyclic products have to undergo additional transformations or cyclizations. This review covers the years from 2018-2023, regarding the synthesis of linear, cyclic and polycyclic peptidomimetics, employing Ugi reactions eventually followed by post-Ugi transformations. Organo-catalyzed reactions, base-promoted reactions, and metal-free reactions toward peptidomimetics are highlighted.

An Efficient and Scalable "Second Generation" Total Synthesis of the Marine Polyketide Limaol Endowed with Antiparasitic Activity.

The cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this dinoflagellate-derived marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate-controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much-improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.

Diffusion Nuclear Magnetic Resonance Measurements on Cationic Gold (I) Complexes in Catalytic Conditions: Counterion and Solvent Effects.

The amount of free ions, ion pairs, and higher aggregate of the possible species present in a solution during the gold(I)-catalyzed alkoxylation of unsaturated hydrocarbon, i.e., ISIP (inner sphere ion pair) [(NHC)AuX] and OSIP (outer sphere ion pairs) [(NHC)Au(TME)X] [NHC 1,3-bis(2,6-di-isopropylphenyl)-imidazol-2-ylidene; TME = tetramethylethylene (2,3-bis methyl-butene); X- = Cl-, BF4-, OTf-; and OTs- BArF4- (ArF = 3,5-(CF3)2C6H3)], has been determined. The 1H and 19F DOSY NMR measurements conducted in catalytic conditions indicate that the dissociation degree (α) of the equilibrium ion pair/free ions {[(NHC)Au(TME)X] [(NHC)Au(TME)]+ + X-} depends on the nature of the counterion (X-) when chloroform is the catalytic solvent: while the compounds containing OTs- and OTf- as the counterion gave a low α (which means a high number of ion pairs) of 0.13 and 0.24, respectively, the compounds containing BF4- and BArF4- showed higher α values of 0.36 and 0.32, respectively. These results experimentally confirm previous deductions based on catalytic and theoretical data: the lower the α value, the greater the catalytic activity because the anion that can activate methanol during a nucleophilic attack, although the lower propensity to activate methanol of BF4- and BArF4-, as suggested by the DFT calculations, cannot be completely overlooked. As for the effect of the solvent, α increases as the dielectric constant increases, as expected, and in particular, green solvents with high dielectric constants show a very high α (0.90, 0.84, 0.80, and 0.70 for propylene carbonate, γ-valerolactone, acetone, and methanol, respectively), thus confirming that the moderately high activity of NHC-Au-OTf in these solvents is due to the specific effect of polar functionalities (O-H, C=O, O-R) in activating methanol. Finally, the DOSY measurements conducted in p-Cymene show the formation of quadrupole species: under these conditions, the anion can better exercise its 'template' and 'activating' roles, giving the highest TOF.

Gold-Catalysed Heck Reaction: Fact or Fiction? Correspondence on "Unlocking the Chain Walking Process in Gold Catalysis".

Two recent high-profile publications reported the formation of Heck-type arylated alkenes catalysed by MeDalPhosAuCl/AgOTf (J. Am. Chem. Soc. 2023, 145, 8810) and their cyclisation to tetralines (Angew. Chem. Int. Ed. 2023, e202312786). It was claimed that these were the first demonstrations in gold catalysis of alkene insertion into Au-aryl bonds, ß-H elimination and chain-walking by Au-H dications. We show here that in fact this chemistry is a two-stage process. Only the first step, the production of an alkyl triflate ester as the primary organic product by the well-known alkene heteroarylation sequence, involves gold. The subsequent formation of Heck-type olefins and their cyclisation to tetralines represent classical H+-triggered carbocationic chemistry. These steps proceed in the absence of gold with identical results. Literature claims of new gold reactivity such as chain walking by the putative [LAuH]2+ dication have no basis in fact.

Highly Stable Carboranyl Ligated Gold Nano-Catalysts for Regioselective Aromatic Bromination.

Achieving electronic/steric control and realizing selectivity regulation in nanocatalysis remains a formidable challenge, as the dynamic nature of metal-ligand interfaces, including dissolution (metal leaching) and structural reconstruction, poses significant obstacles. Herein, we disclose carboranyls (CBs) as unprecedented carbon-bonded functional ligands (Eads.CB-Au(111)=-2.90 eV) for gold nanoparticles (AuNPs), showcasing their exceptional stabilization capability that is attributed by strong Au-C bonds combined with B-H⋅⋅⋅Au interactions. The synthesized CB@AuNPs exhibit core(Aun)-satellite(CB2Au-) structure, showing high stability towards multiple stimuli (110 °C, pH=1-12, thiol etchants). In addition, different from conventional AuNP catalysts such as triphenylphosphine (PPh3) stabilized AuNPs, dissolution of catalytically active gold species was suppressed in CB@AuNPs under the reaction conditions. Leveraging these distinct features, CB@AuNPs realized outstanding p : o selectivities in aromatic bromination. Unbiased arenes including chlorobenzene (up to >30 : 1), bromobenzene (15 : 1) and phenyl acrylate were examined using CB@AuNPs as catalysts to afford highly-selective p-products. Both carboranyl ligands and carboranyl derived counterions are crucial for such regioselective transformation. This work has provided valuable insights for AuNPs in realizing diverse regioselective transformations.

