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International audience; The four stereoisomers of 1-amino-2-fluoro-2-(phosphonomethyl)cyclopropane-1-carboxylic acid (FAP4) were synthesized via diastereoselective Rh(II)-catalysed cyclopropanation of a phosphonylated fluoroalkene. Different isomers of FAP4 and the corresponding non-fluorinated analogs showed a similar pharmacological profile against the isoforms of metabotropic glutamate receptor (mGluR). Within the fluorinated series, (-)-(Z)-FAP4 and (-)-(E)-FAP4 demonstrated the highest agonist activity against mGlu4 (EC50 0.10 microM). Our results suggest that fluorocyclopropanes bearing an amino-acid function can be suitable for the development of potent conformationally restricted mGluR agonists.

Herein, we report the first access to diethyl glycosamine-1-difluoromethylphosphate as phosphate mimic. The diethyl 2-nitro-glycosides-β-1-difluoromethylphosphonate were obtained from a Michael addition of diethyl(difluoro-(trimethylsilyl)methyl)phosphonate on 2-nitroglycals in the presence of a fluoride promoter in good to excellent yields. A subsequent reduction of the nitro group leads to the N-acetyl glycosides derivative giving a straightforward access to phosphate analogs.

International audience; Herein we describe the diastereoselective synthesis of glutamic acid analogs and the evaluation of their agonist activity towards metabotropic glutamate receptor subtype 4 (mGluR4). These analogs are based on a monofluorinated cyclopropane core substituted with an α-aminoacid function. The potential of this new building block as a tool for the development of a novel class of drugs is demonstrated with racemic analog 11a that displayed the best agonist activity with an EC50 of 340 nM.

The chemoselective and stereoselective synthesis of gem -difluoro-β-aminoesters or gem -difluoro-β-lactams was investigated from ethylbromodifluoroacetate and imines during Reformatsky reaction. Influence of various reaction parameters, such as nature of the amine part, nature of the chiral auxiliary, was evaluated. High levels of stereoselectivity (up to 98%) were obtained for gem -difluoro-β-aminoesters and gem -difluoro-β-lactams using either ( R )-phenylglycinol or ( R )-methoxyphenylglycinol.

The synthesis of a new generation of chiral phosphine-amides derived from d -glucosamine is described. The palladium-catalyzed asymmetric allylic alkylation of racemic 1,3-diphenyl-2-propenyl acetate with dimethyl malonate has been investigated. The results obtained from these new ligands showed the importance of the rigidity of the complex and of the d -glucosamine skeleton on the enantioselectivity of the reaction.

A new mixed chiral phosphine–phosphinite 4 obtained from enantiomerically pure ( S )-(+)-3-boronatodiphenyl-phosphanyl butanoic acid 1 was synthesized in four steps. This new chiral ligand was used in the asymmetric hydrogenation of dehydroamino acids with enantioselectivities being obtained of up to 90.8%.

Phosphine–borane can be diastereoselectively added to chiral α,β-unsaturated amides 3 , using amino-alcohols as chiral inducers, leading to α-substituted β-amidophosphine boranes 4 with up to 74% diastereomeric excess. Selective deprotection afforded optically pure carboxylic derivatives 5 which are key intermediates for the synthesis of various potential chiral ligands for asymmetric catalysis.

α-Fluoro-α,β-unsaturated esters 2 were efficiently synthetized via diethylzinc-promoted Wittig reaction using a phosphonium-supported triphenylphosphine SCG–PPh3 1, which possesses similar reactivity as its parent analog triphenylphosphine. The main advantage of this system is the use of a novel low-molecular-weight support that is soluble in solvents of medium polarities for the attachment of reagents and insoluble in solvents of low polarities.

Various diisopropyl cycloalkylphosphonates were easily prepared in an one-pot sequence under mild conditions, by electrolysing diisopropyl trichloromethylphosphonate in the presence of ω,ω-dibromoalkanes. The use of an electrochemical activated magnesium amode significantly improved the rate and the yield of the two first steps of the reaction.

The synthesis of α-fluorinated cyclopropylphosphonates is efficiently achieved for the first time by electroreduction of diisopropyl dibromofluoromethylphosphonate in the presence of Michael acceptors in a one-compartment cell equipped with a magnesium sacrificial anode.