1. The synthesis of a cyclopropyl taxane analog via sequential Diels-Alder reactions. 2. The design and synthesis of novel epothilone analogs

This dissertation describes two independent research projects related to the synthesis of analogs of the microtubule-stabilizing anti-cancer compounds paclitaxel (1) and the epothilones (3 and 4).* The first section describes the application of tandem Diels-Alder methodology to the synthesis, of the cyclopropyl taxane skeleton 79. The construction of 79 is accomplished by an intermolecular Diels-Alder cycloaddition followed by minimal functional group manipulations to prepare for the intramolecular Diels-Alder cycloaddition of 65. The desired trans-B/C ring fusion, as well as the natural C1–C3 hydrogen relationships are established in this cascade. The synthesis of 79 illustrates the power of this methodology for the stereoselective synthesis of complex ring systems from simple acyclic precursors.* The second project described herein illustrates the utility of molecular modeling for the design of novel epothilone analogs. Literature reports highlighting the importance of the eastern hemisphere of epothilone prompted the design of two generations of eastern hemisphere analogs of the molecule, 119 and 167. These analogs were designed with the intention that they would be restricted to adopt the known X-ray conformation in this highly-functionalized region of the molecule.* The key steps in the syntheses of 119 and 167 include diastereoselective aldol reactions and ring-closing olefin metathesis (RCOM) cyclizations. The synthesis of 119 provided the first reported application of RCOM methodology to the synthesis of an eleven-membered ring. The biological evaluation of these analogs allowed us to probe the viability of the eastern hemisphere of the natural product on its own for cytotoxicity. Neither analog proved to be biologically active, however, conformational analysis showed that 167 successfully mimicked the X-ray conformation of the natural product. From these results we concluded that if this is the active conformation for epothilone, the eastern hemisphere alone is not capable of producing the desired biological response.* *Please refer to dissertation for diagrams