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Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols

Nature Synthesis volume 1, pages 548–557 (2022)Cite this article

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Abstract

Chiral amines are among the most important organic compounds and have widespread applications. Enantioselective construction of chiral amines is a major aim in organic synthesis. Among synthetic methods, direct functionalization of omnipresent C–H bonds with common organic nitrogen compounds represents one of the most attractive strategies. However, C–H amination strategies are largely limited to constructing a specific type of N-heterocycles or amine derivatives. To maximize the synthetic potential of asymmetric C–H amination, we report here an approach that unites the complementary reactivities of radical and ionic chemistry for streamlined synthesis of functionalized chiral amines. This synthesis merges the development of an enantioselective radical process for 1,5-C(sp3)–H amination of alkoxysulfonyl azides via Co(II)-based metalloradical catalysis with an enantiospecific ionic process for ring-opening of the resulting five-membered chiral sulfamidates by nucleophiles. Given that alkoxysulfonyl azides are derived from the corresponding alcohols, this approach offers a powerful synthetic tool for enantioselective β-C–H amination of common alcohols while converting the hydroxy group to other functionalities through formal nucleophilic substitution.

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Fig. 1: Combined radical and ionic approach for enantioselective synthesis of chiral amines from alcohols.
Fig. 2: Mechanistic studies on Co(II)-catalysed radical 1,5-C–H amination of alkoxysulfonyl azides.
Fig. 3: Regioselective ring-opening of enantioenriched sulfamidates for stereospecific synthesis of β-functionalized chiral amines.
Fig. 4: Synthesis of 1,2,3-trifunctionalized cyclohexane derivatives via ring-opening of cyclohexane-fused sulfamidates.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2097080 (2l), 2097081 (2t), 2097082 (2ae), 2097083 (2e), 2097084 (2a), 2097085 (3m), 2097086 (3v), 2097087 (3i), 2097088 (N-Bn-2ad), 2097089 (2u), 2097090 (2r) and 2097091 (2c). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.

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Acknowledgements

We are grateful for financial support by the NIH (R01-GM132471) (X.P.Z.) and in part by the NSF (CHE-1900375) (X.P.Z.).

Author information

Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA, USA

    Kai Lang, Wan-Chen Cindy Lee & X. Peter Zhang

  2. Department of Chemistry, University of South Florida, Tampa, FL, USA

    Yang Hu

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Contributions

K.L. and Y.H. conducted the experiments. Y.H. initiated the project. K.L. completed the project. W.C.C.L. assisted the project. X.P.Z conceived the work and directed the project. K.L., Y.H. and X.P.Z. designed the experiments. K.L. and X.P.Z. wrote the manuscript.

Corresponding author

Correspondence to X. Peter Zhang.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Bas de Bruin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–6, Discussion and Table 1.

Supplementary Data 1

Crystallographic data for compound 2a, CCDC 2097084.

Supplementary Data 2

Crystallographic data for compound 2ae, CCDC 2097082.

Supplementary Data 3

Crystallographic data for compound 2c, CCDC 2097091.

Supplementary Data 4

Crystallographic data for compound 2e, CCDC 2097083.

Supplementary Data 5

Crystallographic data for compound 2l, CCDC 2097080.

Supplementary Data 6

Crystallographic data for compound 2r, CCDC 2097090.

Supplementary Data 7

Crystallographic data for compound 2t, CCDC 2097081.

Supplementary Data 8

Crystallographic data for compound 2u, CCDC 2097089.

Supplementary Data 9

Crystallographic data for compound 3i, CCDC 2097087.

Supplementary Data 10

Crystallographic data for compound 3m, CCDC 2097085.

Supplementary Data 11

Crystallographic data for compound 3v, CCDC 2097086.

Supplementary Data 12

Crystallographic data for compound NBn2ad, CCDC 2097088.

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Lang, K., Hu, Y., Lee, WC.C. et al. Combined radical and ionic approach for the enantioselective synthesis of β-functionalized amines from alcohols. Nat. Synth 1, 548–557 (2022). https://doi.org/10.1038/s44160-022-00107-3

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