Premium
TiCl 3 ‐Mediated Synthesis of 2,3,3‐Trisubstituted Indolenines: Total Synthesis of (+)‐1,2‐Dehydroaspidospermidine, (+)‐Condyfoline, and (−)‐Tubifoline
Author(s) -
Delayre Bastien,
Piemontesi Cyril,
Wang Qian,
Zhu Jieping
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202005380
Subject(s) - chemistry , nitrone , total synthesis , alkyl , substituent , stereochemistry , sequence (biology) , combinatorial chemistry , organic chemistry , catalysis , cycloaddition , biochemistry
2,3,3‐Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl 3 ‐mediated reductive cyclization of tetrasubstituted alkenes bearing a 2‐nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)‐1,2‐dehydroaspidospermidine featuring a late‐stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π‐electron‐5‐atom electrocyclization and a 1,2‐alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)‐condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2‐alkyl shift. The exclusive formation of (+)‐condyfoline indicates that the 1,2‐alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro‐Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)‐condyfoline to (−)‐tubifoline by way of a retro‐Mannich/1,3‐prototropy/transannular cyclization cascade are also documented.