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Title: Biomimetic synthesis of resorcylates natural products and analogues
Author: Barrett, Tim Nicholas
ISNI:       0000 0004 6423 1115
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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The resorcylate unit (2, 4-dihydroxybenzoic acid) is found in numerous biologically active natural products. This thesis outlines the application of a novel biomimetic synthesis strategy to the syntheses of resorcylate natural products and analogues. A synthetic pathway to the meroterpenoid antibiotic Hongoquercin B has been successfully developed in nine steps from trans, trans-farnesyl acetate using a double biomimetic strategy. A regioselective decarboxylative farnesyl migration and cycloaromatisation gave the resorcylate, which undergoes a lewis acid mediated diastereoselective cationic epoxy-diene cascade cyclisation to give the tetracyclic core. The single epoxy-farnesyl stereocentre was used to control the remaining 4 stereocentres of the tetracyclic core. This cascade tetracyclisation sequence simplifies the synthesis of terpenoid resorcylate natural products. Efficient syntheses of a range C-5 substituted resorcylates and resorcinamides from functionalised keto-dioxinones are also described. Functionalized keto-dioxinones, generated via enolate acylation or alkylation reactions, were subsequently C-formylated and cyclised to the corresponding arenes. Further manipulations gave a wide range of structures of potential pharmaceutical interest including C-5-substituted, C-4,5-cyclo-fused and C-5,6-cyclo-fused resorcylates, as well as resorcinamides. The syntheses are noted for brevity with a maximum of 5 synthetic steps and without the need for protection of phenol groups (b).
Supervisor: Barrett, Anthony Sponsor: European Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral