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Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre

Nature Chemistry volume 10, pages 99108 (2018) | Download Citation

Abstract

A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that an intimate understanding of this distinction provides ways for addressing limitations in reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic enantioselective Cu–boryl addition to alkenes as the model process, we elucidate several key mechanistic principles. We show that higher electrophile concentration can lead to elevated enantioselectivity. This is because diastereoselective Cu–H elimination may be avoided and/or achiral Cu–boryl intermediates can be converted to allyl–B(pin) rather than add to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the deleterious influence of achiral Cu–alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper–hydride elimination is faster with an achiral Cu-alkyl species.

  • Compound

    allyl-1,1-d2 diethyl phosphate

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-phenylpent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(2-methoxyphenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(2-fluorophenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(2-(trifluoromethyl)phenyl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(naphthalen-2-yl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)phenyl)-1,3,2-dioxaborolane

  • Compound

    tert-butyl (R)-3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)benzoate

  • Compound

    tert-butyl (R)-3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl-5,5-d2)benzoate

  • Compound

    tert-butyl 3-((1S,2R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl-1-d)benzoate

  • Compound

    tert-butyl 3-((1R,2R)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl-1-d)benzoate

  • Compound

    (R)-2-(2-(4-methoxyphenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(4-fluorophenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)phenyl)-1,3,2-dioxaborolane

  • Compound

    tert-butyl (R)-4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)benzoate

  • Compound

    tert-butyl 4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl-1-d)benzoate

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(4-(trifluoromethyl)phenyl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    4,4,5,5-tetramethyl-2-((1S,2R)-2-(4-(trifluoromethyl)phenyl)pent-4-en-1-yl-1-d)-1,3,2-dioxaborolane

  • Compound

    4,4,5,5-tetramethyl-2-((1R,2R)-2-(4-(trifluoromethyl)phenyl)pent-4-en-1-yl-1-d)-1,3,2-dioxaborolane

  • Compound

    tert-butyl (R)-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)-1H-indole-1-carboxylate

  • Compound

    (R)-2-(2,4-diphenylpent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    2-((1S,2R)-2,4-diphenylpent-4-en-1-yl-1-d)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    2-((1R,2R)-2,4-diphenylpent-4-en-1-yl-1-d)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(4-methyl-2-phenylpent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-trimethyl(4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-1-en-2-yl)silane

  • Compound

    (R)-6-methyl-2-(4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)phenyl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound

    (R)-2-(2-(2,5-dimethoxy-4-methylphenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(o-tolyl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(m-tolyl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(p-tolyl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-trimethyl(4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)phenyl)silane

  • Compound

    (R)-2-(2-(4-bromophenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(naphthalen-1-yl)pent-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(benzofuran-2-yl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(benzo[b]thiophen-5-yl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-4,4,5,5-tetramethyl-2-(2-(o-tolyl)hex-4-en-1-yl)-1,3,2-dioxaborolane

  • Compound

    (R)-2-(2-(3-(allyloxy)phenyl)pent-4-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

  • Compound

    (R)-(4-(3-(allyloxy)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-1-en-2-yl)trimethylsilane

  • Compound

    1,4-dimethoxy-2-methyl-5-vinylbenzene

  • Compound

    (3R,5R)-3-(2,5-dimethoxy-4-methylphenyl)-6-methylheptane-1,5,6-triol

  • Compound

    (S)-N,N-dibenzyl-1,2,3,4-tetrahydronaphthalen-1-amine

  • Compound

    (R)-2-(1-(3,4-dihydroisoquinolin-2(1H)-yl)octyl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine

  • Compound

    tert-butyl (E)-4-(vinyl-2-d)benzoate

  • Compound

    tert-butyl (Z)-4-(vinyl-2-d)benzoate

  • Compound

    tert-butyl (E)-3-(vinyl-2-d)benzoate

  • Compound

    tert-butyl (Z)-3-(vinyl-2-d)benzoate

  • Compound

    trans-styrene-(β)-d

  • Compound

    cis-styrene-(β)-d

  • Compound

    tert-butyl 4-(cyclopropylidenemethyl)benzoate

  • Compound

    tert-butyl 4-(1-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)but-3-en-1-yl)benzoate

  • Compound

    4-bromo-2-chloro-1-vinylbenzene

  • Compound

    tert-butyl 3-chloro-4-vinylbenzoate

  • Compound

    tert-butyl 3-allyl-4-vinylbenzoate

  • Compound

    tert-butyl 3-allyl-4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2-yl)benzoate

  • Compound

    (R)-4-phenyldihydrofuran-2(3H)-one

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Acknowledgements

This research was supported by a grant from the National Institutes of Health (GM-47480) and the National Science Foundation (CHE-1362763). J.d.P. is an Alfonso Martin Escudero Foundation postdoctoral fellow. The authors thank M. Miura, K. Hirano and D. Nishikawa (University of Osaka) for their assistance in measuring enantioselectivity for the formation of compound 16 and F. Romiti and Y. Shi for discussions.

Author information

Author notes

    • Jaehee Lee
    •  & Suttipol Radomkit

    These authors contributed equally to this work.

Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA

    • Jaehee Lee
    • , Suttipol Radomkit
    • , Sebastian Torker
    • , Juan del Pozo
    •  & Amir H. Hoveyda

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Contributions

J.L. and S.R. identified the optimal catalyst and conditions, developed the catalytic enantioselective transformations and performed the labelling and related experiments. S.T. and J.d.P. designed and performed the computational and spectroscopic studies, respectively, and developed the related mechanistic hypotheses. A.H.H. directed the investigations and composed the manuscript with revisions provided by the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amir H. Hoveyda.

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    Supplementary information

    Crystallographic data for compound 35

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DOI

https://doi.org/10.1038/nchem.2861