The Potential of Self-Activating Au(I) Complexes in Gold Catalysis.

Gold catalysis has emerged as a groundbreaking field in synthetic chemistry, revolutionizing numerous organic transformations. Despite the significant achieved advancements, the mechanistic understanding behind many gold-catalyzed reactions remains elusive. This Concept article covers the so-called "self-activating" Au(I) complexes, sorting out their pivotal role in gold catalysis. We comment on how Au(I) complexes can undergo self-activation, triggering diverse catalytic transformations without the need for external additives. The most important examples reported so far that underlie the catalytic activity of these species are discussed. This intrinsic reactivity represents a paradigm shift in gold catalysis, offering new avenues for the design of efficient and sustainable catalytic systems. Furthermore, we explore the factors influencing the stability, reactivity, and selectivity of these Au(I) complexes, providing insights into their synthetic utility and potential applications. This area of research not only advances our fundamental understanding of gold catalysis but also paves the way for the development of novel catalytic strategies with broad implications in organic synthesis and the chemical industry.

Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

Invited for the cover of this issue are the groups of Raquel P. Herrera and M. Concepción Gimeno at the Instituto de Síntesis Química y Catálisis Homogénea (University of Zaragoza-CSIC). The image depicts the light of the full moon illuminating a bridge between the gold(I) metal centers. Two dragons, symbolizing the use of bridging ligands, confront each other to determine the ultimate victor. Read the full text of the article at 10.1002/chem.202303585.

Unlocking the catalytic potential of gold(II) complexes: a comprehensive reassessment.

Gold(II) complexes, unlike their gold(I) and gold(III) counterparts, have been sparsely employed in the field of catalysis. This is primarily due to the challenges associated with isolating and characterising these open-shell species. However, these complexes offer a wide range of possibilities. On one hand, this intermediate oxidation state has proven to be more easily accessible through reduction and oxidation processes compared to the gold(I)/gold(III) redox couple, thereby facilitating potential homo-coupling and cross-coupling reactions. On the other hand, gold(II) exhibits Lewis acid behaviour, bridging the characteristics of the soft acid gold(I) and the hard acid gold(III). In this review, we focus on mono- and dinuclear gold(II) complexes, whether they are isolated and well-studied or proposed as intermediates in cross-coupling reactions induced by the action of oxidants or light. We delve into the unique reactivity and potential applications of these gold(II) species, shedding light on their role in this field. This comprehensive exploration aims to underscore the latent promise of gold(II) complexes in catalysis, offering insights into their structural and mechanistic aspects while highlighting their relevance in contemporary chemical transformations.

Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

The combination of the ferrocene moiety with gold(I) catalysis remains a relatively unexplored field. In this article, we delve into the synthesis, characterization, and potential catalytic activity of four complexes utilizing both monodentate and bidentate ferrocenyl diphenylphosphane ligands (ppf and dppf), coordinated with two gold(I) metal centers, linked by either chloride or pentafluorophenylthiolate bridging ligands. This leads to the formation of cationic "self-activated" precatalysts capable of initiating the catalytic cycle without the need for external additives. The catalytic activity of these complexes was assessed through a model reaction in gold(I) catalysis, specifically the cyclization of a N-propargylbenzamide to produce an oxazole. In addition, we studied and compared the influence exerted by both the phosphane and the bridging ligand on the performance of these catalysts.

Catalysis-free synthesis of thiazolidine-thiourea ligands for metal coordination (Au and Ag) and preliminary cytotoxic studies.

