biostudies-literatureGu HNatural Science Foundation of Hebei ProvinceResearch Grants Council, University Grants CommitteeHebei Provincial Department of Human Resources and Social SecurityHebei Normal University2164-2168https://www.ebi.ac.uk/biostudies/studies/S-EPMC12671562biostudies-literatureUnknown17(4)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 toChemical scienceTotal syntheses of <i>ent</i>-aogacillin A and aogacillin B.PMC1267156216304023C20230340B20232050071630352416308922C6022-22WL2023B17Tong RZhang WLi XMa BQiu WYang ZLi ZGu HSang RRen JZhang XChen XfalseTotal 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 to2026-01-01T00:00:00Z2026 Jan2026-06-17T04:53:42.521Z2026-06-17T03:06:19.587ZS-EPMC126715624134092110.1039/d5sc04554a