Synthesis of the fungal macrolide berkeleylactone A and its inhibition of microbial biofilm formation

The fungal macrolide berkeleylactone A was synthesised in 13 steps and 24% yield using (R)-propylene oxide and an asymmetric Noyori hydrogenation of a beta-ketoester to install the stereogenic centres. A domino addition-Wittig olefination of a 13-hydroxytetradecanal intermediate with the cumulated ylide Ph3PCCO closed the macrocyle by establishing the alpha,beta-unsaturated ester group, necessary for the attachment of the sidechain thiol via a thia-Michael reaction. The synthetic berkeleylactone A inhibited the formation of Staphylococcus aureus biofilms and showed significant dispersive effects on preformed biofilms of Candida albicans by at least 45% relative to untreated controls at concentrations as low as 1.3 mu g mL(-1).