Philippe Meunier’s research while affiliated with Université Bourgogne Europe and other places

Supported phosphine ligands are auxiliaries of topical academic and industrial interest in catalysis promoted by transition metals. However, both controlled implantation and controlled conformation of ligands should be achieved to produce immobilized catalysts that are able to structurally “copy” efficient homogeneous systems. We provide herein a general synthetic strategy for assembling a new class of branched tetra- and triphosphine ligands with a unique controlled rigid conformation, and thus providing a high local density of phosphorus atoms for extended coordination to the metal center. We prepared new functionalized cyclopentadienyl (Cp) salts to design polyphosphines that were “ready for immobilization”. These protected Cp fragments might also be of synthetic utility for generating other supported metallocenes. Tetra- and triphosphines were then formed and diversely functionalized for immobilization on virtually any kind of support. As evidenced by 31P NMR spectroscopy and the strong “through-space” spin–spin TSJ(P,P) coupling observed between P atoms, these modified polyphosphines induce, when immobilized on a support, a high local concentration of phosphorus donors that are spatially very close to each other (3–5 Å). These functionalized ligands have been incorporated into polystyrene to give either soluble or insoluble polymers and on inorganic supports such as silica. We report the catalytic performance at 0.05–0.5 mol % low palladium loading of the resulting immobilized polyphosphine ligands. This study provides proof-of-concept of supported catalytic materials built from modular polyphosphines with a novel approach to structurally controlled polydentate heterogeneous catalysts.

The modular design of polyphosphines, diversely functionalized for facile immobilization on virtually any kind of support, is reported. Previously unobserved ABCD (31)P NMR spin-spin systems evidence the control exercised on the polyphosphines conformation. We illustrate the catalytic performance at low Pd loading of the recyclable immobilized polyphosphines in C-C bond formation reactions.

Further advances in understanding the mechanism of action of resveratrol and its application require new analogs to identify the structural determinants for the cell proliferation inhibition potency. Therefore, we synthesized new trans-resveratrol derivatives by using the Wittig and Heck methods, thus modifying the hydroxylation and methoxylation patterns of the parent molecule. Moreover, we also synthesized new ferrocenylstilbene analogs by using an original protective group in the Wittig procedure. By performing cell proliferation assays we observed that the resveratrol derivatives show inhibition on the human colorectal tumor SW480 cell line. On the other hand, cell viability/cytotoxicity assays showed a weaker effects on the human hepatoblastoma HepG2 cell line. Importantly, the lack of effect on non-tumor cells (IEC18 intestinal epithelium cells) demonstrates the selectivity of these molecules for cancer cells. Here, we show that the numbers and positions of hydroxy and methoxy groups are crucial for the inhibition efficacy. In addition, the presence of at least one phenolic group is essential for the antitumoral activity. Moreover, in the series of ferrocenylstilbene analogs, the presence of a hidden phenolic function allows for a better solubilization in the cellular environment and significantly increases the antitumoral activity.

Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity.

Seven resveratrol-related monomeric stilbenoids were submitted to biomimetic oxidative coupling in the presence of laccase from Trametes versicolor (TvL), and gave racemic dihydrobenzofuran dehydrodimers (�)-15 to (�)-21. These products, after spectral characterization, were submitted to an antiproliferative activity bioassay against SW480 human colon cancer cells. Five racemates were found to be active, and were resolved by chiral HPLC. The pure enantiomers were subjected to circular dichroism measurements to establish their absolute configurations at C-7 and C-8. These enantiomerically pure compounds were submitted to the antiproliferative activity assay towards SW480 cells, and were all shown to be active with IC50 values in the approximate range 20–90 μM. In some cases, a significant difference between the activity of the 7R,8R and 7S,8S enantiomers was observed, but a defined configuration of the stereogenic centers does not appear to be a structural requirement for the activity. The comparison between the most active compounds and the inactive ones strongly suggests that the presence of a methoxy group in the position ortho to the C-4 hydroxy group is highly detrimental to the activity.

Improved protocols for Wittig reaction and palladium-catalyzed Heck coupling give expedient access to a series of unprecedented polyfunctionalized artificial-resveratrol derivatives. In the modified Wittig protocol, trimethylsilyl was used as a highly valuable protective group of the phenolic functions of starting aromatic materials. A clean O-alkylation of hydroxylated stilbenes with ethylene carbonate was also conducted. Thus, Wittig reaction followed by hydroxyethylation take place one-pot with only carbon dioxide as waste. Additionally, a palladium-catalyzed Heck coupling strategy was developed by using ferrocenyl phosphane ligands, and multi-functionalized hydroxylated stilbenes were obtained without the need of any protection/deprotection sequence. Up to six functional groups are introduced by these procedures, which limit the number of reactions steps, the waste toxicity, and the use of costly reagents.

The efficient palladium-catalyzed alkynylation of electron-rich bromoheteroarenes, incorporating deactivating electrondonating methyl and methoxy groups, and the (hetero)arylation of diynes, take place in the imidazolium ionic liquid [BMIM][BF4], as a highly polar non-volatile solvent. This method may constitute a sustainable alternative to classical solvents such as dioxane, DMF, NMP, or DMAc. New enynes are formed in the presence of a system encompassing a copper-free palladium catalyst, triphenylphosphine as ligand, and various inexpensive bases. The enyne molecules reported are selectively synthesized in high yields and are mostly unprecedented.