Palladium-Catalyzed Synthesis of Ketenimines from Isocyanides and Synthetic Studies Towards the Total Synthesis of Mersilongine

In the first chapter of this thesis, the development of two new reactions for the synthesis of vinyl ketenimines and alpha-oxo-ketenimines from isocyanides is presented. These palladium-catalyzed transformations both feature an isocyanide insertion / beta-hydride elimination sequence. Vinyl ketenimines were generated from allyl carbonates and were then hydrolyzed to beta,gamma-unsaturated carboxamides or converted to 1,5-disubstituted tetrazoles by treatment with hydrazoic acid. alpha-Oxo-ketenimines were efficiently prepared from alpha-halocarbonyl compounds with broad functional group tolerance and their reactivity profile was investigated. This led to the development of a one-pot three-component synthesis of pharmaceutically relevant tetrasubstituted 5-aminopyrazoles and to the synthesis of beta-ketoamidines in high yields.

In the second chapter, synthetic studies towards the total synthesis of the alkaloid Mersilongine are presented. An advanced intermediate containing the quinolinic / bridged aminal core of this natural product was synthesized from vanillin in 20 steps. Three key transformations were successfully exploited or developed in this synthetic sequence : 1) A high yielding Tsuji-Trost reaction to create two adjacent tertiary carbon centers with high diastereoselectivity, 2) a substrate-controlled fully diastereoselective alpha-allylation of a lactone to form a quaternary center, 3) the first application of the iORC sequence for the synthesis of a quinolinic scaffold having three contiguous chiral centers. (iORC = integrated Oxidation / Reduction / Cyclization)