American Chemical Society
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A General Synthetic Entry to the Pentacyclic Strychnos Alkaloid Family, Using a [4 + 2]-Cycloaddition/Rearrangement Cascade Sequence

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journal contribution
posted on 2008-05-02, 00:00 authored by Jutatip Boonsombat, Hongjun Zhang, Majid J. Chughtai, John Hartung, Albert Padwa
The total synthesis of (±)-strychnopivotine, (±)-tubifolidine, (±)-strychnine, and (±)-valparicine is reported. The central step in the synthesis consists of an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran that delivers an aza-tetracyclic substructure containing the ABCE-rings of the Strychnos alkaloid family. A large substituent group on the amide nitrogen atom causes the reactive s-trans conformation of the amidofuran to be more highly populated, thereby facilitating the Diels–Alder cycloaddition. The reaction also requires the presence of an electron-withdrawing substituent on the indole nitrogen for the cycloaddition to proceed. The cycloaddition/rearrangement cascade was remarkably efficient given that two heteroaromatic systems are compromised in the reaction. Closure to the remaining D-ring of the Strychnos skeleton was carried out from the aza-tetracyclic intermediate by an intramolecular palladium-catalyzed enolate-driven cross-coupling between the N-tethered vinyl iodide and the keto functionality. The cycloaddition/rearrangement approach was successfully applied to (±)-strychnopivotine (2), the only Strychnos alkaloid bearing a 2-acylindoline moiety in its pentacyclic framework. A variation of this tactic was then utilized for a synthesis of the heptacyclic framework of (±)-strychnine. The total synthesis of (±)-strychnine required only 13 steps from furanyl indole 18 and proceeded in an overall yield of 4.4%.