Abstract
Amino acids are fundamental to virtually every aspect of biological science and healthcare serving as the cornerstone of molecular structure and function. Research has now expanded beyond naturally occurring amino acids to tailor-made derivatives enabling precise control over biological processes and unlocking new functionalities unattainable with standard amino acids and peptides. One of the most exciting advancements is the development of fluorine-containing amino acids which integrate the powerful pharmacological effects of fluorine with the structural adaptability of amino acid frameworks. This review explores the synthesis of fluorinated amino acids bearing unsaturated residues—a highly valuable and distinct subgroup within the broader class of fluorinated amino acids. These specialized molecules feature fluorine directly bonded to sp2-hybridized carbon atoms, effectively replicating the electronic properties of aromatic substitution without relying on an aromatic system. The olefinic placement of fluorine enhances molecular stability and imparts specific steric, geometric, chemical, and biological characteristics critical for drug design and bioactive compound development. The synthetic strategies presented herein are organized around key transformations, including α alkylation of amino acids, side chain elaboration, introduction of amino and/or carboxylic functionalities, and the generation of unsaturation within fluoro-amino acid cores. By compiling these methodologies we aim to provide a comprehensive resource and a source of inspiration for researchers engaged in synthetic and medicinal chemistry, drug discovery, and organofluorine chemistry.
References
Vickery H.B., Schmidt C.L.A. The history of the discovery of the amino acids. Chem. Rev. 1931. 9(2): 169–318.
doi: 10.1021/cr60033a001.
Wong J.T.-F. A Co-Evolution Theory of the Genetic Code. Proc. Natl. Acad. Sci. USA. 1975. 72(5): 1909–1912.
doi: 10.1073/pnas.72.5.1909.
Trifonov E.N. Consensus temporal order of amino acids and evolution of the triplet code. Gene. 2000. 261(1): 139–151.
doi: 10.1016/s0378-1119(00)00476-5.
Higgs P.G., Pudritz R.E. A thermodynamic basis for prebiotic amino acid synthesis and the nature of the first genetic code. Astrobiology. 2009. 9(5): 483–490.
doi: 10.1089/ast.2008.0280.
Asymmetric Synthesis and Application of alpha-Amino Acids. ACS Symposium Series #1009. Soloshonok V.A., Izawa K. Eds. Oxford University Press. 2009. doi: 10.1021/bk-2009-1009.
Meierhenrich U. Amino acids and the asymmetry of life. Berlin: Springer. 2008.
doi: 10.1007/978-3-540-76886-9.
McCoy R.H., Meyer C.E., Rose W.C. Feeding experiments with mixtures of highly purified amino acids. VIII. Isolation and identification of a new essential amino acid. J. Biol. Chem. 1935. 112(1): 283–302.
https://doi.org/10.1016/S0021-9258(18)749 85-5.
Sakami W., Harrington H. Amino acid metabolism. Ann. Rev. Biochem. 1963. 32(1): 355–398.
doi: 10.1146/annurev.bi.32.070163.002035.
Marasco D., Perretta G., Sabatella M., Ruvo M. Past and future perspectives of synthetic peptide libraries. Curr. Protein Pept. Sci. 2008. 9(5): 447–467.
doi: 10.2174/138920308785915209.
Soloshonok V.A., Cai C., Hruby V.J., Meervelt L.V. Asymmetric synthesis of novel highly sterically constrained (2S,3S)-3-methyl-3-trifluoromethyl- and (2S,3S,4R)-3-trifluoromethyl-4-methylpyroglutamic acids. Tetrahedron. 1999. 55(41): 12045–12058.
doi: 10.1016/S0040-4020(99)00711-5.
Blaskovich M.A.T. Unusual amino acids in medicinal chemistry. J. Med. Chem. 2016. 59(24): 10807–10836.
doi: 10.1021/acs.jmedchem.6b00319.
Han J., Konno H., Sato T. et al. Peptidomimetics and Peptide-Based Blockbuster Drugs. Curr. Org. Chem. 2021. 25(14): 1627–1658.
doi: 10.2174/1385272825666210610155047.
Liu J., Han J., Izawa K. et al. Cyclic tailor-made amino acids in the design of modern pharmaceuticals. Eur. J. Med. Chem. 2020. 208: 112736.
doi: 10.1016/j.ejmech.2020.112736.
Stevenazzi A., Marchini M., Sandrone G. et al. Amino acidic scaffolds bearing unnatural side chains: An old idea generates new and versatile tools for the life sciences. Bioorg. Med. Chem. Lett. 2014. 24(23): 5349–5356.
doi: 10.1016/j.bmcl.2014.10.016.
Han J., Konno H., Sato T. et al. Tailor-made amino acids in the design of small-molecule blockbuster drugs. Eur. J. Med. Chem. 2021. 220: 113448.
doi: 10.1016/j.ejmech.2021.113448.
Yin Z., Hu W., Zhang W. et al. Tailor-made amino acid-derived pharmaceuticals approved by the FDA in 2019. Amino Acids. 2020. 52(9): 1227–1261.
doi: 10.1007/s00726-020-02887-4.
Liu A., Han J., Nakano A. et al. New pharmaceuticals approved by FDA in 2020: Small-molecule drugs derived from amino acids and related compounds. Chirality. 2022. 34(1): 86–103.
doi: 10.1002/chir.23376.
Mei H., Han J., White S. et al. Tailor-made amino acids and fluorinated motifs as prominent traits in modern pharmaceuticals. Chem.–Eur. J. 2020. 26(50): 11349–11390.
doi: 10.1002/chem.202000617.
Wang Q., Han J., Sorochinsky A. et al. The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine. Pharmaceuticals. 2022. 15(8): 999.
doi.org/10.3390/ ph150809991847558.
Han J., Wzorek A. Dhawan G. et al. New drugs on the pharmaceutical market containing fluorine and residues of tailor-made amino acids. Ukr. Chem. J. 2024. 90(9): 31–56.
doi: 10.33609/2708-129X.90.9.2024.31-56.
