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

Kim, Alexia N. and Ngamnithiporn, Aurapat and Welin, Eric R. and Daiger, Martin T. and Grünanger, Christian U. and Bartberger, Michael D. and Virgil, Scott C. and Stoltz, Brian M. (2020) Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines. ACS Catalysis, 10 (5). pp. 3241-3248. ISSN 2155-5435. https://resolver.caltech.edu/CaltechAUTHORS:20200211-083029861

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscatal.0c00211DOIArticle
ORCID:
AuthorORCID
Ngamnithiporn, Aurapat0000-0002-5389-8171
Welin, Eric R.0000-0002-1760-4121
Bartberger, Michael D.0000-0002-5167-3139
Virgil, Scott C.0000-0001-8586-5641
Stoltz, Brian M.0000-0001-9837-1528
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.
Funders:
Funding AgencyGrant Number
NIHR01GM127972A
CaltechUNSPECIFIED
Royal Thai GovernmentUNSPECIFIED
American Cancer SocietyPF-16-011-01-CDD
Alexander von Humboldt FoundationUNSPECIFIED
Subject Keywords:hydrogenation, asymmetric catalysis, heterocycles, isoquinolines, tetrahydroisoquinolines
Issue or Number:5
Record Number:CaltechAUTHORS:20200211-083029861
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200211-083029861
Official Citation:Iridium-Catalyzed Enantioselective and Diastereoselective Hydrogenation of 1,3-Disubstituted Isoquinolines. Alexia N. Kim, Aurapat Ngamnithiporn, Eric R. Welin, Martin T. Daiger, Christian U. Grünanger, Michael D. Bartberger, Scott C. Virgil, and Brian M. Stoltz. ACS Catalysis 2020 10 (5), 3241-3248; DOI: 10.1021/acscatal.0c00211
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101219
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Feb 2020 17:05
Last Modified:09 Mar 2020 16:58

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