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.

Gold-Catalyzed Double Cycloisomerization of 1-Ene-4,10-diynyl Esters to Bicyclo[6.3.0]undeca-2,4,9-trienyl Esters.

A synthetic method to prepare bicyclo[6.3.0]undeca-2,4,9,trienyl esters efficiently from gold(I)-catalyzed Rautenstrauch rearrangement/1,5-hydride shift/8-endo-dig cyclization of 1-ene-4,10-diynyl esters is described. The suggested double cycloisomerization mechanism delineates the first example of an unactivated all-carbon tethered 1,7-enyne, either preformed or formed in situ, which undergoes an 8-endo-dig cyclization pathway to give a cyclooctane motif. It also offers an extremely rare synthetic method in organic chemistry that can sequentially assemble both ring components of the bicyclic motif from an acyclic precursor in one step.

Silver-Catalyzed 1,3-Acyloxy Migration/Diels-Alder Reaction of 1,9-Dien-4-yne Esters to Partially Hydrogenated Isoquinolines.

A synthetic method to prepare partially hydrogenated isoquinolines efficiently from silver-mediated [3,3]-sigmatropic rearrangement/Diels-Alder reaction of 1,9-dien-4-yne esters is described. The reactions were shown to be robust with a wide variety of substitution patterns tolerated to provide the corresponding nitrogen-containing heterocyclic products in good to excellent yields. This includes examples containing a bridgehead sp3 quaternary carbon center as well as the cycloisomerization of one substrate to give the corresponding bicyclic adduct in excellent yield at the gram scale.

Gold-Catalyzed Sequential Cyclization of 1-En-3,9-Diyne Esters to Partially Hydrogenated 3H-Dicyclopenta[a,b]naphthalenes.

A synthetic method that relies on a gold(I)-catalyzed cycloisomerization of 1-en-3,9-diyne esters to spiro[4.4]non-2-ene-substituted 1,2-dihydronaphthalenes is described. Robust with a wide variety of substitution patterns tolerated, the reaction provides the first example of a one-step strategy to construct such novel and architecturally challenging members of the carbocycle family in good to excellent yields. A mechanism is proposed in which the sequential cycloisomerization pathway was thought to involve a gold-catalyzed 1,3-acyloxy migration/Nazarov cyclization followed by a formal [4+2] cycloaddition to give the tetracarbocyclic product.

Synthesis of 1,4-amino alcohols by Grignard reagent addition to THF and N-tosyliminobenzyliodinane.

The synthesis of 1,4-amino alcohols from THF treated with N-tosyliminobenzyliodinane (PhINTs) followed by a Grignard reagent under mild reaction conditions at room temperature is described herein. Various Grignard reagents were shown to be compatible, furnishing the corresponding 4-substituted-N-1,4-tosylamino alcohols in good to excellent yields. A partial or full detosylation of the N-tosyl-1,4-amino alcohol was observed in instances involving a sterically bulky Grignard reagent, leading to the deprotected 1,4-amino alcohol product in moderate to good yields. The synthetic utility of this protocol was demonstrated by the synthesis of a 5-substituted-N-tosyl-1,5-amino alcohol from THP and the conversion of two examples to their corresponding γ-lactam and pyrrolidine adducts.

Pharmacophore modeling for the identification of small-molecule inhibitors of TACE.

Tumor necrosis factor α-converting enzyme (TACE) plays a critical role in diverse physiological processes such as inflammation, hematopoiesis, and development. In this study, a pharmacophore model constructed from a training set of TACE inhibitors was used to screen an in-house database of organic compounds, from which compound 1 emerged as a top candidate. In a cell-free assay, compound 1 inhibited TACE enzymatic activity in a dose-dependent manner. Moreover, compound 1 inhibited the production of soluble TNF-α in human acute monocytic leukemia THP-1 cells without impacting nitric oxide production, and exhibited anti-proliferative activity against THP-1 cells. We envisage that compound 1 may be employed as a useful scaffold for the development of more potent TACE inhibitors. This study also validates the use of pharmacophore modeling to identify enzyme inhibitors.

