The applicant is seeking funding to support research on late stage biomimetic syntheses of resorcylates from readily available non-aromatic precursors. A series of diketo-dioxinones will be synthesised using mild Claisen condensation reactions and converted into the reactive intermediates triacyl-ketenes by retro-Diels Alder reactions. These will be trapped with alcohols to directly provide the corresponding resorcylate esters and related macrocyclic lactones. These compounds are of considerable importance in that they occur in structurally complex natural products, which are active as anticancer agents, antibiotics, immunosuppressants or analgesics. Examples include aigialomycin D, radicicol, cruentaren A and mycophenolic acid. Late aromatisation avoids the severe problems associated with existing syntheses based on aromatic precursors. Our studies will allow for the development of very concise total syntheses of the biologically potent Hsp90 inhibitor radicicol and mitochondrial F-ATPase inhibitor cruentaren A. The methods will be amenable for the synthesis of libraries of synthetic natural product analogues in the quest for superior drugs to treat cancer. The novel ring opening, ring closing and crossed metathesis of cyclooctyne derivatives will be introduced and will simplify the route to cruentaren A. Resorcylate methodology will be extended to terpenoid-resorcylates, using a new decarboxylative allyl transfer process, which will greatly simplify routes to angelicoin A, cristatic acid, mycophenolic acid and hongoquercin B. Finally, both the aromatisation strategy and ring opening metathesis polymerisation of cyclooctyne derivatives will be applied in the synthesis of novel oligomers and polymers including polyfunctional polyesters and poly-ynes.
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