UCLA

Chapter one details my work associated with the photorearrangement of [8]-pyridinophane N-oxide and its application in to an eight-step asymmetric synthesis of (+)-marineosin A. The route proceeds by condensing fragments of reversed polarity relative to conventional prodiginine constructions. The resultant unstable chromophore is disrupted by a unique cycloisomerization promoted at a tailored manganese surface providing a premarineosin and subsequently marineosin A in a particularly concise manner. A pyridinophane N-oxide photorearrangement in flow and structural isomers of premarineosin are discussed, as is the reassignment of marineosin stereochemistry. The route gives access to the natural product as well as diastereomers, congeners and analogs that are currently inaccessible by other means. Following completion of this route, I began studying the mechanism of the pyridinophane N-oxide photorearrangement using time course studies with support from DFT calculations. Based on the data and the isolation of two previously unknown heterocyclophanes, I outlined a unified mechanistic scheme that explains competing processes under varying photochemical conditions. Chapter two describes my work characterizing of prodiginine–microRNA binding interactions. I developed a fluorescence-based binding assay to determine the binding strength of prodiginines to an oncogenic microRNA precursor. After identifying the small molecule’s binding site, I fused it to a readily crystallizable riboswitch with the aim of obtaining a co-crystal structure. I also explored several other crystallization constructs and developed a structure-affinity relationship by synthesizing and assaying novel prodiginine compounds. From this I identified a lead compound which is one of the strongest microRNA binders discovered to date.