Wang N., Mei H., Dhawan G. et al. New Approved Drugs Appearing in the Pharmaceutical Market in 2022, Featuring Fragments of Tailor-Made Amino Acids and Fluorine. Molecules. 2023. 28(9): 3651.
doi: 10.3390/molecules28093651.
Han J., Wzorek A., Dhawan G. et al. New drugs appearing on the market in 2023: molecules containing fluorine and fragments of tailor-made amino acids. Ukr. Bioorg. Acta. 2024. 19(1): 3–20.
doi: 10.15407/bioorganica2024.01.003.
Han J., Wzorek A., Dhawan G. et al. Chiral, fluorine-containing pharmaceuticals. Ukr. Chem. J. 2025. 91(2): 55–90.
doi.org/10.33609/2708-129X.91.2.2025.55-90.
Han J., Wzorek A., Ono T., Klika K.D., Soloshonok V.A. Aliphatic fluorine substitution in the design of modern pharmaceutical drugs. Ukr. Chem. J. 2025. 91(X), ??–??.
Lyutenko N., Han J., Wzorek A. et al. Carbon nanotubes-catalyzed synthesis of fluorine-containing heterocycles. Ukr. Chem. J. 2024. 90(6): 71–86.
doi: 10.33609/2708-129X.90.6.2024.71-86.
Current fluoroorganic chemistry: new synthetic directions, technologies, materials, and biological applications. ACS Symposium Series #949. Soloshonok V.A., Mikami K., Yamazaki T., Welch J.T., Honek J.F. Eds. Oxford University Press. 2007.
doi: 10.1021/bk-2007-0949.
Du Y., Bian Y., Baecker D. et al. Fluorine in the Pharmaceutical Industry: FDA‐Approved Fluorine‐Containing Drugs in 2024. Chem. Eur. J. 2025. e202500662.
doi.org/10.1002/chem.202500662.
Wang Q., Bian Y., Dhawan G. et al. FDA approved fluorine-containing drugs in 2023. Chin. Chem. Lett. 2024. 35(11): 109780.
doi: 10.1016/j.cclet.2024.109780.
Koley M., Han J., Soloshonok V.A. et al. Latest developments in coumarin-based anticancer agents: mechanism of action and structure–activity relationship studies. RSC Med. Chem. 2024. 15(1): 10–54.
doi: 10.1039/d3md00511a.
Monnie C.M., Hernández I., Meléndez‐Pacheco R. et al. Synthesis of 4,6‐Difluoro‐Tryptophan as a Probe for Protein 19F NMR. Adv. Synth. Cat. 2024. 366(16): 3417–3422.
doi.org:10.1002/adsc.202400031.
Bravo P., Guidetti M., Viani F. et al. Chiral sulfoxide controlled asymmetric additions to C N double bond. An efficient approach to stereochemically defined α-fluoroalkyl amino compounds. Tetrahedron. 1998. 54(42): 12789–12806.
doi: 10.1016/S0040-4020(98)00779-0.
Cai C., Soloshonok V.A., Hruby V.J. Michael Addition Reactions between Chiral Ni(II) Complex of Glycine and 3-(trans-Enoyl)oxazolidin-2-ones. A Case of Electron Donor–Acceptor Attractive Interaction-controlled Face Diastereoselectivity. J. Org. Chem. 2001. 66(4): 1339–1350.
doi: 10.1021/jo0014865.
Ohkura H., Berbasov D.O., Soloshonok V.A. Chemo-and regioselectivity in the reactions between highly electrophilic fluorine containing dicarbonyl compounds and amines. Improved synthesis of the corresponding imines/enamines. Tetrahedron. 2003. 59(10): 1647–1656.
doi.org/10.1016/S0040-4020(03)00138-8.
Soloshonok V.A., Kukhar V.P. Biomimetic transamination of α-keto perfluorocarboxylic esters. An efficient preparative synthesis of β,β,β-trifluoroalanine. Tetrahedron. 1997. 53(25): 8307–8314.
doi: 10.1016/S0040-4020(97)00517-6.
Soloshonok V.A., Cai C., Hruby V.J. Asymmetric Michael addition reactions of chiral Ni(II)-complex of glycine with (N-trans-enoyl) oxazolidines: improved reactivity and stereochemical outcome. Tetrahedron: Asymmetry. 1999. 10(22): 4265–4269.
doi.org/10.1016/S0957-4166(99)00483-8.
Soloshonok V.A., Cai C., Hruby V.J. A unique case of face diastereoselectivity in the Michael addition reactions between Ni(II)-complexes of glycine and chiral 3-(E-enoyl)-1, 3-oxazolidin-2-ones. Tetrahedron Lett. 2000. 41(49): 9645–9649.
doi.org/10.1016/S0040-4039(00)01737-8.
Krause H.W., Kreuzfeld H.J., Döbler C. Unusual amino acids: II. Asymmetric synthesis of fluorine containing phenylalanines. Tetrahedron: Asymmetry. 1992. 3(4): 555–566.
doi: 10.1016/S0957-4166(00)80262-1.
Soloshonok V.A., Avilov D.V., Kukhar V.P. et al. An efficient asymmetric synthesis of (2S,3S)-3-trifluoromethylpyroglutamic acid. Tetrahedron Lett. 1997. 38(27): 4903–4904.
doi: 10.1016/S0040-4039(97)01054-X.
Bravo P., Capelli S., Meille S.V. et al. Synthesis of optically pure (R)- and (S)-α-trifluoromethyl-alanine. Tetrahedron: Asymmetry. 1994. 5(10): 2009–2018.
doi: 10.1016/S0957-4166(00)86276-X.
Yamada T., Okada T., Sakaguchi K. et al. Efficient asymmetric synthesis of novel 4-substituted and configurationally stable analogues of thalidomide. Org. Lett. 2006. 8(24): 5625–5628.
doi: 10.1021/ol0623668.
