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Synthetic chemistry in water: applications to peptide synthesis and nitro-group reductions

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Abstract

Amide bond formation and aromatic/heteroaromatic nitro-group reductions represent two of the most commonly used transformations in organic synthesis. Unfortunately, such processes can be especially wasteful and hence environmentally harmful, and may present safety hazards as well, given the reaction conditions involved. The two protocols herein describe alternative technologies that offer solutions to these issues. Polypeptides can now be made in water at ambient temperatures using small amounts of the designer surfactant TPGS-750-M, thereby eliminating the use of organic solvents as the reaction medium. Likewise, a safe, inexpensive and efficient procedure is outlined for nitro-group reductions, using industrial iron in the form of carbonyl iron powder (CIP), an inexpensive item of commerce. The peptide synthesis will typically take, overall, 3–4 h for a simple coupling and 8 h for a two-step deprotection/coupling process. The workup usually consists of a simple extraction and acidic/basic aqueous washings. The nitro reduction procedure will typically take 6–8 h to complete, including setup, reaction time and workup.

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The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files.

References

  1. Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    Article  CAS  Google Scholar 

  2. European Chemicals Agency. Member state committee support document for identification of N,N-dimethylformamide as a substance of very high concern because of its CMR properties. ECHA https://echa.europa.eu/documents/10162/13638/supdoc_n_n-dimethylformamide_3204_en.pdf/3f575bea-5a96-4f18-a110-d294d37422c7 (2012).

  3. US Environmental Protection Agency. Toxicological review of dichloromethane (methylene chloride). EPA.gov https://cfpub.epa.gov/ncea/iris/iris_documents/documents/toxreviews/0070tr.pdf (2011).

  4. Datta, S., Sood, A. & Török, M. A step toward green peptide synthesis. Curr. Org. Synth. 8, 262–280 (2011).

    Article  CAS  Google Scholar 

  5. Sabatini, M. T., Boulton, L. T. & Sheppard, T. D. Borate esters: simple catalysts for the sustainable synthesis of complex amides. Sci. Adv. 3, e1701028 (2017).

    Article  Google Scholar 

  6. Sabatini, M. T. et al. Protecting-group-free amidation of amino acids using lewis acid catalysts. Chem. Eur. J. 24, 7033–7043 (2018).

    Article  CAS  Google Scholar 

  7. Jad, Y. E. et al. Peptide synthesis beyond DMF: THF and ACN as excellent and friendlier alternatives. Org. Biomol. Chem. 13, 2393–2398 (2015).

    Article  CAS  Google Scholar 

  8. Lopez, J., Pletscher, S., Aemissegger, A., Bucher, C. & Gallou, F. N-butylpyrrolidinone as alternative solvent for solid-phase peptide synthesis. Org. Process Res. Dev. 22, 494–503 (2018).

    Article  CAS  Google Scholar 

  9. Lawrenson, S. B., Arav, R. & North, M. The greening of peptide synthesis. Green Chem. 19, 1685–1691 (2017).

    Article  CAS  Google Scholar 

  10. Wilson, K. L., Murray, J., Jamieson, C. & Watson, A. J. B. Cyrene as a bio-based solvent for HATU mediated amide coupling. Org. Biomol. Chem. 16, 2851–2854 (2018).

    Article  CAS  Google Scholar 

  11. Declerck, V., Nun, P., Martinez, J. & Lamaty, F. Solvent‐free synthesis of peptides. Angew. Chem. Int. Ed. Engl. 48, 9318–9321 (2009).

    Article  CAS  Google Scholar 

  12. Métro, T.-X. et al. Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery. Chem. Commun. 48, 11781–11783 (2012).

    Article  Google Scholar 

  13. Bonnamour, J., Métro, T.-X., Martinez, J. & Lamaty, F. Environmentally benign peptide synthesis using liquid-assisted ball-milling: application to the synthesis of Leu-enkephalin. Green Chem. 15, 1116–1120 (2013).

    Article  CAS  Google Scholar 

  14. Hojo, K., Maeda, M. & Kawasaki, K. 2-(4-Sulfophenylsulfonyl)ethoxycarbonyl group: a new water-soluble N-protecting group and its application to solid phase peptide synthesis in water. Tetrahedron Lett. 45, 9293–9295 (2004).