Discovery of a small-molecule inhibitor of STAT3 by ligand-based pharmacophore screening.

STAT3 modulates the transcription of a wide variety of regulatory genes involved in cell proliferation, differentiation, migration, apoptosis, and other critical cellular functions. Constitutive activation of STAT3 has been detected in a wide spectrum of human malignancies. A pharmacophore model constructed from a training set of STAT3 inhibitors binding to the SH2 domain was used to screen an in-house database of compounds, from which azepine 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with comparable potency to the well-known STAT3 inhibitor S3I-201. A fluorescence polarization assay revealed that compound 1 targeted the SH2 domain of STAT3. Furthermore, compound 1 inhibited STAT3 phosphorylation in cells without affecting the total expression of STAT3. This study also validates the use of pharmacophore modeling to identify inhibitors of protein-protein interactions.

Ligand-controlled product selectivity in gold-catalyzed double cycloisomerization of 1,11-dien-3,9-diyne benzoates.

A synthetic method to prepare tricyclic bridged heptenones and hexenones from gold(I)-catalyzed double cycloisomerization of 1,11-dien-3,9-diyne benzoates is described. A divergence in product selectivity was achieved by fine-tuning the steric nature of the ligand of the Au(I) catalyst. In the presence of [MeCNAu(JohnPhos)](+)SbF6(-) (JohnPhos = (1,1'-biphenyl-2-yl)-di-tert-butylphosphine) as the catalyst, tandem 1,3-acyloxy migration/metallo-Nazarov cyclization/1,6-enyne addition/Cope rearrangement of the substrate was found to selectively occur to afford the bridged heptenone adduct. In contrast, changing the Au(I) catalyst to [MeCNAu(Me4tBuXPhos)](+)SbF6(-) (Me4tBuXPhos = di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine) was observed to result in the 1,11-dien-3,9-diyne benzoate undergoing a more rapid tandem 1,3-acyloxy migration/metallo-Nazarov cyclization/[4 + 2]-cyclization pathway to give the bridged hexenone derivative.

Gold-Catalyzed Cycloisomerization and Diels-Alder Reaction of 1,4,9-Dienyne Esters to 3 a,6-Methanoisoindole Esters with Pro-Inflammatory Cytokine Antagonist Activity.

A synthetic method to prepare 3a,6-methanoisoindole esters efficiently by gold(I)-catalyzed tandem 1,2-acyloxy migration/Nazarov cyclization followed by Diels-Alder reaction of 1,4,9-dienyne esters is described. We also report the ability of one example to inhibit binding of tumor necrosis factor-α (TNF-α) to the tumor necrosis factor receptor 1 (TNFR1) site and TNF-α-induced nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation in cell at a half-maximal inhibitory concentration (IC50 ) value of 6.6 µM. Along with this is a study showing the isoindolyl derivative to exhibit low toxicity toward human hepatocellular liver carcinoma (HepG2) cells and its possible mode of activity based on molecular modeling analysis.

A label-free G-quadruplex-based mercury detection assay employing the exonuclease III-mediated cleavage of T-Hg2+-T mismatched DNA.

We report herein the use of an exonuclease III and G-quadruplex probe to construct a G-quadruplex-based luminescence detection platform for Hg2+. Unlike common DNA-based Hg2+ detection methods, when using the dsDNA probe to monitor the hairpin formation, the intercalation of the dsDNA probe may be influenced by the distortion of dsDNA. This 'mix-and-detect' methodology utilized the G-quadruplex probe as the signal transducer and is simple, rapid, convenient to use and can detect down to 20 nM of Hg2+.

Iminoiodane- and Brønsted base-mediated cross dehydrogenative coupling of cyclic ethers with 1,3-dicarbonyl compounds.

