SCATE

Organometallic asymmetric catalysis is a powerful tool for the synthesis of chiral non racemic molecules. Indeed, catalyzed reactions present many assets: frequent atom economy reactions, reduction of organic wastes, increase of reaction rate, mild reaction conditions (temperature) and possibility of catalyst recycling. Thus, these reactions are also attractive in terms of economical and environmental aspects. Nevertheless, some limitations have hampered until now a large development of this technology. Among them, both the regioselectivity and the enantioselectivity remain the major hurdles to overcome. Some key reactions in term of potential applications in synthesis are still poorly developed; this is particularly the case of some C-C and C-Si bond formation reactions on polyenic substrates, in which both complete regio- and enantioselectivities are strongly required. This represents a straightforward access to useful chiral fragments present in many natural molecules. Therefore, new methodologies dedicated to the regio- and stereocontrol of the metal-catalyzed nucleophilic addition on polyenic substrates need to be intensively studied. To reach that aim, easily accessible chiral ligands (DiPPAM or phosphoramidites, which are obtained in one step without any purification, and hydroxyalkyl-NHC) developed within the teams involved in the project will be used. These ligands will be combined with a cheap, abundant low-toxic metal (Cu) to afford highly efficient catalytic systems. These catalysts will be used to study the following methodologies: i) A sequential process involving a Cu-catalyzed asymmetric 1,6/1,4-conjugate addition on cyclic dienones followed by the trapping of the metallic enolate arising from the 1,4-addition step. Different nucleophiles having various carbon radicals (such as alkenyl, alkynyl) and various metals (Zn, Mg, Al, B) will be evaluated in the presence of Cu complexes. The trapping of the metallic enolates will be studied both in intra- and inter-molecular versions. In the latter case, fused bicyclic products will be obtained. The global process will give access to chiral products having three (new) chiral centres. The potentialities of this methodology will be illustrated through the total synthesis of Coronarin E. ii) A sequential asymmetric 1,4/1,6-conjugate addition on aryldienones and dienals. A special attention will be directed towards methyl-type nucleophiles and silyl-based magnesiates and zincates. Indeed, in the case of dienals, the development of an iterative process combining a sequential 1,6/1,4-conjugate addition and an olefination will give access to 1,3-polymethylated or 1,3-polyols skeletons (in the latter case through the unmasking of the silyl groups using the Tamao-Fleming reaction). The potential of this methodology will be demonstrated through the achievement of the total synthesis of Tautomycetine and RK-397. For both parts, quantum chemistry modeling of the structure of the bimetallic copper / Lewis acid (Zn, Al, Mg, B) complexes proposed as reaction intermediate or transition states in the conjugate addition or enolate trapping processes will be carried out to rationalize the obtained selectivities and propose strategies to improve them. The SCATE project will involve 5 partners. Methodological studies will be undergone in the laboratories of Dr. Mauduit at ENSCR and Pr. Alexakis at Université de Genève whose expertise is related to the search for new tools for asymmetric catalysis and who have already initiated collaborations in this area. Computational studies and their interpretation will be undertaken by Pr. Gérard at the UPMC-LCT team. Applications in total synthesis will be conducted by Pr. Campagne at ENSCM and Pr Williams (Queensland University), who have a great expertise in this area.