Fluorescent bicolour sensor for low-background neutrinoless double ß decay experiments.

Observation of the neutrinoless double ß decay is the only practical way to establish that neutrinos are their own antiparticles1. Because of the small masses of neutrinos, the lifetime of neutrinoless double ß decay is expected to be at least ten orders of magnitude greater than the typical lifetimes of natural radioactive chains, which can mimic the experimental signature of neutrinoless double ß decay2. The most robust identification of neutrinoless double ß decay requires the definition of a signature signal-such as the observation of the daughter atom in the decay-that cannot be generated by radioactive backgrounds, as well as excellent energy resolution. In particular, the neutrinoless double ß decay of 136Xe could be established by detecting the daughter atom, 136Ba2+, in its doubly ionized state3-8. Here we demonstrate an important step towards a 'barium-tagging' experiment, which identifies double ß decay through the detection of a single Ba2+ ion. We propose a fluorescent bicolour indicator as the core of a sensor that can detect single Ba2+ ions in a high-pressure xenon gas detector. In a sensor made of a monolayer of such indicators, the Ba2+ dication would be captured by one of the molecules and generate a Ba2+-coordinated species with distinct photophysical properties. The presence of such a single Ba2+-coordinated indicator would be revealed by its response to repeated interrogation with a laser system, enabling the development of a sensor able to detect single Ba2+ ions in high-pressure xenon gas detectors for barium-tagging experiments.

Dehydration of alcohols catalyzed by copper(II) sulfate: type II dyotropic reactions and stepwise mechanisms.

Dehydration of alcohols in the presence of copper(II) sulfate has been analyzed computationally. Density functional theory (DFT) calculations on selected alcohols indicate that this reaction can take place via two possible mechanisms: (a) concerted - although asynchronous - type II dyotropic reactions, or (b) stepwise E1-like processes, in which cleavage of the C-O bond occurs in the first step, followed by syn proton elimination. Our calculations show the relationship between the initial alcohol structure and the preferred mechanism, which is a type II dyotropic reaction for primary alcohols, whereas a stepwise process is the favored one when stable carbocation intermediates are energetically accessible. The dehydration of dehydrolinalool (2,7-dimethyl-6-en-1-yn-3-ol, DHL) to yield different alkenes of interest in the fragrance industry is discussed as a case study of its regiochemistry.

Enantiopure [6]-Azairidahelicene by Dynamic Kinetic Resolution of a Configurationally Labile [4]-Helicene.

A pair of enantiopure [6]-azairidahelicenes incorporating chirality at the metal center and on the helicenic ligand were synthesized by dynamic kinetic resolution (dkr) of a configurationally labile [4]-helicenic ligand (4-(2-pyridyl)-benzo[g]phenanthrene, L1H) using bis-cyclometalated chiral-at-metal only iridium(III) precursors as chiral inductors. The origin of the observed dkr is attributed to the different conformation and stability of diastereomeric reaction intermediates formed during the cyclometalation process. The isolated enantiomers exhibited circularly polarized phosphorescence (CPP), with |gphos| values of 1.8×10-3.

Selectivity in Cationic Cyclizations Involving Alkynes: A Computational Study on the Biomimetic Synthesis of Steroids.

Computational studies on the electrophilic cyclization between alkynes and transient carbocations or Lewis-acid-activated epoxides show that the regiochemistry of the reaction depends on the terminal or internal position of the triple bond. Reactants possessing terminal alkynyl groups lead to six-membered rings, whereas internal alkynes yield five-membered rings through 6-endo-dig and 5-exo-dig electrophilic cyclizations, respectively. The regiochemistry of the reaction is not determined by two-electron interactions, but by the minimization of Pauli repulsion. This scenario is preserved in related biomimetic reactions leading to steroid scaffolds. In this latter case, the stereochemistry of the cyclization reaction is oriented towards the formation of equatorial C-C bonds connecting the new six-six- and six-five-membered fused rings.

Selectivity in Cationic Cyclizations Involving Alkynes: A Computational Study on the Biomimetic Synthesis of Steroids.

Invited for the cover of this issue are Abel de Cózar, Ana Arrieta and Fernando P. Cossío at the University of the Basque Country. The image depicts the evolution of a reactive cation to the corresponding cyclic intermediate in the course of a regio- and stereocontrolled biomimetic cyclization. Read the full text of the article at 10.1002/chem.202204028.

Phenanthrene-Extended Phenazine Dication: An Electrochromic Conformational Switch Presenting Dual Reactivity.

