Progress Towards the Biomimetic Total Synthesis of Meroterpenoid Natural Products

Abstract

This thesis outlines synthetic efforts towards three different natural product families. Norascyronones A, B and C are complex polycyclic polyprenylated acylphloroglucinols (PPAPs) isolated from Hypericum ascyron in 2019. A total synthesis of norascyronone C was achieved in 8 steps from commercially available 3-ethoxy-2-cyclohexanone. With norascyronone C in hand, the biosynthetically-inspired radical cascade reaction to norascyronone A was explored. We discovered intriguing reactivity under radical oxidation conditions. A similar synthetic approach was taken in the efforts of synthesising a structurally related (not yet published) natural product. These synthetic efforts led to the synthesis of a precursor which we propose to be an “undiscovered natural product”. Investigation of the key radical cyclisation gave access to several structurally unique side products. The furaquinocin and neomarinone natural product family is a class of meroterpenoid natural products isolated from marine actinomycete bacteria. We proposed that the dihydrobenzofuran motif could be installed by aromatic Claisen rearrangement followed by intramolecular cyclisation of a geranyl or farnesyl side chain. A synthetic model system was developed to investigate this biomimetic theory. Several rearranged intermediates with fascinating structures have been made through three different synthetic routes. Furobinordentatin, furobiclausarin and claudimerines-A and -B are dimeric pyranocoumarin natural products isolated from Citrus plants. We proposed and investigated two possible pathways to access these dimeric natural products from simpler precursor molecules, nordentatin and clausarin. Nordentatin was successfully synthesised in 5 steps from commercially available phloroglucinol. With the synthetic precursor in hand, the oxidative dimerisation was attempted. However, even after an extensive screening of reaction conditions we were unable to access the dimeric natural products.