Gold Catalysis: From Fundamentals to the Synthesis of Bullvalenes and Naturally Occurring Sesquiterpenes

Identifier:  TDX:2867

Handle: https://hdl.handle.net/20.500.11797/TDX2867

Authors:  Ferrer Cabrera, Sofia

Abstract:
The present thesis relies on the development of novel gold(I)-catalyzed transformations for the construction of complex polycyclic frameworks and their application to methodology and total synthesis of natural products. Organometallic investigations in gold(I) systems and mechanistic studies through DFT calculations have been also performed. The first total synthesis of the natural product repraesentin F, a sesquiterpene isolated from the fungus Lactarius repraesentaneous which possesses biological activity related to the regulation of plant growth, has been accomplished in 16 steps and 2% overall yield. The synthetic preparation of this molecule allowed its structure reassignment. The key step of the synthesis features a novel cascade reaction involving a gold(I)-catalyzed tandem enyne cyclization/ring expansion/Prins reaction of the appropriate cyclopropylenyne substrate to build the atypical anti-ring fused tricyclic skeleton of the molecule in one step, using a remarkably low 0.5 mol% of catalyst loading. The mechanism of this key transformation was studied through DFT calculations. An efficient methodology for the synthesis of 1-substitued barbaralones from 7-ethynyl-1,3,5-cycloheptatriene substrates via a gold(I)-catalyzed oxidative cyclization has been developed. It constitutes one of the shortest (2 steps), mildest and most efficient synthesis (good to excellent yields) of barbaralones to date. This methodology simplified the synthesis of related fluxional molecules such as bullvalones and bullvalenes and allowed access to complex cage-type structures. Organometallic studies to shed light on the role of σ-monogold and σ,π-digold alkyne complexes in gold(I)-catalyzed reactions of enynes have been performed. The investigations showed that gold(I) acetylides and σ,π-digold(I) alkyne complexes derived from 1,6-enynes fail to cyclize under temperature demanding conditions, being the latest poor catalysts in these transformations. The results confirmed that the aforementioned species are not catalytic intermediates; rather, these complexes are “dead ends” in catalytic reactions of enynes. Computational studies fully supported the experimental observations.