UC Santa Barbara

The development of efficient strategies for the synthesis of complex organic molecular architectures is a fundamentally important aspect in both the process of the total synthesis of natural products and the manufacture of pharmaceuticals. The necessity for the rapid construction of these complicated structures is often inspiration for the development of new methods for forming chemical bonds and for the creative implementation of previously known reactivity. The content of this dissertation focuses on the development of efficient and stereocontrolled total syntheses of natural products and the necessary methodology for their completion.The first chapter of the dissertation outlines a straight-forward synthetic route to a common intermediate which can be used to access multiple members of the rearranged spongian diterpene family. The key intermediate is then used to complete the first total synthesis of (±)-cadlinolide A and the unnatural derivative (±)-desmethylcadlinolide A. A model study was conducted to establish the potential for the intermediates’ use in the total synthesis of (+)-darwinolide; a spongian diterpene bearing a 7-membered ring as opposed to the more common 6-membered ring. The initial results demonstrate a strong support for its use in the total synthesis of this natural product and efforts to complete the construction of this biologically active scaffold are currently underway. The second chapter of this dissertation will focus on the development of methodology for the diastereoselective installation of cyclic guanidines. We demonstrated that a guanidine carbamate, synthesized from a homoallylic alcohol and guanidine hydrochloride, can be used to direct the cyclization of guanidine onto an unactivated, terminal alkene with excellent diastereoselectivity. This method for guanidine installation is more efficient than conventional methods as it allows for the use of a complete, intact guanidine unit. In the third chapter, we demonstrate the utility of this methodology in the total synthesis of (+)-guadinomic acid. (+)-Guadinomic acid is part of a cyclic-guanidine-containing family called the guadinomines; a family possessing potent anti-proliferation properties towards gram-negative bacteria. The synthesis of guadinomic acid that we developed was a considerably shorter pathway than the pathways developed previously, which we attribute to the use of our methodology.