Functional group exchange alters the 1,5-hydrogen atom transfer propensity in radical cascade reactions

In 2023, we reported a total synthesis of puberuline C (1), a C₁₉-diterpenoid alkaloid with an intricately fused hexacyclic ABCDEF-ring system. The B- and F-rings were constructed in a single step by a radical cascade reaction. After 7-endo cyclization of the B-ring, a facile 1,5-hydrogen atom transfer on the tertiary amine generated an electron-rich α-amino radical, thereby enabling 6-exo cyclization of the F-ring. To explore the generality of this unique cascade process, we exchanged the tertiary amine with an ether, prepared a radical precursor, and examined the radical reaction. We found that only the first cyclization occurred from the radical precursor, while the 1,5-hydrogen atom transfer leading to formation of the α-alkoxy radical was inhibited. The disparate outcomes between the tertiary amine and ether were rationalized by the density functional theory calculation, providing new valuable information for designing substrates for radical cascade reactions.