Photocycloaddition reactions and their application to natural product synthesis

Photochemistry can promote reaction between substrates that would not react under thermal conditions. Intramolecular photocycloaddition reactions, a subset of photochemical transformations, allow for the formation of multiple rings in a facile manner. The Winkler group has utilized such photocycloadditions to great effect in the efficient total synthesis of numerous natural products. This thesis will first describe the use of the [2+2] photocycloaddition/Pauson-Khand/retro-Aldol fragmentation methodology toward a second-generation synthesis of ingenol. Next, the development and substrate scope of a novel thioarene enone photocycloaddition will be discussed. Lastly, the aforementioned thioarene enone photocycloaddition will be applied toward the synthesis of morphine.;Although our group completed the first total synthesis of ingenol, we believed that the synthesis could be improved via a second-generation synthesis. The change incorporated the use of a Pauson-Khand reaction to introduce functionality in the western portion of ingenol, which was the portion that required multiple steps in the endgame. Unfortunately, the [2+2] photocycloaddition/Pauson-Khand/retro-Aldol fragmentation method provided the undesired out/out cis intrabridgehead stereochemistry.;However, these studies of a photochemical method toward ingenol led to the discovery of a novel photocycloaddition involving thioarene tethered enones. This photoreaction provided thiolane oxides incorporating a quaternary center in excellent yields. Expansion of the substrate scope allowed for a subsequent Pummerer reaction to generate highly functionalized products. Sulfur reduction then enabled access to dihydrobenzofuran cores.;The dihydrobenzofuran core could be mapped onto the substructure of morphine. Elaboration of the photosubstrate for the synthesis of morphine provided an advanced photoadduct. Unfortunately, low yields hindered the effort toward the total synthesis of morphine. However, the information gained from these photochemical studies has allowed us to propose an alternative synthesis that may lead to a formal synthesis of morphine.