Abstract
Functionalization of the β-C–H bonds of aliphatic acids is emerging as a valuable synthetic disconnection that complements a wide range of conjugate addition reactions1,2,3,4,5. Despite efforts for β-C–H functionalization in carbon–carbon and carbon–heteroatom bond-forming reactions, these have numerous crucial limitations, especially for industrial-scale applications, including lack of mono-selectivity, use of expensive oxidants and limited scope6,7,8,9,10,11,12,13. Notably, the majority of these reactions are incompatible with free aliphatic acids without exogenous directing groups. Considering the challenge of developing C–H activation reactions, it is not surprising that achieving different transformations requires independent catalyst design and directing group optimizations in each case. Here we report a Pd-catalysed β-C(sp3)–H lactonization of aliphatic acids enabled by a mono-N-protected β-amino acid ligand. The highly strained and reactive β-lactone products are versatile linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl and amino groups at the β position of the parent acid, thus providing a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide as the oxidant to promote the desired selective reductive elimination from the Pd(iv) centre, as well as the ease of product purification without column chromatography, render this reaction amenable to tonne-scale manufacturing.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The data supporting the findings of this study are available within the article and its Supplementary Information files.
Change history
23 September 2020
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
References
Daugulis, O., Roane, J. & Tran, L. D. Bidentate, monoanionic auxiliary-directed functionalization of carbon–hydrogen bonds. Acc. Chem. Res. 48, 1053–1064 (2015).
Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).
He, J., Wasa, M., Chan, K. S. L., Shao, Q. & Yu, J.-Q. Palladium-catalyzed transformations of alkyl C–H bonds. Chem. Rev. 117, 8754–8786 (2017).
Giri, R., Guo Foxman, C. B. M. & Yu, J.-Q. et al. Pd-catalyzed stereoselective oxidation of methyl groups by inexpensive oxidants under mild conditions: a dual role for carboxylic anhydrides in catalytic C–H bond oxidation. Angew. Chem. Int. Ed. 44, 7420–7424 (2005).
Giri, R. et al. Palladium-catalyzed methylation and arylation of sp 2 and sp 3 C–H bonds in simple carboxylic acids. J. Am. Chem. Soc. 129, 3510–3511 (2007).
Wang, D.-H., Wasa, M., Giri, R. & Yu, J.-Q. Pd(ii)-catalyzed cross-coupling of sp 3 C–H bonds with sp 2 and sp 3 boronic acids using air as the oxidant. J. Am. Chem. Soc. 130, 7190–7191 (2008).
Shabashov, D. & Daugulis, O. Auxiliary-assisted palladium-catalyzed arylation and alkylation of sp 2 and sp 3 carbon–hydrogen bonds. J. Am. Chem. Soc. 132, 3965–3972 (2010).
Zhang, S.-Y., Li, Q., He, G., Nack, W. A. & Chen, G. Stereoselective synthesis of β-alkylated α-amino acids via palladium-catalyzed alkylation of unactivated methylene C(sp 3)–H bonds with primary alkyl halides. J. Am. Chem. Soc. 135, 12135–12141 (2013).
Zhuang, Z. et al. Ligand-enabled β-C(sp 3)–H olefination of free carboxylic acids. J. Am. Chem. Soc. 140, 10363–10367 (2018).
Wasa, M., Engle, K. M. & Yu, J.-Q. Pd(ii)-catalyzed olefination of sp 3 C–H bonds. J. Am. Chem. Soc. 132, 3680–3681 (2010).
Ano, Y., Tobisu, M. & Chatani, N. Palladium-catalyzed direct ethynylation of C(sp 3)–H bonds in aliphatic carboxylic acid derivatives. J. Am. Chem. Soc. 133, 12984–12986 (2011).
Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of sp 3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155 (2005).
Shen, P.-X., Hu, L., Shao, Q., Hong, K. & Yu, J.-Q. Pd(ii)-catalyzed enantioselective C(sp 3)–H arylation of free carboxylic acids. J. Am. Chem. Soc. 140, 6545–6549 (2018).
Wang, Y., Tennyson, R. L. & Romo, D. β-Lactones as intermediates for natural product total synthesis and new transformations. Heterocycles 64, 605–658 (2004).
