Iridium-catalyzed asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines |
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| Authors: | Alexia
N Kim Aurapat Ngamnithiporn Michael D Bartberger Brian M Stoltz |
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| Institution: | Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena CA 91125 USA.; Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6 Road, Bangkok 10210 Thailand ; 1200 Pharma LLC, 844 East Green Street, Suite 204, Pasadena CA 91101 USA |
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| Abstract: | The development of the first asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines is reported. Utilizing Ir(cod)Cl]2 and a commercially available chiral Josiphos ligand, a variety of differentially substituted isoquinolines are hydrogenated to produce enantioenriched trans-tetrahydroisoquinolines in good yield with high levels of enantioselectivity. Directing group studies demonstrate that the hydroxymethyl functionality at the C1 position is critical for hydrogenation to favor the trans-diastereomer. Preliminary mechanistic studies reveal that non-coordinating chlorinated solvents and halide additives are crucial to enable trans-selectivity. trans-Selective asymmetric hydrogenation of 1,3-disubstituted isoquinolines. |
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