The synthesis of 3-azabicyclo[4.3.0]nonane scaffolds from Brefeldin A

Abstract Brefeldin A (BFA) is a fungal metabolite that displays a wide range of biological activities making it an attractive target for drug discovery. To explore the biological potential of the BFA scaffold an amine-macrocycle target 3 was proposed. To access, we dissembled BFA into smaller building blocks in preparation for regenerating the macro-lactone. These entities can then be used to synthesise new brefeldin analogues with various new structural features for biological testing. To overcome supply issues a scaled fermentation process of Penicillium camemberti was employed generating 4.5 kg of BFA. Novel N-BFA type derivatives were generated and herein we describe the synthesis of two new scaffolds 12 and 14 from BFA over six steps in 24% and 17% yield, respectively. A trans-fused bicyclic cyclopentanoid piperidine scaffold 16 can be generated from 12 that may serve as a valuable new scaffold for the synthesis of novel natural product-like compounds.