Toward the total synthesis of spongistatin 2: Construction of the C(29) to C(51) subtarget

A stereoselective synthesis of the first generation C3-C 12 AB and the second generation C29-C51 EF fragments of the extraordinarily potent tubulin polymerization inhibitor spongistatin 2 is described herein. Chapter one highlights the isolation, biological profiles and structural determination of the spongipyran molecules; and summarizes the only syntheses of spongistatin 1 and 2 to date. Chapter two recounts the initial approach of the Smith group toward the spongistatins, which laid the foundation for the development of a successful second generation strategy. Outlined in chapter three, retrosynthetic disconnection of the macrocycle provided the AB, CD, and EF subtargets. The synthesis of each subtarget is described, with a major focus on the synthesis of the EF hemisphere of spongistatin 2.* Degradation studies of natural spongistatin 1 were planned such that intermediates obtained from these studies would be compared to synthetic versions thereof, allowing confirmation of the absolute structure. The synthesis of the degradation intermediate derived from the E pyran (Chapter 1) provided an ideal point of departure in application to the total synthesis of the EF hemisphere of spongistatin 2 (Chapter 3).* In our initial synthetic approach, a truncated version of the fully elaborated AB subtarget was synthesized exploiting the utility of 1,3-dithiane as a linchpin. Noteworthy in this endeavor were studies involving diastereoselection improvements of a Sharpless mismatched asymmetric epoxidation via increased catalyst loading, and temperature effects on the regioselective opening of the resultant oxirane species using a titanium chelate. Though ultimately unsuccessful, this initial strategy laid the foundation for the completion of the second generation AB subtarget.* The synthesis of the EF subtarget of spongistatin 2 was predicated on the stereoselective chelation-controlled alkylation of an α-pyranyl aldehyde via a metallated dithiane. The construction of the aldehyde coupling partner derived from a linear hydroxy-olefin precursor via electrophillic cyclization followed by oxidation of the resultant organomercury species. Oxidation to the thermodynamically preferred equatorial aldehyde (+)- 268 was achieved via Swern conditions with concomitant epimerization at the α center.* The caveat in the crucial alkylation of this aldehyde was that HMPA was essential for effective coupling. Ultimately it was discovered that zinc chloride was an effective Lewis acid for the induction of chelation-control, and cerium trichloride minimized enolization of the aldehyde substrate.* Elaboration to the EF bis-pyran differentiated at the C(41) and C(42) hydroxyls was achieved uneventfully. However, studies modeling macrocyclization at the C(41) hydroxyl prompted a change of strategy as steric congestion prohibited esterification. A route to the C(41), C(42) di-TES bis-pyran was developed with the purpose of macrocyclization employing the corresponding diol. Upon completion of this bis-pyran, installation of the sidechain was achieved via sulfone alkylation followed by exo-methylene formation using a carbenoid species. Subsequent transformations completed the synthesis of the C(29) - C(51) EF northern hemisphere of spongistatin 2.* Subsequent transformations allowed the desired macrocycle to be formed in excellent yield with complete regioselectivity. (Abstract shortened by UMI.) *Please refer to dissertation for diagrams