The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, have been successfully accomplished by way of a biomimetic strategy that proceeds through a bio-inspired 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 which 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 bio-inspired intermediate bearing three differentiated oxygen-containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.
