Synthesis of Halogenated Dibenzo[1,2,6]triazonines and Late-Stage Functionalization of the Triazonine Ring.

Dibenzotriazonine represent a new class of nine-membered cyclic azobenzenes with a nitrogen atom embedded in the bridging chain. To enable future applications of this photoactive backbone, we propose in this study the synthesis of mono- and dihalogenated triazonines, that allow the late-stage introduction of different functionalized aryl groups and heteroatoms (N, O, and P) via palladium-catalyzed reactions. Indeed, different diphenylphosphoryl-triazonines were synthesized with functional groups such as aniline or phenol. Bis(diphenylphosphoryl)phenyl mono- and bis-carbamate-triazonines were also isolated in good yields.

Synthesis and Characterization of a [1,2,6]Diazaphosphonine Oxide: An Example of a Photoswitchable Phosphorus-Containing Cyclic Azobenzene.

We report herein the synthesis and characterization of a phosphorus-containing cyclic azobenzene as a new photoswitchable scaffold. This backbone reveals high bidirectional photoswitching yields and high thermal stability for both isomers, with t1/2 > 90 days at 60 °C. Both E- and Z-isomers have been characterized by UV-vis spectroscopy and X-ray crystallography.

Anti-Cancer and Radio-Sensitizing Properties of New Bimetallic (N-Heterocyclic Carbene)-Amine-Pt(II) Complexes.

Bioactive NHC-transition metal complexes have shown promise as anti-cancer agents, but their potential use as radiosensitizers has been neglected so far. We disclose here a new series of bimetallic platinum(II) complexes displaying NHC-type bridging ligands, (bis-NHC)[trans-Pt(RNH2)I2]2, that have been synthesized via a simple, two-step procedure. They display cytotoxicity in the micromolar range on cancerous cell lines, accumulate in cells, and bind to genomic DNA, by inducing DNA damages. Notably, these bimetallic complexes demonstrate significant radiosensitizing effects on both ovarian cells A2780 and nonsmall lung carcinoma cells H1299. Further investigations revealed that bimetallic species make irradiation-induced DNA damages more persistent by inhibiting repair mechanisms. Indeed, a higher and persistent accumulation of both γ-H2AX and 53BP1 foci post-irradiation was detected, in the presence of the NHC-Pt complexes. Overall, we provide the first in vitro evidence for the radiosensitizing properties of NHC-platinum complexes, which suggests their potential use in combined chemo-radio therapy protocols.

Enantioselective Au(I)-catalyzed dearomatization of 1-naphthols with allenamides through Tethered Counterion-Directed Catalysis.

The Tethered Counterion-Directed Catalysis (TCDC) approach has been applied to the enantioselective Au(I) catalyzed dearomatizations of 1-naphthols with allenamides. Stereocontrol is ensured by the intramolecular ion-pairing between the chiral gold-tethered phosphate and an iminium unit, that provides a rigid, well-defined chiral environment to the key electrophilic intermediate.

Triazonine-based bistable photoswitches: synthesis, characterization and photochromic properties.

We disclose here dibenzotriazonines as a new class of nine-membered cyclic azobenzenes displaying a nitrogen function in the saturated ring chain. The specific features of these compounds are (i) a preferred E-configuration, (ii) high bi-directional photoswitching and (iii) good thermal stability of both E- and Z-forms.

Synthesis and properties of photoswitchable diphosphines and gold(I) complexes derived from azobenzenes.

Diphosphines displaying azobenzene scaffolds and the corresponding bis-gold chloride complexes have been prepared and fully characterized by photophysical, spectroscopic and X-ray diffraction studies. DFT calculations provide complementary information on their electronic, structural and spectroscopic properties. Comparative investigations have been carried out on compounds featuring phosphorus functions in the meta- and para-positions, respectively, with respect to the azo functions, as well as on diphosphines with an ortho-tetrafluoro substituted azobenzene core. The effects of the substitution patterns on structural and spectroscopic properties are discussed.

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.

Enantioselective Gold(I)-Catalyzed Hydrative Cyclizations of N-Propargyl-ynamides into 3,6-Dihydropyridinones.

This study discloses the first enantioselective variant of the gold(I)-catalyzed hydrative cyclizations of ynamides, which have been implemented by using bis-gold(I) complexes of chiral diphosphines. Starting from N-propargyl-ynamides and water in the presence of p-toluenesulfonic acid, the cyclization reactions afford N-tosyl-3,6-dihydropyridin-2(1H)-ones in good isolated yields and with high levels of stereocontrol (20 examples, enantiomeric ratios up to 94:6).

Phosphahelicenes with (Thio)Phosphinic Acid and Ester Functions by the Oxidative Photocyclisation Approach.

Phosphahelicenes with thiophosphinic acid and ester functions have been obtained by the oxidative photocyclisation of olefins bearing both a benzophenanthrene and a benzophosphole unit. When the method has been extended to olefins bearing a partially saturated benzophospholene unit, a divergent regioselectivity of the photocyclisation step has been observed, leading to new helicenes in which the phosphorus function is located on the external rim of the helical backbone. The observed regioselectivity correlates well with the free-valence numbers of the atoms involved in the photocyclisation reaction (DFT calculations).