Increasing the Donor Strength of Alkenylphosphines by Twisting the C=C Double Bond.

Electron-rich phosphines play a crucial role in transition metal-based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N-heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N-heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold-catalyzed hydroamination and cyclo-isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

Solid-State Oxidation of Alcohols in Gold-Coated Milling Vessels via Direct Mechanocatalysis.

This paper presents a novel approach for the selective oxidation of alcohols to their corresponding aldehydes through direct mechanocatalysis, employing a gold-coated milling vessel as catalyst and air as the oxidation agent. By adjusting milling frequency, media, and duration, high catalytic efficiencies and selectivities are achieved. Remarkably, yields of up to 99 % are obtained for specific substrates, with a turnover number (TON) of 8200 and a turnover frequency (TOF) of 0.77 s-1, surpassing existing alternatives. Confirmation of the catalytic reaction indeed occurring on the milling tool surface was achieved through X-ray photoelectron spectroscopy (XPS).

Gold-Catalyzed Diyne-Ene Annulation for the Synthesis of Polysubstituted Benzenes through Formal [3+3] Approach with Amide as the Critical Co-Catalyst.

The one-step synthesis of tetra-substituted benzenes was accomplished via gold-catalyzed diyne-ene annulation. Distinguished from prior modification methods, this novel strategy undergoes formal [3+3] cyclization, producing polysubstituted benzenes with exceptional efficiency. The critical factor enabling this transformation was the introduction of amides, which were reported for the first time in gold catalysis as covalent nucleophilic co-catalysts. This interesting protocol not only offers a new strategy to achieve functional benzenes with high efficiency, but also enlightens potential new reaction pathways within gold-catalyzed alkyne activation processes.

Title Selective Coupling of ß-(Borylvinyl)silanes by a Gold-catalyzed Hiyama Reaction - An Easy Way to Diaryl-Substituted Vinyl Boronates.

Diaryl-substituted vinyl boronates as potent building modules are challenging to synthesize. Herein, we present a convenient strategy based on a gold-catalyzed Hiyama arylation of (Z)-ß-(borylvinyl)silanes which are easily accessible by hydroboration of silylalkynes. By exploiting the highly electronegative nature of the Au(III) intermediate (which is accessed by the light-assisted oxidation with aryl diazonium salts), a selective activation of the silyl group in the presence of the boron moiety is achieved. This opens a route to selectively synthesize diaryl-substituted vinyl boronates. The reaction shows a broad substrate range, excellent functional group tolerance and perfect chemo-selectivity. Experimental studies and DFT calculations allowed us to elucidate the mechanism of the reaction, the synthetic potential was demonstrated by downstream transformations providing a facile route to bifunctional phenanthrenes and triaryl-substituted olefins.

Gold-Catalyzed Arylative Cope Rearrangement.

Cope rearrangements have garnered significant attention owing to their ability to undergo structural reorganization in stereoselective manner. While substantial advances have been achieved over decades, these rearrangements remained applicable exclusively to parent 1,5-hexadienes. Herein, we disclose the gold-catalyzed arylative Cope rearrangement of 1,6-heptadienes via a cyclization-induced [3,3]-rearrangement employing ligand-enabled gold redox catalysis. Detailed mechanistic investigations including several control experiments, cross-over experiment, HRMS analysis, 31P NMR and DFT studies have been performed to underpin the mechanism.

Gold-Catalyzed Alkoxy-Carbonylation of Aryl and Vinyl Iodides.

Herein, for the first time, we disclose the gold-catalyzed alkoxy-carbonylation of aryl and vinyl iodides utilizing ligand-enabled Au(I)/Au(III) redox catalysis. The present methodology is found to be general, efficient, employs mild reaction conditions and showcases a broad substrate scope even with structurally complex molecules. Density functional theory (DFT) calculations revealed mechanistic pathways distinct from those of conventional transition metal-catalyzed carbonylation reactions.

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination.

Kinetic studies on the intramolecular hydroamination of protected variants of 2,2-diphenylpent-4-en-1-amine were carried out under a variety of conditions with cationic gold catalysts supported by phosphine ligands. The impact of ligand on gold, protecting group on nitrogen, and solvent and additive on reaction rates was determined. The most effective reactions utilized more Lewis basic ureas, and more electron-withdrawing phosphines. A DCM/alcohol cooperative effect was quantified, and a continuum of isotope effects was measured with low KIE's in the absence of deuterated alcoholic solvent, increasing to large solvent KIE's when comparing reactions in pure MeOH to those in pure MeOH-d4. The effects are interpreted both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls.

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt.

