Chemistry:Fluoroalanine

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Fluoroalanine, specifically 3-fluoro-alanine, is a fluorinated analogue of the amino acid alanine. Historically considered as an antibiotic, it also has potential applications as a radioactive tracer in positron emission tomography (PET).[1]

Synthesis

The first reported syntheses of fluoroalanine in 1976 involved treating cysteine with difluorine under an inert atmosphere. This produced a mixture of 3-fluoroalanine and 3,3-difluoroalanine, with the former as the major component.[2]

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3-Fluoroalanine, 3,3-difluoroalanine, and 3,3,3-trifluoroalanine can also be synthesised by treating alanine directly with UV-irradiated trifluoromethyl hypofluorite.[2]

Optically pure 3-fluoroalanines can be produced through an oxazolidinone intermediate that can be obtained from L- or D-serine.[3] Enzymatic synthesis of alanine with varying degrees of fluorination has been reported, using substrates such as 3-fluoropyruvate and a serine-derivatised sulfamidate.[4][5]

Applications

3-Fluoroalanine produced using the radioactive 18F isotope has potential applications in Positron Emission Tomography as a radioactive tracer. The D-enantiomer has shown promise in differentiating between bacterial infection and sterile inflammation.[1] A deuterated L-enantiomer expressed enhanced tumour uptake, warranting further biological investigation into its use as a cancer imaging agent.[5]

3-Fluoroalanine is described as unstable and generally unsuitable for peptide synthesis. Under basic conditions, it is prone to dehydrofluorination, and the proximity of the fluorine substituent to the amine group reduces the nucleophilicity of the latter. However, it has been successfully used in developing analogues to the immunosuppressant Cyclosporin A. Additionally, dehydrofluorination of 3-fluoroalanine produces a double-bond, providing a route for further amino acid functionalisation.[6] In 2015, the synthesis of N-Fmoc-protected 3-fluoroalanine grants viable routes towards incorporating fluorinated alanine probes within synthetic peptides.[7]

While fluoroalanine may refer to various isomers of 3-fluoroalanine, other functional analogues and isotopologues are of note.

Isomers

Functional analogues and derivatives

Isotopologues

  • Fludalanine (3-Fluoro-D-alanine-2-d): 3-fluoroalanine that has been deuterated at C2. This molecule was a promising antibiotic candidate that inhibited alanine racemases, which are integral to bacterial cell wall synthesis. At high concentrations, bacteria use fludalanine itself for cell wall synthesis. The compound ultimately failed clinical trials due to toxic metabolites.[13]

