Synthetic, Biomimetic and Chemoenzymatic Studies of Meroterpenoid Natural Products

Abstract

Meroterpenoid natural products are interesting bioactive molecules produced by both terrestrial and marine organisms in nature. In Streptomyces bacteria, these natural products are derived from the polyketide 1,3,6,8-tetrahydroxynaphthalene (THN), giving a structurally complex group of antibiotic molecules. The biological activity and interesting scaffolds of these natural products has inspired many attempts at their chemical synthesis. This thesis will highlight how biosynthetic studies of these compounds has inspired their biomimetic and chemoenzymatic syntheses, gaining insight into their biosynthesis. The naphterpins and marinones are two families of naphthoquinone-based meroterpenoids, isolated form Streptomyces bacteria. Biosynthetic speculation inspired the first total syntheses of two members from the naphterpin and marinone families, 7-demethylnaphterpin and debromomarinone, mimicking the entire proposed biosynthetic pathway. In validation of this biogenetic hypothesis, proposed biosynthetic intermediates from these biomimetic total syntheses were used in chemoenzymatic studies. These studies stimulated the discovery of multiple enzymes responsible for interconverting several of the proposed biosynthetic intermediates within these natural product biosyntheses, therefore confirming the biosynthetic proposal. Following these biomimetic total syntheses, a concise and divergent strategy for the synthesis of more members from the naphterpin and marinone families was developed. This approach utilised a plethora of pericyclic reactions, enabling the efficient synthesis of six meroterpenoid natural products, in the absence of protecting group strategies. This synthetic approach facilitated the first total synthesis of naphterpin in five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage oxidation and bromination reactions were also investigated, resulting in the first total syntheses of naphterpins B and C, and isomarinone