Investigations into the Divergent, Biogenically Inspired Synthesis of Structurally Related Natural Products

Abstract

Natural products are pivotal in the development of new pharmaceutical agents as they may possess novel mechanisms of actions, inherent to their structural framework. Such intriguing metabolites are of interest to various fields of research, such as pharmacology, biochemistry and total synthetic chemistry. Perhaps the most compelling synthetic method is found with the biomimetic approach, which in addition to affording the natural product of interest in an efficient manner, such strategies may also offer insight into a given metabolite’s biosynthetic origins. This thesis will detail our investigations into the biogenic origins of two structural related families of natural products via a biomimetic total synthetic approach. The total synthesis of the structurally related marine natural products from Aka coralliphaga, has been achieved via a biogenically inspired divergent approach. This divergent strategy detailed siphonodictyal B as the biogenic precursor to liphagal, corallidictyals A – D and siphonodictyals B1 – B3. We report the successful total synthesis and stereochemical reassignment of siphonodictyal B, in accordance with our proposal. Additionally, the total synthesis of liphagal and the corallidictyals A – D was achieved directly fromour confirmed reassigned configuration of siphonodictyal B. We propose these transformations of siphonodictyal B to liphagal and the corallidictyals, detailed within this work, are representative of biosynthetic reactions that occur within the host organism, Aka coralliphaga. Progress towards the biogenically inspired, total synthesis of virgatolide B has been made. Our method sought to afford virgatolide B via a hetero-Diels-Alder reaction between a Z-exocyclic enol ether dienophile and an o-QM, generated in situ from an analogue of pestaphthalide A. Synthesis of the key biogenic precursors, that would in our opinion be representative of those that may occur in nature, was been achieved. However, upon investigating various thermal and basic conditions, synthesis of virgatolide B could not be achieved. Despite our failed attempts at synthesising virgatolide B, we still assert that the virgatolides A – C are biosynthesised in nature via a divergent, [4 + 2] cycloaddition of an appropriate Z-exocyclic enol ether with an o-QM derived from either of the co-isolated pestaphthalides A or B.