Reductive cyclodimerization of chalcones: exploring the "self-adaptability" of galvanostatic electrosynthesis.

The "self-adaptability" of galvanostatic electrolysis was shown to assist a multistage unprecedented chemo- and diastereoselective electrochemically promoted cyclodimerization of chalcones. The process, all involving the reductive events, delivered densely functionalized cyclopentanes featuring five contiguous stereocenters (25 examples, yields of up to 95%, dr values up to >20 : 1). Dedicated and combined experimental as well as electrochemical investigation revealed the key role of a dynamic kinetic resolution of the aldol intermediate for the reaction mechanism.

Nickel Catalyzed Carbonylation/Carboxylation Sequence via Double CO2 Incorporation.

A carbonylation-carboxylation synthetic sequence, via double CO2 fixation, is described. The productive merger of a Ni-catalyzed cross-electrophile coupling manifold, with the use of AlCl3, triggered a cascade reaction with the formation of three consecutive C-C bonds in a single operation. This strategy traces an unprecedented synthetic route to ketones under Lewis acid assisted carbon dioxide valorization. Computational insights revealed a unique double function of AlCl3, and labeling (13CO2) experiments validate the genuine incorporation of CO2 in both functional groups.

Ru-Controlled Thymine Tautomerization Frozen by a k1(O)-, k2(N,O)-Metallacycle: An Experimental and Theoretical Approach.

The reaction of mer-(Ru(H)2(CO)(PPh3)3) (1) with one equivalent of thymine acetic acid (THAcH) unexpectedly produces the macrocyclic dimer k1(O), k2(N,O)-(Ru(CO)(PPh3)2THAc)2 (4) and, concomitantly, the doubly coordinated species k1(O), k2(O,O)-(Ru(CO)(PPh3)2THAc) (5). The reaction promptly forms a complicated mixture of Ru-coordinated mononuclear species. With the aim of shedding some light in this context, two plausible reaction paths were proposed by attributing the isolated or spectroscopically intercepted intermediates on the basis of DFT-calculated energetic considerations. The cleavage of the sterically demanding equatorial phosphine in the mer-species releases enough energy to enable self-aggregation, producing the stable, symmetric 14-membered binuclear macrocycle of 4. The k1-acetate iminol (C=N-OH) unit of the mer-tautomer k1(O)-(Ru(CO)(PPh3)2(THAc)) (2) likely exhibits a stronger nucleophilic aptitude than the prevalent N(H)-C(O) amido species, thus accomplishing extra stabilization through concomitant k2(N,O)-thymine heteroleptic side-chelation. Furthermore, both the ESI-Ms and IR simulation spectra validated the related dimeric arrangement in solution, in agreement with the X-ray determination of the structure. The latter showed tautomerization to the iminol form. The 1H NMR spectra in chlorinated solvents of the kinetic mixture showed the simultaneous presence of 4 and the doubly coordinated 5, in rather similar amounts. THAcH added in excess preferentially reacts with 2 or trans-k2(O,O)-(RuH(CO)(PPh3)2THAc) (3) rather than attacking the starting Complex 1, promptly forming the species of 5. The proposed reaction paths were inferred by spectroscopically monitoring the intermediate species, for which the results were strongly dependent on the of conditions the reaction (stoichiometry, solvent polarity, time, and the concentration of the mixture). The selected mechanism proved to be more reliable, due to the final dimeric product stereochemistry.

Synthesis and Antiproliferative Insights of Lipophilic Ru(II)-Hydroxy Stearic Acid Hybrid Species.

Metallodrugs represent a combination of multifunctionalities that are present concomitantly and can act differently on diverse biotargets. Their efficacy is often related to the lipophilic features exhibited both by long carbo-chains and the phosphine ligands. Three Ru(II) complexes containing hydroxy stearic acids (HSAs) were successfully synthesized in order to evaluate possible synergistic effects between the known antitumor activity of HSA bio-ligands and the metal center. HSAs were reacted with [Ru(H)2CO(PPh3)3] selectively affording O,O-carboxy bidentate complexes. The organometallic species were fully characterized spectroscopically using ESI-MS, IR, UV-Vis, and NMR techniques. The structure of the compound Ru-12-HSA was also determined using single crystal X-ray diffraction. The biological potency of ruthenium complexes (Ru-7-HSA, Ru-9-HSA, and Ru-12-HSA) was studied on human primary cell lines (HT29, HeLa, and IGROV1). To obtain detailed information about anticancer properties, tests for cytotoxicity, cell proliferation, and DNA damage were performed. The results demonstrate that the new ruthenium complexes, Ru-7-HSA and Ru-9-HSA, possess biological activity. Furthermore, we observed that the Ru-9-HSA complex shows increased antitumor activity on colon cancer cells, HT29.