Diaryliodonium(III) salts have been established as powerful halogen-bond donors in recent years. Herein, a new structural motif for this compound class was developed: iodoloisoxazolium salts, bearing a cyclic five-membered iodolium core fused with an isoxazole ring. A derivative of this class was synthesized and investigated in the solid state by X-ray crystallography. Finally, the potential as halogen-bonding activator was benchmarked in solution in the gold-catalyzed cyclization of a propargyl amide.

Gold-Catalyzed Cyclization of Yndiamides with Isoxazoles via α-Imino Gold Fischer Carbenes.

Gold catalysis is an important method for alkyne functionalization. Here we report the gold-catalyzed formal [3+2] aminative cyclization of yndiamides and isoxazoles in a direct synthesis of polysubstituted diaminopyrroles, which are important motifs in drug discovery. Key to this process is the formation, and subsequent cyclization, of an α-imino gold Fischer carbene, which represents a new type of gold carbene intermediate. The reaction proceeds rapidly under mild conditions, with high regioselectivity being achieved by introducing a subtle steric bias between the nitrogen substituents on the yndiamide. DFT calculations revealed that the key to this regioselectivity was the interconversion of isomeric gold keteniminiun ions via a low-barrier π-complex transition state, which establishes a Curtin-Hammett scenario for isoxazole addition. By using benzisoxazoles as substrates, the reaction outcome could be switched to a formal [5+2] cyclization, leading to 1,4-oxazepines.

Gold(I)-Catalyzed Ring-Closing Alkyne-Carbonyl Metathesis for the Synthesis of Butenolides.

Alkyne-carbonyl metathesis is a type of carbon-carbon forming reaction involving the construction a carbon-carbon double bond and a carbonyl group in one transformation. Herein, a Au(I)-catalyzed ring-closing alkyne-carbonyl metathesis protocol has been developed to make densely substituted γ-butenolides from propargyl α-ketoesters. It features 100 % atom economy, excellent substrate flexibility and benign functional group tolerance. Mechanistic studies demonstrate that the coordinative interaction between the gold catalyst and the alkyne might initiate the transfer of an oxygen atom and the formation of the carbon-carbon double bond. By using this gold-catalyzed ring-closing alkyne-carbonyl metathesis as a key step reaction, four naturally occurring butenolide-type compounds including decumbic acid (45 % yield for 3 steps), deoxyisosporothric acid (32 % yield for 5 steps), lichesterinic acid (34 % yield for 5 steps) and isomuronic acid (6 % yield for 8 steps) have been synthesized starting from commercially available starting materials.

Gold-Catalyzed Cascade Reaction of Diynamides with Allylic Alcohols: A Versatile Platform to Allenamide, 2-Aminofuran and Bridged [2.2.2]Octadiene Derivatives.

Transition metal-catalyzed divergent synthesis through alternation of the catalyst is appealing, as it provides an operationally simple way to access different valuable products, while using the same reactants as starting materials. Herein, a gold-catalyzed cascade reaction of conjugated diynamides with allylic alcohols is described. By variation of the catalysts, substituted allenes and furans could be obtained selectively. Mechanistic studies indicate that, after the addition of allylic alcohol to gold-activated diynamide, a [3,3]-sigmatropic rearrangement would take place and lead to the formation of a common reactive intermediate, which would further convert to the final products selectively. Further variation of the structure of diynamides has unveiled an additional reaction sequence involving intramolecular Himbert arene/allene Diels-Alder cycloaddition to afford a series of dearomatized products bearing bicyclo[2,2,2]octadiene core.

Divergent Construction of N-Doped Polycyclic Aromatic Hydrocarbons with Indole as the Nitrogen Source Building Block.

An Ag/Au-catalyzed divergent cascade reaction of alkyne embedded diazoketones with indoles has been described. Preliminary mechanistic studies indicate that the reaction goes through a [4+2]-cycloaddition of an in situ formed isobenzopyrylium intermediate with indole, followed by a sequential retro-Michael addition/carbene N-H insertion process to give the benzo[i]phenanthridines products with gold catalysis; whereas a dearomatization/rearomatization sequence occurs favourably when the reaction is catalyzed by a silver catalyst, delivering benzo[b]carbazoles in generally high to excellent yields. Notably, this is a rare example of using indole as the dienophile for cycloaddition with the isobenzopyrylium species, providing a concise and practical approach for the selective construction of N-doped polycyclic aromatic hydrocarbons (PAHs) with structural diversity and broad functional-group compatibility.

Gold(I)-Mediated Cyclizations of Triene-Yne Systems: An Easy Access to Cyclopenta-Fused Anthracenes.

The direct synthesis of cyclopenta-fused anthracenes (CP-anthracenes) through a gold(I)-catalyzed cyclization reaction of easily available triene-yne systems bearing a benzofulvene substructure, is reported. The targets are of great interest due to the potential use as organic materials and the preparation of these compounds is gaining huge importance. The applied starting materials are readily available through a three-step synthesis, which further contributes to the advantages of this route. In addition, UV-Vis and fluorescent spectra of the obtained CP-anthracenes were recorded.