Total Synthesis of Terpenoid Natural Products: A Platform for Discovery in Chemical Biology and for the Development of New Chemical Methods

Abstract

Natural product synthesis exists today as a crucible for method development, a test of strategic disconnections, and, perhaps most importantly, a means of generating bioactive small molecules and testing biological hypotheses. Indeed, many small molecule diterpenoids, upon isolation from plant material, are tested for their ability to serve as cytotoxins in cancer and for their ability to reduce signals of inflammation. These diterpenoids often bear sterically complex, densely functionalized cage-like core structures, making their synthesis a significant endeavor and providing opportunities for the development of new methods and strategic disconnections. NF-κB is a family of transcription factors that drive both inflammation and cancer cell survival, and many diterpenoids that were shown to have anti-cancer anti-inflammatory activities have also been shown to interact with this pathway. The focus of this thesis work has been to apply synthetic approaches to the challenge of studying if, and how, small molecule diterpenoids inhibit the NF-κB pathway. The aromatic gibberellin, pharbinilic acid, was selected as a synthetic target based upon its structural homology to a known NF-κB binder and based upon its anti-cancer and anti-inflammatory properties. In the course of the first successful synthesis of this molecule a potent, selective inhibitor of the NF-κB pathway was discovered and demonstrated to have thousand-fold selectivity for killing inflammatory cancer derived cell lines over cell lines derived from healthy fibroblasts. A unified approach to the bioactive ent-kaurene diterpenoids is disclosed. These studies were initiated in order to differentiate between specific activities inherent to the diverse cage-like structures of these molecules and those misattributed to pan assay interfering enone moieties present in many such molecules. Of particular interest is the synthesis of eriocalyxin B it has been shown to covalently label the DNA binding domain of NF-κB. Finally, the development of a new method to enable a key disconnection towards the synthesis of the terpene alkaloid isopalhinine A is discussed.