Isoquinoline-based compounds are among the most significant naturally occurring alkaloids and constitute a substantial group of biologically active compounds. These isoquinoline molecules exhibit a wide range of pharmacological actions owing to their structural similarities with endogenous neurotransmitters. For example, 1-methyl-1,2,3,4-tetrahydroisoquinoline (THIQ) exhibits anti-Parkinsonian properties, and its methoxylated derivatives have been explored [1]. The 1,2,3,4-THIQ structural motif frequently appears in bioactive molecules, such as species I–II, which exhibit strong biological activity. Compound I exhibits CXCR4 antagonistic activity against anti-HIV [2], whereas species II exhibits antinociceptive effects (Fig. 1) [3,4]. Modern synthetic chemistry focuses on developing efficient methods for producing optically pure amines [5,6]. Enantiomerically enriched active amines are important synthetic precursors of physiologically active compounds in the medical, pharmaceutical, agricultural, flavor, and fragrance sectors [7,8]. Recently, various approaches have been used to synthesize enantiomerically pure amines. In our previous study, we reported the synthesis of BPR1M97, a racemic mixture, as a potent μ-opioid receptor (MOR) agonist that exhibited notable antinociceptive activity [3]. The interactions between compounds and their target G protein-coupled receptors influence the pharmacological effects of the compounds [9,10]. Although enantiomers share the same molecular formula and constitutional skeleton, they have different configurations at their stereocenters and form mirror images. These configurational differences can result in distinct interactions with the target, thereby exhibiting different pharmacological effects [11–13]. Therefore, we developed an asymmetric transfer hydrogenation (ATH) method to synthesize both R- and S-1,2,3,4-THIQ-1-methylamines with high enantioselectivities, which are intermediates for the preparation of (S)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide and (R)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide.

ATH is the preferred method for asymmetric imine reduction owing to its ease of operation and lack of need for dangerous hydrogen gas or pressure vessels [14]. Various chiral catalysts have been investigated for the ATH of ketones and imines, among which the most prominent are the Ru(II) [[15], [16], [17], [18], [19]], Rh(III) [[20], [21], [22], [23]], and Ir(III) [24,25] complexes bearing optically active tosyl-1,2-diphenylethylenediamine (TsDPEN, where DPEN = 1,2-diphenylethylenediamine) ligands. These catalysts are typically employed in organic solvents using a formic acid/triethylamine (HCOOH/Et₃N) azeotropic mixture as the hydrogen source. The application of [Ru(II)Cl2(η6-arene)2(N-tosyl-(1S,2S)-DPEN)] complexes in ATH for the reduction of 2-[(3,4-dihydroisoquinolin-1-yl)methyl]isoindoline-1,3-dione was reported by Czarnocki et al. in 2006 (Scheme 1, Eq. 1) [26]. However, enantiopure forms of this compound cannot be obtained without recrystallization. Roszkowski reported that the ATH of 2-[(3,4-dihydroisoquinolin-1-yl)methyl]isoindoline-1,3-dione using a Ru-diamine complex yielded the desired product in 34% ee (Scheme 1, Eq. 2) [27]. In this study, we developed an ATH of 2-[(3,4-dihydroisoquinolin-1-yl)methyl]isoindoline-1,3-dione, affording the corresponding enantiopure S- and R-isomers with excellent enantiomeric excesses (ee) of 99.3% and 94.6%, respectively (Scheme 1, Eqs. 3 and 4). Excellent enantioselectivity was achieved without recrystallization. Furthermore, we synthesized (S)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide (+)-(S)-5a and (R)-4-ethyl-N-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]benzamide (−)-(R)-5a and investigated their pharmacological properties. The (S)-enantiomer exhibited superior MOR agonism and in vivo antinociceptive effect on R-enantiomer, revealing enantiomer discrimination receptor activation.