Gold-catalyzed Cycloisomerization Research Articles

The regioselectivity in the gold-catalyzed cycloisomerization of alcohols: a full DFT study on carbene versus non-carbene mechanisms

The regioselectivity in the gold-catalyzed cycloisomerization of alcohols: a full DFT study on carbene versus non-carbene mechanisms

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.

Total Synthesis of (-) and (+)-Zingibergingerols A.

The first total synthesis of both of the enantiomers of Zingibergingerol A has been accomplished. The distinctive 3,7,9-trioxabicyclo[4.2.1]nonane skeleton is crafted through gold-catalyzed alkynol cycloisomerization. The synthesis comprises sequential C-C bond formations at both ends of epichlorohydrin: first opening the epoxide with eugenol-derived alkyne, followed by subsequent epoxide installation, and again opening with a Grignard reagent. The resulting alkynol with a fixed C5 stereochemistry was subjected to O-allylation, followed by dihydroxylation and alkynol cycloisomerization.

Stereoselective Double Spirocyclization of 2-Benzyl-3-alkynyl Chromone with Nitrone via Gold-Catalyzed Cascade Reactions.

A novel, highly stereoselective gold-catalyzed spirocyclization of 2-benzyl-3-alkynyl chromone with nitrone is described. This cascade reaction involves gold-catalyzed cycloisomerization, nitrone-olefin [3 + 2]-annulation, alkene oxidation, and rearrangement for the formation of spirocyclic products. Interestingly, the isoxazolidine ring generated from [3 + 2]-annulation donates oxygen to alkene to generate a new pyran-3(4H)-one and azetidine ring for dispiro-benzofuran formation upon heating. This work demonstrates the one-pot, gold-catalyzed, multiple-step reaction, and the reaction temperature directly affects the formation of spirocyclic products.

Gold-Catalyzed Cascade Cycloisomerization of 3-Allyloxy-1,6-diynes to Cyclopropyl- and Cyclobutyl-Fused Benzofurans and Chromen-3a(1H)-ols.

A synthetic method for the efficient preparation of partially hydrogenated benzo[f]cyclobuta[cd]cyclopenta[h]benzofurans and cyclopropa[c]chromen-3a(1H)-ols that relies on the gold(I)-catalyzed cascade cycloisomerization of 3-allyloxy-1,6-diynes is described.

Cellulose-Supported Heterogeneous Gold-Catalyzed Cycloisomerization Reactions of Alkynoic Acids and Allenynamides.

Herein, we describe efficient nanogold-catalyzed cycloisomerization reactions of alkynoic acids and allenynamides to enol lactones and dihydropyrroles, respectively (the latter via an Alder-ene reaction). The gold nanoparticles were immobilized on thiol-functionalized microcrystalline cellulose and characterized by electron microscopy (HAADF-STEM) and by XPS. The thiol-stabilized gold nanoparticles (Au0) were obtained in the size range 1.5-6 nm at the cellulose surface. The robust and sustainable cellulose-supported gold nanocatalyst can be recycled for multiple cycles without losing activity.

Hexafluoroisopropanol (HFIP) as a Multifunctional Agent in Gold-Catalyzed Cycloisomerizations and Sequential Transformations

Despite the unique position of gold catalysis in contemporary organic synthesis, this area of research is notorious for requiring activators and/or additives that enable catalysis by generating cationic forms of gold catalysts. Cycloisomerization reactions occupy a significant portion of the gold-catalyzed reaction space, while they represent a diverse family of reactions that are frequently utilized in synthesis. Herein, hexafluoroisopropanol (HFIP) is shown to be a uniquely simple tool for gold-catalyzed cycloisomerizations, rendering the use of external activators obsolete and leading to highly active catalytic systems with ppm levels of catalyst loading in certain cases. HFIP assumes a dual role as a solvent and an activator, operating via the dynamic activation of the Au–Cl bond through hydrogen bonding, which initiates the catalytic cycle. This special mode of catalysis can enable efficient and scalable cyclization reactions of propargylamides and ynoic acids with simple [AuCl(L)] complexes. A thorough screening of ancillary ligands and counter anions has been performed, establishing this methodology as an alternative to elaborate ligand/catalyst design and to the use of activators. Additionally, this concept is applied in C–C bond-forming cycloisomerization reactions leading to 2H-chromenes and to the design of catalytic systems for sequential or one-pot transformations leading to activated ketoesters, a functionalized N-heterocyclic carbene (NHC) precursor salt, and a compound bearing the bioactive indole core, among others. Importantly, through mechanistic investigations, including a “snapshot” of the species of interest in the solid state, we were able to unambiguously detect the key H-bonding interaction between HFIP and the gold catalyst, shedding light on the intermolecular mode of activation that enables catalysis. In the cases examined herein, HFIP is not only an excellent solvent but also a potent activator and a valuable synthetic handle when incorporated into functional groups of products.

