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.     

Tandem cycloisomerization/Suzuki coupling of arylethynyl MIDA boronates

A tandem gold-catalyzed cycloisomerization/Suzuki cross-coupling sequence involving arylethynyl-N-methyliminodiacetic acid boronates is described. Combining the mildness of homogeneous gold catalysis with the versatility of N-methyliminodiacetic acid (MIDA) boronates, this tandem two-step method enables the rapid assembly of various aryl-substituted heterocycles without having to isolate or purify any heterocyclic MIDA boronate intermediates. Another major advantage of this method is that a wide range of heterocycles bearing different aryl groups may be made from a single MIDA boronate alkyne precursor.     

Gold-Catalyzed Oxidative Aminocyclizations of Propargyl Alcohols and Propargyl Amines to Form Two Distinct Azacyclic Products: Carbene Formation versus a 3,3-Sigmatropic Shift of an Initial Intermediate

Gold-catalyzed oxidations of propargyl alcohols with nitrones by using a P(tBu)₂(o-biphenyl)Au⁺ catalyst, afforded bicyclic annulation products from the Mannich reactions of gold enolates. The same reactions of propargyl amines with nitrones by using the same gold catalyst gave distinct oxoarylation products. Our DFT calculations indicate that oxidation of propargyl alcohols with nitrones by using electron-rich gold catalysts lead only to gold carbenes, which can generate gold enolates or oxoarylation intermediates with enolate species having a barrier smaller than that of oxoarylation species.     

Ligand effects and ligand design in homogeneous gold(I) catalysis

Gold catalysis is considered one of the most important breakthroughs in organic synthesis during the past decade, but a rational understanding of ligand effects in gold catalysis is lacking. Most gold-catalyzed reactions go through three major stages: (i) electronic activation of alkyne (or allene) to generate a vinyl gold intermediate; (ii) protodeauration to generate the product and regenerate the cationic gold catalyst; (iii) decay of the active gold catalyst. Our research provides a clearer understanding of how ligands influence each of the three stages in the gold catalytic cycle. What is even more important, by not focusing on a particular gold-catalyzed reaction, we have been able to categorize most gold-catalyzed reactions and propose a ligand design protocol for each category of gold-catalyzed reactions.     

Dual Catalysis for the Redox Annulation of Nitroalkynes with Indoles: Enantioselective Construction of Indolin‐3‐ones Bearing Quaternary Stereocenters

The enantioselective redox annulation of nitroalkynes with indoles is enabled by gold/chiral phosphoric acid dual catalysis. A range of indolin‐3‐one derivatives bearing quaternary stereocenters at the C2 position were afforded in good yields and excellent enantioselectivities (up to 96 % ee) from readily available starting materials.     

Gold-catalyzed deoxygenative nazarov cyclization of 2,4-dien-1-als for stereoselective synthesis of highly substituted cyclopentenes

Treatment of 2,4-dien-1-als with allylsilanes and PPh(3)AuSbF(6) (3 mol %) led to formation of 1,4-bis(allyl)cyclopentenyl products; this gold catalyst is superior to commonly used Lewis acids according to catalyst screening. Such gold-catalyzed deoxygenative cyclizations are compatible with various oxygen-, amine-, sulfur-, hydrogen-, and carbon-based nucleophiles. The value of this new catalysis is demonstrated by the diverse annulations of 2,4-dien-1-als with electron-rich alkenes and arenes, providing an easy access to complicated cyclopentenyl frameworks. Structural analysis of annulation products reveals evidence for the participation of Nazarov cyclization. This deoxygenative cyclization is extensible to a tandem intramolecular cyclization/nucleophilic addition cascade, giving polycyclic carbo- or oxacyclic compounds with controlled stereochemistry. This new gold catalysis is applied to a short synthesis of natural compounds of the brazilane family, including brazilane, O-trimethyl-, and O-tetramethyl brazilane.     

Gold‐Catalyzed Oxidative [2+2+1] Annulations of Aryldiazo Nitriles with Imines To Yield Polyarylated Imidazolium Salts

Gold‐catalyzed oxidative [2+2+1] annulations between two imines and one α‐cyano arylgold carbene afforded polyarylated imidazolium salts and molecular hydrogen efficiently. Control experiments suggest that the gold catalyst alone facilitates the main annulation, whereas Ag⁺ avoids the formation of inactive LAuCN. DFT calculations suggest that the success of this annulation relies on a 6 π‐electrocyclization of cyano‐free intermediates with cis ‐configured imines as initial reagents.     

