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Synthetic And DFT Studies Towards A Unified Approach To Phlegmarine Alkaloids: Aza-Michael Intramolecular Processes Leading To 5-oxodecahydroquinolines.

Ben Bradshaw, Carlos Luque-Corredera, Gisela V. Saborit, C. Cativiela, Ruth Dorel, C. Bo, J. Bonjoch
Published 2013 · Chemistry, Medicine

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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.
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