Ruthenium(II)-catalyzed asymmetric transfer hydrogenation for enantioselective synthesis of (S)-/(R)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide exhibiting differing antinociceptive effects

In this study, we developed a modified asymmetric transfer hydrogenation (ATH) methodology to reduce 2-[(3,4-dihydroisoquinolin-1-yl)methyl]isoindoline-1,3-diones, yielding both S- and R-enantiomers with excellent enantioselectivities. Chiral ligands (S,S)-TIPSDPEN and (R,R)-TIPSDPEN were employed to generate ruthenium complexes with [RuCl₂(C₆H₆)]₂, thereby establishing efficient reduction conditions. Subsequently, we synthesized both enantiomers of compound 44 from our previous study using the developed ATH method and evaluated their in vitro μ-opioid receptor agonist activity, as well as their in vivo antinociceptive effects, and gastrointestinal transit inhibition side effects. Our findings highlight that each enantiomer exhibits distinct interactions with its target receptor, resulting in different pharmacological profiles. Notably, (S)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide [(+)-(S)-5a] demonstrated superior antinociceptive activity and reduced constipation and hERG channel inhibition compared to its (-)-(R)-5a enantiomer and the racemic mixture, indicating promising potential for drug development. These results confirm that chirality plays a pivotal role in determining pharmacological activity.

Antinociceptive effect; Asymmetric transfer hydrogenation; Ruthenium(II) catalyst; TIPSDPEN ligand; μ-Opioid receptor agonist.