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

Abstract

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 SN 2 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.