The reaction of propargylamines with isothiocyanates results in the selective formation of iminothiazolidines, aminothiazolines or mixed thiazolidine-thiourea compounds under mild conditions. It has been observed that secondary propargylamines lead to the selective formation of cyclic 2-amino-2-thiazoline derivatives, while primary propargylamines form iminothiazoline species. In addition, these cyclic thiazoline derivatives can further react with an excess of isothiocyanate to give rise to thiazolidine-thiourea compounds. These species can also be achieved by reaction of propargylamines with isothiocynates in a molar ratio of 1 : 2. Coordination studies of these heterocyclic species towards silver and gold with different stoichiometries have been carried out and complexes of the type [ML(PPh3)]OTf, [ML2]OTf (M = Ag, Au) or [Au(C6F5)L] have been synthesised. Preliminary studies of the cytotoxic activity in lung cancer cells have also been performed in both ligands and complexes, showing that although the ligands do not exhibit anticancer activity, their coordination to metals, especially silver, greatly enhances the cytotoxic activity.

Heterocycles in Breast Cancer Treatment: The Use of Pyrazole Derivatives.

Among the aromatic heterocycle rings, pyrazole -a five-membered ring with two adjacent nitrogen atoms in its structure has been postulated as a potent candidate in the pharmacological context. This moiety is an interesting therapeutic target covering a broad spectrum of biological activities due to its presence in many natural substances. Hence, the potential of the pyrazole derivatives as antitumor agents has been explored in many investigations, showing promising results in some cases. In this sense, breast cancer, which is already the leading cause of cancer mortality in women in some countries, has been the topic selected for this review, which covers a range of different research from the earliest studies published in 2003 to the most recent ones in 2021.

Stereoselective Three-Step One-Pot Cascade Combining Amino- and Biocatalysis to Access Chiral γ-Nitro Alcohols.

The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due to both compatibility of reaction conditions and complementary reactivity. Herein, we describe the telescopic synthesis of chiral nitro alcohols starting from commercially available benzaldehyde derivatives through the one-pot three-step chemoenzymatic cascade combination of a Wittig reaction, chiral-thiourea-catalysed asymmetric conjugate addition, and ketoreductase-mediated reduction to access the corresponding target compounds in moderate to excellent overall isolated yields (36-80 %) and high diastereomeric and enantiomeric ratios (up to >97 : 3). This represents the first example of the combination of an organocatalysed asymmetric conjugate addition via iminium ion activation and a bioreduction step catalysed by ketoreductases.

Gold-Catalyzed 1,3-Thiazine Formation and Uncommon Tautomer Isolation.

This work represents the first example of a gold-catalyzed formation of 1,3-thiazine/1,3-thiazinane by means of a catalytic approach and further uncommon isolation of the two tautomers. The developed protocol gives rise to a broad scope of 1,3-thiazine derivatives with excellent yields in short reaction times. Interestingly, different isomers could be obtained depending on the state of the compound, and in the crystal state the 1,3-thiazinane isomer is obtained, while in solution the 1,3-thiazine is the unique isomer. This work represents an interesting approach for the synthesis of potential biologically relevant molecules and a crucial precedent in tautomerism isolation and characterization.

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties.

In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with T1, in particular the complexes [AuT1(PPh3)]OTf, the bis(thiourea) [Au(T1)2]OTf and the gold-thiolate species [Au(SR)T1]. In contrast, with T2 better results are obtained with silver species [AgT1(PPh3)]OTf and the [Ag(T1)2]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents.

Main Avenues in Gold Coordination Chemistry.

In this contribution, we provide an overview of the main avenues that have emerged in gold coordination chemistry during the last years. The unique properties of gold have motivated research in gold chemistry, and especially regarding the properties and applications of gold compounds in catalysis, medicine, and materials chemistry. The advances in the synthesis and knowledge of gold coordination compounds have been possible with the design of novel ligands becoming relevant motifs that have allowed the preparation of elusive complexes in this area of research. Strong donor ligands with easily modulable electronic and steric properties, such as stable singlet carbenes or cyclometalated ligands, have been decisive in the stabilization of gold(0) species, gold fluoride complexes, gold hydrides, unprecedented π complexes, or cluster derivatives. These new ligands have been important not only from the fundamental structure and bonding studies but also for the synthesis of sophisticated catalysts to improve activity and selectivity of organic transformations. Moreover, they have enabled the facile oxidative addition from gold(I) to gold(III) and the design of a plethora of complexes with specific properties.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

Self-Assembly of Hollow Organic Nanotubes Driven by Arene Regioisomerism.

