Gold‐Catalyzed Oxa‐Povarov Reactions for the Synthesis of Highly Substituted Dihydrobenzopyrans from Diaryloxymethylarenes and Olefins

Oxa‐Povarov reactions involving readily available diaryloxymethylarenes and aryl‐substituted alkenes are reported. Their [4+2] cycloadditions were efficiently catalyzed by IPrAuSbF₆ (IPr=1,3‐bis(diisopropylphenyl)imidazol‐2‐ylidene) with high diastereoselectivity. Product analysis revealed that the reactions likely proceed by a stepwise ionic mechanism, because both E‐ and Z‐configured β‐methylstyrene gave the same cycloadducts in the same proportions.     

Gold‐Catalyzed 1,2‐Oxoarylations of Nitriles with Pyridine‐Derived Oxides

We report the first success in the gold‐catalyzed oxoarylations of nitriles with pyridine‐derived N‐oxides using gold carbenes as initiators. These oxoarylations were also achieved satisfactorily in intermolecular three‐component oxidations, including diverse alkenyldiazo esters, nitriles, and pyridine‐based oxides.     

Skeletal Rearrangement of O‐Propargylic Formaldoximes by a Gold‐Catalyzed Cyclization/Intermolecular Methylene Transfer Sequence

Skeletal rearrangement of O‐propargylic formaldoximes, in the presence of gold catalysts, afforded 4‐methylene‐2‐isoxazolines in good to excellent yields by an intermolecular methylene transfer. In addition, the cascade reaction with maleimide in the presence of a gold catalyst afforded isoxazole derivatives by cyclization/methylene transfer and a subsequent ene reaction, whereas that using a copper catalyst gave oxazepines through a 2,3‐rearrangement.     

Gold‐Catalyzed Cyclization Leads to a Bridged Tetracyclic Indolenine that Represses β‐Lactam Resistance

A gold‐catalyzed desilylative cyclization was developed for facile synthesis of bridged tetracyclic indolenines, a common motif in many natural indole alkaloids. An antimicrobial screen of the cyclization products identified one compound which selectively potentiates β‐lactam antibiotics in methicillin‐resistant S. aureus (MRSA), and re‐sensitizes a variety of MRSA strains to β‐lactams.     

Gold‐Catalyzed Cycloaddition Reactions of Ethyl Diazoacetate,Nitrosoarenes, and Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and Benzo[b]azepine Derivatives

Gold‐catalyzed cycloadditions of ethyl diazoacetate, nitrosoarenes, and vinyldiazo carbonyl species to yield isoxazolidine derivatives stereoselectively are described. Treatment of these isoxazolidine products with the same catalyst results in a novel 1,2‐H shift/[3,3] rearrangement to give benzo[b]azepine compounds. The mechanism of this skeletal rearrangement is elucidated with deuterium‐labeling experiments.     

Silver‐Catalyzed 7‐exo‐dig Cyclization of Silylenolether‐ynesulfonamides

Cyclization of silylenolether‐ynesulfonamides proceeds at ambient temperature under mild reaction conditions under silver catalysis. Bridged compounds were obtained exclusively through 7‐exo‐dig reactions. The protocol is applicable to a wide range of substrates, thus leading to azabicyclic frameworks.     

Regiocontrolled Gold‐Catalyzed [2+2+2] Cycloadditions of Ynamides with Two Discrete Nitriles to Construct 4‐Aminopyrimidine Cores

Reported herein is the novel gold‐catalyzed intermolecular [2+2+2] cycloaddition of ynamides with two discrete nitriles to form monomeric 4‐aminopyrimidines, which are pharmaceutically important structural motifs. The utility of this new cycloaddition is demonstrated by the excellent regioselectivity obtained using a variety of ynamides and nitriles.     

Furan‐Based o‐Quinodimethanes by Gold‐Catalyzed Dehydrogenative Heterocyclization of 2‐(1‐Alkynyl)‐2‐alken‐1‐ones: A Modular Entry to 2,3‐Furan‐Fused Carbocycles

A strategy for in situ generation of furan‐based ortho‐quinodimethanes (o‐QDMs) by the gold(I)‐mediated dehydrogenative heterocyclization of 2‐(1‐alkynyl)‐2‐alken‐1‐ones in the presence of pyridine N‐oxide under mild reaction conditions was developed. These in situ furan‐based o‐QDMs were trapped by electron‐deficient olefins and alkynes, thus furnishing various 2,3‐furan‐fused carbocycles in good yields with high diastereo‐ and regioselectivities.     