Gold(I)-Catalyzed Highly Diastereo- and Enantioselective Cyclization–[4+3] Annulation Cascades between 2-(1-Alkynyl)-2-alken-1-ones and Anthranils

This work reports gold-catalyzed [4+3]-annulations of 2-(1-alkynyl)-2-alken-1-ones with anthranils to yield epoxybenzoazepine products with excellent exo-diastereoselectivity (dr>25:1). The utility of this new gold catalysis is manifested by applicable substrates over a broad scope. More importantly, the enantioselective versions of these [4+3]-cycloadditions have been developed satisfactorily with chiral gold catalysts under ambient conditions (DCM, 0 °C); the ee levels range from 88.0–99.9 %. With DFT calculations, we postulate a stepwise pathway to rationalize the preferable exo-stereoselection.     

Permethylated NHC-Capped α- and β-Cyclodextrins (ICyDMe) Regioselective and Enantioselective Gold-Catalysis in Pure Water

A series of water-soluble encapsulated copper(I), silver(I) or gold(I) complexes based on NHC-capped permethylated cyclodextrins ( ICyD^Me ) were developed and used as catalysts in pure water for hydration, lactonization, hydroarylation and cycloisomerization reactions. ICyD^Me ligands gave cavity-based high regioselectivity in hydroarylations, and high enantioselectivities in gold-catalyzed cycloisomerizations reactions giving up to 98 % ee in water. These ICyD^Me are therefore useful ligands for selective catalysis in pure water.     

Asymmetric Synthesis of Dihydropyranones via Gold(I)‐Catalyzed Intermolecular [4+2] Annulation of Propiolates and Alkenes

Intermolecular asymmetric gold catalysis involving alkyne activation presents a significant challenge due to its distinct mechanistic mode from other metals. Herein, we report a highly enantioselective synthesis of α,β‐unsaturated δ‐lactones from [4+2] annulation of propiolates and alkenes in upto 95 % ee. Notably, for the desired chiral recognition, the choice of 1,1,2,2‐tetrachloroethane as solvent was found to be crucial. Furthermore, an anionic surfactant (sodium dodecyl sulfate) improved the product selectivity in the divergence of the cyclopropyl gold carbene intermediate.     

An efficient [2 + 2 + 1] synthesis of 2,5-disubstituted oxazoles via gold-catalyzed intermolecular alkyne oxidation

The first efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation has been realized using nitriles as both the reacting partner and the reaction solvent, offering a generally efficient synthesis of 2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2 + 2 + 1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant. The reaction conditions are exceptionally mild, and a range of functional groups are easily tolerated. With complex and/or expensive nitriles, only 3 equiv could be sufficient to achieve serviceable yields in the absence of any solvent and using only 1 mol % BrettPhosAuNTf(2) as the catalyst.     

Gold-catalyzed intermolecular reactions of propiolic acids with alkenes: [4 + 2] annulation and enyne cross metathesis

A gold-catalyzed intermolecular reaction of propiolic acids with alkenes led to a [4 + 2] annulation or enyne cross metathesis. The [4 + 2] annulation proceeds with net cis-addition with respect to alkenes and provides an expedient route to α,β-unsaturated δ-lactones, for which preliminary asymmetric reactions were also demonstrated. For 1,2-disubstituted alkenes, unprecedented enyne cross metathesis occurred to give 1,3-dienes in a completely stereospecific fashion. DFT calculations and experiments indicated that the cyclobutene derivatives are not viable intermediates and that the steric interactions during concerted σ-bond rearrangements are responsible for the observed unique stereospecificity.     

Enantioselective Synthesis of Spirocyclohexadienones by NHC‐Catalyzed Formal [3+3] Annulation Reaction of Enals

The enantioselective synthesis of pyrazolone‐fused spirocyclohexadienones was demonstrated by the reaction of α,β‐unsaturated aldehydes with α‐arylidene pyrazolinones under oxidative N‐heterocyclic carbene (NHC)catalysis. This atom‐economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all‐carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC‐catalyzed generation of chiral α,β‐unsaturated acyl azoliums from enals, and base‐mediated tandem generation of dienolate/enolate intermediates from pyrazolinones.     

