Crick, Peter John (2011)
Ph.D. thesis, University of Birmingham.
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The asperparalines belong to a large family of prenylated indole alkaloids possessing a characteristic bicyclo[2.2.2]diazaoctane core structure. More than 70 examples are known to have been isolated from various diverse sources. Chapter 1 discusses the isolation and structure of these compounds along with an introduction to their biosynthesis and biological activities.
A combination of unique structural features and intriguing biological profiles has inspired a large body of work regarding the chemical synthesis of this alkaloid family. Chapter 2 gives an overview of the most important strategies for the construction of the central bicyclo[2.2.2]diazaoctane and presents these in the context of several total syntheses.
Chapter 3 details an approach to the bicyclo[2.2.2]diazaoctane core using a free radical cascade comprised of a 1,6-hydrogen atom translocation followed by 6-exo-trig and 5-exotrig cyclisations. An initial model system is presented consisting of a series of DKPs synthesised from a propargylated proline derived from a modification of Seebach’s procedure for the self-reproduction of chirality. Addition of a sulfur radical to the acetylene triggers the desired reaction in good to excellent yield and favours the asperparaline stereochemistry.
In Chapter 4 the application of this strategy to the synthesis of an advanced asperparaline core structure is presented. While construction of the key cyclisation intermediate proved difficult, the radical cascade proceeds in modest yield to furnish a bicyclo[2.2.2]diazaoctane possessing the key structural features of the asperparalines.
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