A one-pot, two-step approach to prepare 2-tetrahydrofuran and -pyran substituted 1,3-dicarbonyl compounds by PhI=NTs-mediated amination/Brønsted base-catalyzed cross dehydrogenative coupling (CDC) reaction of the cyclic ether and 1,3-dicarbonyl derivative under mild conditions is reported. The reaction is compatible with a variety of cyclic ethers and 1,3-dicarbonyl compounds, affording the corresponding coupled products in moderate to good yields of up to 80% over two steps.

Gold-catalyzed [2+2+1] cycloaddition of 1,6-diyne carbonates and esters with aldehydes to 4-(cyclohexa-1,3-dienyl)-1,3-dioxolanes.

A synthetic method to stereoselectively prepare 4-(cyclohexa-1,3-dienyl)-1,3-dioxolanes in good to excellent yields by gold(I)-catalyzed [2+2+1] cycloaddition of 1,6-diyne carbonates and esters with aldehydes is described. The cascade process involves 1,2-acyloxy migration followed by cyclopropenation and cycloreversion. This leads to an unprecedented [2+2+1] cycloaddition of the resulting alkenylgold carbenoid species, examples of which are extremely rare, with two aldehyde molecules at catalyst loadings as low as 1 mol %. The usefulness of this cycloisomerization chemistry was further demonstrated by the transformation of one example to the corresponding phenol.

Gold-catalyzed cycloisomerization of 1,6,8-dienyne carbonates and esters to cis-cyclohepta-4,8-diene-fused pyrrolidines.

A synthetic approach that provides access to cis-cyclohepta-4,8-diene-fused pyrrolidines efficiently through Au(I) -catalyzed cycloisomerization of 1,6,8-dienyne carbonates and esters at a low catalyst loading of 2 mol % is reported. Starting carbonates and esters with a pendant alkyl group on the terminal alkenyl carbon center were found to favor tandem 1,2-acyloxy migration/cyclopropanation followed by Cope rearrangement of the resulting cis-3-azabicyclo[3.1.0]hexane intermediate. On the other hand, substrates containing a terminal diene or starting materials in which the distal alkene moiety bears a phenyl substituent were observed to undergo competitive but reversible 1,3-acyloxy migration prior to the nitrogen-containing bicyclic ring formation. The delineated reaction mechanism also provides experimental evidence for the reversible interconversion between the oft-proposed organogold intermediates obtained in this step of the tandem process.

Gold-catalyzed cycloisomerization of 1,6-diyne esters to 1H-cyclopenta[b]naphthalenes, cis-cyclopenten-2-yl δ-diketones, and bicyclo[3.2.0]hepta-1,5-dienes.

A synthetic method to chemoselectively prepare 1H-cyclopenta[b]naphthalenes, cis-cyclopenten-2-yl δ-diketones, and bicyclo[3.2.0]hepta-1,5-dienes efficiently by gold-catalyzed cycloisomerization of 1,6-diyne esters is described. These three product classes were accessed divergently by taking advantage of the electronic and steric differences between a phosphine and NHC (NHC = N-heterocyclic carbene) ligand in the respective gold(I) complexes and that of gold(III) complex combined with substrate substitution patterns and optimized reaction conditions. In the presence of [PhCNAuIPr](+)SbF6(-) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidine) as the catalyst, substrates with a pendant aryl group at the acetate alkynyl position were found to undergo preferential 1,3-acyloxy migration/5-exo-dig cyclization/Friedel-Crafts reaction to give 1H-cyclopenta[b]naphthalenes. In contrast, the analogous reactions with PicAuCl2 (Pic =2-picolinate) were found to proceed by selective 1,3-acyloxy migration/5-exo-dig cyclization/1,5-acyl migration to afford cis-cyclopenten-2-yl δ-diketones. Changing the catalyst to [MeCNAu(JohnPhos)](+)SbF6(-) (JohnPhos = (1,1'-biphenyl-2-yl)-di-tert-butylphosphine) and the acetate alkynyl position from an aryl to vinyl substituent in the starting ester led to 1,3-acyloxy migration/5-exo-dig cyclization/Prins-type [2 + 2]-cycloaddition to provide bicyclo[3.2.0]hepta-1,5-dienes.

