Approaches toward the synthesis of two families of cytotoxic natural products: The Otteliones and the Sclerophytins.

摘要

Chapter 1. The otteliones are terpenoids isolated from the Egyptian freshwater plant Ottelia alismoides. These compounds display remarkable levels of cytotoxicity in the 100 pM range, and possess an unusual bicyclic structure containing a methylene cyclohexenone and four stereocenters. These properties render the otteliones as attractive synthetic targets. Furthermore, the structures are well suited to synthetic routes involving key thermal Diels-Alder reactions between quinone monoketals and the appropriately derived dienes. We have shown that this cycloaddition methodology can provide valuable intermediates in the synthesis of both possible diastereomeric structures of ottelione A. Although the routes were thwarted by problematic oxidation steps and unstable intermediates, two new synthetic strategies will hopefully result in the first total syntheses of both possible structures of ottelione A.; Chapter 2. The sclerophytins are unique members of the cladiellin family of diterpenes isolated from the marine soft coral Sclerophytum capitalis. These metabolites feature an exotic polycyclic skeleton containing two bridging oxygen atoms. Furthermore, sclerophytin A displays potent in vitro cytotoxicity against the L1210 cell line (IC50 = 1 ng/mL). We have been interested in the development of a practical synthesis of the tricyclic core and derivatives because of the compound's unprecedented structure and potent cytotoxicity. To this end, various synthetic routes and ring-closing strategies have been explored. During these studies, a novel [2,3]-sigmatropic rearrangement was discovered in which allenic hydroxyketones can be formed upon treatment of propargylic alcohols with diazoketones with catalytic dirhodium tetraacetate. Unfortunately, however, all attempts to form the bridged nine-membered ring of the core of sclerophytin A were unsuccessful, likely due to unfavorable enthalpic and entropic factors. In addition, the original structure proposed for sclerophytin A has recently come into question, and thus a synthesis of the core still remains elusive.