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Published March 6, 2020 | Supplemental Material + Accepted Version
Journal Article Open

Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines


The development of a general method utilizing a hydroxymethyl directing group for asymmetric hydrogenation of 1,3-disubstituted isoquinolines to provide chiral 1,2,3,4-tetrahydroisoquinolines is reported. The reaction, which utilizes [Ir(cod)Cl]₂ and a commercially available chiral xyliphos ligand, proceeds in good yield with high levels of enantioselectivity and diastereoselectivity (up to 95% ee and >20:1 dr) on a range of differentially substituted isoquinolines. Directing-group studies demonstrate that the hydroxymethyl functional group at the C1 position is more efficient at enabling hydrogenation in comparison to other substituents, although high levels of enantioselectivity were conserved across a variety of polar and nonpolar functional groups. By utilization of the generated chiral β-amino alcohol as a functional handle, the synthetic utility is further highlighted via the synthesis of 1,2-fused oxazolidine, oxazolidinone, and morpholinone tetrahydroisoquinolines in one step. Additionally, a non-natural analogue of the tetrahydroprotoberberine alkaloids was successfully synthesized.

Additional Information

© 2020 American Chemical Society. Received: January 13, 2020; Revised: February 6, 2020; Published: February 10, 2020. We thank the NIH-NIGMS (R01GM127972A) and Caltech for the support of our research program. A.N. thanks the Royal Thai Government Scholarship Program. E.R.W. was supported by a Postdoctoral Fellowship (PF-16-011-01-CDD) from the American Cancer Society. C.U.G. was supported by a Feodor Lynen Research Fellowship from the Alexander von Humboldt Foundation. We thank Dr. David VanderVelde (Caltech) and Maximilian B. Kaiser for NMR expertise and Dr. Michael Takase (Caltech) for assistance with X-ray analysis. Author Contributions: A.N.K. and A.N. contributed equally to this work and are listed alphabetically. The authors declare no competing financial interest.

Attached Files

Accepted Version - nihms-1561287.pdf

Supplemental Material - cs0c00211_si_001.pdf

Supplemental Material - cs0c00211_si_002.cif

Supplemental Material - cs0c00211_si_003.xlsx

Supplemental Material - cs0c00211_si_004.xlsx


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August 19, 2023
October 19, 2023