A pair of o-quinol-based substrates which exist in equilibrium are first synthesized, composed of an open form and a closed form. It is found that treatment of the substrates using an acyl transferase called PigD and a β-ketothioester leads to the linear azaphilone product, likely through the selective acylation of the open form. Investigation of the reaction mechanism by synthesizing just the closed form substrate with a β-ketoester group attached (which is therefore primed for cyclization) shows that when this substrate is subjected to buffer conditions, the angular product is exclusively formed. Conversely, when an open form substrate is synthesized with a β-ketoester group attached, the reaction proceeds with the linear product being favoured. Kinetic studies also show that PigD favours the open form of the equilibrating substrates in the acylation reaction.
The scope of the substrate-selective acylation reaction using PigD shows tolerance of various alkyl functional groups to form the linear products over the angular products. Interestingly, for the chain length of the thioester (blue circle pictured), shorter alkyl chains appear to give lower yields than longer chains of between 5 and 7 carbon atoms. However, the use of chain lengths greater than 7 carbon atoms leads to issues with solubility and therefore a lower conversion. This approach also allows for the preparation of natural products such as rubropunctatin, which itself is shown to be a useful intermediate to access a range of other azaphilone natural products and derivatives.
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