Recent Advances in the Gold-Catalyzed Reactions of Propargyl Esters.

ConspectusLate-transition-metal-based complexes represent an indispensable catalytic tool in chemical synthesis due to their ability to increase molecular complexity rapidly and efficiently from readily accessible substrates in a single operation. Added to this is the exquisite control of product chemo-, diastereo-, enantio-, and site-selectivities achieved by catalytic systems of the transition-metal salts that have been developed to mediate a wide range of functional group transformations. Within this venerable synthetic toolbox, complexes and salts of Au(I) and Au(III) have emerged in recent years as an invaluable addition as a result of their potent σ- and π-Lewis acidities and ability to stabilize cationic reaction intermediates. The insights provided by mechanistic studies examining the various electronic, steric, and stereoelectronic factors at play in the organogold species that are expected to be formed in the catalytic chemistry of the transition-metal complex have also been pivotal in understanding and exploring their potential synthetic utility. Illustrative of this, for example, is the contribution made by the gold-catalyzed cycloisomerization chemistry of propargyl esters in synthetic strategies to a variety of bioactive natural products and compounds of current pharmaceutical and materials interest. This Account summarizes our efforts over the past decade toward realizing new single-step strategies for carbocyclic and heterocyclic synthesis that relied on the gold-catalyzed reactions of propargyl esters. It outlines synthetic methods developed by the group that exploited the unique reactivities of the gold-carbene species typically generated from the [2,3]-sigmatropic rearrangement of the compound class containing a terminal or electron-deficient alkyne moiety on exposure to the transition-metal salt. This Account also describes the realization of synthetic methods initiated by the gold-catalyzed 1,3-acyloxy migration of propargyl esters with an electronically unbiased disubstituted C≡C bond that delivers the corresponding allenyl ester that is primed for further reactivity on activation by the group 11 metal complex. The studies formed a part of an ongoing overarching program within our group that was focused on determining reactivities in gold catalysis that would enable their application as readily recognizable disconnections in retrosynthetic analysis. They were additionally a part of efforts aimed at evaluating the opportunities offered by the relativistic effects possessed by a Au(I) and Au(III) complex, the most pronounced among the d-block elements and thus the catalyst of choice in alkyne activation chemistry, to generate new chemical space. For instance, we demonstrated in several studies the cycloisomerization of 1,3- and 1,4-enyne esters to be a reliable strategy for the in situ formation of a wide range of 1,4-cyclopentadienyl derivatives. Their further reaction with an appropriately placed functional group or a second starting material was then shown to afford a variety of synthetic targets containing the five-membered ring structure. An example of this was the assembly of a new member of the 1H-isoindole compound family that was found to exhibit potent TNF-α (tumor necrosis factor-α) inhibitor activity.

Bifunctional Phosphine-Enabled Regioselective Cycloisomerization of Enynyl Esters En Route to Bicyclo[2.2.1]heptenes.

Expedient access to bridged enol benzoates is realized via a tandem gold-catalyzed cycloisomerization of enynyl esters and the Diels-Alder reaction. The gold catalysis permits the use of enynyl substrates without additional propargylic substitution and achieves the highly regioselective formation of less stable cyclopentadienyl esters. The regioselectivity is enabled by a bifunctional phosphine ligand, the remote aniline group of which facilitates α-deprotonation of a gold carbene intermediate. The reaction works with different alkene substitution patterns and various dienophiles.

Synthesis of α-pyrones via gold-catalyzed cycloisomerization/[2 + 1] cycloaddition/rearrangement of enyne-amides and sulfur ylides

A novel gold-catalyzed cycloisomerization/[2 + 1]cycloaddition/rearrangement of enyne-amides and sulfur ylides is reported. This strategy enables rapid and efficient construction of a series of α-pyrone derivatives.

Construction of the quinobenzoxazine core via gold-catalyzed dual annulation of azide-tethered alkynones with anthranils.

A new catalytic method for the construction of the quinobenzoxazine core has been developed employing the gold-catalyzed cyclization of o-azidoacetylenic ketones in the presence of anthranils. The overall process comprises of a gold-catalyzed 6-endo-dig cyclisation of o-azidoacetylenic ketone leading to a α-imino gold carbene and subsequent carbene transfer to anthranil leading to the 3-aryl-imino-quinoline-4-one intermediate, which undergoes 6π-electrocyclization and aromatization to form the central quinobenzoxazine core. This transformation provides a new approach to a diverse array of quinobenzoxazine structures, in addition to being scalable and having mild reaction conditions.

Gold-Catalyzed Regioselective Synthesis of Crowded Cyclopentadienes by Migratory Cycloisomerization of Vinylallenes.

