Asymmetric Total Syntheses of the Fontonamides Via Formanilide-Directed Palladium-Catalyzed C-H Functionalization and Synthetic Studies Towards (+)-Welwitindolinone A

Using a novel route that takes advantage of the directing ability of the natural formanilide directing group, the first total synthesis of two members of the hapalonamide family, (-)-fontonamide and (-)-dechlorofontonamide, are reported herein. The syntheses are highly convergent, coupling the A ring formanilide fragment and the D ring highly-decorated-cyclohexanone fragment through a Friedel-Crafts reaction and a ortho-directed C-H functionalization. Both syntheses have been rendered asymmetric. A third member of the hapalonamide family. 13-hydroxy dechlorofontonamide, was also synthesized, however it was determined upon its synthesis that the original isolation paper had misassigned the isolated compound, which was in actuality fontonamide. This thesis also describes the synthetic effort undertaken towards welwitindolinone A, with the goal of using a novel intramolecular palladium-mediated alkenylation to create the core cyclobutene ring of the compound. This reaction was successful in model studies, but ultimately failed on the fully-decorated molecule. Finally, this thesis describes the successful development of a novel 1,1-disubstituted diene for use in the Diels-Alder reaction. The novel diene allows access to 6-substituted and 6,6-disubstituted cyclohexenones and 6-substituted 5,6-dihydropyran-2-ones. The synthesis of the diene is highly scalable and operationally facile, and kinetics experiments show the reactivity of the diene is high compared to other highly active dienes.