A Concise Enantioselective Total Synthesis of (−)‐Deoxoapodine

• Published in: Angewandte Chemie International Edition Vol. 59; no. 51; pp. 23089 - 23093
• Main Authors: Yoshida, Kei, Okada, Kosuke, Ueda, Hirofumi, Tokuyama, Hidetoshi
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 14.12.2020; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: alkaloids; Alkylation; Allyl compounds; Amides; Chemical reactions; Chemistry; Chemistry, Multidisciplinary; C−H functionalization; Enantiomers; haloetherification; Indoles; oxidation; Physical Sciences; Science & Technology; Tetrahydrofuran; total synthesis; (+/-)-VINCADIFFORMINE; STRATEGY; alkaloids; BOND-FORMING REACTIONS; oxidation; GENERAL ENTRY; FLUORINATION; C-H functionalization; haloetherification; FUNCTIONALIZATION; CYCLOADDITION; INDOLE; total synthesis; EFFICIENT; ASPIDOSPERMA ALKALOIDS; C−H functionalization
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202010759

We have established a highly convergent 10‐step route for the total synthesis of (−)‐deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral‐phosphoric‐acid‐catalyzed enantioselective bromocycloetherification in a 5‐endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine‐membered lactam by a catalytic C−H palladation/alkylation cascade at the indole 2‐position and an iron‐catalyzed oxidative transannular reaction at a late‐stage of the synthesis. In a highly convergent route to (−)‐deoxoapodine, the quaternary center of the tetrahydrofuran ring was formed by an enantioselective organocatalytic bromocycloetherification reaction and subsequent Keck allylation. The aspidosperma skeleton was constructed by a C−H palladation/alkylation cascade at the indole 2‐position to form a nine‐membered lactam and an iron‐catalyzed oxidative transannular reaction at a late stage of the synthesis (see scheme).