Synthetic Studies toward the Anacolosin Family of Clerodane Diterpene Natural Products.

The anacolosins are an underexplored family of clerodane diterpenes with intriguing bioactivity and unique structural complexity. These molecules present a dense architectural challenge, featuring seven stereogenic centers and a distinctive five-membered bis-acetal ring system within their tricyclic core. We describe here the successful development of a scalable synthesis that completes two of three intended phases toward the total synthesis of the anacolosins. Obstacles that were overcome include the navigation of the steric demands of a Diels-Alder cycloaddition and exploiting inherent torsional strain to achieve high selectivity during a critical bridgehead allylation. Investigations into a late-stage oxidative reorganization sequence provided unique triacetal intermediates resembling those of the natural product scaffold, which taught valuable chemical lessons in the delicate balance of electronic and steric factors governing these complex scaffolds. This research establishes a clear trajectory for accessing the anacolosin family and offers critical insights into the reactivity and stability of highly functionalized decalin systems.