Making Marinomycin A

With its power to fight both methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, the macrodiolide antibiotic marinomycin A is a worthy target for total synthesis. But it’s really the molecule’s symmetrical structure that makes it something of a siren song to synthetic chemists: Its simplicity beckons, only to confound efforts to couple the compound’s two halves. Rather than form the desired 44-membered macrocycle, the polyketide chains tend to cyclize intra­molecularly, forming a macrolide rather than the desired macrodiolide. Chemists led by P. Andrew Evans of England’s University of Liverpool have now successfully navigated the synthesis of this compound, using its salicylate moieties as molecular switches. Depending on how the salicyl­ate is functionalized, it can mediate the reactivity of its ester group, either by de­activating it or by making it electrophilic. The salicylate, Evans points out, reduces the electrophilicity of the aryl ester through an intramolecular hydrogen bond, essen­tially making the group function as an amide in terms of electronics and conformation. “This strategy raises new questions regarding the biosynthetic role of the salicylate and its potential impact on the mechanism of action of these types of agents,” the researchers note in their paper (Nat. Chem., DOI: 10.1038/nchem.1330).