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. 2022 May 19;5(1):63.
doi: 10.1038/s42004-022-00678-4.

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chengyu Liu  1 , Lei Zhang  1 , Liming Cao  1 , Yan Xiong  2 , Yueyue Ma  3 , Ruihua Cheng  4   5 , Jinxing Ye  6   7
Affiliations

Iridium-catalyzed enantioselective synthesis of chiral γ-amino alcohols and intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine

Chengyu Liu et al. Commun Chem. .

Abstract

Chiral γ-amino alcohols are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules. Enantioselective hydrogenation of β-amino ketones provides a straightforward and powerful tool for the synthesis of chiral γ-amino alcohols, but the asymmetric transformation is synthetically challenging. Here, a series of tridentate ferrocene-based phosphine ligands bearing modular and tunable unsymmetrical vicinal diamine scaffolds were designed, synthesized, and evaluated in the iridium-catalyzed asymmetric hydrogenation of β-amino ketones. The system was greatly effective to substrates with flexible structure and functionality, and diverse β-tertiary-amino ketones and β-secondary-amino ketones were hydrogenated smoothly. The excellent reactivities and enantioselectivities were achieved in the asymmetric delivery of various chiral γ-amino alcohols with up to 99% yields, >99% ee values, and turnover number (TON) of 48,500. The gram-scale reactions with low catalyst loading showed the potential application in industrial synthesis of chiral drugs, such as (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. The designed ligand for asymmetric hydrogenation of β-amino ketones.
a Drugs and potential analgesic agent containing γ-amino alcohol units. b Methods for the synthesis of chiral γ-amino alcohols. c The designed ligand for asymmetric hydrogenation of β-amino ketones.
Fig. 2
Fig. 2. Asymmetric hydrogenation of various N-Boc-β-amino ketones with Ir–(RC,SP,RC)-L6 catalyst.
Reaction conditions: 0.4 mmol scale, 0.05 mol% [Ir(COD)Cl]2, 0.105 mol% (RC,SP,RC)-L6, 5 mol% NaOtBu, 2.0 mL toluene, room temperature (25–30 °C). Isolated yields. The ee determined by HPLC. aat 60 °C.
Fig. 3
Fig. 3. Asymmetric synthesis of chiral intermediates of (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine.
Reaction conditions: 0.4 mmol scale, 0.05 mol% [Ir(COD)Cl]2, 0.105 mol% (RC,SP,RC)-L6, 5 mol% NaOtBu, 2.0 mL toluene, room temperature (25–30 °C). Isolated yields. The ee determined by HPLC. a0.4 mmol 3·HCl, 0.44 mmol NaOtBu. bIr–(SC,RP,SC)-L6 as catalyst. c0.4 mmol 3·HCl, 0.44 mmol NaOtBu, Ir–(SC,RP,SC)-L6 as catalyst.
Fig. 4
Fig. 4. Asymmetric hydrogenation of various β-tertiary-amino ketones with Ir-(RC,SP,RC)-L6 catalyst.
aCondition A: 0.4 mmol 5·HCl, 0.05 mol% [Ir(COD)Cl]2, 0.105 mol% (RC,SP,RC)-L6, 0.44 mmol NaOtBu, 3.0 mL toluene, room temperature (25–30 °C). bCondition B: 0.4 mmol 5, 0.05 mol% [Ir(COD)Cl]2, 0.105 mol% (RC,SP,RC)-L6, 5 mol% NaOtBu, 3.0 mL toluene, room temperature (25–30 °C). Isolated yields. The ee determined by HPLC.
Fig. 5
Fig. 5. Gram-scale reactions.
The asymmetric hydrogenation of 1a, 3g, and 5ac with high S/C.
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