Robinson, S. L., Christenson, J. K. & Wackett, L. P. Biosynthesis and chemical diversity of β-lactone natural products. Nat. Prod. Rep. 36, 458–475 (2019).
Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).
Kao, L.-C. & Sen, A. Platinum(ii) catalysed selective remote oxidation of unactivated C–H bonds in aliphatic carboxylic acids. J. Chem. Soc. Chem. Commun. 1242–1243 (1991).
Dangel, B. D., Johnson, J. A. & Sames, D. Selective functionalization of amino acids in water: a synthetic method via catalytic C–H bond activation. J. Am. Chem. Soc. 123, 8149–8150 (2001).
Lee, J. M. & Chang, S. Pt-catalyzed sp 3 C–H bond activation of o-alkyl substituted aromatic carboxylic acid derivatives for the formation of aryl lactones. Tetrahedr. Lett. 47, 1375–1379 (2006).
Novák, P., Correa, A., Gallardo-Donaire, J. & Martin, R. Synergistic palladium-catalyzed C(sp 3)–H activation/C(sp 3)–O bond formation: a direct, step-economical route to benzolactones. Angew. Chem. Int. Ed. 50, 12236–12239 (2011).
Mei, T.-S., Wang, X. & Yu, J.-Q. Pd(ii)-catalyzed amination of C–H bonds using single-electron or two-electron oxidants. J. Am. Chem. Soc. 131, 10806–10807 (2009).
Engle, K. M., Mei, T.-S., Wang, X. & Yu, J.-Q. Bystanding F+ oxidants enable selective reductive elimination from high-valent metal centers in catalysis. Angew. Chem. Int. Ed. 50, 1478–1491 (2011).
Zhang, Q. et al. Stereoselective synthesis of chiral α-amino-β-lactams through palladium(ii)-catalyzed sequential monoarylation/amidation of C(sp 3)–H bonds. Angew. Chem. Int. Ed. 52, 13588–13592 (2013).
McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510, 129–133 (2014); corrigendum 512, 338 (2014).
Canty, A. J., Jin, H., Skelton, B. W. & White, A. H. Oxidation of complexes by (O2CPh)2 and (ER)2 (E = S, Se), including structures of Pd(CH2CH2CH2CH2)(SePh)2(bpy) (bpy = 2,2′-bipyridine) and MMe2(SePh)2(L2) (M = Pd, Pt; L2 = bpy, 1,10-phenanthroline) and C···O and C···E bond formation at palladium(iv). Inorg. Chem. 37, 3975–3981 (1998).
Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319 (2010).
Todd, P. A. & Ward, A. Gemfibrozil – a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36, 314–339 (1988).
Sato, T., Kawara, T., Kawashima, M. & Fujisawa, T. Copper-catalyzed reaction of Grignard reagents with β-propiolactones: a convenient method for the synthesis of β-substituted propionic acids. Chem. Lett. 9, 571–574 (1980).
Smith, N. D., Wohlrab, A. M. & Goodman, M. Enantiocontrolled synthesis of α-methyl amino acids via Bn2N-α-methylserine-β-lactone. Org. Lett. 7, 255–258 (2005).
Arnold, L. D., Kalantar, T. H. & Vederas, J. C. Conversion of serine to stereochemically pure β-substituted α-amino acids via β-lactones. J. Am. Chem. Soc. 107, 7105–7109 (1985).
Acknowledgements
We acknowledge The Scripps Research Institute and the NIH (NIGMS, R01GM084019) for financial support.
Author information
Authors and Affiliations
Contributions
J.-Q.Y. conceived the concept. Z.Z. developed the lactonization reaction. J.-Q.Y. directed the project.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature thanks Michael Doyle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
This file contains general information, an experimental section, additional references, and 1H and 13C NMR spectra.
Rights and permissions
About this article
Cite this article
Zhuang, Z., Yu, JQ. Lactonization as a general route to β-C(sp3)–H functionalization. Nature 577, 656–659 (2020). https://doi.org/10.1038/s41586-019-1859-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-019-1859-y
This article is cited by
-
Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity
Nature Chemistry (2023)
-
Unconventional mechanism and selectivity of the Pd-catalyzed C–H bond lactonization in aromatic carboxylic acid
Nature Communications (2022)
-
Palladium catalyzed radical relay for the oxidative cross-coupling of quinolines
Nature Communications (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.