Evolution of a Synthetic Strategy toward the Heptacyclic Core Framework of Nominine

We report a full account of the strategic evolution en route to the heptacyclic core framework of nominine, a representative hetisine-type diterpenoid alkaloid featuring a dense cage architecture. Guided by redox-economical and step-efficient design principles, our route relies on two pivotal transformations: an ODI-Diels–Alder cycloaddition and a modified MHAT-initiated transannular radical cyclization, which rapidly assembles a functionalized pentacyclic skeleton. Initial late-stage C(sp 3 )–H amination and reductive amination efforts failed due to severe steric hindrance and regioselectivity issues, triggering a critical strategic revision centered on the preinstallation of the C19 oxygen functionality to bypass late-stage functionalization barriers. This revised design enabled a concise cascade Borch reductive amination to forge the embedded azabicyclo[2.2.1]heptane motif. This work highlights the value of strategic functional group prepositioning in addressing the synthetic challenges of cage-like diterpenoid alkaloids.