Harnessing P450 hydroxylation of multi-ring amines for target synthesis

Thesis

This thesis describes synthetic studies towards the carbon framework of the natural product phlegmadine A and the application of variant P450 enzymes in the synthesis of tropane-based natural product anisodamine.

The Introduction provides a short summary of existing C–H activation and biocatalytic strategies in synthesis, as well as an overview of P450 enzymes.

Chapter 2: The first project concerns enzyme-catalysed hydroxylation of variably protected tropanes. Substrate engineering was deployed to alter the selectivity patterns of the P450 enzymes in the variant library; the N-Boc, N-Ms, N-Ips and N-PO(OEt)2 derivatives of tropane were tested against the initial library. Different selectivity trends were observed for these derivatives against the same library of variants.

Chapter 3: The late-stage oxidation of the tropane motif was then utilised in the synthesis of the natural product anisodamine. The synthesis of this natural product follows the three-phase process of preparing the cyclic core, screening against a P450BM3 variant library and then performing the final chemical synthetic steps.

Chapter 4: The final project describes methods to prepare the tricyclic carbon skeleton of lobscurinol, starting from the cyclopentenone unit. Various disconnections of the ninemembered ring are explored, and the challenges encountered in the preparation of their precursors are discussed.

Authors: Wilson, M

• DOI: 10.5287/ora-vydbvyy9x
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English