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Asymmetric hydrogenation of ketimines with minimally different alkyl groups

Abstract

Asymmetric catalysis enables the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates1. Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a notable challenge2,3. Here we introduce a class of Earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, such as ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number of up to 107,800. Our mechanistic studies indicate that exceptional stereoselectivity arises from the modular assembly of confined chiral catalysts and cooperative non-covalent interactions between the catalyst and the substrate.

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Fig. 1: The distinction between two minimally differentiated alkyl groups.
Fig. 2: Optimization of reaction parameters.
Fig. 3: Mechanistic studies and DFT calculations.
Fig. 4: Substrate scope of imines with primary, secondary and tertiary alkyl and primary alkyl groups.

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Acknowledgements

We thank Y. Xi from the National University of Singapore and J. Xiao from the University of Liverpool for helpful discussions and valuable revisions. Financial support from the National Key R&D Program of China (2021YFF0701600) and the National Natural Science Foundation of China (22225103 and 22171159) is greatly appreciated.

Author information

Authors and Affiliations

Authors

Contributions

M.W., Y.L. and Q.L. did the conceptualization of the study. M.W., S.L. and H.L. contributed to the methodology. M.W., S.L. and H.L. did the investigation. Y.L. and Q.L. were involved in funding acquisition. Y.L. and Q.L. did the project administration. Y.L. and Q.L. supervised the work. M.W., S.L., Y.W. and Q.L. wrote the original draft. M.W., Y.L. and Q.L. contributed to the writing, review and editing of the paper.

Corresponding authors

Correspondence to Yu Lan or Qiang Liu.

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The authors declare no competing interests.

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Nature thanks Rhett Kempe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Comparison of free energy profiles.

Free energy profiles for the hydride transfer of 1a promoted by fac-Int4 and fac-Int5. Ar = o-bromophenyl.

Extended Data Fig. 2 Catalytic cycle.

Proposed mechanism for the Mn-Catalyzed asymmetric hydrogenation of ketimines.

Extended Data Fig. 3 Substrate scope of imines with primary/secondary/tertiary alkyl and methyl groups.

aReaction conditions: 1 (0.25 mmol), Mn-17 (2 mol%) and NaHMDS (5 mol%) in PhF (0.5 mL) at 5 °C for 20 h. Isolated yields (%) were given and enantioselectivities (%ee) were determined by chiral-phase HPLC. bMn-15 was used instead of Mn-17 at 25 °C. cMn-6 was used instead of Mn-17 at 25 °C. dMn-1 (2 mol%) and NaOtBu (10 mol%) in 1,4-dioxane (0.8 mL) at 60 °C for 20 h. eMn-1 (2 mol%) and KOtBu (20 mol%) in diethylene glycol dimethyl ether (0.8 mL) at 25 °C.

Extended Data Fig. 4 Synthetic applications.

a, Test of catalytic activity, TON experiment on a scale of grams. b, Deprotection of N-PG for the synthesis of primary amine. c, Preparation of (S)-Levdobutamine. d, Preparation of bioactive MER tyrosine kinase inhibitor (TCCA = trichloroisocyanuric acid; HATU = 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate).

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Wang, M., Liu, S., Liu, H. et al. Asymmetric hydrogenation of ketimines with minimally different alkyl groups. Nature 631, 556–562 (2024). https://doi.org/10.1038/s41586-024-07581-z

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