Development of a general strategy to the 12-hydroxydaphnetoxins, application to the synthesis of des-epoxy- and C6, C7-epi-yuanhuapin, isolation, identification, and biological evaluation of natural apoptolidins [electronic resource]

Research in the Wender group is broadly based on the relationship between structure, mechanism, and synthesis. More specifically, the synthetic projects that are pursued are inspired by unique structures that display exquisite biological activities. Due to the challenging architectures of many of these leads, novel methods are adopted to facilitate further study. Included among these strategies are function-oriented synthesis and semi-synthesis. Of particular relevance to this thesis are two additional approaches: "gateway synthesis, " a term coined to describe a strategy intended to allow access to families of targets, and natural products isolation. These strategies are highlighted in this thesis in the context of the biologically fascinating daphnane dipterpene orthoester family of natural products and the selective anti-cancer agent, apoptolidin. The former inspired the development of a gateway synthesis and ultimately lead to the completion of two non-natural analogues, and the SAR of the latter was expanded through the isolation of additional congeners from the producing organism In Chapter 1, a review of the naturally occurring 12-hydroxydaphnetoxin family of daphnane diterpene orthoesters is presented. Several specific examples are described in detail, highlighting the role of protein kinase C in their myriad biological activities. This chapter is intended to provide the context and justification for development of a general synthetic strategy to this class of natural products and designed analogues, which is the focus of Chapters 2 and 3. Chapter 2 details the synthetic strategy employed to access a gateway intermediate to the 12-hydroxydaphnetoxins. This intermediate, accessed in 33 steps from a commercially available tartrate derivative, displays sites for the introduction of all functionality present in the natural products and also opens the way for analogue design and synthesis. Key transformations employed include a unique Claisen rearrangement, a completely diastereoselective oxidopyrylium [5C + 2C] cycloaddition, a palladium-catalyzed enyne cyclization, and a selective allylic oxidation. In Chapter 3, the conversion of the gateway intermediate to two analogues of the daphnane diterpene orthoester, yuanhuapin, is described. These two agents, des-epoxy-yuanhuapin and C6, C7-epi-yuanhuapin, were evaluated alongside the natural product in a number of biological assays. Significantly, the natural product and des-epoxy-yuanhuapin were both identified as potent ligands for protein kinase C, a previously unreported target for the natural product. Activation of this kinase was further implicated in the mode of action of these agents in growth inhibition assays in two human-derived cancer cell lines. Chapter 4 provides an overview of apoptolidin, a macrolide isolated from Nocardiopsis sp. displaying impressive selectivity for E1A-transformed cells. In addition to analogues produced as part of total synthesis efforts, the lessons learned from semi-synthetic analogues are also highlighted. Finally, Chapter 5 describes the isolation, structure determination, and preliminary biological evaluation of additional apoptolidins isolated from Nocardiopsis sp. The naturally occurring analogues, apoptolidins B-F and apoptolidin H, expanded current understanding of the structure-activity relationship for this unique natural product. In general, modest variation about the macrolactone core was tolerated; however, more drastic changes, including removal of the disaccharide, resulted in loss of biological activity as determined in a growth inhibition assay.

Keywords: Chemistry
Advisor: Wender Paul A. primary advisor. Thesis advisor
Cegelski Lynette advisor. Thesis advisor
Wandless Thomas advisor. Thesis advisor