Total Synthesis of (−)‐Daphenylline

• Published in: Angewandte Chemie International Edition 2019-04, Vol.58 (17), p.5754-5757
• Main Authors: Xu, Bo, Wang, Bingyang, Xun, Wen, Qiu, Fayang G.
• Format: Article
• Language: English
• Subjects: Alkaloids; Carvone; Chemical reactions; Chemical synthesis; daphenylline; Diels–Alder cycloaddition; Friedel–Crafts alkylation; Organic chemistry; Stereoselectivity; total synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201902268

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (−)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO4)2‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (−)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield. Round, round, get around: A concise and highly enantioselective total synthesis of (−)‐daphenylline was accomplished in 19 steps and 7.6 % overall yield from (S)‐carvone. It features an Mg(ClO4)2‐catalyzed intramolecular amide cyclization and a Diels–Alder cycloadditon to construct the tetracyclic motif, a tandem Robinson annulation with oxidative aromatization, and an intramolecular Friedel–Crafts acylation and Nazarov‐type cyclization to construct the DF rings.