Bravo P., Farina A., Kukhar V.P. et al. Stereoselective additions of α-lithiated alkyl-p-tolylsulfoxides to N-PMP fluoroalkyl aldimines. An efficient approach to enantiomerically pure fluoro amino compounds. J. Org. Chem. 1997. 62(11): 3424–3425.
doi: 10.1021/jo970004v.
Tsushima T., Kawada K., Nishikawa J. et al. Fluorine-containing amino acids and their derivatives. 3. Stereoselective synthesis and unusual conformational features of threo- and erythro-3-fluorophenylalanine. J. Org. Chem. 1984. 49(7): 1163–1169.
doi: 10.1021/jo00181a003.
Soloshonok V.A., Kacharov A.D., Avilov D.V. et al. Transition Metal/Base-Catalyzed Aldol Reactions of Isocyanoacetic Acid Derivatives with Prochiral Ketones, a Straightforward Approach to Stereochemically Defined β,β-Disubstituted-β-hydroxy-α-amino Acids. 1 Scope and Limitations. J. Org. Chem. 1997. 62(11): 3470–3479.
doi.org/10.1021/jo9623402.
Vine W.H., Hsieh K.H., Marshall G.R. Synthesis of fluorine-containing peptides. Analogs of angiotensin II containing hexafluorovaline. J. Med. Chem. 1981. 24(9): 1043–1047.
doi: 10.1021/jm00141a005.
Smits R., Cadicamo C.D., Burger K., Koksch B. Synthetic strategies to α-trifluoromethyl and α-difluoromethyl substituted α-amino acids. Chem. Soc. Rev. 2008. 37(8): 1727–1739.
doi: 10.1039/B800310F.
Gutiérrez-Bonet Á., Liu W. Synthesis of alkyl fluorides and fluorinated unnatural amino acids via photochemical decarboxylation of α-fluorinated carboxylic acids. Org. Lett. 2023. 25(3): 483–487.
doi: 10.1021/acs.orglett.2c04144.
Shibata N., Nishimine T., Shibata N. et al. Organic base-catalyzed stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids. Chem. Commun. 2012. 48(34): 4124–4126.
doi: 10.1039/C2CC30627A.
Soloshonok V.A., Kirilenko A.G., Kukhar V.P., Resnati G. Transamination of fluorinated β-keto carboxylic esters. A biomimetic approach to β-polyfluoroalkyl-β-amino acids. Tetrahedron Lett. 1993. 34(22): 3621–3624.
doi.org/10.1016/S0040-4039(00)73652-5.
Brittain W.D., Lloyd C.M., Cobb S.L. Synthesis of complex unnatural fluorine-containing amino acids. J. Fluor. Chem. 2020. 239: 109630.
doi: 10.1016/j.jfluchem.2020.109630.
Soloshonok V.A., Ono T. The effect of substituents on the feasibility of azomethine-azomethine isomerization: New synthetic opportunities for biomimetic transamination. Tetrahedron. 1996. 52(47): 14701–14712.
doi: 10.1016/0040-4020(96)00920-9.
Ouchakour L., Ábrahámi R.A., Forró E. et al. Stereocontrolled Synthesis of Fluorine‐Containing Piperidine γ‐Amino Acid Derivatives. Eur. J. Org. Chem. 2019. 2019(12): 2202–2211.
doi: 10.1002/ejoc.201801540.
Soloshonok V.A., Ohkura H., Yasumoto M. Operationally convenient asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-trifluorobutanoic acid: Part II. Enantioselective biomimetic transamination of 4,4,4-trifluoro-3-oxo-N-[(R)-1-phenylethyl)butanamide. J. Fluor. Chem. 2006. 127(7): 930–935.
doi: 10.1016/j.jfluchem.2006.04.004.
Turcheniuk K.V., Poliashko K.O., Kukhar V.P. et al. Efficient asymmetric synthesis of trifluoromethylated β-aminophosphonates and their incorporation into dipeptides. Chem. Commun. 2012. 48(94): 11519–11521.
doi: 10.1039/C2CC36702E.
Zhang X.-X., Gao Y., Hu X.-S. et al. Recent advances in catalytic enantioselective synthesis of fluorinated α‐and β‐amino acids. Adv. Synth. Catal. 2020. 362(22): 4763–4793.
doi: 10.1002/adsc.202000966.
Tolman V. Syntheses of fluorinated amino acids: from the classical to the modern concept. Amino Acids. 1996. 11(1): 15–36.
doi: 10.1007/BF00805718.
Vera-Ayoso Y., Borrachero P., Cabrera-Escribano F. et al. Towards cyclic, conformationally constrained, fluorine-containing β-amino acid derivatives from D-glucose. Tetrahedron: Asymmetry. 2001. 12(14): 2031-2041.
doi: 10.1016/S0957-4166(01)00354-8.
Kukhar V.P. Fluorine-containing amino acids. J. Fluor. Chem. 1994. 69(3): 199–205.
doi: 10.1016/0022-1139(94)03131-2.
Qiu X.-L., Qing F.-L. Recent advances in the synthesis of fluorinated amino acids. Eur. J. Org. Chem. 2011. 2011(18): 3261–3278.
doi: 10.1002/ejoc.201100032.
Qiu X.-L., Meng W.-D., Qing F.-L. Synthesis of fluorinated amino acids. Tetrahedron. 2004. 60(32): 6711–6745.
doi: 10.1016/j.tet.2004.05.051.
Sutherland A., Willis C.L. Synthesis of fluorinated amino acids. Nat. Prod. Rep. 2000. 17(6): 621–631.
doi: 10.1039/A707503K.
Kiss L., Fülöp F. Selective synthesis of fluorine‐containing cyclic β‐amino acid scaffolds. Chem. Rec. 2018. 18(3): 266–281.
doi: 10.1002/tcr.201700038.
