George, JonathanHarris, Hughzur Bonsen, Andreas Benedikt2024-04-042024-04-042023https://hdl.handle.net/2440/140501An unprecedented cascade of an uncatalyzed, intramolecular carbonyl-ene reaction followed by α-hydroxy-β-diketone rearrangement has been proposed as the unifying concept in the obscure biosynthesis of structurally complex meroterpenoid natural product families. This bold hypothesis is investigated via biomimetic total synthesis, model studies and computational analysis. After introducing the key theoretical background to this work, a model study for the biosynthesis of the hyperireflexolides is described. The results demonstrate unambiguously, that the intramolecular tricarbonyl-ene reaction occurs spontaneously. After expanding this reaction into a methodology study, the α-hydroxy-β-diketone rearrangement is probed. The findings provide valuable insights into the nature of this reaction and fully support our biosynthetic proposal. Encouraged by the conclusive model study, a biomimetic total synthesis of the hyperireflexolides is conducted. Starting from an achiral simple precursor, the hyperireflexolides are first synthesised via a cascade of alternating cyclisations and rearrangements. This efficient synthesis confirms the biosynthetic speculations, enables the structure revision of hyperireflexolide B and showcases the power of biomimetic total synthesis. In an alternative route, the hyperireflexolides are synthesised in a highly convergent, fully stereoselective approach, Lastly, another model study is performed to emulate the putative biosynthesis of multiple meroterpenoid natural product families. Both by experiment and in silico, it is shown that an anionic α-hydroxy-β-diketone rearrangement occurs with highly sensitive regioselectivity and can even be followed by an intramolecular aldol reaction. All resulting reaction products map unto the scaffolds of the respective natural products and further support the initial hypotheses.entotal synthesisnatural productsbiomimetic synthesismeroterpenoidsThesis