    Article  CAS  Google Scholar 

  15. Hojo, K. et al. Aqueous microwave-assisted solid-phase peptide synthesis using Fmoc strategy. III: racemization studies and water-based synthesis of histidine-containing peptides. Amino Acids 46, 2347 (2014).

    Article  CAS  Google Scholar 

  16. Gabriel, C. M., Keener, M., Gallou, F. & Lipshutz, B. H. Amide and peptide bond formation in water at room temperature. Org. Lett. 17, 3968–3971 (2015).

    Article  CAS  Google Scholar 

  17. Lipshutz, B. H. When does organic chemistry follow nature’s lead and “make the switch”? J. Org. Chem. 82, 2806–2816 (2017).

    Article  CAS  Google Scholar 

  18. Wehrstedt, K. D., Wandrey, P. A. & Heitkamp, D. Explosive properties of 1-hydroxybenzotriazoles. Hazard. Mater. 126, 1–7 (2005).

    Article  CAS  Google Scholar 

  19. Cortes-Clerget, M., Berthon, J.-Y., Krolikiewicz-Renimel, I., Chaisemartin, L. & Lipshutz, B. H. Tandem deprotection/coupling for peptide synthesis in water at room temperature. Green Chem. 19, 4263–4267 (2017).

    Article  CAS  Google Scholar 

  20. Orlandi, M., Brenna, D., Harms, R., Jost, S. & Benaglia, M. Recent developments in the reduction of aromatic and aliphatic nitro compounds to amines. Org. Process Res. Dev. 22, 430–445 (2018).

    Article  CAS  Google Scholar 

  21. K. Kadam, H. & G. Tilve, S. Advancement in methodologies for reduction of nitroarenes. RSC Adv. 101, 83391–83407 (2015).

    Article  Google Scholar 

  22. Lee, N. R., Bikovtseva, A. A., Cortes-Clerget, M., Gallou, F. & Lipshutz, B. H. Carbonyl iron powder: a reagent for nitro group reductions under aqueous micellar catalysis conditions. Org. Lett. 19, 6518–6521 (2017).

    Article  CAS  Google Scholar 

  23. Macaluso, A. et al. Antiinflammatory influences of alpha-MSH molecules: central neurogenic and peripheral actions. J. Neurosci. 14, 2377–2382 (1994).

    Article  CAS  Google Scholar 

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Author notes

  1. These authors contributed equally: Margery Cortes-Clerget, Nicholas R. Lee.

Authors and Affiliations

  1. Department of Chemistry & Biochemistry, University of California, Santa Barbara, Santa Barbara, CA, USA

    Margery Cortes-Clerget, Nicholas R. Lee & Bruce H. Lipshutz

Authors
  1. Margery Cortes-Clerget
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  2. Nicholas R. Lee
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  3. Bruce H. Lipshutz
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Contributions

M.C.-C., N.R.L. and B.H.L. wrote, reviewed and edited the manuscript.

Corresponding author

Correspondence to Bruce H. Lipshutz.

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The authors declare no competing interests.

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Key references using this protocol

Gabriel, C. M., Keener, M., Gallou, F. & Lipshutz, B. H. Org. Lett. 17, 3968–3971 (2015): https://pubs.acs.org/doi/abs/10.1021/acs.orglett.5b01812

Cortes-Clerget, M., Berthon, J.-Y., Krolikiewicz-Renimel, I., Chaisemartin, L. & Lipshutz, B. H. Green Chem. 19, 4263−4267 (2017): https://pubs.rsc.org/en/content/articlelanding/2017/gc/c7gc01575e#!divAbstract

Lee, N. R., Bikovtseva, A. A., Cortes-Clerget, M., Gallou, F. & Lipshutz, B. H. Org. Lett. 19, 6518–6521 (2017): https://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03216

Video tutorials

Peptide synthesis in water—episode 1: coupling: https://youtu.be/WvRVfaR7dwM

Peptide synthesis in water—episode 2: 1-pot deprotection/coupling: https://youtu.be/eNqan3L4LrQ

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Cortes-Clerget, M., Lee, N.R. & Lipshutz, B.H. Synthetic chemistry in water: applications to peptide synthesis and nitro-group reductions. Nat Protoc 14, 1108–1129 (2019). https://doi.org/10.1038/s41596-019-0130-1

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