Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo- regio- and stereoselectivities.

Iridium-Catalyzed ortho-Selective Borylation of Aromatic Amides Enabled by 5-Trifluoromethylated Bipyridine Ligands.

Iridium-catalyzed borylations of aromatic C-H bonds are highly attractive transformations because of the diversification possibilities offered by the resulting boronates. These transformations are best carried out using bidentate bipyridine or phenanthroline ligands, and tend to be governed by steric factors, therefore resulting in the competitive functionalization of meta and/or para positions. We have now discovered that a subtle change in the bipyridine ligand, namely, the introduction of a CF3 substituent at position 5, enables a complete change of regioselectivity in the borylation of aromatic amides, allowing the synthesis of a wide variety of ortho-borylated derivatives. Importantly, thorough computational studies suggest that the exquisite regio- and chemoselectivity stems from unusual outer-sphere interactions between the amide group of the substrate and the CF3 -substituted aryl ring of the bipyridine ligand.

Transition Metal-Promoted Reactions in Aqueous Media and Biological Settings.

During the last decade, there has been a tremendous interest for developing non-natural biocompatible transformations in biologically relevant media. Among the different encountered strategies, the use of transition metal complexes offers unique possibilities due to their high transformative power. However, translating the potential of metal catalysts to biological settings, including living cells or small-animal models such as mice or zebrafish, poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Herein, we describe the most relevant advances in this direction, with a particular emphasis on the systems' structure, their mode of action and the mechanistic bases of each transformation. Thus, the key challenges from an organometallic perspective might be more easily identified.

Catalytic addition of C-H bonds across C-C unsaturated systems promoted by iridium(i) and its group IX congeners.

Transition metal-catalyzed hydrocarbonations of unsaturated substrates have emerged as powerful synthetic tools for increasing molecular complexity in an atom-economical manner. Although this field was traditionally dominated by low valent rhodium and ruthenium catalysts, in recent years, there have been many reports based on the use of iridium complexes. In many cases, these reactions have a different course from those of their rhodium homologs, and even allow performing otherwise inviable transformations. In this review we aim to provide an informative journey, from the early pioneering examples in the field, most of them based on other metals than iridium, to the most recent transformations catalyzed by designed Ir(i) complexes. The review is organized by the type of C-H bond that is activated (with C sp2, sp or sp3), as well as by the C-C unsaturated partner that is used as a hydrocarbonation partner (alkyne, allene or alkene). Importantly, we discuss the mechanistic foundations of the methods highlighting the differences from those previously proposed for processes catalyzed by related metals, particularly those of the same group (Co and Rh).

Remote Activation of Hollow Nanoreactors for Heterogeneous Photocatalysis in Biorelevant Media.

Major current challenges in nano-biotechnology and nano-biomedicine include the implementation of predesigned chemical reactions in biological environments. In this context, heterogeneous catalysis is emerging as a promising approach to extend the richness of organic chemistry onto the complex environments inherent to living systems. Herein we report the design and synthesis of hybrid heterogeneous catalysts capable of being remotely activated by near-infrared (NIR) light for the performance of selective photocatalytic chemical transformations in biological media. This strategy is based on the synergistic integration of Au and TiO2 nanoparticles within mesoporous hollow silica capsules, thus permitting an efficient hot-electron injection from the metal to the semiconductor within the interior of the capsule that leads to a confined production of reactive oxygen species. These hybrid materials can also work as smart NIR-responsive nanoreactors inside living mammalian cells, a cutting-edge advance toward the development of photoresponsive theranostic platforms.

Exporting Metal-Carbene Chemistry to Live Mammalian Cells: Copper-Catalyzed Intracellular Synthesis of Quinoxalines Enabled by N-H Carbene Insertions.

Implementing catalytic organometallic transformations in living settings can offer unprecedented opportunities in chemical biology and medicine. Unfortunately, the number of biocompatible reactions so far discovered is very limited, and essentially restricted to uncaging processes. Here, we demonstrate the viability of performing metal carbene transfer reactions in live mammalian cells. In particular, we show that copper (II) catalysts can promote the intracellular annulation of alpha-keto diazocarbenes with ortho-amino arylamines, in a process that is initiated by an N-H carbene insertion. The potential of this transformation is underscored by the in cellulo synthesis of a product that alters mitochondrial functions, and by demonstrating cell selective biological responses using targeted copper catalysts. Considering the wide reactivity spectrum of metal carbenes, this work opens the door to significantly expanding the repertoire of life-compatible abiotic reactions.

