P-Stereogenic, Bicyclic Phosphorus Heterocycles and Temporary Tether Strategies for the Synthesis of Complex Polyols

Abstract

The development of atom-, redox-, and step-, and pot-economonical strategies for the streamlined synthesis of biologically active small molecules stands at the forefront of modern-day organic synthesis and early-stage drug discovery. In particular, those approaches that employ methods which allow for the reliable, predictable, and high-yielding coupling of a variety of both simple and elaborate chemical fragments to common core structural motifs represent some of the most efficient and versatile strategies to accomplish this goal. Since its first report in 2005, the use of phosphate triesters as temporary tethers has proven to be a powerful method for the facile formation of complex 1,3-skipped polyol-containing small molecules and biologically active natural products. The ability of phosphate tethers to impart differential olefin reactivity (exocyclic versus endocyclic), serve as temporary protecting groups, as well as latent leaving groups, and mediate several reactions in one-pot, sequential reactions continues to provide unique reactivity pathways to stereochemically rich intermediates, while minimizing chemical waste and the need for time-consuming purification. To date, phosphate-tether methods have served as the cornerstone in the total syntheses of dolabelide C, tetrahydrolipstatin, strictifolione, and Sch-725674, the formal synthesis of salicylihalimide A, and synthetic efforts toward lyngbouilloside and spirastrellolide B. Current efforts in the group are focused on the expansion and diversification of phosphate tether-mediated RCM strategies for the two-directional synthesis of biologically active small molecules. This thesis is dedicated to describing synthetic studies that augment previous work reported by our group involving P-stereogenic bicyclic phosphorus heterocycles and temporary tether strategies for the synthesis of complex polyols. Chapter 2 outlines a detailed study on the effects of stereochemical complexity, ring size, and olefin substitution on phosphate tether-mediated RCM. Studies focus on the formation of bicyclo[4.3.1]-, bicyclo[5.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates, with a special emphasis on the factors that affect the success and stereochemical outcome of the P-tether mediated RCM event to form 10- and 11-membered bicyclic phosphates. Chapter 3 focuses on the synthesis of P-stereogenic bicyclo[4.3.1]phosphite-borane systems for the two-directional synthesis of complex polyols. These studies highlight the P-tether systems’ ability to facilitate chemoselective olefin functionalization, divergent oxidation strategies that allow access to the corresponding phosphate or thiophosphate, and a stereocontrolled, iterative SN2’-cuprate displacement protocol that marries the chemistry of phosphite borane tethers with that of their all oxygen-containing counterparts to generate polyol stereotetrads that were previously inaccessible via phosphate tether strategies alone. Chapter 4 presents the application of phosphate tether-mediated, one-pot sequential processes toward the total synthesis of 2S-sanctolide A and outlines plans for the application of the method to the total synthesis of 2R-sanctolide A and its analogs.