Synthesis of AE and BE Ring Analogues of the Alkaloid Methyllycaconitine

Abstract

Abstract The synthesis of AE and BE analogues of the alkaloid methyllycaconitine is reported. The analogues contain two key pharmacophores: a 2‐(2‐methylmaleimido)benzoate ester and a homocholine motif formed from a tertiary N ‐(3‐phenylpropyl)amine incorporated into either a 3‐azabicyclo[3.3.1]nonane (AE) or octahydroquinoline (BE) ring system. An additional aromatic group is introduced into the AE bicyclic system using a Horner–Wadsworth–Emmons reaction. The BE analogues are synthesised by a one‐pot cyclisation using ethyl α‐(bromomethyl)acrylate, a primary amine and cyclohexanone leading to an efficient assembly of an octahydroquinoline ring system that mimics the BE‐rings of methyllycaconitine. In both the AE and BE analogues, the key 2‐(2‐methylsuccinimido)benzoate ester pharmacophore is introduced by esterification of the alcohol precursors with 2‐(2‐methylmaleimido)benzoic acid ( 10 ) under Steglich conditions followed by hydrogenation over palladium on charcoal.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)