Sequential 1,6/1,4-Asymmetric Conjugate Addition and Tandem Enolate Trapping: Applications in Total Synthesis of Natural Products – SCATE

The main goal of the SCATE project is the development of catalytic processes dedicated to the sequential 1,6/1,4-enantioselective conjugate addition of organometallic nucleophiles to cyclic and acyclic electron poor dienic substrates. New and powerful methodologies dedicated to organic
synthesis had to be developed taking into account the demand for a more economically and environmentally friendly chemistry: use of ligands accessed in short, efficient, costless synthetic routes; use of non-toxic cheap metal; use of highly efficient catalytic systems requiring no–drastic conditions while keeping a high chirality transfer, allowing to make significant progresses in the synthesis of natural products. The first objective is to develop a sequential Copper-catalyzed 1,6/1,4 additions process on cyclic dienones. Cyclic scaffolds bearing two chiral carbons having a 1,3-relationship, one being a quaternary center, had to be obtained. Dealing with the trapping of the intermediate enolate the main
target was the formation of chiral bi-cyclic scaffolds. In parallel, theoretical studies about the mechanisms of both conjugate additions (1,6 and 1,4) had to be undergone in order to find the parameters, which determine the selectivities of the transformations. The second objective was to
develop a process based on a sequential 1,6/1,4-Cu catalyzed addition on acyclic polyenic substrates. In parallel, DFT-theoretical studies associated to this objective had to be undertaken in order to optimize the selectivity of the catalytic systems. An iterative process had to be undertaken in order to form linear 1,3-polymethylated and 1,3-polyhydroxylated scaffolds. The last objective was to apply these methodologies to the synthesis of natural products.

After 48 months a research, this collaborative project led to significant progresses in the area of Enantioselective Conjugate Addition (ECA), notably:
1° Novel one-pot synthesis of chiral hydroxyalkyl and carboxyalkyl imidazolium salts, which proved to give high selectivities (>98% ee) in the addition of dialkylzinc reagents to cyclic dienones and trisubstituted
enones (formation of chiral quaternary centers)
2° Highly regio- and enantio-selective 1,6/1,4-Sequential additions of dialkylzinc and trialkylaluminiums reagents to cyclic dienones catalyzed by a Cu/phosphoramidite system. Determination of the absolute configurations of the 1,6 and 1,4 stereogenic centers by VCD/calculations of optical rotations, supported by X-Ray analysis. Application to the synthesis of the Drimane skeleton (coronarine E) through an intramolecular cyclisation of enolate. Proposition of an original heterobimetallic Cu/Zn mechanism for the regio- and enantio-selective 1,6 addition (DFT studies). Understanding of the origin of 1,6-enantioinduction, that has been confirmed through the determination of the absolute configuration of the newly formed stereogenic center.
3° Highly regio- and enantio-selective addition of dimethylzinc to acyl-N-methylimidazole enones, leading to 1,4-methylated adducts in good yields and high enantioselectivities (up to 95% ee; published in Angewandte Chemie in 2015). Application to the synthesis of fragrances (Florhydral, Ionones) and natural products (Turmarone). Access to enantio-enriched 1,3-polymethylated motifs through an iterative sequential process (> 95% ee and de). Understanding of the origin of 1,4-regioselectivity (DFT
studies).
4° Highly regio- and enantio-selective addition of boron nucleophiles to acyl-N-methylimidazole enones, leading to 1,4-hydroxylated adducts in good yields and high enantioselectivities (up to 95% ee).

This work, initiated in 2016, has been supported by a grant from the “Fondation pour le Développement de la Chimie des Substances Naturelles et ses Applications” for a PhD which started in October.

All these researches led to a French patent (applications in 4 foreign countries in progress), 11 publications in international journals (and one more recently submitted), 9 oral communications and lectures in national or international conférences.

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.