Cascade cyclizations in total synthesis

Abstract

Plant–derived natural products continue to be a valuable source of useful therapies for cancer as well as other diseases. As part of a continuing mission to obtain anticancer agents from natural sources, researchers at the National Cancer Institute (NCI) established the 60 human tumor cell line anticancer screen. The schweinfurthins are one family of unique natural products discovered through this screening process, and most of the schweinfurthins exhibit potent and differential activity in the 60–cell line screen. Importantly, the pattern of activity displayed by the schweinfurthins shows no correlation to any clinically used anticancer drug, indicating that this family of natural products probably acts via a novel mechanism or at a novel target. Our group has conducted extensive structure–activity relationship studies in an effort to illuminate the mechanism of action of the schweinfurthins. In this thesis, the preparation and biological activity of a number of new schweinfurthin F analogues possessing variations in the D–ring alkyl chain and stilbene moiety will be discussed. These studies have clarified the importance of the D–ring substituent to the schweinfurthins’ pharmacophore. Based on the results obtained from the exploration of the structural requirements of these natural products, it was determined that the right–half of the schweinfurthins would be an appropriate site for attachment of a molecular probe to be used in affinity experiments. The synthesis of these biotinylated probes will be presented in detail, and their use in pull–down assays will be summarized. The preparation of key schweinfurthin intermediates has involved the extensive use of Lewis acid–mediated cationic cascade cyclizations terminated by methoxymethyl (MOM)–protected phenols. Those successes have inspired investigations of additional applications of these cyclizations. In particular, a variant of these cyclizations using “MOM–protected” enol ethers as reasonable substitutes for β–keto ester terminating moieties has been studied. These interrelated studies involving the synthesis of