Zhou M., Feng Z., Zhang X. Recent advances in the synthesis of fluorinated amino acids and peptides. Chem. Commun. 2023. 59(11): 1434–1448.
doi: 10.1039/D2CC06787K.
Moschner J., Stulberg V., Fernandes R. et al. Approaches to obtaining fluorinated α-amino acids. Chem. Rev. 2019. 119(18): 10718–10801.
doi: 10.1021/acs.chemrev.9b00024.
Mykhailiuk P.K. Fluorine-containing prolines: Synthetic strategies, applications, and opportunities. J. Org. Chem. 2022. 87(11): 6961–7005.
doi: 10.1021/acs.joc.1c02956.
Otaka A., Mitsuyama E., Watanabe J. et al. Synthesis of fluorine‐containing bioisosteres corresponding to phosphoamino acids and dipeptide units. Pept. Sci. 2004. 76(2): 140–149.
doi: 10.1002/bip.10570.
Tarui A., Sato K., Omote M. et al. Stereoselective synthesis of α‐fluorinated amino acid derivatives. Adv. Synth. Catal. 2010. 352(16): 2733–2744. doi: 10.1002/adsc.201000506.
Soloshonok V.A. Highly diastereoselective Michael addition reactions between nucleophilic glycine equivalents and β-substituted-α,β-unsaturated carboxylic acid derivatives; a general approach to the stereochemically defined and sterically χ-constrained α-amino acids. Curr. Org. Chem. 2002. 6(4): 341–364.
doi: 10.2174/1385272024605014.
Han J., Sorochinsky A.E., Ono T., Soloshonok V.A. Biomimetic transamination - a metal-free alternative to the reductive amination. Application for generalized preparation of fluorine containing amines and amino acids. Curr. Org. Synth. 2011. 8(2): 281–294.
doi: 10.2174/157017911794697277.
Soloshonok V.A., Sorochinsky A.E. Practical methods for the synthesis of symmetrically α,α-disubstituted α-amino acids. Synthesis. 2010. 2010(14): 2319–2344.
doi: 10.1055/s-0029-1220013.
Mikami K., Fustero S., Sánchez-Roselló M. et al. Synthesis of fluorinated β-amino acids. Synthesis. 2011. 2011(19): 3045–3079.
doi: 10.1055/s-0030-1260173.
Sorochinsky A.E., Soloshonok V.A. Asymmetric synthesis of fluorine-containing amines, amino alcohols, α- and β-amino acids mediated by chiral sulfinyl group. J. Fluor. Chem. 2010. 131(2): 127–139.
doi: 10.1016/j.jfluchem.2009.09.015.
Sorochinsky A.E., Aceña J.L., Moriwaki H. et al. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations. Amino Acids. 2013. 45(4): 691–718.
doi: 10.1007/s00726-013-1539-4.
Aceña J.L., Sorochinsky A.E., Soloshonok V.A. Recent advances in asymmetric synthesis of α-(trifluoromethyl)-containing α-amino acids. Synthesis. 2012. 44(11): 1591–1602.
doi: 10.1055/s-0031-1289756.
Sorochinsky A.E., Aceña J.L., Moriwaki H. et al. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids. Amino Acids. 2013. 45(5): 1017–1033.
doi: 10.1007/s00726-013-1580-3.
Aceña J.L., Sorochinsky A.E., Moriwaki H. et al. Synthesis of fluorine-containing α-amino acids in enantiomerically pure form via homologation of Ni(II) complexes of glycine and alanine Schiff bases. J. Fluor. Chem. 2013. 155: 21–38.
doi: 10.1016/j.jfluchem.2013.06.004.
Aceña J.L., Sorochinsky A.E., Soloshonok V.A. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations. Amino Acids. 2014. 46(9): 2047–2073.
doi: 10.1007/s00726-014-1764-5.
Kukhar V.P., Sorochinsky A.E., Soloshonok V.A. Practical synthesis of fluorine-containing α- and β-amino acids: recipes from Kiev, Ukraine. Future Med. Chem. 2009. 1(5): 793–819.
doi: 10.4155/fmc.09.70.
Han J., Remete A.M., Dobson L.S. et al. Next generation organofluorine containing blockbuster drugs. J. Fluor. Chem. 2020. 239: 109639.
doi.org/10.1016/j.jfluchem.2020.109639.
Yu Y., Liu A., Dhawan G. et al. Fluorine-containing pharmaceuticals approved by the FDA in 2020: Synthesis and biological activity. Chin. Chem. Lett. 2021. 32(11): 3342–3354.
doi: 10.1016/j.cclet.2021.05.042.
He J., Li Z., Dhawan G. et al. Fluorine-containing drugs approved by the FDA in 2021. Chin. Chem. Lett. 2023. 34(1): 107578.
doi: 10.1016/j.cclet.2022.06.001.
Ellis T.K., Hochla V.M., Soloshonok V.A. Efficient synthesis of 2-aminoindane-2-carboxylic acid via dialkylation of nucleophilic glycine equivalent. J. Org. Chem. 2003. 68(12): 4973–4976.
doi. org/10.1021/jo030065v.
Wzorek A., Sorochinsky A.E., Klika K.D. et al. Asymmetric synthesis of chi-constrained glutamic acids and related compounds via Michael addition reactions. Ukr. Chem. J. 2024. 90(8): 83–108.
doi: 10.33609/2708-129X.90.8.2024.83-108.
Han J., Liu H., Wang J. et al. Hamari’s contribution to the asymmetric synthesis of tailor-made amino acids. Ukr. Chem. J. 2024. 90(10): 88–134.
doi: 10.33609/2708-129X.90.10.2024.88-134.
Stork G., Leong A.Y., Touzin A.M. Alkylation and Michael additions of glycine ethyl ester. Use in α-amino acid synthesis and as acyl carbanion equivalent. J. Org. Chem. 1976. 41(21): 3491–3493.
doi: 10.1021/jo00883a044.
O’Donnell M.J. Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives. Tetrahedron. 2019. 75(27): 3667–3696.
doi.org/10.1016/j.tet.2019.03.029.
