Total syntheses of <i>ent</i> -aogacillin A and aogacillin B

Aogacillins A and B, circumventors of arbekacin resistance in MRSA, possess a densely oxidized spirolactone moiety and an electron deficient terminal exocyclic double bond. This represents a challenging target for total synthesis. Herein, the evolution of a successful strategy for the total synthesis of <i>ent</i>-aogacillin A and aogacillin B is described. Although the spirocyclic skeleton could be efficiently constructed by the Achmatowicz rearrangement-based strategy, the elaboration of the dihydropyranone moiety to the fully functionalized lactone of aogacillins was not successful. A new strategy is proposed and successfully implemented, which features allylic C-H oxidation and a one-pot sequential aldol reaction and lactonization. This enables us to achieve the first and asymmetric total synthesis of aogacillin B and <i>ent</i>-aogacillin A in 7 steps.