Harnessing the reactivity of alkenyl heteroarenes through copper catalysis and Lewis acids

In this thesis, the development of efficient catalytic asymmetric methodologies for the modification of heterocyclic scaffolds is presented. Leitmotif of this work is the combination of copper (I) salts, chiral diphosphine ligands and Lewis acids (LAs) as main tools to promote the desired transformations.
After a brief overview on commonly used synthetic strategies to access functionalised aromatic heterocycles (Chapter 1), Chapter 2 focus on the copper catalysed asymmetric conjugate addition (ACA) of Grignard reagents to various alkenyl heteroarenes promoted by BF3∙OEt2. The latter proved to be essential to activate the substrates toward the desired process, allowing the synthesis of various chiral aromatic heterocycles with excellent results.
These studies laid the groundwork for the development of the one-pot diastereoselective enolate trapping process discussed in Chapter 3. Main theme is the high chemoselectivity of the process. Once again, BF3∙OEt2 played a crucial role by directing the initial nucleophilic addition towards the heteroaromatic substrates in presence of significantly more reactive electrophiles in the reaction media.
Chapter 4 describes an efficient methodology to access chiral pyridine derivatives. Chiral copper complexes and silicon-based LAs enable ACA of Grignard reagents to alkenyl pyridines. This catalytic system allowed the introduction of different aliphatic chains on a wide range of substrates with remarkable functional group tolerance.
Chapter 5 addresses mechanistic studies aimed to clarify the catalytic cycle of the transformation discussed in Chapter 4. Experimental studies revealed that the role of LAs is not confined to the activation of the substrates but also affects the enantiodetermination.