First Total Synthesis of Spiroaspertrione A, a Fungal Natural Product That Restores MRSA Susceptibility

Researchers at the University of Konstanz in Germany and the Research Center for Bioactive Molecule Synthesis (BiMoS) at Shanghai University of Traditional Chinese Medicine in China reported the enantioselective total synthesis of the natural product (−)-spiroaspertrione A. It is a meroterpenoid of the andiconin family isolated from cultures of Aspergillus fungi, and it has been discussed as a candidate for making methicillin-resistant Staphylococcus aureus (MRSA) responsive again to existing antibiotics. An earlier isolation study reported that it lowered the minimum inhibitory concentration of oxacillin against MRSA by up to 32 times.

A Diels-Alder reaction followed by a key rearrangement to build a cage-like scaffold

A polycyclic scaffold densely packed with functional groups had long been an obstacle to synthesis. The researchers started with a stereoselective Diels-Alder cycloaddition and then built the core spirobicyclo[3.2.2]nonane scaffold through a divinylcyclopropane rearrangement. They confirmed that this rearrangement is reversible and analyzed it with density functional theory (DFT) calculations. They then applied late-stage functionalization to the small, rigid cage-like structure to complete the natural product, and they also suggested a possible biosynthetic relationship with the similar natural product (−)-aspermerodione.

With a synthetic route secured, a path has opened to making derivatives with altered structures and comparing their activity. However, the focus of this paper is synthetic methodology, and the mechanism of the resistance-reversing effect and efficacy in animals or people need separate verification.