Synthesis of Aza-Bridged Perhydroazulene Chimeras of Tropanes and Hederacine A

We report the synthesis of two novel azaperhydroazulene tropane-hederacine chimeras A and B, which contain an 8-azabicyclo[3.2.1]octane ring and a 7-azabicyclo[4.1.1]octane ring, respectively. The synthesis of both chimeras was achieved by epoxide ring opening and was governed by the stereochemistry of the hydroxy-epoxide unit. Finally, a density functional theory study was conducted to explain the regioselectivity of the cyclization and the importance of the stereochemistry of the hydroxyl group

Versatile Synthetic Approach for Selective Diversification of Bicyclic Aza-Diketopiperazines

International audienc

Trifluoromethyl Radical Triggered Radical Cyclization of N-Benzoyl Ynamides leading to Isoindolinones

International audienceUnder photocatalytic reductive conditions, trifluoromethyl radical addition onto an ynamide followed by cyclization on a benzoyl moiety produces diverse isoindolinone platforms with good yields. The selectivity of the radical cyclization, N-benzoyl vs. N-benzyl as radical acceptor and the E/Z ratio of isomers have been rationalized by modeling

Biostimulation of grapevine : mode of action and possible agronomic uses

National audienceAlthough there is a growing interest for the use of biostimulants in agriculture, only few methods allowing a precise description of their effects on plants have been reported. In the IRIS+ FUI project, two major and highly different worldwide crops, wheat (annual, monocotyledon) and grapevine (perennial, broadleaf), were chosen to deepen our knowledge of such compounds and explore their potential additional interest. The first objective is to develop in greenhouse conditions, a panel of tools and methods to study the impact of a series of biostimulants on the development (aerial and root system biomass measurements and corresponding phenotyping), and the physiology (photosynthetic activity, primary and secondary metabolites) of both plants. The second objective is to check if biostimulants, via their effects on the plant physiology, could be associated to resistance inducer-based control strategies against fungal aerial diseases. Unlike fungicides which directly target path! ogens, resistance inducers request plant metabolism dedicated to defense, a fitnesscostly process. Hence, an improvement of both crops' physiological status by biostimulation is expected to increase its responsiveness to resistance inducer application

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels–Alder Pattern Common to Three Classes of Natural Products

Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance

Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein–Ligand Residence Times

Ligand–target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure’s predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol’s reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times