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Published March 21, 2022 | Published + Supplemental Material
Journal Article Open

Iridium-catalyzed asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines


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.

Additional Information

© 2022 The Author(s). Published by the Royal Society of Chemistry. This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Submitted 02 Dec 2021. Accepted 16 Feb 2022. First published 18 Feb 2022. All publication charges for this article have been paid for by the Royal Society of Chemistry. We thank the NIH-NIGMS (R01GM127972A) and Caltech for financial support. A. N. thanks the Royal Thai Government Scholarship Program. We thank Dr David VanderVelde for NMR expertise, Dr Scott Virgil for instrumentation, Dr Mona Shahgholi for mass spectroscopy, and Dr Michael Takase and Larry Henling for assistance with X-ray analysis. Author contributions. B. M. S. conceived and directed the project. A. N. K. and A. N. designed, performed, and analyzed the synthetic chemistry experiments. M. D. B. assisted with VCD studies of THIQ 2a. A. N. K., A. N., M. D. B., and B. M. S. prepared the manuscript. Data availability. Data for this work, including optimization tables, general experimental procedures, characterization data for all new compounds and X-ray data are provided in the ESI. There are no conflicts to declare.

Attached Files

Published - d1sc06729j.pdf

Supplemental Material - d1sc06729j1.pdf

Supplemental Material - d1sc06729j2.cif


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August 22, 2023
October 23, 2023