Delayre, BastienPiemontesi, CyrilWang, QianZhu, Jieping2020-06-172020-06-172020-06-172020-06-0410.1002/anie.202005380https://infoscience.epfl.ch/handle/20.500.14299/169348WOS:0005375055000012,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl3-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 6 pi-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.Chemistry, MultidisciplinaryChemistry1,2-rearrangementsindole alkaloidsnatural productstitanium trichloridetotal synthesisenantioselective total-synthesisaqueous titanium trichloridestereocontrolled total-synthesisasymmetric conjugate additionsaza-cope rearrangementsstrychnos alkaloidsaspidosperma alkaloidsreductive cyclizationmass spectrometryformal synthesistext::journal::journal article::research article