Biomimetic Syntheses of (±)‐Isopalhinine A, (±)‐Palhinine A, and (±)‐Palhinine D

The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early‐stage direct SN2 cyclization to construct the nine‐membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels–Alder reaction of a masked ortho‐benzoquinone using the nine‐membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol‐mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen‐containing functional groups, from which all three total syntheses could be completed in either two or three additional steps. True to life: Total syntheses of the alkaloids isopalhinine A, palhinine A, and palhinine D were accomplished by means of a biomimetic strategy. Key steps for the synthesis of the core 5/6/6/9 tetracyclic skeleton are 1) an early‐stage direct SN2 cyclization to minimized the transannular strain, 2) a diastereoselective Diels–Alder reaction to furnish 6/6/9 tricyclic structure, and 3) an acyl radical cyclization to complete the 5/6/6/9 tetracyclic core architecture.