The synthesis and isolation of one of the few examples of a π-extended diamagnetic phenazine dication have been achieved by oxidizing a phenanthrene-based dihydrophenazine precursor. The resulting dication was isolated and fully characterized, highlighting an aromatic distorted structure, generated by the conformational change upon the oxidation of the dihydrophenazine precursor, which is also correlated with a marked electrochromic change in the UV-vis spectrum. The aromaticity of the dication has also been investigated theoretically, proving that the species is aromatic based on all major criteria (structural, magnetic, and energetic). Moreover, the material presents an intriguing dual reactivity, resulting in ring contraction to a π-extended triarylimidazolinium and reduction to the dihydrophenazine precursor, depending on the nature of the nucleophile involved. This result helps shed light on the yet largely unexplored reactivity and properties of extended dicationic polycyclic aromatic hydrocarbons (PAHs). In particular, the fact that the molecule can undergo a reversible change in conformation upon oxidation and reduction opens potential applications for this class of derivatives as molecular switches and actuators.

Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease.

BACKGROUND AND AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. APPROACH AND RESULTS: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. CONCLUSIONS: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.

Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides.

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.

Additive and Emergent Catalytic Properties of Dimeric Unnatural Amino Acid Derivatives: Aldol and Conjugate Additions.

Different densely substituted L- and D-proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ-nitro-2-alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ-dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ-dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ-dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N-acyloxy-2-oxooctahydro-1H-indoles was observed.

Fluorescent Imidazo[1,2-a]pyrimidine Compounds as Biocompatible Organic Photosensitizers that Generate Singlet Oxygen: A Potential Tool for Phototheranostics.

Photodynamic therapy has been used to treat a variety of diseases, however, there is continuing search for new biocompatible photosensitizers. Herein, we demonstrate for the first time that imidazo[1,2-a]pyrimidine compounds are able to generate singlet oxygen species and can act as photosensitizers in the intracellular environment. Our results show that this class of compounds absorb and emit in the 400-500 nm region, present low cytotoxicity in the dark, are efficiently uptaken by cells, are fluorescent in intracellular medium, and generate singlet oxygen upon irradiation, killing cancer cells within 2 h at low concentration (2.0 µm). The imidazo[1,2-a]pyrimidine compounds are a potential new tool for phototheranostics, because they can be simultaneously used for fluorescence imaging and photodynamic therapy.

Bicolour fluorescent molecular sensors for cations: design and experimental validation.

Molecular entities whose fluorescence spectra are different when they bind metal cations are termed bicolour fluorescent molecular sensors. The basic design criteria of this kind of compound are presented and the different fluorescent responses are discussed in terms of their chemical behaviour and electronic features. These latter elements include intramolecular charge transfer (ICT), formation of intramolecular and intermolecular excimer/exciplex complexes and Förster resonance energy transfer (FRET). Changes in the electronic properties of the fluorophore based on the decoupling between its constitutive units upon metal binding are also discussed. The possibility of generating fluorescent bicolour indicators that can capture metal cations in the gas phase and at solid-gas interfaces is also discussed.

Discovering Biomolecules with Huisgenase Activity: Designed Repeat Proteins as Biocatalysts for (3 + 2) Cycloadditions.

Designed repeat proteins catalyze the 1,3-dipolar reaction between an imine and a π-deficient dipolarophile in THF solution to form unnatural nitroproline esters, a reaction that no enzyme can catalyze. NMR studies and mutation experiments show that both acidic and basic residues can catalyze the reaction. The diastereocontrol of the reaction depends on the flexibility of the protein and on the number and location of the active lysine and glutamate residues, which can participate independently or forming dyads that promote the formation of unusual diastereomeric cycloadducts. QM/MM calculations permit one to rationalize the origins of this Huisgenase activity and of its diastereocontrol.

Stepwise Mechanism for the Bromination of Arenes by a Hypervalent Iodine Reagent.

A mild, metal-free bromination method of arenes has been developed using the combination of bis(trifluoroacetoxy)iodobencene and trimethylsilyl bromide. In situ-formed dibromo(phenyl)-λ3-iodane (PhIBr2) is proposed as the reactive intermediate. This methodology using PIFA/TMSBr has been applied with success to a great number of substrates (25 examples). The treatment of mono-substituted activated arenes led to para-brominated products (2u-z) in excellent 83-96% yields. Density functional theory calculations indicate a stepwise mechanism involving a double bromine addition followed by a type II dyotropic reaction with concomitant re-aromatization of the six-membered ring.

Selective synthesis of trisubstituted pyrroles through the reactions of alkynyl Fischer carbene complexes with oxazolones.

An efficient and simple synthesis of novel trisubstituted 1H-pyrroles 4a-qvia 1,3-dipolar cycloaddition of Δ3-trifluoromethyloxazolones 2a-d with both chromium and tungsten alkynyl Fischer carbene complexes (1a-h) is described. An unexpected and unreported -CF3 group elimination process was observed in the pyrrole structure. Our experimental and theoretical data suggested that the metal fragment may be responsible for this phenomenon. The dipolar cycloaddition proceeded efficiently to produce a single regioisomer, which was unambiguously established through NMR and single-crystal X-ray diffraction studies. Nevertheless, the reaction of alkynyl carbenes bearing an α,ß,γ,δ-unsaturated moiety with excess oxazolone 2a produced a polycyclic compound 6 speculatively formed through a cascade reaction involving 1,6-, 1,4- and 1,2-nucleophilic addition steps.

