Controlling Diastereoselectivity in Dearomatizing Diels-Alder Reactions of Nitroarenes with 2-Trimethylsilyloxycyclohexadiene.

Dearomative Diels-Alder cycloadditions between nitroarenes and 2-trimethylsilyloxycyclohexadiene are carried out under high pressure at room temperature in the absence of any chemical promoter. Reactions are performed with different arenes, including the highly aromatic naphthalenes and quinolines. They lead to 3D-scaffolds with exquisite exo-diastereoselectivity. The exo approach is characterized by lower distortion of the substrates in a late TS and by more favorable orbital interactions presumably between the nitro group and the dienic part, explaining the stereoselectivity.

Tandem Hock and Friedel-Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold.

The Hock cleavage, which is compatible with tandem processes, was applied to the synthesis of 1-aryltetralines through a one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a benzyl moiety on the substrate resulted in tandem Friedel-Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel-Crafts reactions, rather than an oxocarbenium.

Tandem InCl3-Promoted Hydroperoxide Rearrangements and Nucleophilic Additions: A Straightforward Entry to Benzoxacycles.

The acid-catalyzed rearrangement of organic peroxides is generally associated with C-C-bond cleavages (Hock and Criegee rearrangements), with the concomitant formation of an oxocarbenium intermediate. This article describes the tandem process between a Hock or Criegee oxidative cleavage and a nucleophilic addition onto the oxocarbenium species (in particular a Hosomi-Sakurai-type allylation), under InCl3 catalysis. It was applied to the synthesis of 2-substituted benzoxacycles (chromanes and benzoxepanes), including a synthesis of the 2-(aminomethyl)chromane part of sarizotan, and a total synthesis of erythrococcamide B.

Total Synthesis of (+)-Cinereain and (-)-Janoxepin through a Fragment Coupling/Retro-Claisen Rearrangement Cascade.

Total syntheses of (+)-cinereain and (-)-janoxepin, two fungal cyclotripeptides featuring a complex heterocyclic core and interesting phytotoxic and antimalarial activities, have been achieved in a convergent manner. A key step in this synthesis is a one-pot cascade initiated by the cyclocondensation of two fragments-a hindered 2-vinylcyclopropane-1-acyl fluoride and an electron-deficient cyclic amidine-to release a reactive spiro[2-vinylcyclopropane-1,5'-pyrimidine-4',6'-dione]. This intermediate underwent a spontaneous retro-Claisen rearrangement that was rationalized by DFT calculations. The cascade directly afforded a 2,5-dihydrooxepin-fused heterotricyclic product, and the challenging oxepin ring was finally forged by the palladium-catalyzed ß-hydride elimination of an allylic fluoride intermediate.

Chemical Processes Involving 18-Crown-6-Ether in Activated Noncovalent Complexes with Protonated Peptides.

These last decades, it has been widely assumed that 18-crown-6-ether (CE) plays a spectator role during the chemical processes occurring in isolated host-guest complexes between peptides or proteins and CE after activation in mass spectrometers. Our present experimental and theoretical results challenge this hypothesis by showing that CE can abstract a proton or a protonated molecule from protonated peptides after activation by collisions in argon or electron capture/transfer. Furthermore, thanks to comparison between experimental and calculated values of collision cross-sections, we demonstrate that CE can change binding site after electron transfer. We also propose detailed mechanisms for these processes.

Tethered Counterion-Directed Catalysis: Merging the Chiral Ion-Pairing and Bifunctional Ligand Strategies in Enantioselective Gold(I) Catalysis.

Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in asymmetric counteranion-directed catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of a phosphine displaying a chiral phosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst are demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee) at an unusually low 0.2 mol % catalyst loading. Remarkably, the method is also compatible with a silver-free protocol.

Comparison of Chemical and Interpretative Methods: the Carbon-Boron π-Bond as a Test Case*.

Quantum chemical calculations and NBO, ETS-NOCV, QTAIM and ELF interpretative approaches have been carried out on C-donor ligand-stabilized dihydrido borenium cations. Numerous descriptors of the C-B π-bond strength obtained from orbital localization, energy partitioning or topological methods as well as from structural and chemical parameters have been calculated for 39 C-donor ligands including N-heterocyclic carbenes and carbones. Comparison of the results allows the identification of relative and absolute descriptors of the π interaction. For both families of descriptors excellent correlations are obtained. This enables the establishment of a π-donation capability scale and shows that the interpretative methods, despite their conceptual differences, describe the same chemical properties. These results also reveal noticeable shortcomings in these popular methods, and some precautions that need to be taken to interpret their results adequately.

Insights into the Ochratoxin A/Aptamer Interactions on a Functionalized Silicon Surface by Fourier Transform Infrared and UV-Vis Studies.