Arene regioisomerism in low-molecular-weight gelators can be exploited as a tool to modulate the micro-structures of the corresponding xerogel networks by using the three different possible substitution patterns ortho, meta and para. This aromatic regioisomer-driven strategy has been used with a cholesterol-based gelator to prepare hollow self-assembled organic nanotubes (S-ONTs) with inside and outside diameters of ca. 35 and 140 nm, respectively. Electron microscopy imaging and theoretical calculations were employed to rationalize the formation mechanism of these S-ONTs. From the three possible regioisomers, only the ortho-disubstituted cholesteryl-based gelator showed the optimal angle and distance between substituents to afford the formation of the cyclic assemblies required for nanotube growth by assembling 30-40 units of the gelator. This study opens fascinating opportunities to expand the synthesis of controllable and unique microstructures by modulating geometrical parameters through aromatic regioisomers.

Ultrasound-assisted multicomponent synthesis of 4H-pyrans in water and DNA binding studies.

A simple approach to synthesize new highly substituted 4H-pyran derivatives is described. Efficient Et3N acts as a readily accessible catalyst of this process performed in pure water and with only a 20 mol% of catalyst loading. The extremely simple operational methodology, short reaction times, clean procedure and excellent product yields render this new approach extremely appealing for the synthesis of 4H-pyrans, as potentially biological scaffolds. Additionally, DNA interaction analysis reveals that 4H-pyran derivatives behave preferably as minor groove binders over major groove or intercalators. Therefore, this is one of the scarce examples where pyrans have resulted to be interesting DNA binders with high binding constants (Kb ranges from 1.53 × 104 M-1 to 2.05 × 106 M-1).

Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies.

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted ß-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Simple iodoalkyne-based organocatalysts for the activation of carbonyl compounds.

A novel approach for the formation of bisindolylmethane derivatives (BIMs) is described as a proof of concept to evaluate the catalytic capacity of iodoalkynes. The use of these derivatives is reported as an example of simple halogen bond-based organocatalyst. This kind of activation has not been used before for the synthesis of bisindolylmethane derivatives 3. Interestingly, the preparation of 3-(1H-indol-3-yl)-1-phenylbutan-1-one (8) has been also achieved for the first time with an iodoalkyne derivative. We prove the efficiency of this family of new catalysts by developing a simple and easy operational methodology, opening the door to the development of alternative catalysts in the area of halogen bond-based organocatalysts.

Sulfonamide as amide isostere for fine-tuning the gelation properties of physical gels.

(S)-2-Stearamidopentanedioic acid (C18-Glu) is a known LMW gelator that forms supramolecular gels in a variety of solvents. In this work, we have carried out the isosteric substitution of the amide group by a sulfonamide moiety yielding the new isosteric gelator (S)-2-(octadecylsulfonamido)pentanedioic acid (Sulfo-Glu). The gelation ability and the key properties of the corresponding gels were compared in terms of gelation concentration, gel-to-sol transition temperature, mechanical properties, morphology, and gelation kinetics in several organic solvents and water. This comparison was also extended to (S)-2-(4-hexadecyl-1H-1,2,3-triazol-4-yl)pentanedioic acid (Click-Glu), which also constitutes an isostere of C18-Glu. The stabilizing interactions were explored through computational calculations. In general, Sulfo-Glu enabled the formation of non-toxic gels at lower concentrations, faster, and with higher thermal-mechanical stabilities than those obtained with the other isosteres in most solvents. Furthermore, the amide-sulfonamide isosteric substitution also influenced the morphology of the gel networks as well as the release rate of an embedded antibiotic (vancomycin) leading to antibacterial activity in vitro against Staphylococcus aureus.

Thiolate Bridged Gold(I)-NHC Catalysts: New Approach for Catalyst Design and its Application to Trapping Catalytic Intermediates.