References

  1. ↑ 1.0 1.1 Li, Kaixuan; Tolentino Collado, Jinnette; Marden, Jocelyn A.; Pollard, Alyssa C.; Guo, Shuwen; Tonge, Peter J.; Qu, Wenchao (2024-08-22). "Biological Evaluation of d-[18FFluoroalanine and d-[18F]Fluoroalanine-d3 as Positron Emission Tomography Imaging Tracers for Bacterial Infection"]. Journal of Medicinal Chemistry 67 (16): 13975–13984. doi:10.1021/acs.jmedchem.4c00783. ISSN 0022-2623. PMID 39082959. PMC 11342404. https://doi.org/10.1021/acs.jmedchem.4c00783. 
  2. ↑ 2.0 2.1 Tolman, V. (1996-03-01). "Syntheses of fluorinated amino acids: from the classical to the modern concept" (in en). Amino Acids 11 (1): 15–36. doi:10.1007/BF00805718. ISSN 1438-2199. PMID 24178635. https://doi.org/10.1007/BF00805718. 
  3. ↑ Hoveyda, Hamid R.; Pinault, Jean-François (2006-12-01). "(2 R )- and (2 S )-3-Fluoroalanine and Their N -Methyl Derivatives: Synthesis and Incorporation in Peptide Scaffolds" (in en). Organic Letters 8 (25): 5849–5852. doi:10.1021/ol062434q. ISSN 1523-7060. PMID 17134288. https://pubs.acs.org/doi/10.1021/ol062434q. 
  4. ↑ Nieto-Domínguez, Manuel; Sako, Aboubakar; Enemark-Rasmussen, Kasper; Gotfredsen, Charlotte Held; Rago, Daniela; Nikel, Pablo I. (2024-05-09). "Enzymatic synthesis of mono- and trifluorinated alanine enantiomers expands the scope of fluorine biocatalysis" (in en). Communications Chemistry 7 (1): 104. doi:10.1038/s42004-024-01188-1. ISSN 2399-3669. PMID 38724655. 
  5. ↑ 5.0 5.1 Li, Kaixuan; Gilberti, Alexa L.; Marden, Jocelyn A.; Akula, Hari K.; Pollard, Alyssa C.; Guo, Shuwen; Hu, Bao; Tonge, Peter J. et al. (2024-06-27). "Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection". Journal of Medicinal Chemistry 67 (12): 10293–10305. doi:10.1021/acs.jmedchem.4c00774. ISSN 0022-2623. PMID 38838188. PMC 11258582. https://doi.org/10.1021/acs.jmedchem.4c00774. 
  6. ↑ Salwiczek, Mario; Nyakatura, Elisabeth K.; Gerling, Ulla I. M.; Ye, Shijie; Koksch, Beate (2012). "Fluorinated amino acids: compatibility with native protein structures and effects on protein–protein interactions" (in en). Chem. Soc. Rev. 41 (6): 2135–2171. doi:10.1039/C1CS15241F. ISSN 0306-0012. PMID 22130572. https://xlink.rsc.org/?DOI=C1CS15241F. 
  7. ↑ Carpentier, Claudia; Godbout, Raphaël; Otis, François; Voyer, Normand (2015-03-04). "Synthesis and use of N-Fmoc-l-fluoroalanine". Tetrahedron Letters 56 (10): 1244–1246. doi:10.1016/j.tetlet.2015.01.117. ISSN 0040-4039. https://www.sciencedirect.com/science/article/pii/S0040403915001550. 
  8. ↑ Johnson, Martin R.; Barnes, Stephen; Sweeny, David J.; Diasio, Robert B. (1990). "2-Fluoro-β-alanine, a previously unrecognized substrate for bile acid coenzyme A:Amino acid:N-acyltransferase from human liver" (in en). Biochemical Pharmacology 40 (6): 1241–1246. doi:10.1016/0006-2952(90)90389-3. PMID 2119585. https://linkinghub.elsevier.com/retrieve/pii/0006295290903893. 
  9. ↑ Boutahri, Yazid; Ben Haj Salah, Khoubaib; Tisserand, Nicolas; Lensen, Nathalie; Crousse, Benoît; Brigaud, Thierry (2023-09-22). "Difluoroalanine: Synthesis, Incorporation in Peptides, and Hydrophobic Contribution Assessment". Organic Letters 25 (37): 6937–6941. doi:10.1021/acs.orglett.3c02853. ISSN 1523-7060. PMID 37695729. https://doi.org/10.1021/acs.orglett.3c02853. 
  10. ↑ Wang, Elizabeth A.; Walsh, Christopher (1981-12-01). "Characteristics of .beta.,.beta.-difluoroalanine and .beta.,.beta.,.beta.-trifluoroalanine as suicide substrates for E. coli B alanine racemase". Biochemistry 20 (26): 7539–7546. doi:10.1021/bi00529a032. ISSN 0006-2960. PMID 7034778. https://doi.org/10.1021/bi00529a032. 
  11. ↑ Höss, E.; Sewald, N.; Gaa, K.; Burger, K. (1989-10-01). "New efficient syntheses for 3.3.3-trifluoroalanine, 2-deutero-3.3.3-trifluoroalanine and their N-protected derivatives". Journal of Fluorine Chemistry 45 (1): 165. doi:10.1016/S0022-1139(00)84537-6. ISSN 0022-1139. https://www.sciencedirect.com/science/article/pii/S0022113900845376. 
  12. ↑ Dessipri, E.; Tirrell, D. A. (1994). "Trifluoroalanine N-Carboxy Anhydride: A Reactive Intermediate for the Synthesis of Low Surface Energy Polypeptides" (in en). Macromolecules 27 (19): 5463–5470. doi:10.1021/ma00097a028. ISSN 0024-9297. https://pubs.acs.org/doi/abs/10.1021/ma00097a028. 
  13. ↑ Cordes, Eugene H. (2020-09-17), "Fludalanine: nice try but no hallelujah" (in en), Hallelujah Moments (Oxford University PressNew York): pp. 139–152, doi:10.1093/oso/9780190080457.003.0009, ISBN 978-0-19-008045-7, https://academic.oup.com/book/41768/chapter/354382422, retrieved 2026-01-12 



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