Gold‐Catalyzed Cyclization Processes: Pivotal Avenues for Organic Synthesis

Over the years, gold catalysis has materialized as an incredible synthetic approach among the scientific community. Due to the trivial reaction conditions and great functional compatibility, these progressions are synthetically expedient, because practitioners can implement them to build intricate architectures from readily amassed building blocks with high bond forming indices. The incendiary growth of gold catalysts in organic synthesis has been demonstrated as one of the most prevailing soft Lewis acids for electrophilic activation of carbon‐carbon multiple bonds towards a great assortment of nucleophiles. Nowadays, organic chemists consistently employ gold catalysts to carry out a diverse array of organic transformations to build unprecedented molecular architectures. Despite all these achievements and a plethora of reports, many vital challenges remain. In this account, we describe the reactivity of various gold catalysts towards cyclization processes developed over the years. These protocols give access to a wide scope of polyheterocyclic structures, containing different medium‐sized ring skeletons. This is interesting, as the quest for highly selective reactions to assemble diversely functionalized products has attracted much attention. We envisage that these newly developed chemo‐, regio‐, and diastereoselective protocols could provide an expedient route to architecturally cumbersome heterocycles of importance for the pharmaceutical industry.     

Gold‐Catalyzed Annulations of 2‐Alkynyl Benzaldehydes with Vinyl Ethers: Synthesis of Dihydronaphthalene,Isochromene, and Bicyclo[2.2.2]octane Derivatives

With the suitable selection of a gold catalyst as well as the appropriate control of the reaction conditions, various new gold‐catalyzed cyclizations of 2‐alkynyl benzaldehyde with acyclic or cyclic vinyl ethers have been developed. Acetal‐tethered dihydronaphthalene and isochromenes were obtained from the reactions of 2‐alkynyl benzaldehydes with acyclic vinyl ethers under mild conditions. And, more interestingly, the gold‐catalyzed reactions of 2‐alkynyl benzaldehyde with a cyclic vinyl ether afforded the bicyclo[2.2.2]octane derivative involving two molecules of cyclic vinyl ethers. These products contain interesting substructures that have been found in many biologically active molecules and natural products. In addition, a gold‐catalyzed homo‐dimerization of 2‐phenylethynyl benzaldehyde 1 a was observed when the reaction was carried out in the absence of vinyl ether, affording a set of separable diastereomeric products. Plausible mechanisms for these transformations are discussed; a gold‐containing benzopyrylium was regarded as the crucial intermediate by which a number of these new transformations took place.     

Gold‐ or Silver‐Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects

3‐Oxo‐5‐alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6‐endo‐dig cyclization reactions to furnish either 2‐pyrones or 4‐pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π‐acid. This transformation is compatible with a variety of acid‐sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4‐pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co‐solvent, which is thought to favor the protodeauration of the reactive alkenyl‐gold intermediates as the likely rate‐determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off‐cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem‐diaurated complexes 12 and 15 . Furthermore, silver catalysis allowed access to be gained to 2‐alkoxypyridine and 2‐alkoxyisoquinoline derivatives starting from readily available imidate precursors.     

Gold‐Catalyzed 1,2‐Acyloxy Migration/Intramolecular [3+2] 1,3‐Dipolar Cycloaddtion Cascade Reaction: An Efficient Strategy for Syntheses of Medium‐Sized‐Ring Ethers and Amines

A highly efficient strategy for the formation of medium‐sized‐ring ethers and amines based on a gold‐catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium‐sized‐ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium‐sized ring synthesis.     

Bifunctional Ligand Enables Efficient Gold‐Catalyzed Hydroalkenylation of Propargylic Alcohol

Using the previously designed biphenyl‐2‐ylphosphine ligand, featuring a remote tertiary amino group, the first gold‐catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general‐base catalyst for promoting this novel gold catalysis with good efficiency.     

Gold‐Catalyzed Diastereoselective Cycloisomerization of Alkylidene‐Cyclopropane‐Bearing 1,6‐Diynes

An unprecedented gold‐catalyzed diastereoselective cycloisomerization of 1,6‐diynes bearing an alkylidene cyclopropane moiety has been developed. This methodology enables rapid access to a variety of 1,2‐trimethylenenorbornanes, which are important building blocks in the preparations of abiotic and sesquiterpene core structures.     

Gold‐Catalyzed Cascade Reactions for Synthesis of Carbo‐ and Heterocycles: Selectivity and Diversity

This account describes our recent efforts devoted to gold chemistry since 2009. Based on furyl–Au 1,3‐dipole analogues and related gold carbene intermediates, a rich variety of gold‐catalyzed cascade reactions have been developed, which provide facile access to a diverse range of novel carbo‐ and heterocycles. In these reactions, the selectivity can be well controlled by the catalyst (ligand and metal), substrate or reagent. In addition, we have also developed the corresponding enantioselective variants, which are guided by bis(phosphinegold) complexes derived from axially chiral scaffolds and asymmetric gold/chiral Brønsted acid relay catalysis.     

Gold‐Catalyzed C(sp3)H/C(sp)H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C? H/C? H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³)? H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.