The association of a mycotoxin-ochratoxin A (OTA)-with a high-affinity DNA aptamer (anti-OTA) immobilized on a functionalized surface has been investigated at the molecular level. Anti-OTA aptamers are coupled by aminolysis in several steps on an acid-terminated alkyl monolayer grafted on a silicon substrate, and Fourier transform infrared spectroscopy in attenuated total reflection geometry is used to assess the immobilization of anti-OTA (in its unfolded single-strand form) and determine its areal density (ca. 1.4/nm2). IR spectra further demonstrate that the OTA/anti-OTA association is efficient and selective and that several association/dissociation cycles may be conducted on the same surface. The areal density of OTA measured after association on the surface (IR spectroscopy) and after dissociation from the surface (UV-vis spectroscopy) falls in the range 0.16-0.3/nm2 which is close to the areal density of a closed-packed monolayer of anti-OTA aptamers folded to form their G-quadruplex structure. The interactions between OTA and its aptamer at the surface are discussed with the help of density functional theory calculations-to identify the complex IR vibrational modes of OTA in solution-and UV-vis spectroscopy-to determine the protonation state of the adsorbing species (i.e., OTA dissolved in the buffer solution).

Can an Elusive Platinum(III) Oxidation State be Exposed in an Isolated Complex?

Platinum(IV) complexes are extensively studied for their activity against cancer cells as potential substitutes for the widely used platinum(II) drugs. PtIV complexes are kinetically inert and need to be reduced to PtII species to play their pharmacological action, thus acting as prodrugs. The mechanism of the reduction step inside the cell is however still largely unknown. Gas-phase activation of deprotonated platinum(IV) prodrugs was found to generate products in which platinum has a formal +3 oxidation state. IR multiple photon dissociation spectroscopy is thus used to obtain structural information helping to define the nature of both the platinum atom and the ligands. In particular, comparison of calculations at DFT, MP2 and CCSD levels with experimental results demonstrates that the localization of the radical is about equally shared between the dxz orbital of platinum and the pz of nitrogen on the amino group, the latter acting as a non-innocent ligand.

One-Pot Synthesis of Metastable 2,5-Dihydrooxepines through Retro-Claisen Rearrangements: Method and Applications.

A one-pot methodology to synthesize metastable bicyclic 2,5-dihydrooxepines from cyclic 1,3-diketones and 1,4-dibromo-2-butenes through the retro-Claisen rearrangement of syn-2-vinylcyclopropyl diketone intermediates is reported. DFT calculations were performed to understand the reaction selectivity and mechanisms towards [1,3]- or [3,3]-sigmatropic rearrangements, highlighting the crucial influence of the temperature. The reaction was successfully applied to a short protecting group-free total synthesis of radulanin A, a natural 2,5-dihydrobenzoxepine. Moreover, the strong herbicidal potential of this natural product is demonstrated for the first time.

Palladium-Catalyzed C8-Arylation of Naphthalenes through C-H Activation: A Combined Experimental and Computational Study.

Herein, a direct C8-arylation reaction of 1-amidonaphthalenes is described. By using diaryliodonium salts as arylating agents, the palladium-catalyzed C-H activation reaction showed perfect C8 regioselectivity and a wide functional group tolerance. In most cases, the desired polyaromatic compounds were isolated in good to excellent yields. To explain the observed regioselectivity, DFT calculations were performed and highlighted the crucial role of the amide directing group. Finally, the utility of this method is showcased by the synthesis of benzanthrone derivatives.

Structure of Electronically Reduced N-Donor Bidentate Ligands and Their Heteroleptic Four-Coordinate Zinc Complexes: A Survey of Density Functional Theory Results.

The role of Hartree-Fock exchange in describing the structural changes occurring upon reduction of bipyridine-based ligands and their complexes is investigated within the framework of density functional theory (DFT) calculations. A set of four free ligands in their neutral and radical anionic forms, and two of their zinc complexes in their dicationic and monocationic radical forms, is used to compare a large panel of pure, conventional, and long-range corrected hybrid DFT functionals; coupled cluster single and double calculations are used alongside experimental results as benchmarks. Particular attention has been devoted to the magnitude of the change, upon reduction, of the Δ-parameter, which measures the difference between the Cpy-Cpy and the C-N bond lengths in bipyridine ligand and is known to experimentally correlate with the charge of the ligands. Our results indicate that the structural changes significantly depend on the amount of exact exchange included in the functional. A progressive evolution is observed for the free ligands, whereas two distinct sets of results are obtained for the complexes. Functionals with a small degree of HF exchange, e.g., B3LYP, do not adequately describe geometric changes for the considered species, and, quite surprisingly, the same holds for the CC2 method. The best agreement to experimental and CCSD values is obtained with functionals that include a significant but not excessive part of exact exchange, e.g., CAM-B3LYP, M06-2X, and ωB97X-D. The calculated localization of the added electron after reduction, which depends on the self-interaction error, is used to rationalize these outcomes. Static correlation is also shown to play a role in the accurate description of the electronic structure.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

Revised Theoretical Model on Enantiocontrol in Phosphoric Acid Catalyzed H-Transfer Hydrogenation of Quinoline.

