Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (−)‐17‐nor‐Excelsinidine

• Published in: Angewandte Chemie International Edition Vol. 57; no. 38; pp. 12294 - 12298
• Main Authors: Jarret, Maxime, Tap, Aurélien, Kouklovsky, Cyrille, Poupon, Erwan, Evanno, Laurent, Vincent, Guillaume
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 17.09.2018; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Edition: International ed. in English
• Subjects: Acetic acid; alkaloids; Ammonium; Biosynthesis; Chemical Sciences; Chemistry; Chemistry, Multidisciplinary; Coupling; excelsinidine; geissoschizine; Indoles; Organic chemistry; oxidative coupling; Physical Sciences; Science & Technology; (+/-)-AKUAMMICINE; geissoschizine; excelsinidine; STRATEGY; alkaloids; FORMAL TOTAL-SYNTHESIS; oxidative coupling; (+/-)-STRICTAMINE; biosynthesis; (-)-GEISSOSCHIZOL; STRICTAMINE; INDOLE ALKALOIDS; ENANTIOSELECTIVE TOTAL-SYNTHESIS; ASYMMETRIC TOTAL-SYNTHESIS
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201802610

We report the first total synthesis of (−)‐17‐nor‐excelsinidine, a zwitterionic monoterpene indole alkaloid that displays an unusual N4−C16 connection. Inspired by the postulated biosynthesis, we explored an oxidative coupling approach from the geissoschizine framework to forge the key ammonium–acetate connection. Two strategies allowed us to achieve this goal, namely an intramolecular nucleophilic substitution on a 16‐chlorolactam with the N4 nitrogen atom or a direct I2‐mediated N4−C16 oxidative coupling from the enolate of geissoschizine. Selectivity! Two unprecedented oxidative cyclization strategies starting from the complete geissoschizine skeleton enabled the first selective total synthesis of the monoterpene indole alkaloid 17‐nor‐excelsinidine over the mavacuran and akuammilan alkaloids.