Semisynthetic diversification of the fungal azaphilone austdiol highlights scaffold-encoded reactivity in natural products.

In this study, we leveraged access to a prolific fungal producer of the azaphilone austdiol to explore the chemical space around this important mycotoxin. Systematic treatment of austdiol with a variety of acids, bases, oxidising agents, reducing agents, and amines afforded a diverse library of nine new and four previously reported semisynthetic analogues. Of particular note, austdiol underwent an intermolecular Michael-type conjugate addition under mild alkaline conditions, forming a novel C-C-linked asymmetric dimer, which we named biaustdiol. Under oxidative conditions, an unusual stereospecific 6- to 5-membered ring contraction yielded a new analogue, 8-noraustdiol. Amination reactions yielded mono- and di-substituted austdiolamines and iminoaustdiolamines, with substitution initially favouring exchange at the pyran oxygen. Additionally, semisynthesis of the previously reported methylene-bridged dimer mycoleptone A was achieved from the reduced austdiol analogue 10-hydroxyaustdiol under acidic conditions via a putative Friedel-Crafts alkylation reaction. Austdiol provides a fascinating example of how Nature encodes latent chemical reactivity into natural products, enabling diversification of the core scaffold into a wide range of analogues with no additional biochemical expense.