Article | Published:

Direct, enantioselective α-alkylation of aldehydes using simple olefins

Nature Chemistry volume 9, pages 10731077 (2017) | Download Citation

Abstract

Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes—photoredox, enamine and hydrogen-atom transfer (HAT) catalysis—enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.

  • Compound

    bis[2-(4-fluorophenyl)-4-(methylpyridinyl)-N,C]-(4,4'-di-tert-butyl-2,2'-bipyridine-N)iridium(III) hexafluorophosphate

  • Compound

    2,4,6-triisopropylbenzenethiol

  • Compound

    (2R,5R)-2-(tert-butyl)-3-methyl-5-(naphthalen-1-ylmethyl)imidazolidin-4-one

  • Compound

    (3R,4S)-3-isopropyl-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4S)-tert-butyl 4-formyl-3-isopropylpiperidine-1-carboxylate

  • Compound

    (3R,4S)-3-isopropyltetrahydro-2H-pyran-4-carbaldehyde

  • Compound

    (3R,4S)-3-ethyl-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4S)-3-((1,3-diphenyl-1H-pyrazol-4-yl)methyl)-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4S)-di-tert-butyl 4-formyl-3-isopropylcyclohexane-1,1-dicarboxylate

  • Compound

    (1S,2R)-2-isopropylcyclohexanecarbaldehyde

  • Compound

    (3R,4S)-3-cyclopentyl-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4S)-1-tosyl-3-(2-(trimethylsilyl)ethyl)piperidine-4-carbaldehyde

  • Compound

    (3R,4S)-3-((S)-6-methylhept-5-en-2-yl)-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4S)-3-isopropyl-3-methyl-1-tosylpiperidine-4-carbaldehyde

  • Compound

    (3R,4R)-4-isopropyl-1-tosylpyrrolidine-3-carbaldehyde

  • Compound

    (4R,6R)-6-methyl-1-tosylazepane-4-carbaldehyde

  • Compound

    (3R,5S)-di-tert-butyl 5-formyl-3-methylcycloheptane-1,1-dicarboxylate

  • Compound

    bis[2-(4-methylphenyl)-4-(methylpyridine)-N,C]-(4,4'-di-tert-butyl-2,2'-bipyridine-N)iridium(III) hexafluorophosphate

  • Compound

    (S)-2-(bis(3,5-bis(trifluoromethyl)phenyl)((trimethylsilyl)oxy)methyl)pyrrolidine

  • Compound

    2,4,6-tri-tert-butylbenzenethiol

  • Compound

    (R)-2-phenethyloctanal

  • Compound

    (R)-2-methyl-4-phenylbutanal

  • Compound

    (S)-2-isopropyl-4-phenylbutanal

  • Compound

    (R)-6-chloro-2-phenethylhexanal

  • Compound

    (R)-ethyl 5-formyl-7-phenylheptanoate

  • Compound

    (S)-benzyl (2-formyl-4-phenylbutyl)carbamate

  • Compound

    (R)-2-(4-methoxyphenethyl)octanal

  • Compound

    (R)-2-(4-fluorophenethyl)octanal

  • Compound

    (R)-2-(4-(trifluoromethyl)phenethyl)octanal

  • Compound

    (R)-2-(2-(1-benzyl-1H-pyrazol-4-yl)ethyl)octanal

  • Compound

    (R)-2-(2-(pyridin-3-yl)ethyl)octanal

  • Compound

    (R)-2-(2,3-dihydro-1H-inden-2-yl)octanal

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Acknowledgements

Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS), the NIH (under award no. R01 GM078201-05) to D.W.C.M., A.G.C., J.T.M., N.J.M. and J.K. and by gifts from Merck, Abbvie, BMS and Janssen. J.T.M. acknowledges the NIH for a postdoctoral fellowship (F32 GM108217-02). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.

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Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA

    • Andrew G. Capacci
    • , Justin T. Malinowski
    • , Neil J. McAlpine
    • , Jerome Kuhne
    •  & David W. C. MacMillan

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Contributions

A.G.C., J.T.M., N.J.M. and J.K. performed and analysed experiments. A.G.C., J.T.M., N.J.M., J.K. and D.W.C.M. designed experiments to develop the intramolecular variant of this reaction and probe its utility. A.G.C., N.J.M., and D.W.C.M. designed experiments to develop the intermolecular variant of this reaction and probe its utility. A.G.C. and D.W.C.M. prepared this manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David W. C. MacMillan.

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DOI

https://doi.org/10.1038/nchem.2797

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