Lübke M., Jung M., Haufe G. New histone deacetylase inhibitors based on 4-fluoro-2-amino acid esters: Synthesis and activity. J. Fluor. Chem. 2013. 152: 144–156.
doi.org/10.1016/j.jfluchem.2013.03.011.
Schilson S.S., Keul P., Shaikh R.S. et al. Synthesis of new ligands for targeting the S1P1 receptor. Bioorg. Med. Chem. 2015. 23(5): 1011–1026.
doi.org/10.1016/j.bmc.2015.01.014.
Takeda R., Kawamura A., Kawashima A. et al. Chemical dynamic kinetic resolution and S/R interconversion of unprotected α‐amino acids. Angew. Chem., Int. Ed. 2014. 53(45): 12214–12217.
doi.org/10.1002/anie.201407944.
Nian Y., Wang J., Zhou S. et al. Recyclable ligands for the non‐enzymatic dynamic kinetic resolution of challenging α‐amino acids. Angew. Chem., Int. Ed. 2015. 54(44): 12918–12922.
doi.org/10.1002/anie.201507273.
Sorochinsky A.E., Ueki H., Aceña J.L. et al. Chemical approach for interconversion of (S)- and (R)-α-amino acids. Org. Biomol. Chem. 2013. 11(27): 4503–4507.
doi:10.1039/C3OB40541A.
Soloshonok V.A., Tang X., Hruby V.J., Meervelt L.V. Asymmetric synthesis of α, β-dialkyl-α-phenylalanines via direct alkylation of a chiral alanine derivative with racemic α-alkylbenzyl bromides. A case of high enantiomer differentiation at room temperature. Org. Lett. 2001. 3(3): 341–343.
doi.org/10.1021/ol000330o.
Ellis T.K., Martin C.H., Tsai G.M. et al. Efficient synthesis of sterically constrained symmetrically α,α-disubstituted α-amino acids under operationally convenient conditions. J. Org. Chem. 2003. 68(16): 6208–6214.
doi.org/10.1021/jo030075w.
Soloshonok V.A., Tang X., Hruby V.J. Large-scale asymmetric synthesis of novel sterically constrained 2′,6′-dimethyl- and α,2′,6′-trimethyltyrosine and -phenylalanine derivatives via alkylation of chiral equivalents of nucleophilic glycine and alanine. Tetrahedron. 2001. 57(30): 6375–6382.
doi.org/10.1016/S0040-4020(01)00504-X.
Berkowitz D.B., Charette B.D., Karukurichi K.R., McFadden J.M. α-Vinylic amino acids: occurrence, asymmetric synthesis, and biochemical mechanisms. Tetrahedron: Asymmetry. 2006. 17(6): 869–882.
doi.org/10.1016/j.tetasy.2006.02.026.
McCune C.D., Beio M.L., Sturdivant J.M. et al. Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators. J. Am. Chem. Soc. 2017. 139(40): 14077–14089.
doi.org/10.1021/jacs.7b04690.
Laue K.W., Kröger S., Wegelius E., Haufe G. Stereoselective Synthesis of γ‐Fluorinated α‐Amino Acids Using 2‐Hydroxy‐3‐pinanone as an Auxiliary. Eur. J. Org. Chem. 2000. 2000(22): 3737‒3743.
doi.org/10.1002/1099-0690(200011)2000:22< 3737::AID-EJOC3737>3.0.CO;2-A.
Laue K.W., Mück-Lichtenfeld C., Haufe G. Enantioselective syntheses of 2-amino-4-fluoropent-4-enoic acids. Isosteres of asparagine. Tetrahedron. 1999. 55(34): 10413–10424.
doi.org/10.1016/S0040-4020(99)00581-5.
Shendage D.M., Fröhlich R., Bergander K., Haufe G. Asymmetric Synthesis of γ‐Fluorinated α‐Amino Acid Derivatives. Eur. J. Org. Chem. 2005. 2005(4): 719–727.
doi.org/10.1002/ejoc.200400665.
Polt R., Seebach D. Stereoselective alkylation of glycine units in dipeptide derivatives. "Chirality transfer" via a pivalaldehyde N,N-acetal center. J. Am. Chem. Soc. 1989. 111(7): 2622–2632. doi.org/10.1021/ja00189a042.
Wang Y., Song X., Wang J. et al. Recent approaches for asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes. Amino Acids. 2017. 49(9): 1487–1520.
doi.org/10.1007/s00726-017-2458-6.
Zou Y., Han J., Saghyan A.S. et al. Asymmetric Synthesis of Tailor-Made Amino Acids Using Chiral Ni(II) Complexes of Schiff Bases. An Update of the Recent Literature. Molecules. 2020. 25(12): 2739.
doi.org/10.3390/molecules25122739.
Wang J., Lin D., Zhou S. et al. Asymmetric synthesis of sterically and electronically demanding linear ω-trifluoromethyl containing amino acids via alkylation of chiral equivalents of nucleophilic glycine and alanine. J. Org. Chem. 2011. 76(2): 684–687.
doi.org/10.1021/jo102031b.
Sato T., Izawa K., Aceña J.L. et al. Tailor‐made α‐amino acids in the pharmaceutical industry: synthetic approaches to (1R,2S)‐1‐amino‐2‐vinylcyclopropane‐1‐carboxylic acid (vinyl‐ACCA). Eur. J. Org. Chem. 2016. 2016(16): 2757–2774.
doi.org/10.1002/ejoc.201600112.
Ellis T.K., Martin C.H., Ueki H., Soloshonok V.A. Efficient, practical synthesis of symmetrically α,α-disubstituted α-amino acids. Tetrahedron Lett. 2003. 44(5): 1063–1066.
doi.org/10.1016/S0040-4039(02)02719-3.
Joerres M., Aceña J.L., Soloshonok V.A., Bolm C. Asymmetric carbon–carbon bond formation under solventless conditions in ball mills. ChemCatChem. 2015. 7(8): 1265–1269.
doi.org/10.1002/cctc.201500102.
