Asymmetric Brønsted Acid-Catalyzed Cyclization involving Alkyne Activation – BAC-C

The BAC-C project deals with the development of an original methodology of enantioselective formation of carbon-carbon bonds by an electrophilic activation of alkynes towards nucleophilic attack in the presence of Brønsted superacids organocatalysts. The use of these catalysts allows the selective protonation of the alkyne carbon-carbon triple bond in the presence of a directing group that induces (i) an increase of the electron density of the alkyne function, increasing its reactivity and promoting chemoselectivity, (ii) its polarization leading to enhanced regioselectivity for the formation of the vinyl cation intermediate, (iii) a conformational restriction by hydrogen bonding which could result in asymmetric induction if the conjugated base of the acid is chiral during the enantiodeterminent step of attack by the nucleophile. So far, the activation of an alkyne function towards nucleophilic attack was mainly described in the presence of late transition metal complexes exhibiting carbophilic Lewis acid properties, such as platinum, gold and mercury, characterized either by their rarity and high cost, or by their toxicity. The possibility to offer a metal-free alternative involving a catalytic system of higher activity and selectivity represents an economic and environmental interest. At first, this project will involve the synthesis of derivatives of different families of Brønsted superacids and their evaluation in enantioselective catalysis. The study of a variety of cycloisomerization reactions, involving carbon nucleophiles and leading to the formation of molecules possessing either axial, central or helicoidal chirality, will be engaged. The development of new types of directing groups allowing the selective protonation of the alkyne function will also be studied. The possibility to employ other electrophilic reagents than the proton to activate the alkyne function towards nucleophilic attack will be evaluated. The use of computational methods to understand and rationalize the organic reactivity will constitute a key aspect of the project via (i) the establishment of a scale of acidity of the different families of chiral superacids, (ii) the analysis of the catalytic cycles in the presence of either metallic complexes or Brønsted acids, and (iii) the study of the interactions of the vinyl cation intermediates with the catalyst in order to define the rules of selectivity that governs the enantiodeterminent step of attack by the nucleophile.