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. 2022 Feb 18;13(11):3227-3232.
doi: 10.1039/d1sc06729j. eCollection 2022 Mar 16.

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

Alexia N Kim  1 , Aurapat Ngamnithiporn  1   2 , Michael D Bartberger  3 , Brian M Stoltz  1
Affiliations

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

Alexia N Kim et al. Chem Sci. .

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.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) Challenges in diastereoselectivity of trans-selective arene hydrogenation. (B) Our research on iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines.
Scheme 1
Scheme 1. Synthetic derivatizations of product 5a.
Scheme 2
Scheme 2. Control experiments of the asymmetric trans-selective hydrogenation by using (A) TBAI instead of TBABr and (B) THF instead of 1,2-DCE.
Scheme 3
Scheme 3. Deuterium experiments of (A) D2 and CD3COOD, (B) observed β-hydride elimination pathway, (C) D2 and protic AcOH, and (D) H2 and CD3COOD.
See this image and copyright information in PMC

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