The enantioselective H-transfer hydrogenation of quinoline by Hantzsch ester is a relevant example of Brønsted acid catalyzed cascade reactions, with phosphoric acid being a privileged catalyst. The generally accepted mechanism points out the hydride transfer step as the rate- and stereodetermining step, however computations based on these models do not totally fit with experimental observations. We hereby present a computational study that enlightens the stereochemical outcome and quantitatively reproduces the experimental enantiomeric excesses in a series of H-transfer hydrogenations. Our calculations suggest that the high stereocontrol usually attained with BINOL-derived phosphoric acids results mostly from the steric constraints generated by an aryl substituent of the catalyst, which hinders the access of the Hantzsch ester to the catalytic site and enforces approach through a specific way. It relies on a new model involving the preferential assembly of one of the stereomeric complexes formed by the chiral phosphoric acid and the two reaction partners. The stereodetermining step thus occurs prior to the H-transfer step.

Iron and Cobalt Metallotropism in Remote-Substituted NHC Ligands: Metalation to Abnormal NHC Complexes or NHC Ring Opening.

Metallotropism of the M[N(SiMe3 )2 ]2 metal fragment in the tautomeric system IAR ⇌ACR involving imidazolium salts/N-heterocyclic carbenes with remote aminide/amine substituents, respectively, is manifested by its CNHC carbophilicity (R=tBu, M=Co, Fe) or NRaminido nitrogenophilicity (R=Cy, M=Co, Fe; R=Mes, M=Fe) and has been rationalized on the basis of steric and electronic effects. The thermolysis products of the [M{N(SiMe3 )2 }2 ]/ IAR ⇌ACR system are also substituent-dependent, leading to a rearranged aminide-functionalized aNHC Co2 complex of an unprecedented type or to ring-opened metallaketenimines; they are postulated to originate from different metalloisomers. The results are interpreted on the basis of the X-ray diffraction analysis of 11 new compounds.

Improved Infrared Spectra Prediction by DFT from a New Experimental Database.

This work aims to improve the computation of infrared spectra of gas-phase cations using DFT methods. Experimental infrared multiple photon dissociation (IRMPD) spectra for ten Zn and Ru organometallic complexes have been used to provide reference data for 64 vibrational modes in the 900-2000 cm-1 range. The accuracy of the IR vibrational frequencies predicted for these bands has been assessed over five DFT functionals and three basis sets. The functionals include the popular B3LYP and M06-2X hybrids and the range-separated hybrids (RSH) CAM-B3LYP, LC-BLYP, and ωB97X-D. B3LYP gives the best mean absolute error (MAE) and root-mean-square error (RMSE) values of 7.1 and 9.6 cm-1 , whilst the best RSH functional, ωB97X-D, gives 12.8 and 16.6 cm-1 , respectively. Using linear correlations instead of scaling factors improves the prediction accuracy significantly for all functionals. Experimental and computed spectra for a single complex can show significant differences even when the molecular structure is calculated correctly, and a means of defining confidence limits for any given computed structure is also provided.

Estimating π binding energy of N-heterocyclic carbenes: the role of polarization.

In this work, the tuneability of the π acceptor or donor properties of a set of N-heterocyclic carbenes (NHCs) with a wide spectrum of electronic characteristics is established by means of density functional theory and energy decomposition analysis (EDA) tools. Even though the main orbital interaction contribution to the NHC coordination is the σ donation, a significant contribution of the π interactions to the bond is observed. By means of carefully selected coordination sites, different contributions to the π interactions could be identified and isolated. It includes not only the well known back donation and donation interactions, but also the intrafragment polarization, which has not been considered in previous studies. This can be obtained through the use of the extended transition state method for EDA combined with the natural orbitals for chemical valence and the constrained space orbital variation analysis. The contributions vary with the position of the heteroatoms and the presence of exocyclic substituents; the donation/backdonation π interactions between NHC and the coordination site can range between 2 and 61% of the total π orbital interactions, while the rest is owed to intrafragment polarization. Our results do not only contribute to the understanding of the electronic structure of NHC-based complexes, giving ways to improve their catalytic properties, but also provide comprehension on the modelization methods used to study their donor-acceptor interactions.

Combining gas phase electron capture and IRMPD action spectroscopy to probe the electronic structure of a metastable reduced organometallic complex containing a non-innocent ligand.

Combining electron capture dissociation mass spectrometry and infrared multiple photon dissociation action spectroscopy allows the formation, selection and characterisation of reduced metal complexes containing non-innocent ligands. Zinc complexes containing diazafluorenone ligands have been studied and the localisation of the single electron on the metal atom in the mono-ligated complex has been demonstrated.

Planar chiral phosphoric acids with biphenylene-tethered paracyclophane scaffolds: synthesis, characterization, and catalytic screening.

Phosphoric acids with planar chiral paracyclophane scaffolds have been prepared in optically pure form starting from 1,8-dibromobiphenylene, by means of a chiral phosphorodiamidate as the phosphorylating agent. Structural characterization and configurational assignment have been performed by X-ray diffraction studies. The acids promote the organocatalytic enantioselective H-transfer reduction of α-arylquinolines with up to 90% enantiomeric excess.