AbstractThis thesis describes the development of a bioinspired approach for the efficient synthesis of bicyclic heterocycles assembled on a 2,8-dioxabicyclo[4.4.0]decane core decorated with 4 side chains. The key step involves an acid mediated dimerisation of a linear dihydroxydiarylheptanoid to produce two oxane rings and 4 stereocenters in one pot. This route was used for the total synthesis of (+)-blepharocalyxin D in 4 steps and 13% overall yield from simple starting materials. Further analogues were also synthesised.
The conditions for the key dimerisation step were optimised in terms of temperature, Lewis acid and solvent, concluding in the use of TMSOTf in CH2Cl2 at0 °C. A mechanism for the reaction was proposed via a cascade involving carbocationic intermediates and verified by an oxygen-18 label study.
The second chapter describes the synthesis of 3-deoxo-11-dehydroxy-mutilin 183 the first cyclic intermediate on the biosynthetic pathway to pleuromutilin. It was used as a standard to verify the structure of the metabolite isolated from extracts of cultures of Aspergillus oryzae, which has genes heterologously expressed from C. passeckerianus.
|Date of Award||28 Nov 2019|
|Supervisor||Laura M Chavda (Supervisor) & Chris L Willis (Supervisor)|