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A general synthetic entry to the pentacyclic Strychnos alkaloid family, using a [4 + 2]-cycloaddition/rearrangement cascade sequence

Journal of Organic Chemistry, ISSN: 0022-3263, Vol: 73, Issue: 9, Page: 3539-3550
2008
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Article Description

(Chemical Equation Presented) 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%. © 2008 American Chemical Society.

Bibliographic Details

Boonsombat, Jutatip; Zhang, Hongjun; Chughtai, Majid J; Hartung, John; Padwa, Albert

American Chemical Society (ACS)

Chemistry

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