BLANC - Blanc

Comparison of Complete Genomes: an algorithmic and statistical approach to investigate the mechanisms of bacterial genome evolution – FLASH

Submission summary

Asymmetric intramolecular olefin hydroamination allows an atom economic synthesis of chiral nitrogen heterocycles that are building blocks for numerous natural products. Recently several lanthanide complexes have been reported as enantioselective catalysts of a test cyclisation/hydroamination, but there are to date no efficient catalysts for performing the reactions under mild conditions and for giving rise to satisfactory activities and enantioselectivities for a wide range of compounds. We have prepared a new family of enantioselective catalysts for intramolecular hydroamination, differing in their structures from formerly described catalysts. These catalysts are lanthanide anions coordinated by two binaphthylamine ligands, associated to alcaline cations. These complexes allow the preparation of pyrrolidines and a piperidine with asymmetric inductions similar to those reported in the literature. The aim of our project is the optimisation of the catalysts in terms of activity and asymmetric inductions and to widen the scope of the methodology to the preparation of new alkaloid analogues for the synthesis of biologically valuable molecules as an ultimate goal. One part of the project is the synthesis of various lanthanide complexes coordinated by two binaphthylamine ligands and their evaluation as enantioselective catalysts for the formation of pyrrolidines and piperidines. As these catalysts are easily tunable, the influence of the nitrogen substituents, of the lanthanide nature and of the alkaline cation will be studied. Other chiral diamine ligands will also be investigated. Mechanistical studies will be realised by synthetic and spectroscopic approaches and by DFT calculations. After optimisation of the catalysts, their application scopes will be examined in order to access chiral functionalised nitrogen-containing heterocycles. Studies on the size of the cycle and the influence of the substituents of the double-bond of the substrate on the activity and enantioselectivity of the reaction will be carried out. Finally, the synthesis and screening of new heterocycles of biological relevance using asymmetric hydroamination reactions as the key-step will be realised. A library of constrained analogues of catecholamines will be prepared from diversely substituted benzylamines and screened by biological tests. The study of new asymmetric domino reactions will be realized with the aim to synthesize new analogues of cytotoxic alkaloids. The strategy is to initiate the reactions by asymmetric intramolecular hydroamination followed by an addition on a conjugated acceptor. These reactions will be applied to the synthesis of analogues of Camphothecin or Yohimbane that will be further tested for their anti-tumor activity. The knowledge of the Laboratoire de Catalyse Moléculaire in enantioselective catalysis and in the chemistry of lanthanides should allow a rapid improvement of the first results. Investigations in this laboratory will be devoted to the optimization of catalysts, the preparation of various substrates and the determination of enantiomeric excesses. The preparation and characterization of lanthanide complexes will be realized with the collaboration of the team of Dr Trifonov (Nizhny Novgorod, Russia), well known in this field. The Laboratoire de Chimie Structurale Organique will work on the evaluation of enantiomeric excesses and on mechanistical studies that will be realised also with the collaboration of Pr Calhorda (Lisbon, Portugal) for calculations. The expertise of the Laboratoire des Procédés et de Synthèse des Substances Naturelles is crucial for the synthesis of sophisticated substrates and for the application of asymmetric hydroamination reactions to the synthesis of valuable molecules, a task never realised to the best of our knowledge. The collaboration with the Institut Curie and the French national chemical librairies will allow the biological screening of our molecules. These common skills should contribute to the success of this green chemistry project and to the valorisation of atom economic reactions. Optimisation of lanthanide-catalysed asymmetric hydroamination is crucial for the synthesis of biologically active nitrogen-heterocycles by economic and sustainable processes.

Project coordination

Emmanuelle SCHULZ (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 290,000 euros
Beginning and duration of the scientific project: - 36 Months

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