Fast MacMillan's Imidazolidinone-Catalyzed Enantioselective Synthesis of Polyfunctionalized 4-Isoxazoline Scaffolds.

The enantioselective 1,3-dipolar cycloaddition of nitrones and arylpropionaldehydes to generate highly functionalized scaffolds for application in drug discovery was herein investigated. The use of a second-generation MacMillan catalyst as hydrochloride salt consistently accelerated the reaction speed, allowing a decrease in the reaction time up to >100 times, still affording 4-isoxazolines with good to excellent enantiomeric ratios at room temperature. As a proof of concept, further functionalization of the isoxazoline core through Pd-catalyzed cross-coupling was performed, generating differently functionalized chemical architectures in high yield.

Convenient synthesis of tricyclic N(1)-C(2)-fused oxazino-indolones via [Au(I)] catalyzed hydrocarboxylation of allenes.

A new [Au(I)] catalyzed intramolecular hydrocarboxylation of allenes is presented as a valuable synthetic route to oxazino-indolones. The use of 3,5-(CF3)2-C6H3-ImPyAuSbF6 as the optimal catalyst (5 mol%) was necessary to guarantee (i) wide tolerance of functional groups, (ii) mild reaction conditions (r.t., 16 h), and (iii) high yields (up to 90%). Preliminary attempts towards an enantioselective version (81 : 19 er) are also documented by means of a new family of chiral C1-symmetric ImPyAuCl complexes.

Merging C-C σ-bond activation of cyclobutanones with CO2 fixation via Ni-catalysis.

A carboxylative Ni-catalyzed tandem C-C σ-bond activation of cyclobutanones followed by CO2-electrophilic trapping is documented as a direct route to synthetically valuable 3-indanone-1-acetic acids. The protocol shows an adequate functional group tolerance and useful chemical outcomes (yield up to 76%) when AlCl3 is adopted as an additive. Manipulations of the targeted cyclic scaffolds and a mechanistic proposal based on experimental evidence complete the investigation.

Boosting Gold(I) Catalysis via Weak Interactions: New Fine-Tunable Impy Ligands.

A series of modular ImPy-carbene-Au(I) complexes are synthesized and fully characterized both in the solid state and in solution. The presence of oligoaryl units (phenyl and thienyl rings) at the C5-position of the ImPy core (in close proximity to the gold center) imprints on the organometallic species fine-tunable and predictable catalytic properties. A marked accelerating effect was recorded in several [Au(I)]-catalyzed electrophilic activations of unsaturated hydrocarbons when a CF3-containing aromatic ring was accommodated at the ImPy core.

Enantioselective CO2 Fixation Via a Heck-Coupling/Carboxylation Cascade Catalyzed by Nickel.

A novel asymmetric nickel-based procedure has been developed in which CO2 fixation is achieved as a second step of a truncated Heck coupling. For this, a new chiral ligand has been prepared and shown to achieve enantiomeric excesses up to 99 %. The overall process efficiently furnishes chiral 2,3-dihydrobenzofuran-3-ylacetic acids, an important class of bioactive products, from easy to prepare starting materials. A combined experimental and computational effort revealed the key steps of the catalytic cycle and suggested the unexpected participation of Ni(I) species in the coupling event.

Evaluation of the Pharmacophoric Role of the O-O Bond in Synthetic Antileishmanial Compounds: Comparison between 1,2-Dioxanes and Tetrahydropyrans.

Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro, and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania.

Site-selective synthesis of 1,3-dioxin-3-ones via a gold(i) catalyzed cascade reaction.

