Total synthesis of millingtonine and incargranines A and B

Abstract

Biomimetic synthesis is the branch of synthetic organic chemistry which attempts to learn from nature into order to solve the challenges of chemical synthesis. This thesis describes application of biomimetic principles to the total synthesis of three phenylethanoid alkaloid natural products: incargranine B; millingtonine and incargranine A. Chapter 1 provides a general introduction to the area. Specific introductions can be found at the start of each chapter. Chapter 1 introduces the concept of biomimicry and provides a brief overview of the development of the underlying concepts and terminology. The major biosynthetic pathways involved in the production of incargranine B, millingtonine and incargranine A (shikimic acid, ornithine alkaloids) are also introduced. Chapter 2 discusses the synthesis of incargranine B. Biosynthetic analysis of this dimeric alkaloid led us to question its structural assignment and suggest a structural revision. This speculative reassignment was validated through a biomimetic total synthesis of our proposed structure. Incargranine B was successfully prepared in a longest linear sequence of six steps, forming three new rings, four bonds and three contiguous stereocentres in a single biomimetic domino condensation/Mannich/SEAr sequence. Chapter 3 describes the synthesis of millingtonine. We proposed that millingtonine is biosynthetically related to incargranine B through a divergent/re-convergent network of pathways. Synthetic exploration of this hypothesis culminated in the total synthesis of millingtonine and discovery of an unanticipated biosynthetic intermediate, dia-millingtonine, which we propose as a previously unidentified natural product. . Chapter 4 details the synthesis of incargranine A. Incorporating dia-millingtonine into our biosynthetic hypothesis allowed the development of a four step bioimimetic total syntheses of incargranine A which was scaled-up to provide over one gram of natural product. Chapter 5 summarises the work presented and provides a perspective on its contribution to the field.