| This dissertation has been divided into five chapters, and describes our synthetic efforts towards (+)-sorangicin A, a macrolide antibiotic known to inhibit RNA polymerization.; Chapter one initially discusses the isolation, structure elucidation, and biological profile of the sorangicins. Subsequently, the structure-activity relationship and chemical modification studies of (+)-sorangicin A, as well as other synthetic approaches, are presented.*; Chapter two initially discloses the three main challenges we envisioned that our synthetic plan would address, namely: (1) the construction of the novel 2,6-dioxabicyclo[3.2.1]octane ring system through an epoxide ring-opening cascade initiated by a Co2(CO)6-alkyne complex; (2) the extension of the Petasis-Ferrier linchpin union/rearrangement tactic to aldehydes possessing alpha- and beta-oxygenation, as well as an acid sensitive acetonide group; and (3) implementation of the Kocienski-modified Julia olefination to couple highly advanced and complex fragments.; Chapter 2 then describes the development of a first generation synthesis of the 2,6dioxabicyclo[3.2.1]octane ring system. Our strategy, based on the precedent of Mukai and Hanoaka, entailed a series of epoxide ring-openings. The first, facilitated by an TMS-alkyne Co2(CO)6 complex, proceeded in a highly regio- and stereoselective fashion. Overall, the first generation synthesis was achieved in 23 steps and 1.5% overall yield.*; Based on the lessons learned from the first generation strategy, Chapter 3 describes our improved second generation synthesis of the 2,6-dioxabicyclo[3.2.1]octane ring system. Specifically, in this revised approach, a more rapid synthesis of a modified cyclization precursor was achieved. Overall, the second generation synthesis proceeded in 17 steps and 1.7% overall yield.*; Chapter 4 then describes the stereocontrolled assembly of the C(1)-C(15) aldehyde fragment. The highlights of the synthesis included: (1) a stereoselective conjugate addition reaction to install the C(8,9) bond; (2) chemo- and stereoselective C(10) oxidation of the resulting TES-enol ether; and (3) installation of the C(11,12) olefin via reduction of the corresponding enol triflate. Overall, the synthesis of the C(1)-C(15) aldehyde fragment was achieved in 19 steps and 8% overall yield.*; Finally, Chapter 5 discloses our fragment coupling results, presents our model study experiments, discusses our end-game strategy, and outlines a third generation approach to the 2,6-dioxabicyclo[3.2.1]octane ring system of (+)-sorangicin A.*; *Please refer to dissertation for diagrams. |