We report the regioselective synthesis of silyl-substituted cyclopentadienyl esters through gold-catalyzed migratory cycloisomerization of silyl-substituted vinylallenes. This transformation is proposed to proceed through a perfectly orchestrated sequence of events including Nazarov-like cyclization and several silyl and hydrogen rearrangements. Furthermore, exploiting the multifaceted nature of the gold catalyst, we have also identified suitable conditions for the synthesis of these cyclopentadienes in a more straightforward manner through gold-catalyzed reaction of propargyl esters and alkynylsilanes.

Collective Total Syntheses of Five Lycopodium Alkaloids.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Hydrogen bonding-enabled gold catalysis: ligand effects in gold-catalyzed cycloisomerizations in hexafluoroisopropanol (HFIP).

Gold catalysis has witnessed immense evolution in recent years, yet it still requires the use of activators to render the common [AuCl(L)] complexes catalytically active. Herein, the H-bonding donor properties of hexafluoroisopropanol (HFIP) are utilized for Au-Cl bond activation and the ancillary ligand and counteranion effects on cycloisomerization reactions are showcased in HFIP as solvent.

Gold-Catalyzed Cycloisomerization of Propargyl Pyruvates Enabling Unified Access to Tricladolides C and D, Chaetomellic Anhydride A, and Tyromycin A

Gold-catalyzed cycloisomerization of propargyl pyruvates has been developed as a key reaction to prepare maleic anhydride-type natural products. By combining with chemoselective epoxidation of the formed γ-alkylidenebutenolides and oxidative cleavage of epoxides, the first synthesis of tricladolide D and racemic tricladolide C has been achieved in 52 and 16% overall yields with five to seven steps starting from commercially available compounds. Further catalytic hydrogenation of alkenylated maleic anhydrides derived from γ-alkylidenebutenolides produced chaetomellic anhydride A (19% yield for six steps) and tyromycin A (15% yield for six steps), which provides flexible synthetic approaches to these naturally occurring dialkylated maleic anhydrides distinct from the documented ones.

Cover Picture: Construction of Enantioenriched 4,5,6,7‐Tetrahydrofuro[2,3‐b]pyridines through a Multicatalytic Sequence Merging Gold and Amine Catalysis (Adv. Synth. Catal. 19/2021)

The inside cover picture, designed by Fabrice Goursaud, holder of a PhD in organic chemistry and recently graduated from art school, illustrates the stereoselective synthesis of tetrahydro[2,3-b]pyridine frameworks via one-pot metal-organo relay catalysis. The strategy, which involves a gold-catalyzed cycloisomerization and a chiral amine mediated cycloaddition reaction, provides the targeted molecules in yields ranging from 27 to 90% and high levels of stereoselectivity (de>95%, 93–99% ee). Details can be found in the Communication by Manon Genet, Abdelilah Takfaoui, Jérôme Marrot, Christine Greck and Xavier Moreau. (M. Genet, A. Takfaoui, J. Marrot, C. Greck, X. Moreau, Adv. Synth. Catal. 2021, 363, 4516–4520; DOI: 10.1002/adsc.202100756).

Gold-Catalyzed Complementary Nitroalkyne Internal Redox Process: A DFT Study

Gold-catalysis, in this century, is one of the most emerging and promising new areas of research in organic synthesis. During the last two decades, a wide range of distinct synthetic methodologies have been unveiled employing homogeneous gold catalysis and aptly applied in the synthesis of numerous natural products and biologically active molecules. Among these, the reactions involving α-oxo gold carbene/α-imino gold carbene intermediates are of contemporary interest, in view of their synthetic potential and also due to the need to understand the bonding involved in these complexes. In this manuscript, we document the theoretical investigations on the regio-selectivity dependence of substitution on the gold-catalyzed cycloisomerization of o-nitroarylalkyne derivatives. We have also studied the relative stabilities of α-oxo gold carbene intermediates.

Silicon on the Run in a Gold-Catalyzed Cycloisomerization

Silicon on the Run in a Gold-Catalyzed Cycloisomerization

Merging Molecular Recognition and Gold(I) Catalysis with Triphoscalix[6]arene Ligands.

We report the synthesis and characterization of novel triphosphine calix[6]arene ligands. These supramolecular wheels, with recognition features governed by the hydrogen-bonding domain, were employed to synthesize multitasking trinuclear gold(I) complexes as a new platform for the synthesis of interwoven (pseudo)rotaxane species. In parallel, the multivalent, metal-bonded upper rim displayed catalytic features promoting highly selective gold-catalyzed cycloisomerization reactions of 1,6-enynes.

Total Synthesis of Ritterazine B.

The first total synthesis of the cytotoxic alkaloid ritterazine B is reported. The synthesis features a unified approach to both steroid subunits, employing a titanium-mediated propargylation reaction to achieve divergence from a common precursor. Other key steps include gold-catalyzed cycloisomerizations that install both spiroketals and late stage C-H oxidation to incorporate the C7' alcohol.