Synthetic studies on the spongistatin family of natural products: I. Development of a practical synthesis of the (16)-C(28) CD spiorketal. II. Computer aided design and synthetic progress towards spongistatin analogs with simplified molecular architecture

This dissertation describes studies directed toward (1) the large-scale total synthesis of (+)-spongistatin 1, a marine macrolide that possesses considerable tumor cell growth inhibitory activity, and (2) elucidation of the structure activity relationships (SAR) of the spongistatin family of natural products. Chapter 1 provides an introduction to the spongistatin family of natural products. Specifically, the isolation, structure elucidation and biological activity of the spongistatins are discussed. Furthermore, previous total synthesis of (+)-spongistatin 1 (1) and (+)-spongistatin 2 (2) are delineated.* Chapter 2 discusses the development of a route to the C(16)–C(28) CD spiroketal of (+)-spongistatin 1 that is efficient enough to allow for production of one gram of the natural product. Central to this approach is the Smith-Tietze Multicomponent Dithiane Linchpin Coupling, which allows for the highly convergent assembly of complex fragments from relatively simple starting materials. Other highlights of the chapter include the synthesis of coupling partner (−)-206 and final elaboration of the linchpin product to the CD spiroketal. These studies ultimately resulted in the development of a route to the CD spiroketal that would be utilized to produce 15 g of this advanced intermediate.* Chapter 2 describes the design of simplified spongistatin analogs using the MacroModel™ molecular modeling program and the published solution structure of a spongistatin congener (5-desacetyl altohyrtin A). Several analogs were designed in which portions of the molecule\u27s backbone were replaced with simplified tethers designed to orchestrate the EF ring system of the molecule in a conformation similar to the one found in the solution structure. The development of our approach to the analog design, as well as the synthetic progress toward two of the analogs, 262 and 295, is presented in detail.* *Please refer to dissertation for diagrams