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Synthetic and DFT Studies Towards a Unified Approach to Phlegmarine Alkaloids: Aza‐Michael Intramolecular Processes Leading to 5‐Oxodecahydroquinolines
Author(s) -
Bradshaw Ben,
LuqueCorredera Carlos,
Saborit Gisela,
Cativiela Carlos,
Dorel Ruth,
Bo Carles,
Bonjoch Josep
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201301715
Subject(s) - intramolecular force , michael reaction , chemistry , diastereomer , epimer , annulation , stereocenter , ketone , stereochemistry , stereospecificity , organic chemistry , enantioselective synthesis , catalysis
A diastereoselective synthesis of cis ‐5‐oxodecahydroquinolines is described in which three stereocenters are generated in a one‐pot reaction. The reaction involves a lithium hydroxide‐promoted Robinson annulation/intramolecular aza‐Michael domino process from an achiral acyclic tosylamine‐tethered β‐keto ester. The development and scope of this reaction was facilitated through the use of DFT‐based mechanistic studies, which enabled the observed diastereodivergent course of the azacyclization to be rationalized. The varying stereochemistry and stability of the resulting decahydroquinolines was found to depend on whether a β‐keto ester or ketone were embedded in the substrates undergoing aminocyclization. This synthetic approach gave access not only to both diastereomeric cis ‐decahydroquinolines from the same precursor, but also to the corresponding trans isomers, through an epimerization processes of the corresponding N‐unsubstituted cis ‐5‐oxodecahydroquinolines. The described methodology provides advanced building‐blocks with the three relative stereochemistries required for the total synthesis of phlegmarine alkaloids.