Pseurotins are a small family of secondary microbial metabolites isolated from the fermentation broth of Pseudeurotium ovalis. Pseurotin natural products possess a wide range of biological activities including inhibition of chitin synthase, inhibition of monoamine oxidase, antifungal, anti-angiogenic, and dopamine antagonistic activity. Structurally, the pseurotin family contains a highly substituted 1-oxa-7-azaspiro[4,4]non-2-ene-4,6-dione core (highlighted in red) that has been implicated in the biological activities of these natural products. Access to these natural products is limited due to poor fermentation yields or lengthy syntheses. To exploit therapeutic potential of the pseurotins, we are developing a biomimetic approach to the pseurotin core structure starting from readily available amino acids. The biomimetic approach consists of three main features: i) Condensation of a β-ketoester 4 and an amino acid 5 to form an epoxide 3; ii) α-Acylation to form a diketone 2; iii) Nucleophilic ring opening of epoxide to form the spiro-core 1.