Development of a cascade reaction to access complex tetrahydro-3,4'-biisoquinoline

19 December 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

C-3-functionalized tetrahydroisoquinolines (THIQs) structural motifs are found in numerous natural products such as the tetrahydroprotoberberine alkaloids (coralydine and corytenchirine) and the benzophenanthridine alkaloids (homochelidonine, norchelidonine and chelamine). These scaffolds are also highly valuable compounds in drug discovery. Therefore, in the past few years, there has been a growing interest in developing new methods for the synthesis of this building block. However, unlike C-1-functionalized tetrahydroisoquinolines which are easily accessible, construction of C-3-functionalized tetrahydroisoquinolines is highly challenging. Methodologies such as the Bischler-Napieralski cyclization/reduction sequence, radical cyclization approach, and palladium-catalysed aryl–aryl coupling/reduction reactions were mostly used. However, all of these methods require multi step synthesis and prefunctionalization of the substrate. Moreover, none of these strategies are of sufficiently general applicability, especially for the synthesis of tetrahydro-3,4'-biisoquinoline. Herein, we have successfully developed an unprecedented cascade approach under mild conditions to access complex C-3-functionalized tetrahydroisoquinolines. The keystone of the present cascade process is the successive formation of two iminium intermediates resulting to the formation of 3 new bonds, therefore allowing creation of molecular complexity and diversity starting from simple substrates.

Keywords

tetrahydroisoquinoline
isoquinoline
cascade reaction
vinyl ether
alkaloid

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