Étude de la cyclisation de lactones à 9 membres par réaction de métathèse et formation catalytique de liens benzyliques asymétriques
Previously, a synthesis of aliskiren, a renin inhibitor developed for the treatment of hypertension, was developed in the Hanessian group. As part of that synthesis, they used a ring-closing metathesis which led to the formation of a nine-membered lactone, a key intermediate of the synthesis. During the reaction, we observed a difference in reactivity between the various diastereoisomers leading to the formation of mono- and dilactones, inciting us to study the various factors involved. The present master’s thesis reports and details the results of the study of monomers versus dimers formation by cyclization using Grubbs’s catalysts and the effect of various reaction conditions and relative configuration on the reaction.  An interest for the formation of benzylic bonds drove us to deepen our comprehension of a methodology of diastereselective nucleophilic substitution catalysed by acids. The rational brought forth by the Bach and Olah groups served as a basis for our understanding of the mechanism involved upon which we based our following observations. We focused our attention on the alkylation of arenes, phenols and sulfonamides. Various regioselectivities and diastereoselectivities were observed on substrates derived from the aliskiren’s synthesis, nitroaocohols and azidoalcohols while using various Lewis and Brønsted acids.
Aliskiren Macrocycle Catalyse acide Diaryles Sulfonamide Empilement π – π Nine-membered ring lactone Dimerization Ring-closing metathesis Acid catalysts Benzylic carbocation Diaryls Diastereoselective alkylation Benzylic ethers π – π stacking