UCLA

Chapter one outlines my work surrounding the investigation of the reaction pathways operative upon the photoirradiation of [8]-(2,6)-pyridinophane N-oxide. Herein, I describe the isolation and characterization of two previously undiscovered heterocyclophanes identified as photolabile intermediates in the production of a ketopyrrolophane compound central to our synthetic approach to the natural product (+)-marineosin A. In addition, I outline a unified and computationally supported mechanistic framework developed in collaboration with Janice B. Lin and Selbi Nuryyeva under the guidance of Professor Ken Houk. This framework describes the formation and interconversion of all isolated products and intermediates. This framework greatly adds to our overall understanding of the photochemistry of pyridine N-oxides.

Chapter two details my work surrounding the exploration of an unprecedented alkyl chain migration observed in the assembly of the tripyrrolic core of the prodiginine natural product (+)-marineosin A. Various experiments demonstrating the generality of this reaction are shown through the utilization of electronically perturbed heterobiaryl systems. Further detailed is an in- depth examination of my efforts to elucidate the mechanism of this unique migration which is complimented by computational analysis carried out in collaboration by Mark A. Maskeri formerly of the Houk Group.

Chapter three outlines my progress towards establishing the first total synthesis of the natural product JBIR-141. Further detailed is our plan towards completion of the route as well as a set of proposed analogs, all of which are easily accessed due to the modularity of our synthetic pathway. These analogs will play a crucial role in identifying the natural product's active pharmacophore, elucidating its mechanism of action, and maximizing its potential as a chemotherapeutic agent.

Chapter four details my work surrounding the development of peptide macrocyclization methodology utilizing commercial octafluorocyclopentene (OFCP). Herein, I showcase the ability of OFCP to engage linear, unprotected peptides in polysubstitution cascade reactions to generate complex fluorinated polycycles. In addition, I show that intermediates of these cascades can be intercepted by exogenous nucleophiles, enabling access to a diverse range of hybrid compounds composed of peptides, sugars, lipids, and heterocyclic components. Further detailed is the use of small molecular inserts which greatly expands the diversity of polycyclic structures accessible using this methodology. Lastly, I delve into my work in the field of computational analysis where I discuss the capability of polycycles generated using this methodology to structurally mimic protein surface loops central to mediating a wide variety of protein-protein interactions.