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.

Enantioselective and Regiodivergent Gold and Chiral Brønsted Acid Catalyzed Cycloisomerization/Diels-Alder Reaction of 1,10-Dien-4-yn-3-yl Acetates: Synthesis of Norbornene-Embedded Tricarbocycles.

A synthetic method for the enantioselective and regiodivergent synthesis of hexahydro-2H-2,4a-methanonaphthalen-4-yl and octahydro-2,4-methanoazulen-1-yl esters that relies on the gold(I)- and chiral Brønsted acid-catalyzed cycloisomerization/Diels-Alder (CDA) reaction of (E)-1,10-dien-4-yn-3-yl acetates is described.

Gold-Catalyzed Double Spirocyclization of 3-Ene-1,7-diyne Esters to Dispiroheterocycles.

A synthetic method to prepare dispiroheterocycles containing two all-carbon quaternary centers efficiently that relies on the gold(I)-catalyzed double spirocyclization of 3-ene-1,7-diyne esters is described. The suggested mechanism delineates a rare example of a dispirocyclization featuring two 1,n-acyloxy shifts comprising a 1,3-acyloxy migration and an interrupted 1,5-acyl migration that was achieved with the assistance of residual water in the reaction media.

Rhodium(I)-Catalyzed Cascade Annulation of 1,n-Diynyl Nitrones to 3,4-Fused Fully Substituted Furans.

A method for the assembly of fully substituted furans containing a 3,4-fused 5-8-membered carbocycle, heterocycle, or spirocycle from rhodium(I)-catalyzed and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)-assisted cascade annulation of 1,n-diynyl nitrones has been developed.

Enhanced Nitric Oxide Delivery Through Self-Assembling Nanoparticles for Eradicating Gram-Negative Bacteria.

In the current battle against antibiotic resistance, the resilience of Gram-negative bacteria against traditional antibiotics is due not only to their protective outer membranes but also to mechanisms like efflux pumps and enzymatic degradation of drugs, underscores the urgent need for innovative antimicrobial tactics. Herein, this study presents an innovative method involving the synthesis of three furoxan derivatives engineered to self-assemble into nitric oxide (NO) donor nanoparticles (FuNPs). These FuNPs, notably supplied together with polymyxin B (PMB), achieve markedly enhanced bactericidal efficacy against a wide spectrum of bacterial phenotypes at considerably lower NO concentrations (0.1-2.8 µg mL-1), which is at least ten times lower than the reported data for NO donors (≥200 µg mL-1). The bactericidal mechanism is elucidated using confocal, scanning, and transmission electron microscopy techniques. Neutron reflectometry confirms that FuNPs initiate membrane disruption by specifically engaging with the polysaccharides on bacterial surfaces, causing structural perturbations. Subsequently, PMB binds to lipid A on the outer membrane, enhancing permeability and resulting in a synergistic bactericidal action with FuNPs. This pioneering strategy underscores the utility of self-assembly in NO delivery as a groundbreaking paradigm to circumvent traditional antibiotic resistance barriers, marking a significant leap forward in the development of next-generation antimicrobial agents.

Gold-catalyzed cycloisomerization of 1,6-diyne carbonates and esters to 2,4a-dihydro-1H-fluorenes.

A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I)-catalyzed 1,2-acyloxy migration/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway provides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM') [our own n-layered integrated molecular orbital and molecular mechanics(quantum mechanics:quantum mechanics')] computational studies based on the proposed Au carbenoid species provide insight into this unique selectivity.