Castelhano A.L., Horne S., Taylor G.J. et al. Synthesis of α-amino acids with β,γ-unsaturated side chains. Tetrahedron. 1988. 44(17): 5451–5466.
doi.org/10.1016/S0040-4020(01)86051-8.
Dunn M.J., Jackson R.F.W., Pietruszka J., Turner D. Synthesis of Enantiomerically Pure Unsaturated α-Amino Acids Using Serine-Derived Zinc/Copper Reagents. J. Org. Chem. 1995. 60(7): 2210–2215.
doi.org/10.1021/jo00112a048.
Kolb M., Barth J., Heydt J.G., Jung M.J. Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors. J. Med. Chem. 1987. 30(2): 267–272.
doi.org/10.1021/jm00385a007.
Silverman R.B., Bichler K.A., Leon A.J. Mechanisms of Inactivation of γ-Aminobutyric Acid Aminotransferase by 4-Amino-5-fluoro-5-hexenoic acid. J. Am. Chem. Soc. 1996. 118(6): 1241–1252.
doi.org/10.1021/ja9527885.
Bera S., Mondal D., Singh M., Kale R.K. Advances in serinals for asymmetric synthesis. Tetrahedron. 2013. 69(3): 969–1011.
doi.org/10.1016/j.tet.2012.11.054.
McCarthy J.R., Huber E.W., Le T. et al. Stereospecific synthesis of 1-fluoro olefins via (fluorovinyl)stannanes and an unequivocal NMR method for the assignment of fluoro olefin geometry. Tetrahedron. 1996. 52(1): 45–58.
doi.org/10.1016/0040-4020(95)00911-Q.
Berkowitz D.B., De La Salud-Bea R., Jahng W. Synthesis of Quaternary Amino Acids Bearing a (2'Z)-Fluorovinyl α-Branch: Potential PLP Enzyme Inactivators. Org. Lett. 2004. 6(11): 1821–1824.
doi.org/10.1021/ol049422u.
Kubyshkin V., Rubini M. Proline Analogues. Chem. Rev. 2024. 124(13): 8130–8232.
doi.org/10.1021/acs.chemrev.4c00007.
Qiu W., Gu X., Soloshonok V.A. et al. Stereoselective synthesis of conformationally constrained reverse turn dipeptide mimetics. Tetrahedron Lett. 2001. 42(2): 145–148.
doi: 10.1016/S0040-4039(00)01864-5.
Cai M., Cai C., Mayorov A.V. et al. Biological and conformational study of β‐substituted prolines in MT‐II template: steric effects leading to human MC5 receptor selectivity. J. Pept. Res. 2004. 63(2): 116–131.
doi.org/10.1111/j.1399-3011.2003.00105.x.
Watanabe K., Suzuki Y. Protein thermostabilization by proline substitutions. J. Mol. Cat. B Enzym. 1998. 4(4): 167–180.
doi.org/10.1016/S1381-1177(97)00031-3.
Qiu X.-L., Qing F.-L. Practical Synthesis of Boc-Protected cis-4-Trifluoromethyl and cis-4-Difluoromethyl-L-prolines. J. Org. Chem. 2002. 67(20): 7162–7164.
doi.org/10.1021/jo0257400.
Han J., Escorihuela J., Fustero S. et al. Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives. Molecules. 2022. 27(12): 3797.
doi.org/10.3390/molecules27123797.
Galeazzi R., Mobbili G., Orena M. Modeling and synthesis of conformationally restricted amino acids. Curr. Org. Chem. 2004. 8(18): 1799–1829.
doi.org/10.2174/1385272043369430.
Krall J., Balle T., Krogsgaard-Larsen N. et al. GABAA receptor partial agonists and antagonists: structure, binding mode, and pharmacology. Adv. Pharmacol. 2015. 72: 201–227.
doi.org/10.1016/bs.apha.2014.10.003.
Pan Y., Qiu J., Silverman R.B. Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor. J. Med. Chem. 2003. 46(25): 5292–5293.
doi.org/10.1021/jm034162s.
Fluorine-Containing Synthons. ACS Symposium Series #911. Soloshonok, V.A. Ed. Oxford University Press. 2005.
doi: 10.1021/bk-2005-0911.
McDonald I.A., Palfreyman M.G., Jung M., Bey P. Synthesis of (E)-β-fluoromethyleneglutamic acid. Tetrahedron Lett. 1985. 26(34): 4091–4092.
doi.org/10.1016/S0040-4039(00)89300-4.
McDonald I.A., Bey P. A general preparation of fluoroallylamine enzyme inhibitors incorporating a β-substituted heteroatom. Tetrahedron Lett. 1985. 26(32): 3807–3810.
doi.org/10.1016/S0040-4039(00)89256-4.
Soloshonok V.A., Hayashi T. Gold(I)-catalyzed asymmetric aldol reactions of fluorinated benzaldehydes with an α-isocyanoacetamide. Tetrahedron: Asymmetry. 1994. 5(6): 1091–1094.
doi.org/10.1016/0957-4166(94)80059-6.
Soloshonok V.A., Hayashi T. Gold(I)-catalyzed asymmetric aldol reaction of methyl isocyanoacetate with fluorinated benzaldehydes. Tetrahedron Lett. 1994. 35(17): 2713–2716.
doi.org/10.1016/S0040-4039(00)77013-4.
Soloshonok V.A., Hayashi T., Ishikawa K., Nagashima N. Highly diastereoselective aldol reaction of fluoroalkyl aryl ketones with methyl isocyanoacetate catalyzed by silver(I)/triethylamine. Tetrahedron Lett. 1994. 35(7): 1055–1058.
doi.org/10.1016/S0040-4039(00)79964-3.
Laćan G., Satyamurthy N., Barrio J.R. (E) and (Z)-β-fluoromethylene-m-tyrosines: Resolution and determination of configuration. Tetrahedron: Asymmetry. 1995. 6(2): 525–536.
doi.org/10.1016/0957-4166(95)00036-O.