Synthesis and X-ray diffraction study of a chiral bis-phosphahelicene palladium (II) complex.

As a complement to our previous studies on the development of a class of chiral phosphahelicenes, this article discloses the synthesis, spectroscopic, and structural characterizations of a new phosphahelicene transition metal complex. It demonstrates the ability of these hindered chiral ligands to coordinate Pd (II) in trans-complexes Cl2 Pd(L*)2 . In the solid state, the complex adopts a C2-symmetric arrangement with two ligands facing each other on the same face of the coordination plane. X-Ray data highlight bending of the Pd (II) unit from the expected planar coordination geometry that might be due to a significant π-π stacking effect between the central rings of two helical units.

Phosphahelicenes: From Chiroptical and Photophysical Properties to OLED Applications.

Herein, the experimental physicochemical and chiroptical properties of a series of phosphahelicenes are reported, focusing on their UV/Vis absorption, luminescence, electronic circular dichroism, optical rotations, and circularly polarized luminescence. Furthermore, detailed analysis of absorption and ECD spectra performed with the help of quantum-chemical calculations allowed us to highlight general features of these helicenic phosphines. Finally, due to well-suited electrochemical properties and thermal stability, the systems were successfully used as emitters in organic light-emitting diodes.

Inhibition of p53-Murine Double Minute 2 (MDM2) Interactions with 3,3'-Spirocyclopentene Oxindole Derivatives.

3,3'-Spirocyclopentene oxindoles structurally related to Wang's spiropyrrolidine oxindoles have been highlighted as a new class of antiproliferative agents against cancer cell lines with wild-type p53 status (IC50 up to 0.96 µM on SJSA-1 and 2.9 µM in HCT116 p53-wt). Inhibition of the MDM2-p53 interactions has been demonstrated through in vitro HTRF assays (IC50 up to 3.1 nM), while Western blot analysis showed activation of p53 selectively in HCT116 cancer cell lines with wild-type p53.

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.

Short Enantioselective Total Synthesis of (-)-Rhazinilam Using a Gold(I)-Catalyzed Cyclization.

(R)-(-)-Rhazinilam has been synthesized in nine steps and 20% overall yield. The key steps involve two metal-catalyzed processes: the enantioselective gold(I)-catalyzed cycloisomerization of an allene-functionalized pyrrole and the palladium-catalyzed hydrocarboxylation of a vinyl moiety with formate as a CO surrogate. This novel strategy represents the shortest and highest yielding enantioselective total synthesis of (-)-rhazinilam.

Enantioselective gold(i)-catalyzed rearrangement of cyclopropyl-substituted 1,6-enynes into 2-oxocyclobutyl-cyclopentanes.

A gold(i)-catalyzed cycloisomerization/ring expansion sequence allows the highly enantioselective synthesis of 2-oxocyclobutylcyclopentane derivatives from cyclopropyl-substituted enynes. The bimetallic [(R)-MeO-DTBM-BIPHEP-(AuCl)2] complex was found to be the best precatalyst, affording the desired cyclobutanones in high yields and enantioselectivities (up to 99% ee). The usefulness of the method was further demonstrated by preparing the tricyclic core scaffold of russujaponol D.

The synthesis of substituted phosphathiahelicenes via regioselective bromination of a preformed helical scaffold: a new approach to modular ligands for enantioselective gold-catalysis.

Substituted phosphathiahelicenes have been prepared via a straightforward two-step procedure involving the regioselective bromination of a preformed helical scaffold, followed by palladium catalyzed coupling reactions. The new helicenes have been used as ligands in gold(i)-catalyzed [4+2] cyclizations of 1,6-enynes. The resulting dihydro-cyclopenta[b]naphthalene derivative was obtained in excellent yields and with up to 91% ee.

Synergistic effects in ambiphilic phosphino-borane catalysts for the hydroboration of CO2.

The benefit of combining both a Lewis acid and a Lewis base in a catalytic system has been established for the hydroboration of CO2, using ferrocene-based phosphine, borane and phosphino-borane derivatives.

Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting.

G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.

Planar Chiral Phosphoramidites with a Paracyclophane Scaffold: Synthesis, Gold(I) Complexes, and Enantioselective Cycloisomerization of Dienynes.

The key structural feature of the new phosphoramidites is a paracyclophane scaffold in which two aryl rings are tethered by both a 1,8-biphenylene unit and a O-P-O bridge. Suitable aryl substituents generate planar chirality. The corresponding gold(I) complexes promote the cycloisomerization of prochiral nitrogen-tethered dienynes. These reactions afford bicyclo[4.1.0]heptene derivatives displaying three contiguous stereogenic centers, with very high diastereoselectivity and up to 95 % ee.

Synthesis of New Phosphahelicene Scaffolds and Development of Gold(I)-Catalyzed Enantioselective Allenene Cyclizations.

This paper reports on the development of an efficient synthesis of enantiopure phospha[6]helicenes through a [2+2+2] alkyne cyclotrimerization reaction. The corresponding gold complexes proved to be highly efficient both in terms of catalytic activity and enantioselectivity in [2+2] and [4+2] cycloaddition reactions. Furthermore, in the presence of an external nucleophile, such as water or alcohols, the tandem cyclization/addition reactions take place in high yields and excellent diastereo- and enantioselectivities.