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.

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.

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.

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-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.

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 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.

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 (110oC, 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.

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.

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(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.

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.

Advancements in Gold-Catalyzed Cascade Reactions to Access Carbocycles and Heterocycles: An Overview.

This review summarizes recent developments (from 2006 to 2022) in numerous important and efficient carbo- and heterocycle generations using gold-catalyzed cascade protocols. Herein, methodologies involve selectivity, cost-effectiveness, and ease of product formation being controlled by the ligand as well as the counter anion, catalyst, substrate, and reaction conditions. Gold-catalyzed cascade reactions covered different strategies through the compilation of various approaches such as cyclization, hydroarylation, intermolecular and intramolecular cascade reactions, etc. This entitled reaction is also useful for the synthesis of spiro, fused, bridged carbo- and heterocycles.

Gold-catalyzed carbocyclization and imidization of alkyne-tethered diazo compounds with nitrosoarenes for the synthesis of nitrones and naphthalene derivatives.

A gold-catalyzed carbocyclization/imidization cascade reaction has been developed,leading a facile access to the synthesis of functionalized nitrones in moderate to good yields under mild conditions. The reaction initiated by a catalytic 6-endo-dig diazo-yne carbocyclization to form the key endocyclic vinyl carbene from alkyne-tethered diazo compounds, followed by addition with nitrosoarenes that features an imidization process. Notably, these resulting nitrone products could be smoothly converted into different substituted naphthalenol analogues, such as 4-aminonaphthalen-1-ol, naphthalene-1,4-dione, and naphthalene-1,4-diol derivatives, in high yields. Moreover, the generated products exhibited potential tumor suppression activity in tested cancer celllines; compound 3c (HCT116 cells, IC50 = 7.41 µM; MCF-7 cells, IC50 = 14.28 µM) exhibits higher anticancer potency than other tested compounds.

Synthesis of Functionalized 3H-pyrrolo-[1,2,3-de] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes.

A gold-catalyzed protocol to obtain functionalized 3H-pyrrolo [1,2,3-de] quinoxalines from suitable substituted N-alkynyl indoles has been proposed. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism. As quinoxaline-containing polycyclic compounds, this class of molecules may represent a valuable template in medicinal chemistry and material science.

Gold-Catalyzed Amine Cascade Addition to Diyne-Ene: Enantioselective Synthesis of 1,2-Dihydropyridines.

With the well-documented chemical and biological applications, piperidine and pyridine are among the most important N-heterocycles, and a new synthetic strategy, especially one with an alternative bond-forming design, is of general interest. Using the gold-catalyzed intermolecular condensation of amine and diyne-ene, we report herein the first example of enantioselective 1,2-dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.).

Asymmetric Dearomatization of Phenols via Ligand-Enabled Cooperative Gold Catalysis.

By employing a chiral bifunctional phosphine ligand, a gold(I)-catalyzed efficient and highly enantioselective dearomatization of phenols is achieved via versatile metal-ligand cooperation. The reaction is proven to be remarkably general in scope, permitting substitutions at all four remaining benzene positions, accommodating electron-withdrawing groups including strongly deactivating nitro, and allowing carbon-based groups of varying steric bulk including tert-butyl at the alkyne terminus. Moreover, besides N-(o-hydroxyphenyl)alkynamides, the corresponding ynoates and ynones are all suitable substrates. Spirocyclohexadienone-pyrrol-2-ones, spirocyclohexadienone-butenolides, and spirocyclohexadenone-cyclopentenones are formed in yields up to 99 % and with ee up to 99 %.

Trinuclear Gold-Catalyzed 1,2-Difunctionalization of Alkenes.

Activated alkyl halides have been extensively explored to generate alkyl radicals with Ru- and Ir- photocatalysts for 1,2-difunctionalization of alkenes, but unactivated alkyl bromides remain challenging substrates due to their strong reduction potential. Here we report a three-component 1,2-difunctionalization reaction of alkenes, unactivated alkyl bromides and nucleophiles (e.g., amines and indoles) using a trinuclear gold catalyst [Au3 (tppm)2 ](OTf)3 . It can achieve the 1,2-aminoalkylation and 1,2-alkylarylation readily. This protocol has a broad reaction scope and excellent functional group compatibility (>100 examples with up to 96 % yield). It also affords a robust formal [2+2+1] cyclization strategy for the concise construction of pyrrolidine skeletons under mild reaction conditions. Mechanistic studies support an inner-sphere single electron transfer pathway for the successful cleavage of inert C-Br bonds.