Soloshonok V.A., Kirilenko A.G., Fokina N.A. et al. Biocatalytic resolution of β-fluoroalkyl-β-amino acids. Tetrahedron: Asymmetry. 1994. 5(6): 1119–1126.
doi.org/10.1016/0957-4166(94)80063-4.
Soloshonok V.A., Kirilenko A.G., Fokina N.A. et al. Chemo-enzymatic approach to the synthesis of each of the four isomers of α-alkyl-β-fluoroalkyl-substituted β-amino acids. Tetrahedron: Asymmetry. 1994. 5(7): 1225–1228.
doi.org/10.1016/0957-4166(94)80163-0.
Sorochinsky A.E., Ueki H., Aceña J.L. et al. Chemical deracemization and (S) to (R) interconversion of some fluorine-containing α-amino acids. J. Fluor. Chem. 2013. 152: 114–118.
doi.org/10.1016/j.jfluchem.2013.02.022.
Harada K. Asymmetric Synthesis of α-Amino-acids by the Strecker Synthesis. Nature. 1963. 200(4912): 1201.
doi.org/10.1038/2001201a0.
Thornberry N.A., Bull H.G., Taub D. et al. 3-Halovinylglycines. Efficient Irreversible Inhibitors of E. coli Alanine Racemase. J. Am. Chem. Soc. 1987. 109(24): 7543–7544.
doi.org/10.1021/ja00258a056.
Garattini S. Glutamic acid, twenty years later. J. Nutr. 2000. 130(4): 901–909.
doi.org/10.1093/jn/130.4.901S.
Weil-Malherbe H. Significance of glutamic acid for the metabolism of nervous tissue. Physiol. Rev. 1950. 30(4): 549–568.
doi.org/10.1152/physrev.1950.30.4.549.
Ali I., Wani W.A., Haque A., Saleem K. Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. Future Med. Chem. 2013. 5(8): 961–978.
doi.org/10.4155/fmc.13.62.
Zieglgänsberger W., Puil E.A. Actions of glutamic acid on spinal neurones. Exp. Brain Res. 1973. 17(1): 35–49.
doi.org/10.1007/BF00234562.
Town B.W. Glutamic acid of proteins. Nature. 1940. 145(3669): 312–313.
doi.org/10.1038/145312b0.
Soloshonok V.A., Ueki H., Tiwari R. et al. Virtually complete control of simple and face diastereoselectivity in the Michael addition reactions between achiral equivalents of a nucleophilic glycine and (S)- or (R)-3-(E-enoyl)-4-phenyl-1, 3-oxazolidin-2-ones: practical method for preparation of β-substituted pyroglutamic acids and prolines. J. Org. Chem. 2004. 69(15): 4984–4990.
doi.org/10.1021/jo0495438.
Soloshonok V.A., Ueki H., Ellis T.K. et al. Application of modular nucleophilic glycine equivalents for truly practical asymmetric synthesis of β-substituted pyroglutamic acids.Tetrahedron Lett. 2005. 46(7): 1107–1110. doi.org/10.1016/j.tetlet.2004.12.093.
Ellis T.K., Ueki H., Yamada T. et al. Design, synthesis, and evaluation of a new generation of modular nucleophilic glycine equivalents for the efficient synthesis of sterically constrained α-amino acids. J. Org. Chem. 2006. 71(22): 8572–8578.
doi.org/10.1021/jo0616198.
Taylor S.M., Yamada T., Ueki H., Soloshonok V.A. Asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylenedimerization of chiral glycine equivalents with dichloromethane under operationally convenient conditions. Tetrahedron Lett. 2004. 45(50): 9159–9162.
doi.org/10.1016/j.tetlet.2004.10.111.
Nadano R., Iwai Y., Mori T., Ichikawa J. Divergent Chemical Synthesis of Prolines Bearing Fluorinated One-Carbon Units at the 4-Position via Nucleophilic 5-Endo-Trig Cyclizations. J. Org. Chem. 2006. 71(23): 8748–8754.
doi.org/10.1021/jo061421n.
Soloshonok V.A., Cai C., Hruby V.J. (S)-or (R)-3-(E-Enoyl)-4-phenyl-1, 3-oxazolidin-2-ones: ideal Michael acceptors to afford a virtually complete control of simple and face diastereoselectivity in addition reactions with glycine derivatives. Org. Lett. 2000. 2(6): 747–750.
doi.org/10.1021/ol990402f.
Soloshonok V.A., Cai C., Hruby V.J. A Practical Asymmetric Synthesis of Enantiomerically Pure 3-Substituted Pyroglutamic Acids and Related Compounds. Angew. Chem., Int. Ed. 2000. 39(12): 2172–2175.
doi.org/10.1002/1521-3773(20000616)39: 12<2172::AID-ANIE2172>3.0.CO;2-0.
Soloshonok V.A., Cai C., Hruby V.J. et al. Rational Design of Highly Diastereoselective, Organic Base-Catalyzed, Room-Temperature Michael Addition Reactions. J. Org. Chem. 2000. 65(20): 6688–6696.
doi.org/10.1021/jo0008791.
Qiu X.-L., Meng W.-D., Qing F.-L. Synthesis of 4-monofluoromethylenyl- and cis-4-monofluoromethyl-L-pyroglutamic acids via a novel dehydrofluorination. Tetrahedron. 2004. 60(24): 5201–5206.
doi.org/10.1016/j.tet.2004.04.044.
Feldman K.S. Modern Pummerer-type reactions. Tetrahedron. 2006. 62(21): 5003–5034.
doi.org/10.1016/j.tet.2006.03.004.
Hugenberg V., Haufe G. Fluoro-Pummerer rearrangement and analogous reactions. J. Fluor. Chem. 2012. 143: 238–262.
doi.org/10.1016/j.jfluchem.2012.06.015.
