Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler–Napieralski/Semipinacol Rearrangement Reaction

• Published in: Angewandte Chemie International Edition Vol. 59; no. 49; pp. 21954 - 21958
• Main Authors: Wang, Shuang‐Hu, Si, Rui‐Qi, Zhuang, Qing‐Bo, Guo, Xiang, Ke, Tian, Zhang, Xiao‐Ming, Zhang, Fu‐Min, Tu, Yong‐Qiang
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.12.2020; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkaloids; Bischler–Napieralski reaction; Chemistry; Chemistry, Multidisciplinary; domino reactions; Heptanes; Indoles; Physical Sciences; Science & Technology; semipinacol rearrangement; Synthesis; total synthesis; MONOTERPENOID INDOLE ALKALOIDS; ACID; domino reactions; alkaloids; semipinacol rearrangement; total synthesis; FACILE; Bischler-Napieralski reaction
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202009238

A tandem Bischler–Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine‐type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids. A tandem Bischler–Napieralski reaction and semipinacol rearrangement was combined with a subsequent Mannich reaction for the expeditious construction of the bicyclo[2.2.1]heptanone motif of four aspidofractinine alkaloids (see scheme). The strategy further highlights the synthetic potential of tandem semipinacol rearrangement reactions in assembling spirocyclic ring systems with a congested chemical environment.