A novel gold(i)-catalyzed protocol for the synthesis of 4H-1,3-dioxin-3-ones is presented. The protocol exploits a metal induced cascade sequence involving a [3,3]-sigmatropic rearrangement followed by regioselective O-annulation reactions. A wide range of oxygen-based heterocyclic scaffolds (21 examples) were achieved in excellent yield (up to 80%) and a detailed computational investigation as well as deuterium-labelling investigations enabled all the plausible reaction pathways to be mapped and the rationalization of the recorded regioselectivity.

Allylic and Allenylic Dearomatization of Indoles Promoted by Graphene Oxide by Covalent Grafting Activation Mode.

The site-selective allylative and allenylative dearomatization of indoles with alcohols was performed under carbocatalytic regime in the presence of graphene oxide (GO, 10 wt % loading) as the promoter. Metal-free conditions, absence of stoichiometric additive, environmentally friendly conditions (H2 O/CH3 CN, 55 °C, 6 h), broad substrate scope (33 examples, yield up to 92 %) and excellent site- and stereoselectivity characterize the present methodology. Moreover, a covalent activation model exerted by GO functionalities was corroborated by spectroscopic, experimental and computational evidences. Recovering and regeneration of the GO catalyst through simple acidic treatment was also documented.

Elusive π-helical peptide foldamers spotted by chiroptical studies.

A series of oligomers containing alternate l-Ala and pGlu (pyroglutamic acid) both in the L and D form have been prepared and conformationally investigated by X-ray, NMR, UV/ECD, IR/VCD and molecular modelling. X-ray diffraction analysis was possible for the shortest oligomers LL-1 and LD-1. Molecular dynamics simulations of the oligomers demonstrated that the energy landscapes of the LL-series are broad. In contrast, the energy landscapes of the LD-series are characterized by well-defined minima corresponding to specific conformational structures. A single well-defined minimum exists in the energy landscape of the largest oligomer LD-8, corresponding to a precise conformation, characterized by i + 5 →i N-HO[double bond, length as m-dash]C hydrogen bonds, typical of a π-helix. ECD and VCD spectra were measured to identify the chiroptical profiles of the oligomers. The most striking element in the ECD spectra of the LD-series is their exceptionally strong intensity, which confirms that these polypeptides attain a high degree of helical order. VCD spectra for the LD-series are well reproduced by frequency calculations when π-helix folds are employed as input structures, suggesting that a symmetrical VCD couplet around 1720 cm-1 can be taken as the VCD signature of π-helices.

Visible-Light-Driven Synthesis of 1,3,4-Trisubstituted Pyrroles from Aryl Azides.

The synthesis of 1,3,4-trisubstituted pyrroles via visible-light mediated photoredox catalyzed condensation of arylazides and aldehydes has been reported herein. The methodology avoids the use of stoichiometric oxidants and provides the corresponding N-containing arenes in good yields (up to 78%) and mild conditions. Mechanistic rationale is provided via a dedicated and combined spectroscopic/experimental investigations.

Redox-Neutral Metal-Free Three-Component Carbonylative Dearomatization of Pyridine Derivatives with CO2.

The TBD (1,3,5-triazabicyclodec-5-ene) assisted three-component carbonylation of pyridine-2-methanamines is documented by means of CO2 as a benign CO surrogate. The redox-neutral methodology enables the realization of densely functionalized imidazo-pyridinones in high yields (up to 93 %) and excellent chemoselectivity. Combined computational and experimental investigations revealed an unprecedented RCOCl/TBD concerted electrophilic activation of carbon dioxide.

Scandium catalysed stereoselective thio-allylation of allenyl-imidates.

The site-selective thio-allylation of electron-deficient 1,2-dienes is documented under scandium catalysis. The methodology enables the realization of α-ß unsaturated, ß-thio, γ-allyl carboxylic acid derivatives via a one-pot Lewis acid promoted Michael addition/[3,3]-sigmatropic rearrangement sequence (20 examples) in high yields (up to 95%). Full rationalization of the reaction mechanism and stereochemical outcome is provided via DFT simulations.

Phosphine-Catalyzed Stereoselective Dearomatization of 3-NO2-Indoles with Allenoates.

