Biomimetic synthesis of resorcylates natural products and analogues

• Main Author: Barrett, Tim Nicholas
• Other Authors: Barrett, Anthony
• Published: Imperial College London 2015
• Subjects: 547
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.724098

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).