On the total synthesis of complex alkaloids

Thesis

Chapter 1 introduces the synthesis of natural products and the Daphniphyllum family of alkaloids. Prior literature syntheses of these natural products are described as well as our own group’s efforts. The daphlongeranine sub-family are introduced and our previous campaign towards these molecules is summarised.

Chapter 2 describes a redesigned strategy towards the natural product daphlongeranine B. Multiple competing strategies are investigated before successfully developing an efficient route to the racemic pentacycle of daphlongeranine B. This strategy hinges upon a Michael addition followed by a Claisen rearrangement and ring-closing metathesis to establish three rings.

Chapter 3 solves two outstanding problems with the synthesis: a site of peripheral oxidation on the pyrrolidine ring and the introduction of enantioselectivity in the synthesis. Following a concerted investigation into C−H oxidation for the former and a transfer of chirality approach for the latter, a Baker’s yeast reduction is adopted as an efficient route towards an enantioenriched, oxidised pyrrolidine building block which is advanced to a pentacyclic intermediate.

Chapter 4 advances from this enantioenriched intermediate and focuses on the re-positioning of an alkene and the installation of the final all-carbon quaternary centre. From this point, attention turns to the final ring and, grappling with unprecedented levels of steric hindrance, a successful route is developed which employs the intramolecular S_N2 reaction of an alkyl triflate with a carboxylic acid.

Chapter 5 focuses on the natural product madangamine E. This additional chapter describes the completion of its total synthesis, advancing from a 25-step intermediate to install the final 11-membered ring in an efficient 5-step sequence.

Authors: Shennan, BDA

• DOI: 10.5287/ora-xqnm44zpy
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: natural products; total synthesis; daphniphyllum
• Subjects: Organic compounds--Synthesis; Total synthesis; Natural products