Bravo P., Capelli S., Crucianelli M. et al. Asymmetric synthesis of α-arylglycinols via additions of lithium methyl p-tolyl sulfoxide to N-(PMP) arylaldimines followed by “non oxidative” Pummerer reaction. Tetrahedron. 1999. 55(10): 3025–3040.
doi.org/10.1016/S0040-4020(99)00064-2.
Zhou H., Van Der Donk W.A. Synthesis of 2-amino-3-fluoroacrylic acid containing peptides. Org. Lett. 2001. 3(4): 593–596.
doi.org/10.1021/ol006997s.
Liu C., Song Y., Ju W. et al. A highly efficient approach to Z-monofluoroolefin-dehydroamino acid derivatives from gem-difluoroalkenes. Chin. Chem. Lett. 2025. In press. 111167.
doi.org/10.1016/j.cclet.2025.111167.
De Jesus I.S., Vélez J.A., Pissinati E.F. et al. Recent Advances in Photoinduced Modification of Amino Acids, Peptides, and Proteins. Chem. Rec. 2024. 24(3): e202300322.
doi.org/10.1002/tcr.202300322.
Toyobe M., Yakushiji F. Synthetic modifications of histones and their functional evaluation. Chem.—Asian J. 2022. 17(13): e202200197.
doi.org/10.1002/asia.202200197.
Wang S., Wu K., Tang Y.J., Deng H. Dehydroamino acid residues in bioactive natural products. Nat. Prod. Rep. 2024. 41(2): 273–297.
doi: 10.1039/D3NP00041A.
Peng X., Xu K, Zhang Q. et al. Dehydroalanine modification sees the light: a photochemical conjugate addition strategy. Trends Chem. 2022. 4(7): 643–657.
doi: 10.1016/j.trechm.2022.04.008.
Mori T., Sumida S., Sakata K., Shirakawa S. Efficient synthetic methods for α,β-dehydroamino acids as useful and environmentally benign building blocks in biological and materials science. Org. Biomol. Chem. 2024. 22(23): 4625‒4636.
doi.org/10.1039/D4OB00507D.
Sorochinsky A.E., Katagiri T., Ono T. et al. Optical Purifications via Self-Disproportionation of Enantiomers by Achiral Chromatography: Case Study of a Series of α-CF3-containing Secondary Alcohols. Chirality. 2013. 25(6): 365–368.
doi: 10.1002/chir.22180.
Nakamura T., Tateishi K. Tsukagoshi, S. et al. Self-disproportionation of enantiomers
of non-racemic chiral amine derivatives through achiral chromatography. Tetrahedron. 2012. 68(21): 4013–4017.
doi:10.1016/j.tet.2012.03.054.
Suzuki Y., Han J., Kitagawa O. et al. A comprehensive examination of the self-disproportionation of enantiomers (SDE) of chiral amides via achiral, laboratory-routine, gravity-driven column chromatography. RSC Adv. 2015. 5(4): 2988–2993.
doi: 10.1039/C4RA13928C.
Ueki H., Yasumoto M., Soloshonok V.A. Rational application of self-disproportionation of enantiomers via sublimation—a novel methodological dimension for enantiomeric purifications. Tetrahedron: Asymmetry. 2010. 21(11–12): 1396–1400.
doi.org/10.1016/j.tetasy.2010.04.040.
Yasumoto M., Ueki H., Ono T. et al. Self-disproportionation of enantiomers of isopropyl 3,3,3-(trifluoro)lactate via sublimation: Sublimation rates vs. enantiomeric composition. J. Fluor. Chem. 2010. 131(4) 535–539.
doi.org/10.1016/j.jfluchem.2009.11.026.
Yasumoto M., Ueki H., Soloshonok V.A. Self-disproportionation of enantiomers of trifluoro lactic acid amides via sublimation. J. Fluor. Chem. 2010. 131(2): 266–269.
doi.org/10.1016/j.jfluchem.2009.10.002.
Soloshonok V.A., Wzorek A., Klika K.D. A question of policy: should tests for the self-disproportionation of enantiomers (SDE) be mandatory for reports involving scalemates? Tetrahedron: Asymmetry. 2017. 28(10): 1430–1434.
doi: 10.1016/j.tetasy.2017.08.020.
Soloshonok V.A., Klika K.D. Terminology Related to the Phenomenon ‘Self-Disproportionation of Enantiomers’ (SDE). Helv. Chim. Acta. 2014. 97(11): 1583–1589.
doi: 10.1002/hlca.201400122.
Han J., Wzorek A., Klika K.D., Soloshonok V.A. Recommended Tests for the Self-Disproportionation of Enantiomers (SDE) to Ensure Accurate Reporting of the Stereochemical Outcome of Enantioselective Reactions. Molecules. 2021. 26(9): 2757.
doi.org/10.3390/molecules26092757.
Han J., Dembinski R., Soloshonok V.A., Klika K.D. A Call for a Change in Policy Regarding the Necessity for SDE Tests to Validate the Veracity of the Outcome of Enantioselective Syntheses, the Inherent Chiral State of Natural Products, and Other Cases Involving Enantioenriched Samples. Molecules. 2021. 26(13): 3994.
doi.org/10.3390/molecules26133994.
De Camp W.H. Chiral drugs: the FDA perspective on manufacturing and control. J. Pharmaceut. Biomed. Anal. 1993. 11(11–12): 1167–1172.
doi.org/10.1016/0731-7085(93)80100-F.
Daniels J.M., Nestmann E.R., Kerr A. Development of Stereoisomers (Chiral) Drugs: A Brief Review Of Scientific and Regulatory Considerations. Ther. Innov. Regul. Sci. 1997. 31: 639–646.
doi.org/10.1177/009286159703100303.
Ceramella J., Iacopetta D., Franchini A. et al. A look at the importance of chirality in drug activity: Some significative examples. App. Sci. 2022. 12(21): 10909.
doi.org/10.3390/app122110909.