Lactonization as a general route to β-C(sp3)–H functionalization

An Author Correction to this article was published on 23 September 2020

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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.

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Fig. 1: β-C(sp3)–H functionalization.
Fig. 2: Aliphatic acid scope for β-C(sp3)–H lactonization.
Fig. 3: Gram-scale β-C(sp3)–H lactonization of Gemfibrozil with 1 mol% Pd and diverse transformations.

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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

  1. 1.

    Daugulis, O., Roane, J. & Tran, L. D. Bidentate, monoanionic auxiliary-directed functionalization of carbon–hydrogen bonds. Acc. Chem. Res. 48, 1053–1064 (2015).

    CAS  Article  Google Scholar 

  2. 2.

    Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    CAS  Article  Google Scholar 

  3. 3.

    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).

    CAS  Article  Google Scholar 

  4. 4.

    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).

    CAS  Article  Google Scholar 

  5. 5.

    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).

    CAS  Article  Google Scholar 

  6. 6.

    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).

    CAS  Article  Google Scholar 

  7. 7.

    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).

    CAS  Article  Google Scholar 

  8. 8.

    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).

    CAS  Article  Google Scholar 

  9. 9.

    Zhuang, Z. et al. Ligand-enabled β-C(sp 3)–H olefination of free carboxylic acids. J. Am. Chem. Soc. 140, 10363–10367 (2018).

    CAS  Article  Google Scholar 

  10. 10.

    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).

    CAS  Article  Google Scholar 

  11. 11.

    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).

    CAS  Article  Google Scholar 

  12. 12.

    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).

    CAS  Article  Google Scholar 

  13. 13.

    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).

    CAS  Article  Google Scholar 

  14. 14.

    Wang, Y., Tennyson, R. L. & Romo, D. β-Lactones as intermediates for natural product total synthesis and new transformations. Heterocycles 64, 605–658 (2004).

    CAS  Article  Google Scholar 

  15. 15.

    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).

    CAS  Article  Google Scholar 

  16. 16.

    Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    ADS  CAS  Article  Google Scholar 

  17. 17.

    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).

  18. 18.

    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).

    CAS  Article  Google Scholar 

  19. 19.

    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).

    CAS  Article  Google Scholar 

  20. 20.

    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).

    Article  Google Scholar 

  21. 21.

    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).

    CAS  Article  Google Scholar 

  22. 22.

    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).

    CAS  Article  Google Scholar 

  23. 23.

    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).

    ADS  CAS  Article  Google Scholar 

  24. 24.

    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).

    ADS  CAS  Article  Google Scholar 

  25. 25.

    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).

    CAS  Article  Google Scholar 

  26. 26.

    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).

    ADS  CAS  Article  Google Scholar 

  27. 27.

    Todd, P. A. & Ward, A. Gemfibrozil – a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia. Drugs 36, 314–339 (1988).

    CAS  Article  Google Scholar 

  28. 28.

    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).

    Article  Google Scholar 

  29. 29.

    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).

    CAS  Article  Google Scholar 

  30. 30.

    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).

    CAS  Article  Google Scholar 

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Acknowledgements

We acknowledge The Scripps Research Institute and the NIH (NIGMS, R01GM084019) for financial support.

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J.-Q.Y. conceived the concept. Z.Z. developed the lactonization reaction. J.-Q.Y. directed the project.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing interests.

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Peer review information Nature thanks Michael Doyle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

This file contains general information, an experimental section, additional references, and 1H and 13C NMR spectra.

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Zhuang, Z., Yu, J. 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

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