Investigations of novel dimerisations and brevianamide-type alkaloids
Item statusRestricted Access
Embargo end date11/03/2023
This thesis describes work towards two discrete projects; Chapter 1-3 methodology development of enantioconvergent reactions, Chapter 5-7 total synthesis of brevianamide type natural products. Both of these studies are linked through the underlying theme of the development of novel dimerisations. CHAPTER 1-3: Classically, asymmetric synthesis has relied upon kinetic resolutions to deal with racemic starting materials. Unfortunately, the use of kinetic resolutions is limited to a maximum 50% yield, which represents a serious inefficiency in modern chemical synthesis. Enantioconvergent reactions offer a method to circumvent this limitation and afford a single enantioenriched product in a maximum theoretical yield of 100%. However, all currently known methods for achieving enantioconvergency are limited in their substrate scope; the starting materials invariably contain stereogenic elements that are amenable to mutation or ablation and are currently unable to contain multiple stereogenic centres. We aimed to overcome this long-standing limitation by developing stereoretentive-enantioconvergent reactions, which would allow the use of racemic substrates with multiple robust stereogenic elements. The new approach would feature a symmetry-breaking dimerisation of racemic starting materials to form of a non-meso dimeric product. To accomplish this we targeted dimerisations that are inherently heterochiral-selective (i.e., opposite enantiomers dimerise), and developed methods to make these reactions enantioconvergent. This thesis will describe our investigations into previously known heterochiral-selective dimerisations; an aza-Darzens dimerization (Chapter 2) and a Diels–Alder dimerization (Chapter 3), and efforts to make them enantioconvergent including the success of performing the first stereoretenetive enantioconvergent aza-Darzens reaction. CHAPTER 4-7: The brevianamides are a family of alkaloid natural products extracted from the Aspergillus and Pencillium fungi. The brevianamides were the first natural products, isolated in 1969, to contain the archetypal bicyclo[2.2.2]diazaoctane ring. Since their first isolation their complex structure and varied biological activities have inspired many total syntheses. Despite decades of experimentation, the synthesis of many members of the brevianamide family have yet to be conquered and many unanswered questions remain about their biosynthetic origin. In 2020 the Lawrence group published the first total synthesis of brevianamide A, over 50 years since its isolation. This thesis continues the Lawrence group’s work and describes the efforts towards the first total synthesis of a dimeric member of the natural product family, in addition to the concise bioinspired total synthesis of other members. These studies also provided new mechanistic insights into the key domino reaction pathway believed to be biosynthetically responsible for constructing the core bicyclo[2.2.2]diazaoctane motif.