Skip to content

Research at St Andrews

Metallaphotoredox-catalysed sp3sp3 cross-coupling of carboxylic acids with alkyl halides

Research output: Contribution to journalArticle

DOI

Author(s)

Craig P. Johnston, Russell T. Smith, Simon Allmendinger, David W. C. MacMillan

School/Research organisations

Abstract

In the past 50 years, cross-coupling reactions mediated by transition metals have changed the way in which complex organic molecules are synthesized. The predictable and chemoselective nature of these transformations has led to their widespread adoption across many areas of chemical research1. However, the construction of a bond between two sp3-hybridized carbon atoms, a fundamental unit of organic chemistry, remains an important yet elusive objective for engineering cross-coupling reactions2. In comparison to related procedures with sp2-hybridized species, the development of methods for sp3sp3 bond formation via transition metal catalysis has been hampered historically by deleterious side-reactions, such as β-hydride elimination with palladium catalysis or the reluctance of alkyl halides to undergo oxidative addition3,4. To address this issue, nickel-catalysed cross-coupling processes can be used to form sp3sp3 bonds that utilize organometallic nucleophiles and alkyl electrophiles5,6,7. In particular, the coupling of alkyl halides with pre-generated organozinc8,9, Grignard10 and organoborane11 species has been used to furnish diverse molecular structures. However, the manipulations required to produce these activated structures is inefficient, leading to poor step- and atom-economies. Moreover, the operational difficulties associated with making and using these reactive coupling partners, and preserving them through a synthetic sequence, has hindered their widespread adoption. A generically useful sp3sp3 coupling technology that uses bench-stable, native organic functional groups, without the need for pre-functionalization or substrate derivatization, would therefore be valuable. Here we demonstrate that the synergistic merger of photoredox and nickel catalysis enables the direct formation of sp3sp3 bonds using only simple carboxylic acids and alkyl halides as the nucleophilic and electrophilic coupling partners, respectively. This metallaphotoredox protocol is suitable for many primary and secondary carboxylic acids. The merit of this coupling strategy is illustrated by the synthesis of the pharmaceutical tirofiban in four steps from commercially available starting materials.
Close

Details

Original languageEnglish
Pages (from-to)322-325
Number of pages4
JournalNature
Volume536
Issue number7616
Early online date17 Aug 2016
DOIs
Publication statusPublished - 18 Aug 2016

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Safe, sustainable and scalable

    Johnston, C. P., 24 Apr 2019, In : Nature Chemistry. 11, 5, p. 400-401

    Research output: Contribution to journalBook/Film/Article review

  2. Anion-initiated trifluoromethylation by TMSCF3: deconvolution of the siliconate–carbanion dichotomy by stopped-flow NMR/IR

    Johnston, C. P., West, T. H., Dooley, R. E., Reid, M., Jones, A. B., King, E. J., Leach, A. G. & Lloyd-jones, G. C., 5 Sep 2018, In : Journal of the American Chemical Society. 140, 35, p. 11112-11124

    Research output: Contribution to journalArticle

  3. Cation-controlled enantioselective and diastereoselective synthesis of indolines: an autoinductive phase-transfer initiated 5-endo-trig process

    Sharma, K., Wolstenhulme, J. R., Painter, P. P., Yeo, D., Grande-Carmona, F., Johnston, C. P., Tantillo, D. J. & Smith, M. D., 21 Oct 2015, In : Journal of the American Chemical Society. 137, 41, p. 13414-13424

    Research output: Contribution to journalArticle

  4. Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization

    Johnston, C. P., Kothari, A., Sergeieva, T., Okovytyy, S. I., Jackson, K. E., Paton, R. S. & Smith, M. D., Feb 2015, In : Nature Chemistry. 7, 2, p. 171-177 7 p.

