UCLA

Nature continues to provide a wide array of structurally novel, biologically active small molecules. This thesis describes synthetic studies on two such compounds. The approach used in each project are different. The first project involves a unique molecule that is produced by Nature in only trace quantities. We attempt to develop the first laboratory synthesis of the compound such that it could become available in sufficient amounts to study its biological properties in detail. In the second project, we work with a compound that is naturally abundant, yet has poor pharmacological properties. In that instance, we use synthesis to selectively modify its complex structure in ways that alter its properties while enabling conjugation to carrier proteins.Portimine is a marine-derived cyclic imine recently discovered as a selective inducer of apoptosis in cancer cells. Moreover, it showed markedly lower in vivo toxicity relative to other macrocycles in its class. Portimine’s biological activities are reminiscent of pro-apoptotic biologics such as TRAIL (TNF-related apoptosis-inducing ligand) and TNFα (tumor necrosis factor alpha). No synthesis of portimine has been published and this work outlines the synthetic studies performed en route to the natural product as well as the exploration and development of novel methodologies along the way. Another natural product, epigallocatechin-3-gallate (EGCG), is a major catechin found in tea that has been shown to inhibit tau through disaggregation of fibrils. The synthesis of several EGCG analogs as well as the biological assays performed with the ultimate goal of developing an Alzheimer’s therapeutic are described. Chapter one describes the development of a highly diastereo- and enantioselective Mukaiyama-Michael reaction for the synthesis of a key chiral intermediate utilized in the subsequent synthetic studies towards portimine. A stereochemical reassignment of the reported isomers of the desired structure is discussed aimed at the elimination of clear inconsistencies in the published reports. Both the racemic, as well as stereoselective synthesis, of both diastereomers are shown that once and for all establish the spectroscopic assignment of the products. Model studies of portimine including both the synthesis of thiophene-based as well as the more elaborate deoxygenated Diels-Alder precursor synthesized in just 3 steps from the published intermediate are reported as well. Optimization of the homoenolate cross-coupling as well as the development of the highly convergent route allowed for the rapid assembly of the chain containing all of the carbons present in portimine. Subsequent Diels-Alder studies as well as the challenges associated with utilizing an acyclic precursor provided useful information for the asymmetric synthesis of portimine. Chapter two describes the synthetic studies toward the natural product. Highly enantio- and diastereoselective aldol reaction as well as the alcohol-directed Narasaka-Prasad reaction allowed for the installation of the key sequence of stereocenters. Both halogenated as well as highly reactive dendralene Diels-Alder precursors have been synthesized which allowed for the in-depth studies of the cycloaddition conditions. The synthesis of a novel heterocycle provided access to the previously unknown motif that will be beneficial for the future syntheses of cyclic imine natural products. Chapter three discusses the synthesis of the EGCG analogs, and the biological studies associated with their potential as tau disaggregants. The development of the efficient click reaction assisted by copper-stabilizing Sharpless polytriazole ligand allowed for the synthesis of the conjugates of varied lengths. Subsequent nanoparticle conjugation showed the conservation of the biological activity as well as confirmed a previously hypothesized EGCG’s mode of action. Diastereoselective B-ring derivatization not only allowed for the installation of the PEGylated linkers at the new position but also for structure-activity relationship studies on EGCG’s D-ring shedding light on the importance of gallate phenols as well as the possibility for the installation of fluorine without sacrificing activity. Improved disaggregating activity of synthesized analogs showcased their promise as potential Alzheimer’s therapeutics.