New dinuclear N-heterocyclic gold complexes with bridging thiolate ligands have been designed as catalytic precursors with desired properties such as stability, recyclability and that do not require additives. The dinuclear compound [(AuNHC)2 (µ-SC6 F5 )]OTf could slowly release the active catalytic species [Au(NHC)]+ and the precursor [Au(SC6 F5 )(NHC)] in solution, which means that both species would remain stable throughout the catalytic cycle and the pre-catalyst could easily be recovered. The properties exhibited by the complexes have been taken advantage of to gain new insights on the gold-catalyzed hydroalkoxylation of alkynes, with the aim of clarifying all the steps of the catalytic cycle, together with the characterization of intermediates and final products. Isolation and characterization of the pure final spiroketals and the thermodynamic intermediate have been achieved for the first time. Moreover, the kinetic intermediate has also been detected for the first time.

Proline bulky substituents consecutively act as steric hindrances and directing groups in a Michael/Conia-ene cascade reaction under synergistic catalysis.

In this study, we report a highly stereoselective and versatile synthesis of spiro pyrazolones, promising motifs that are being employed as pharmacophores. The new synthetic strategy merges organocatalysis and metal catalysis to create a synergistic catalysis using proline derivatives and Pd catalysts. This protocol is suitable for late-stage functionalization, which is very important in drug discovery. Additionally, a thorough computational study proved to be very useful to elucidate the function of the different catalysts along the reaction, showing a peculiar feature: the -CPh2OSiMe3 group of the proline catalyst switches its role during the reaction. In the initial Michael reaction, this group plays its commonly-assumed role of bulky blocking group, but the same group generates π-Pd interactions and acts as a directing group in the subsequent Pd-catalyzed Conia-ene reaction. This finding might be very relevant especially for processes with many steps, such as cascade reactions, in which functional groups are assumed to play the same role during all reaction steps.

Bioactive and luminescent indole and isatin based gold(i) derivatives.

A series of luminescent monometallic [AuL(PPh3)] (1-3) and bimetallic [Au2(µ-dppe)L2] (4, 6, 8) and [Au2(µ-dppp)L2] (5, 7, 9) complexes, where L is either 4-cyano-indole, isatin, or 5,7-dimethyl-isatin, and dppe and dppp are 1,2-bis(diphenylphosphino)ethane and 1,3-bis(diphenylphosphino)propane, respectively, have been synthesised. X-ray diffraction confirmed the tendency to establish aurophillic interations for those complexes containing dppe. Luminescence studies and theoretical calculations revealed a different origin for both families, i.e. indole and isatin species. Thus, indole derivatives presented a ligand-to-ligand-charge-transfer transition (LLCT) from the indole to the PPh3 fragment, whereas for the isatin derivatives an intraligand-charge-transfer transition (ILCT) within the isatin fragment is proposed. In both cases, the gold centre was slightly implicated as a ligand-to-metal-charge transfer transition (LMCT) (from the indole/isatin to Au(i)). Cell antiproliferative assays in lung cancer cells (A549), leukemia Jurkat-pLVTHM and Jurkat-shBak cells (cisplatin sensitive and resistant, respectively) showed excellent cytotoxic values (10.11-0.28 µM), showing the leukemia cells to be the most sensitive and the bimetallic species to be the most active agents. Preliminary studies associated the cytotoxicity with a combination of different factors, the metallic fragment being mainly responsible. Remarkably, these complexes are able to inhibit the cellular growth of cisplatin resistant Jurkat-shBak cells highlighting their promising future as an alternative anticancer agent.

Gold Catalyzed Multicomponent Reactions beyond A³ Coupling.

The preparation of complex architectures has inspired the search for new methods and new processes in organic synthesis. Multicomponent reactions have become an interesting approach to achieve such molecular diversity and complexity. This review intends to illustrate important gold-catalyzed examples for the past ten years leading to interesting skeletons involved in biologically active compounds.