Highly Enantioselective Cobalt-Catalyzed (3+2) Cycloadditions of Alkynylidenecyclopropanes.

Low-valent cobalt complexes equipped with chiral ligands can efficiently promote highly enantioselective (3+2) cycloadditions of alkyne-tethered alkylidenecyclopropanes. The annulation allows to assemble bicyclic systems containing five-membered rings in good yields and with excellent enantiomeric ratios. We also present a mechanistic discussion based on experimental and computational data, which support the involvement of CoI /CoIII catalytic cycles.

Highly Enantioselective Iridium(I)-Catalyzed Hydrocarbonation of Alkenes: A Versatile Approach to Heterocyclic Systems Bearing Quaternary Stereocenters.

We report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five-, six- and seven-membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non-covalent interactions as key factors to control the enantioselectivity.

Bioorthogonal Azide-Thioalkyne Cycloaddition Catalyzed by Photoactivatable Ruthenium(II) Complexes.

Tailored ruthenium sandwich complexes bearing photoresponsive arene ligands can efficiently promote azide-thioalkyne cycloaddition (RuAtAC) when irradiated with UV light. The reactions can be performed in a bioorthogonal manner in aqueous mixtures containing biological components. The strategy can also be applied for the selective modification of biopolymers, such as DNA or peptides. Importantly, this ruthenium-based technology and the standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) proved to be compatible and mutually orthogonal.

Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions.

Cycloaddition reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Especially appealing are formal cycloadditions promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chemistry. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via standard oxidative addition or reductive elimination processes. Curiously, metals of the third row like platinum and, especially, gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addition or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddition reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing number of reports that exploit the peculiar reactivities of allenes and derivatives. In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloadditions of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddition processes. Especially relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties associated with the transfer of stereochemical information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered. This Account is organized considering the number of atoms engaged in the annulation process, and when possible, we present the results in a chronological order.

Assembly of a Ternary Metallopeptide Complex at Specific DNA Sites Mediated by an AT-Hook Adaptor.

The nickel(II)-mediated self-assembly of a multimeric DNA binder is described. The binder is composed of two metal-chelating peptides derived from a bZIP transcription factor (brHis2 ) and one short AT-hook domain equipped with two bipyridine ligands (HkBpy2 ). These peptides reversibly assemble in the presence of NiII ions at selected DNA sequences of 13 base pairs.

Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes.

The generation of catalytically active metalloproteins inside living mammalian cells is a major research challenge at the interface between catalysis and cell biology. Herein we demonstrate that basic domains of bZIP transcription factors, mutated to include two histidine residues at i and i+4 positions, react with palladium(II) sources to generate catalytically active, stapled pallado-miniproteins. The resulting constrained peptides are efficiently internalized into living mammalian cells, where they perform palladium-promoted depropargylation reactions without cellular fixation. Control experiments confirm the requirement of the peptide scaffolding and the palladium staple for attaining the intracellular reactivity.

Intracellular Ruthenium-Promoted (2+2+2) Cycloadditions.

Metal-mediated intracellular reactions are becoming invaluable tools in chemical and cell biology, and hold promise for strongly impacting the field of biomedicine. Most of the reactions reported so far involve either uncaging or redox processes. Demonstrated here for the first time is the viability of performing multicomponent alkyne cycloaromatizations inside live mammalian cells using ruthenium catalysts. Both fully intramolecular and intermolecular cycloadditions of diynes with alkynes are feasible, the latter providing an intracellular synthesis of appealing anthraquinones. The power of the approach is further demonstrated by generating anthraquinone AIEgens (AIE=aggregation induced emission) that otherwise do not go inside cells, and by modifying the intracellular distribution of the products by simply varying the type of ruthenium complex.

Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines.

Benzyl and allyltriflamides can engage in Pd-catalyzed oxidative (4+2) annulations with allenes, to produce highly valuable tetrahydroisoquinoline or dihydropyridine skeletons. The reaction is especially efficient when carried out in the presence of designed N-protected amino acids as metal ligands. More importantly, using this type of chiral ligands, it is possible to perform desymmetrizing, annulative C-H activations of prochiral diarylmethylphenyl amides, and thus obtain the corresponding isoquinolines with high enantiomeric ratios.

