Harnessing hydroxylating enzymes for the synthesis of natural products and their analogues with relevance to dementia Yi Ni Ong, Prof. Jeremy Robertson Department of Chemistry, University of Oxford, UK Total syntheses of the natural product, clausenamide, a potential anti-dementia candidate, 1-3 and its analogues, are described. Work elsewhere is still establishing the SAR profile of clausenamide isomers; the current study will add to this profile by evaluating rigidified clausenamide analogues which will provide information about the contribution of the phenyl groups and their relative spatial distribution to the observed activity. Separate skeleton- building and functionalisation steps are introduced, whereby the functional groups are introduced at the end of the synthesis. Enzymatic 4 late-stage oxidation of lactam cores allows synthetic strategies to focus on skeleton- building without the need for protecting groups. An initial synthetic route involved key steps: [2+2] cycloaddition, reductive dechlorination, ring-expansion to the lactam, and late-stage hydroxylation, the latter to be facilitated by P450 BM3 variants. A more efficient two-step route to the lactams was then developed using enolate alkylation followed by reductive amination with cyclisation in situ . Current research is focused on using P45O BM3 variants, in collaboration with Luet Wong’s group, to perform late-stage hydroxylation on the lactam cores. The clausenamide analogues thus obtained will be assayed for cytotoxicity and for their ability to induce long-term potentiation of the dentate gyrus by electrophysiological assay. 5
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