Lanthanum-Catalyzed Enantioselective Trifluoromethylation by Using an Electrophilic Hypervalent Iodine Reagent.

A highly enantioselective catalytic method for the synthesis of quaternary α-trifluoromethyl derivatives of 3-oxo esters is described. The reaction uses lanthanum(III) triflate and chiral PyBOX-type C2 -symmetric ligands to generate intermediate LaIII complexes that incorporate an enolate moiety of the starting 3-oxo ester and the trifluoromethylation transfer reagent. The enantioselectivity of the reaction stems from the efficient blockage of one of the prochiral faces of the LaIII enolate by one unit of the C2 -symmetric ligand.

Synthesis of Sultones from Chlorosulfates by a Complex Cascade Reaction Occurring under Mild Thermal Conditions.

Chlorosulfate derivatives are interesting reagents that have been traditionally used to get other sulfur-containing compounds by formal nucleophilic substitution of the chlorine atom. This work describes a different mode of reactivity of alkyne-containing chlorosulfates to get sultones, the sulfur analogues of lactones. The complex skeletal rearrangement observed in this transformation is comparable to those intricate processes promoted or catalyzed by organometallic compounds. However, the reaction here described does not require any reagent or additive, being just a thermal process. Computational calculations support a mechanism based on a series of cascade reactions where almost every step is counterintuitive. Some of these steps include original processes related to classical reactions, thus adding complementary views to traditional organic chemistry.

Bio-inspired Total Synthesis of Twelve Securinega Alkaloids: Structural Reassignments of (+)-Virosine†B and (-)-Episecurinol†A.

The so-called Securinega alkaloids constitute a class of tetracyclic biologically active specialised metabolites isolated principally from subtropical plants belonging to the Phyllanthaceae family. Following a strategy based on alternative hypotheses for their biosynthesis, an easy and time-efficient divergent synthesis enabled access to twelve of those alkaloids featuring (neo)(nor)securinane skeletons. Moreover, this work permitted to reassign the absolute configurations of (+)-virosine B and (-)-episecurinol A.

Switching Diastereoselectivity in Catalytic Enantioselective (3+2) Cycloadditions of Azomethine Ylides Promoted by Metal Salts and Privileged Segphos-Derived Ligands.

Catalytic enantioselective 1,3-dipolar cycloaddition between imino esters and electrophilic alkenes, employing chiral metal complexes derived from copper(I) and silver(I) salts and (S)-DM- or (S)-DTBM-Segphos as ligands produces diastereodivergently exo- or endo-cycloadducts, respectively. The effect of the functional group of the dipolarophile and the fine tuning of the catalyst plays an important role in promoting reverse diastereoselectivities. The origins of experimentally observed enantioselectivity and diastereoselectivity data, as well as the origin of the observed switched endo/exo ratios, are also explained by means of density functional theory calculations.

Cooperative Catalysis with Coupled Chiral Induction in 1,3-Dipolar Cycloadditions of Azomethine Ylides.

1,3-Dipolar cycloadditions (1,3-DC) between imino esters (as precursors of N-metallated azomethine ylides) and π-deficient alkenes are promoted by cooperative asymmetric Lewis acid/Brønsted base catalysis. The components of these catalytic pairs are silver salts derived from enantiopure commercially available BINOL-based phosphoric acids and Cinchona alkaloids. Chiral phosphoric silver(I) salts promote HOMO raising of in situ formed 1,3-dipoles, whereas protonated cinchona alkaloids generate a LUMO lowering for the dipolarophiles resulting in a global acceleration of the 1,3-DC. The best results were obtained with BINOL-derived silver phosphate and hydrocinchonine. Matching between both cooperative metallo- and organocatalyst results in an enhanced enantiomeric excess, superior to that reached by both separate components. NOESY experiments and DFT calculations are compatible with a non-covalent interaction (hydrogen bond) between both catalysts, which results in close contacts and mutually coupled chiral environments.

Alkaloids Reactivity: DFT Analysis of Selective Demethylation Reactions.

All possible demethylation reactions of a diverse family of quaternary alkaloids by means of DFT calculations are here described. We aim to develop a rational model that allows the explanation of the high selectivity observed experimentally and predicts the occurrence of new alkaloid derivatives. To this end, we have performed a detailed analysis of the initial reagents and products. In addition, as a proof of concept, an experimentally unknown demethylation reaction of coralyne has been carried out, thus verifying the reliability of the theoretical model presented here.