Preparation of 6-phenyl- and 8-phenyl tetrahydroisoquinolines from boldine
Journal
Heterocycles
Journal Volume
60
Journal Issue
7
Pages
1573-1588
Date Issued
2003
Author(s)
Abstract
Four 6-phenyl-and 8-phenyltetrahydroisoquinolines were prepared by structural modifications of boldine nucleus.These involved four major reaction steps, including solvolysis of 2-hydroxyaporphine, ozonolysis of the C-9,10 double bond of phenanthrene nucleus leading to the key intermediate, and final Pictet-Spengler cyclization to respective target products.Previous study in our laboratory has demonstrated that the phenanthrene alkaloid, litebamine (1) and its N-homologues possess anti-acetylcholinesterase activity. 1 Among these, 1 showed an IC 50 value of 22 µM.These compounds had been prepared via a facile semi-synthetic method starting from boldine (3) with the key solvolysis of 2-hydroxyaporphine by a pull-push mechanism. 2Molecular modeling study revealed that the distance between N 4 and O 2 of 1 is close to corresponding atoms in the extended-conformation of acetylcholine (4.28 Å vs. 3.82 Å).Hence, the substitutions around these two atoms could serve as the key pharmacophore determinant for their biological activity.The effect of N-substitutions has been studied and the best activity was displayed by the N-butyl homologue. 1However further application of these analogues was limited by their poor solubility in organic solvents, arising from strong intermolecular π-electron bonding and hydrogen bonding due to coplanar aryl structure and the attached heteroatoms.To overcome this limitation, this study focused on the breakdown of the coplanar phenanthrene moiety, which led to the preparation of 6-and 8-phenyltetrahydroisoquinolines after appropriate chemical
SDGs
Type
journal article