Dual catalysis for sustainable enantioselective synthesis – PLURICAT

The first task will focus on the use of a dual iminium/dehydrogenation catalyst system to afford a stoechiometric oxidant-free functionalization of alcohols. After initial development, expansion to additional derivatization (by catalytic reduction or oxidation) should also be performed.
The second part of the prolect will be devoted to the development of the redox-neutral iminium/transfer hydrogenation for the functionalization of alcohols. After initial developments of the eaction with allylic alcohols, its implementation to other substrates and to synthetic developments should be performed.
The last task of this project will be devoted to the development of a molecular hydrogen mediated enantioselective reduction of enones. This transformation will be achieved thanks to a cooperative system consisting of two indepedent orgaoncatalysts.

For now, we have focused our efforts at developing the concept of redox-neutral approach for the synthesis of allylic alcohols using 1,3-ketoesters and 1,3-diketones as nucleophiles. In the case of 1,3-diketones, a cascade by acyl transfer allows to rapidly access attractive building blocks. These former have been derivatize to differents fragments of various biologically active natural products.

In the next months, we will focus on expending the scope of the dual iron-amine redox transformation as well as developping the dehydrogenative dual catalysis concept

A review dealing with the catalysis by iron-cyclopentadienone complexes has been accepted for publication in the journal Angewandte Chemie.
A publication on the duaol iron-aminbe catalysis with subsequent cascade acyl transfer has been submitted for publication.

Among crucial challenges currently facing synthetic chemists is the discovery of new efficient and elegant methods able to construct complex molecules in a stereochemically defined manner and limiting waste and energy consumption while starting from simple and readily available raw materials. To fulfill this goal, asymmetric organocatalysis recently emerged as a method of choice that can be combined in spectacular cascade sequences providing genuine solutions. Unfortunately, even thought the newly discovered synthetic approaches have shown impressive efficiency, some limitations of the existing systems have also appeared, particularly with regard to the possible incompatibility of the activation modes of both the substrates and reagents. The ambition of the PLURICAT project is to go beyond these current limitations by developing innovative relay cascades merging two different catalysts with orthogonal and mutually compatible reactant activation modes. The resulting dual activation provides a straightforward way to engineer new reaction cascades in which the product of the first catalytic cycle becomes the unique substrate to be activated in the second catalytic cycle, allowing otherwise impossible transformations to occur.

The central objective of the project is the development of new approaches to catalytically generate and transform in situ, from the alcohol oxidation level, the central carbonyl functionality required for an enantioselective aminocatalytic process. The strategy relies on the use of borrowing hydrogen metal catalysts, able to transfer hydrogen catalytically and reversibly without the requirement of any stoechiometric redox reagent. As a result, the projected relay cascade becomes a fully atom economic and waste-free catalytic transformation particularly attractive for industrial applications. In addition, thanks to the relative low living time of the carbonyl intermediates and their in situ aminocatalytic activation, new reactivities should be discovered where these compounds lack of stability.
In complement, we ambition to extend the relay cascade concept for addressing organocatalytic asymmetric reduction of a,ß-unsaturated carbonyls with molecular hydrogen instead of stoechiometric Hantzch esters, which remains highly sought after synthetically. To this end, we design an original dual organocatalytic system involving a Frustrated Lewis Pair (FLP) driving the transfer of molecular hydrogen to an iminium-activated carbonyl compound generated in situ from a chiral secondary amine organocatalyst.

The experience in dual organo-metal catalysis of the principal investigator combined with the knowledge of the group of Prof. Jean Rodriguez on organocatalyzed Multiple Bond-Forming Transformations (MBFTs) and on the use of 1,3-dicarbonyl compounds in organocatalysis, should lead to a synergistic collaboration decisive for the success of this project and for the development of the group.