    Research output: Contribution to journalArticle

  5. Remote Stereocontrol Transmitted through Helicity

    Johnston, C. P. & Smith, M. D., 24 Mar 2014, In : Angewandte Chemie International Edition. 53, 13, p. 3315-3317

    Research output: Contribution to journalArticle

Related by journal

  1. Nature (Journal)

    Will Cresswell (Reviewer)
    21 Dec 2017

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  2. Nature (Journal)

    Will Cresswell (Reviewer)
    11 Nov 2017

    Activity: Publication peer-review and editorial work typesPeer review of manuscripts

  3. Nature (Journal)

    David Gerard Dritschel (Editor)
    2005 → …

    Activity: Publication peer-review and editorial work typesEditor of research journal

  4. Nature (Journal)

    Ifor David William Samuel (Editor)
    2005 → …

    Activity: Publication peer-review and editorial work typesEditor of research journal

Related by journal

  1. Constraints on the superconducting order parameter in Sr2RuO4 from oxygen-17 nuclear magnetic resonance

    Pustogow, A., Luo, Y., Chronister, A., Su, Y. -S., Sokolov, D., Jerzembeck, F., Mackenzie, A. P., Hicks, C. W., Kikugawa, N., Raghu, S., Bauer, E. & Brown, S., 3 Oct 2019, In : Nature. 574, 7776, p. 72–75 11 p.

    Research output: Contribution to journalArticle

  2. Pluripotency and the origin of animal multicellularity

    Sogabe, S., Hatleberg, W. L., Kocot, K. M., Say, T. E., Stoupin, D., Roper, K., Fernandez-Valverde, S. L., Degnan, S. M. & Degnan, B. M., 12 Jun 2019, In : Nature. 20 p.

    Research output: Contribution to journalArticle

  3. Amphioxus functional genomics and the origins of vertebrate gene regulation

    Marletaz, F., Firbas, P., Maeso, I., Tena, J., Bogdanovic, O., Perry, M., Wyatt, C., de la Calle-Mustienes, E., Bertrand, S., Burguera, D., Acemel, R., van Heeringen, S., Naranjo, S., Herrera-Ubeda, C., Skvortsova, K., Jimenez-Gancedo, S., Aldea, D., Marquez, Y., Buono, L., Kozmikova, I. & 41 others, Permanyer, J., Louis, A., Albuixech-Crespo, B., Le Petillon, Y., Leon Florian, A., Subirana, L., Balwierz, P. J., Duckett, P., Farahani, E., Aury, J. M., Mangenot, S., Wincker, P., Albalat, R., Benito-Gutierrez, E., Canestro, C., Castro, F., D'Aniello, S., Ferrier, D. E. K., Huang, S., Laudet, V., Marais, G., Pontarotti, P., Schubert, M., Seitz, H., Somorjai, I. M. L., Takahashi, T., Mirabeau, O., Xu, A., Yu, J-K., Carninci, P., Martinez-Morales, J., Crollius, H., Kozmik, Z., Weirauch, M., Garcia-Fernandez, J., Lister, R., Lenhard, B., Holland, P., Escriva, H., Gomez-Skarmeta, J. L. & Irimia, M., 21 Nov 2018, In : Nature. 564, 7734, p. 64-70 29 p.

    Research output: Contribution to journalArticle

  4. An absolute sodium abundance for a cloud-free 'hot Saturn' exoplanet

    Nikolov, N., Sing, D. K., Fortney, J. J., Goyal, J. M., Drummond, B., Evans, T. M., Gibson, N. P., De Mooj, E. J. W., Rustamkulov, Z., Wakeford, H. R., Smalley, B., Burgasser, A. J., Hellier, C., Helling, C., Mayne, N. J., Madhusudhan, N., Kataria, T., Baines, J., Carter, A. L., Ballester, G. E. & 3 others, Barstow, J. K., McCleery, J. & Spake, J. J., 7 May 2018, In : Nature. 557, p. 526-529

    Research output: Contribution to journalArticle

ID: 256705189

Top