Synthesis and Applications of Substituted Bullvalenes and The Synthesis of Bicyclo[4.2.0]octadiene Derived Natural Products

Abstract

Cyclooctatetraene (COT) represents a valuable π-rich non-aromatic building block. Its history and chemistry are the subject of Chapter 1. In these works, COT is used as a synthetic entry point to two fascinating groups of molecules - the fluxional molecule bullvalene (Chapters 2-8) and the endiandric acid family of natural products (Chapters 9-10). Bullvalene is a unique fluxional molecule with no permanent carbon-carbon bonds. Rapid intramolecular Cope rearrangements give rise to a structure that is totally degenerate with over 1,000,000 isomers. The introduction of substituents forms non-degenerate isomers, which exist as a shape diverse equilibrating mixture – its synthetic chemistry is reviewed in Chapter 2. Our group developed a two-step method to synthesise substituted bullvalenes – a cobalt(I) catalysed [6+2] cycloaddition of COT and substituted alkynes (Chapter 3), followed by a photochemical di-π-methane rearrangement (Chapter 4). Despite its efficiency, this methodology has its own substrate limitations. Disclosed is a method to synthesise boronate ester functionalised bullvalenes; these functional groups allow for the reliable and versatile introduction of functionality onto bullvalene, particularly through Suzuki cross-couplings – Chapter 5. With practical tools developed to synthesise substituted bullvalenes, a range of new concepts are explored. Dialkenyl-substituted bullvalenes are discovered to rearrange to tetrahydro-1,8-ethenoheptalenes – the first kind of this tricyclic scaffold. The driving force of this rearrangement is explored both computationally and experimentally, ultimately leading to the synthesis of a substituted bullvalene that exists in equilibrium with its tetrahydro-1,8-ethenoheptalene form (Chapter 6). Disubstituted bullvalenes possess chiral isomers and are subject to stereomutation due to bullvalene’s inherent fluxionality. The stereochemical implications of external stereogenicity are explored through synthetic examples. In doing so, we provide a convenient method to describe the stereochemistry of substituted bullvalenes. A tethered bisbullvalene is also synthesised, possessing three stereocentres that continually stereomutate (Chapter 7)! In Chapter 8 we synthesise a fluxional bis-monodentate bullvalene ligand and observe its self-assembly in the presence of Pd2+ or Pt2+ into fluxional M2L4 coordination cages. A pool of over 200,000 isomeric structures resolves itself to a singular ‘all-B’ cage isomer upon the addition of a halide guest. Endiandric acid natural products are distinguished by the beautiful 8π/6π-electrocyclisation, intramolecular Diels–Alder cascade leading to their biosynthesis generating 4 rings and 9 stereocentres in a single step. Past synthetic approaches are reviewed in Chapter 9, and typically rely on the challenging stereoselective synthesis of linear polyunsaturated precursors. Our group recognised the value of cyclooctatetraene as a π-rich starting material to synthesise these natural products and have previously disclosed a method to do so from COT-epoxide. Chapter 10 reports a new synthetic route from cyclooctatetraene – the cyclopropanation of COT followed by nucleophilic ring opening with organocuprates provides expedient access to these, and related, natural products, demonstrated through the formal and total synthesis of a range of compounds. The experimental information for these works is provided in Chapter 11. References are provided at the end of each chapter. Numbering for compounds and figures are done according to each chapter i.e. 3.5 (chapter.number). Authorship statements are provided when required.