The stereoselective phosphine-catalyzed (( pMeOC6H4)3P, 10-20 mol %) dearomatization of 3-NO2-indoles with allenoates is described. A range of densely functionalized indolines (18 examples) is obtained in high yields (up to 96%) under mild reaction conditions (rt, air, reagent-grade solvent). Computational simulations and labeling experiments revealed a stepwise [3 + 2]-type mechanism involving a water-assisted hydrogen shift and accounted for the diastereoselection recorded.

Circularly Polarized Luminescence from an Eu(III) Complex Based on 2-Thenoyltrifluoroacetyl-acetonate and a Tetradentate Chiral Ligand.

A new chiral complex {[EuL(tta)2(H2O)]CF3SO3; L = N, N'-bis(2-pyridylmethylidene)-1,2-( R, R + S, S)-cyclohexanediamine; tta = 2-thenoyltrifluoroacetyl-acetonate} has been synthesized and characterized from a structural and spectroscopic point of view. The molecular structure in the solid state shows the presence of one chiral L, two tta, and one water molecules bound to the metal center. L and tta molecules can efficiently harvest and transfer to Eu(III) the UV light absorbed in the 250-400 nm range. The forced electric-dipole 5D0 → 7F2 emission band dominates the Eu(III) emission spectra recorded in the solid state and in solution of acetonitrile or methanol and the calculated intrinsic quantum yield of the metal ion is around 40-50%. The light emitted by the enantiopure complex shows a sizable degree of polarization with a maximum value of the emission dissymmetry factor ( glum) equal to 0.2 in methanol solution. If compared with the complex in the solid state or in acetonitrile solution, then the first coordination sphere of Eu(III) when the complex is dissolved in methanol is characterized by the presence of one CH3OH molecule instead of water. This fact is related to different Eu(III) CPL signatures in the two solvents.

Regioselectivity in Reactions between Bis(2-benzothiazolyl)ketone and Vinyl Grignard Reagents: C- versus O-alkylation-Part III.

The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave the product derived from attack on the carbonylic carbon- and/or oxygen-atom. The regioselectivity of the attack depends on the kind of substituents bound to the vinylic carbon atoms and on their relative position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium bromide was carried out under different experimental conditions and in the presence of radical scavengers. The results indicate a plausible mechanistic pathway involving radical intermediates in the case of O-alkylation, but a polar ones in the case of classic C-alkylation. This agrees with our previous reports indicating a key role played by the delocalization ability of the substituents bound to the carbonyl group in driving the regioselectivity of the vinylmagnesium bromide attack towards O-alkylation. Further support of this was obtained by diffractometric analysis of four distinct bis(heteroaryl)ketones.

Phenylene-Bridged OSSO-Type Titanium Complexes in the Polymerization of Ethylene and Propylene.

The dichloro titanium complexes (OSSO tBu)TiCl2 (1) and (OSSOCum)TiCl2 (2) bearing o-phenylene-bridged OSSO-type ligands [OSSO tBu-H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-di-tert-butyphenol) and OSSOCum-H = 6,6'-((1,2-phenylenebis(sulfanediyl))bis(methylene))bis(2,4-bis(2-phenylpropan-2-yl)phenol)] were prepared and characterized. The X-ray structure of 1 revealed that Ti atom has an octahedral coordination geometry with an fac-fac wrapping of the [OSSO] ligand. In solution at 25 °C, 1 mainly retains the C 2 symmetric structure, whereas 2 shows an equilibrium between C 2- and C 1-symmetric stereoisomers. Activation of 2 with (Ph3C)[B(C6F5)4] led to a highly active catalytic system with an activity of 238 kgPE·molcat -1·bar-1·h-1; linear polyethylene with a T m of 122 °C and M w of 107 kDa were obtained under these conditions. Catalyst 1 displayed the moderate activity of 59 kgPE·molcat -1·bar-1·h-1. Gel permeation chromatography analysis revealed the formation of high-molecular-weight polyethylenes with very large distributions of the molecular weights, indicating a low control of the polymerization process, probably becaue of the presence of different active species in solution. Density functional theory investigation provides a rational for the relative high-molecular-weight polymers obtained with these complexes. The precatalyst 2 was also active in propylene polymerization producing atactic oligomers terminated with unsaturated end groups.