Synthese totale de la (+)-desoxygaliellalactone et les N-tosyloxycarbamates comme source de nitrenes pour l'aziridination enantioselective des styrenes

This thesis will discuss two different subjects. The first project is the enantioselective total synthesis of (+)-desoxygaliellalactone, whereas the second part is dedicated to the development of an enantioselective aziridination reaction of styrene derivatives with N-tosyloxycarbamates as metal nitrene precursors.;The second part of this thesis explores the development of an enantioselective aziridination of styrenes using metal nitrenes generated from N-tosyloxycarbamates according to a method recently developed in our group. The metal nitrene is formed via the degradation of N-tosyloxycarbamates in the presence of potassium carbonate and a copper salt. The potassium toylate is the only by-product of the reaction and is easily eliminated by filtration or aqueous workup. The enantioselective aziridination reaction of styrenes derivatives uses 5 mol% of acetonitrile copper(I) hexafluorophosphate complex in the presence of 6 mol% of a chiral bisoxazoline. Optimizations of the ligand structure as well as the reaction conditions are presented. Based on previous work within our group on the aziridination reaction, 2,2,2 trichloroethyl- N-tosyloxycarbamate was initially used as a metal nitrene source. However, this precursor having quickly shown its limitation, an optimization of the nitrene source was realized. Sterically different hindered groups were tested, cyclic or not, and the gem-dimethyl group allowed us to obtain the desired aziridine in 85% ee. Furthermore, the chiral mono-substituted N-tosyloxycarbamate led to the formation of aziridines in a diastereoselective manner. A preliminary study of this reaction was realized and a 32:1 diastereoisomic ratio in favour of the syn product was obtained with the 4-nitrostyrene. Based on these results, we were able to propose a transition state model for the nitrene transfer step.;Finally, aziridines formed by this method are protected by a Troc group, cleavable under mild reaction conditions. We also reported the development of a methodology for Troc deprotection, which leads to the corresponding free aziridines in very good yields.;Key words; (+)-desoxygaliellalactone, Methylenation, Diels-Alder reaction, N-Tosyloxycarbamates, Aziridination, Metal Nitrenes;The first part of this thesis describes the total synthesis of the (+)-desoxygaliellalactone, a biological precursor of (-)-galiellalactone, which is a tetrahydro-isobenzofuranone particularly effective as an inhibitor of interleukine IL-6 induced in hepatic cells HepG2 or prostatic cancer cells. The biosynthesis of (-)-galiellalactone involves an intramolecular Diels-Alder reaction with (-)-pregaliellalactone to form desoxygaliellalactone. The transition metal catalyzed methylenation reaction recently developed in our group was used to form the triene species as a key step for the synthesis of (+)-desoxygaliellalactone. In this study, modern methods for the formation of chiral propargylic alcohols were used to achieve the enantioselective addition of an alkyne moiety to an aldehyde intermediate. A one-pot hydrostannylation-lactonization-cross-coupling sequence was also developed to form the requisite lactone. Finally, the copper-catalyzed methylenation reaction was successfully applied to lead to the desired triene. The final Diels-Alder reaction gave the (+)-desoxygaliellalactone in good yield in the presence of a stoichiometric amount of Lewis acid. A one-pot methylenation-Diels-Alder reactions sequence was also developed, avoiding the purification of the triene intermediate. (+)-desoxygaliellalactone was obtained in 18% overall yield in 8 steps.