Diels-Alder and Electrocyclic Strategies in Complex Molecule Synthesis

Abstract

The central theme of this thesis can be considered the study and application of pericyclic reactions, specifically the Diels−Alder and electrocyclisation reaction towards the generation of complex functional molecules. Chapter 1 serves as a brief introduction to these two reactions recounting their respective history, current state and future directions. A Diels–Alder (DA) methodology was developed for the synthesis of a synthetically challenging motif. It involved the synthesis of a 2,5-bis(tert-butyldimethylsilyloxy)furan diene capable of performing a DA cycloaddition followed by an aromatisation sequence to afford a variety of para-hydroquinones among other arenes. DA reactions primarily afford non-aromatic six-membered rings, however the 2,5-bis(tert-butyldimethylsilyloxy)furan diene has been engineered to undergo a facile aromatisation process after the [4+2] cycloaddition. It was therefore appropriate to conduct a non-comprehensive review on a variety of dienes that induce aromatisation after the DA reaction and their application in natural product total synthesis. This review is contained in Chapter 2 and acts as a literature preface for the peer-review published Diels–Alder methodology in Chapter 3 (authorship statement provided). A great portion of the following synthetic work in this thesis utilises 1,3,5,7-cyclooctatetraene (COT) as the starting material. The oddity of using a bare annulene as a starting material inspired Chapter 4, which is a review focusing on total syntheses of natural products that begin with unfunctionalised annulenes: cyclobutadiene, benzene and COT. Endiandric acids are a famous natural product family known for its unique skeletal structures, biological activity and specifically for their unique biosynthesis. Their biosynthesis involves a tetraene undergoing a beautiful 8π-electrocyclisation/6π-electrocyclisation/intramolecular Diels−Alder cascade to form structurally complex molecules. Multiple historical syntheses involved construction of the tetraene, which can be a challenging and lengthy task. Our group recognised alternative routes via COT that drastically shortened the step count to these fascinating products. In our third-generation methodology, kingianic acids A, B, D and endiandric acid M was synthesised via the lithium enolate of cyclooctatrienone (derived from COT), which is covered in Chapter 5. There are limitations to this methodology, encouraging the development of the next generation. At the end of Chapter 5, we report a successful proof-of-concept involving the creation of a bis-Bpin tetraene molecule that can potentially afford natural product related compounds. Torquoselective electrocyclisations have been extensively developed for the 4π electrocyclic variant, however is very limited in 6π and 8π electrocyclisations. Certain bicyclo[4.2.0]octadiene related natural products have shown to possess low to mild levels of torquoselectivity during the electrocyclisation events of their biosynthesis. Chapter 6 is a purely computational study on the kinetics, thermodynamics and torquoselectivity of the biosynthetic cascade of bicyclo[4.2.0]octadiene related natural products. The understanding gained through these experiments inspired hypothetical compounds that have been computationally predicted to undertake fully torquoselective 8π electrocyclisations and aims to stimulate future endeavours in torquoselective electrocyclisations. The supporting information for experimental chapters (3, 5 and 6) is provided in Chapter 7. References are provided at the end of each chapter. Numbering for compounds, figures, schemes and tables are done according to each chapter i.e., 3.5 (chapter.number). Colour is used in many figures, schemes and tables throughout the thesis to aid in their understanding and must be printed in colour if a physical copy is required.