UC Irvine

The first chapter details the synthesis of three collision induced dissociation cross-linkers that have been developed for cross-linking mass spectrometry experiments. One of the cross-linkers is a homobifunctional cysteine targeting linker denoted DBrASO. It exploits the selective reactivity of thiols with α-bromoacetamides; and it is currently being studied in protein-protein interaction experiments. Another cross-linker BrASSO, is a heteobifunctional cross-linker that targets cysteine and lysine residues. The final cross-linker that was synthesized is SDASO, which contains a diazirine ring that can be used for non-specific cross-linking. SDASO proved the ability to cross-link all twenty amino acids, and was able to be used in complex proteosome cross-linking mass-spectrometry studies. These new cross-linkers expands the capability of studying protein structure and protein-protein interactions in tandem with mass-spectrometry.The second chapter details work towards the synthesis of indole alkaloid alstonlarsine A. Many approaches to the natural product were considered and pursued to the cyclohepta[b]indole natural product. Formation of the cycloheptane proved difficult and our initial cyclohepta[b]indole annulation resulted in an unproductive spriocycle. An alternative route targeted a cis-octahydroindolone through many disconnections, but only the trans isomer was favored. This natural product was not pursued further. The third chapter details the first total syntheses of strasseriolide A and B. Strasseriolide B exhibited potent antimalarial activity against the drug-sensitive and drug-resistant strains of malaria. The macrolides were synthesized through a convergent route targeting a carboxylic acid-aldehyde fragment and an alcohol-vinyl iodide fragment. The synthesis of the two fragments were completed by starting from commercially available terpenes. The fragments were coupled through a Yamaguchi esterification and the key macrocyclization event was accomplished via a Nozaki-Hiyama-Kishi cyclization. Strasseriolide B was synthesized in 16 steps (LLS) and strasseriolide A was synthesized in 17 steps (LLS).