Ruthenium-Catalyzed Redox Isomerizations inside Living Cells.

Tailored ruthenium(IV) complexes can catalyze the isomerization of allylic alcohols into saturated carbonyl derivatives under physiologically relevant conditions, and even inside living mammalian cells. The reaction, which involves ruthenium-hydride intermediates, is bioorthogonal and biocompatible, and can be used for the "in cellulo" generation of fluorescent and bioactive probes. Overall, our research reveals a novel metal-based tool for cellular intervention, and comes to further demonstrate the compatibility of organometallic mechanisms with the complex environment of cells.

A chemical approach for the synthesis of the DNA-binding domain of the oncoprotein MYC.

We describe the first chemical synthesis of a functional mutant of the DNA binding domain of the oncoprotein MYC, using two alternative strategies which involve either one or two Native Chemical Ligations (NCLs). Both routes allowed the efficient synthesis of a miniprotein which is capable of heterodimerizing with MAX, and replicate the DNA binding of the native protein. The versatility of the reported synthetic approach enabled the straightforward preparation of MYC and Omomyc analogues, as well as fluorescently labeled derivatives.

Recruitment of RNA molecules by connexin RNA-binding motifs: Implication in RNA and DNA transport through microvesicles and exosomes.

Connexins (Cxs) are integral membrane proteins that form high-conductance plasma membrane channels, allowing communication from cell to cell (via gap junctions) and from cells to the extracellular environment (via hemichannels). Initially described for their role in joining excitable cells (nerve and muscle), gap junctions (GJs) are found between virtually all cells in solid tissues and are essential for functional coordination by enabling the direct transfer of small signalling molecules, metabolites, ions, and electrical signals from cell to cell. Several studies have revealed diverse channel-independent functions of Cxs, which include the control of cell growth and tumourigenicity. Connexin43 (Cx43) is the most widespread Cx in the human body. The myriad roles of Cx43 and its implication in the development of disorders such as cancer, inflammation, osteoarthritis and Alzheimer's disease have given rise to many novel questions. Several RNA- and DNA-binding motifs were predicted in the Cx43 and Cx26 sequences using different computational methods. This review provides insights into new, ground-breaking functions of Cxs, highlighting important areas for future work such as transfer of genetic information through extracellular vesicles. We discuss the implication of potential RNA- and DNA-binding domains in the Cx43 and Cx26 sequences in the cellular communication and control of signalling pathways.

Rhodium-Catalyzed Annulation of ortho-Alkenyl Anilides with Alkynes: Formation of Unexpected Naphthalene Adducts.

o-Alkenyl N-triflylanilides underwent rhodium(III)-catalyzed oxidative annulations with alkynes to produce different types of naphthylamides in a process which involves the cleavage of two C-H bonds. Remarkably, besides formal dehydrogenative (4C+2C) cycloadducts, the reaction also produces variable amounts of isomeric naphthylamides, whose formation requires a formal migration of the alkenyl moiety from the ortho to the meta position of the anilide. The annulation reaction can be efficiently carried out in the absence of external oxidants, such as Cu(OAc)2 .

Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene-Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza-Bridged Medium-Sized Carbocycles.

Piperidine scaffolds are present in a wide range of bioactive natural products and are therefore considered as highly valuable, privileged synthetic targets. In this manuscript, we describe a gold-catalyzed annulation strategy that allows a straightforward assembly of piperidines and piperidine-containing aza-bridged products from readily available alkene-tethered oxime ethers (or esters) and N-allenamides. Importantly, we demonstrate the advantages of using oxime derivatives over imines, something pertinent to the whole area of gold catalysis, and provide relevant mechanistic experiments that shed light into the factors affecting the annulation processes. Moreover, we also describe preliminary experiments demonstrating the viability of enantioselective versions of the above reactions.

Cellular Uptake of Gold Nanoparticles Triggered by Host-Guest Interactions.

We describe an approach to regulate the cellular uptake of small gold nanoparticles using supramolecular chemistry. The strategy relies on the functionalization of AuNPs with negatively charged pyranines, which largely hamper their penetration in cells. Cellular uptake can be activated in situ through the addition of cationic covalent cages that specifically recognize the fluorescent pyranine dyes and counterbalance the negative charges. The high selectivity and reversibility of the host-guest recognition activates cellular uptake, even in protein-rich biological media, as well as its regulation by rational addition of either cage or pyranine.