Chiral nitrogen-containing heterocycles are ubiquitous in natural products and pharmaceuticals. A noteworthy example is chiral 1,4-dihydroquinolines (1,4-DHQs), which are frequently present in pharmaceutically relevant molecules. Specifically, chiral 4-aryl 1,4-dihydroquinolines emerge as a distinctive class of ABCB1 inhibitors, combatting multidrug resistance in anticancer treatments. Lactone-fused 4-aryl 1,4-dihydroquinolines, for example, NSC756093, derivatives of 9-aryl aza-podophyllotoxin, function as a potent and specific inhibitor of GBP1:PIM1 interaction, effectively inhibiting proliferation of paclitaxel resistant cancer cells. Similarly, cyclohexanone-fused 4-aryl 1,4-dihydroquinolines such as SSE1806 act as formidable microtubule/tubulin inhibitors, exhibiting significant anticancer and antiproliferative activities. Additionally, alashanine A, a quinone-terpenoid alkaloid, displays potent antibacterial activity against Bacillus subtilis and induces cytotoxic effects on HepG2 and MCF-7 human cancer cell lines. In parallel, these chiral dihydroquinolines serve as effective precursors in the synthesis of chiral tetrahydroquinolines (THQs). Efforts to synthesize enantioenriched 4-substituted 1,4-dihydroquinolines have been explored synthetically. However, a generally useful enantioselective synthetic route for these chiral N-heterocycles has yet to be reported. Conventional methods typically entail lengthy syntheses and require either stoichiometric chiral building blocks or resolution for stereochemistry control. Prevailing catalytic asymmetric approaches primarily center around organocatalyzed cycloadditions and partial transfer hydrogenation of quinoline derivatives, often requiring high catalyst loadings. While transition-metal-catalyzed asymmetric transformations offer alternative pathways, successful instances are still relatively rare.

Recently, Jian-Hua Xie’s group have presented an asymmetric partial hydrogenation strategy to access enantioenriched 1,4-dihydroquinolines from quinolines. The strategy involves incorporating an ester group at position 3 of the quinoline ring, thereby enhancing the electronic deficiency and polarity of the C3-C4 double bond. Employing a chiral Ir-SpiroPAP catalyst facilitated the hydrogenation of a wide variety of 4-substituted 3-ethoxycarbonylquinolines, yielding chiral 1,4-dihydroquinolines in high yields (up to 95%) with exceptional enantioselectivity and efficiency (up to 99% ee and 1840 TONs). Noteworthy for its scalability and practicality, the method provides a robust avenue for the synthesis of valuable compounds such as 9-aryl aza-podophyllotoxins and melatonin MT₂ receptor modulators. Density functional theory calculations were performed to gain insights into the reaction mechanism and the origins of the enantioselectivity. Relevant achievements were published in J. Am. Chem. Soc., 2025. DOI: 10.1021/jacs.4c13618.