Total synthesis of Epicoccolide A & B and two related analogs

Abstract

The family of epicoccolides has been known for over a decade now and show remarkable biological properties in a variety of fields. Different groups have reported antibacterial, antifungal and antitumor reactivity. More recently, an inhibition of galactosylceramide sulfotransferase by epicoccolide B was patented. This sulfotransferase is involved in the very rare but deadly disease metachromatic leukodystrophy. To be able to use the mentioned biological activities it is essential to gain access to large amounts of the desired natural product. Extraction from nature is a costly and time-consuming venture and no reliable source for the required material. To provide a solution for this problem a successful total synthesis of the natural products epicoccolide A and epicoccolide B was the goal of this thesis. <br/> Efforts into the total synthesis of epicoccolide B have been invested by previous members of our working group and were continued. The first total synthesis of epicoccolide B was achieved after investigating several different routes with varying outcomes and a multitude of challenges that needed to be overcome. In the course of these investigations two structural analogs were synthesized as well. <br/> After the final step of the total synthesis epicoccolide B showed interesting and unprecedented reactivity under mild aqueous conditions. The outcome and reproducibility of this reaction was examined in detail leading to the first total synthesis of epicoccolide A. Comparison of synthetic epicoccolide A to reported literature resulted in structural reassignment and questioning of the previously proposed biosynthetic pathways. To clear up these problems, plausible answers have been provided including a newly proposed biosynthesis. <br/> First attempts at the total synthesis of epicocconigrone A were also initiated but exceeded the final scope of this thesis. The project was handed off to a new member of our working group with the current plans presented herein. Finally, initial testing of the bioactivity of the two structural analogs synthesized during the course of this project revealed valuable data that is worthwhile to be pursued further.