Synthetic evolutions in the nucleophilic addition to alkynes

This short account describes our efforts to transform the simple nucleophilic addition of alkynes into a more efficient, selective and environmentally benign synthetic tool. We have circumvented the lack of regioselectivity in the gold-catalyzed triple bond addition of water through neighboring group participation and in the process we developed a ‘functionalized hydration’ (multiple bond formation and hydration in a one-pot process) using fluorine-engendered cationic gold catalysis. In addition, we have conducted the synthesis of O-heterocycles through a gold-catalyzed tandem addition/cycloisomerization sequence, the synthesis of N-heterocycles through a copper-catalyzed cyclization-triggered addition of alkynes, and a green synthesis of thioethers ‘on water’ without catalyst or initiator. These nucleophilic synthetic evolutions, catapulted by a simple addition to an alkyne, will surely contribute to provide a wider synthetic access to sophisticated biological targets.     

Enantio- and Regioselective Electrooxidative Cobalt-Catalyzed C−H/N−H Annulation with Alkenes

In recent years, the merging of electrosynthesis with 3d metal catalyzed C−H activation has emerged as a sustainable and powerful technique in organic synthesis. Despite the impressive advantages, the development of an enantioselective version remains elusive and poses a daunting challenge. Herein, we report the first electrooxidative cobalt-catalyzed enantio- and regioselective C−H/N−H annulation with olefins using an undivided cell at room temperature (up to 99 % ee). ^tBu-Salox, a rationally designed Salox ligand bearing a bulky tert-butyl group at the ortho-position of phenol, was found to be crucial for this asymmetric annulation reaction. A strong cooperative effect between ^tBu-Salox and 3,4,5-trichloropyridine enabled the highly enantio- and regioselective C−H annulation with the more challenging α-olefins without secondary bond interactions (up to 96 % ee and 97 : 3 rr). Cyclovoltametric studies, and the preparation, characterization, and transformation of cobaltacycle intermediates shed light on the mechanism of this reaction.     

Recent Advances in the Development of Chiral Gold Complexes for Catalytic Asymmetric Catalysis

Asymmetric gold catalysis has been rapidly developed in the past ten years. Breakthroughs have been made by rational design and meticulous selection of chiral ligands. This review summarizes newly developed gold-catalyzed enantioselective organic transformations and recent progress in ligand design (since 2016), organized according to different types of chiral ligands, including bisphosphine ligands, monophosphine ligands, phosphite-derived ligands, and N-heterocyclic carbene ligands for asymmetric gold(I) catalysis as well as heterocyclic carbene ligands and oxazoline ligands for asymmetric gold(III) catalysis.     

N‐Heterocyclic Carbene‐Catalyzed [2+2+2] Annulation of Allenoates with Trifluoromethylketones

In contrast with the reported phosphine‐ and DABCO‐catalyzed [3+2] and [2+2] annulation of allenoates with trifluoromethylketone, the [2+2+2] annulation of allenoates and two molecules of trifluoromethylketone was found under the condition of N‐heterocyclic carbene catalysis.     

Ring Expansion and 1,2‐Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies

Demonstrated herein is an Au^I‐catalyzed annulation of sulfonyl‐protected ynamides with substituted 1,2‐benzisoxazoles for the synthesis of E‐benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold‐activated ynamide, ring expansion of the benzisoxazole fragment to provide an α‐imino vinylic gold intermediate, and 1,2‐migration of the sulfonamide motif to the masked carbene center to deliver the respective ring‐expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α‐imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.     

Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles

In total and formal syntheses of dictyodendrins B, C, E, and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki–Miyaura coupling), C2 (addition to an aldehyde), N3 (alkylation), and C5 positions (Ullman coupling) provided divergent access to dictyodendrins.     

A Facile Approach for Synthesis of Benzofuro[2,3‐c]pyridines via Intramolecular Cascade Annulations

A facile synthesis of benzofuro[2,3‐c]pyridines has been achieved under mild conditions by using ammonium acetate as the nitrogen source through intramolecular cascade annulation. This reaction could efficiently construct pyridine ring and furan ring in one step. Moreover, the key annulation step was demonstrated through dihydrobenzofuran intermediates.