Application of Direct Imine Acylation Methodology in the Synthesis of Nitrogen Heterocycles and Natural Products

This thesis describes the use of direct imine acylation (DIA) methodology in a range of different applications. Firstly, the attempted synthesis of (±)-cytisine is described (Chapter 2). The use of DIA methodology in the formation of the pyridone ring scaffold of (±)-cytisine has been explored. In the most advanced synthesis towards (±)-cytisine achieved in this project, the generation of N-acyliminium ions from imine A and subsequent nucleophilic addition of organometallic allyl reagents was developed to give diene B.

DIA methodology has also been utilised in the synthesis of spirocyclic products from simple indole acids C and imines D (Chapter 3). The reaction provides a broad range of products E in good yields and the indole acid starting materials C are readily synthesised using Fischer indole methodology. The stereoselectivity of the reaction, derivatisation of the products E and 3D shape analysis are also described.

Finally, work towards the synthesis of (±)-aspidospermidine, using the spirocyclisation methodology developed in this project, is introduced (Chapter 4). Two strategies are proposed utilising an intramolecular Heck reaction or a ring-closing metathesis to complete the polycyclic scaffold. A key DIA reaction between the synthesised acid F and imine G is reported and shows formation of the spirocyclic scaffold H.