In nature, tricyclic azaphilone natural products can be classified into two categories, angular and linear, based on the differential selectivity of the lactone ring formation step.<sup>1</sup> Reported examples for selective tricyclic azaphilone cyclization use substrate control to dictate formation of either angular or linear tricyclic products or mixtures. Developing a selective method to access both tricyclic structures from any given substrate would improve synthetic efficiency and provide access to previously inaccessible azaphilone natural products. Working toward this goal, a substrate-selective enzymatic approach to azaphilone tricycles was discovered. By using a flavin-dependent mono-oxygenase in sequence with an acyl transferase (AT) and an acyl donor allowed for the conversion of several orcinaldehyde substrates directly to the corresponding linear tricyclic azaphilones in a single reaction vessel without the need to isolate the dearomatized intermediate. Furthermore, mechanistic studies have shown that an equilibrium and an enzyme substrate selectivity play an import role in the final cyclization selectivity. Tricyclic azaphilone natural products can be synthesized using this strategy.

Substrate-selective catalysis provides new opportunities in azaphilone synthesis

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