Document Type: Original Paper


Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran


L-Tyrosine and L-Dopa are the precursors in the biological synthesis of amine neurotransmitters. On the other hand, phenylalanine as an aromatic amino acid (AAA) is a precursor in the synthesis of L-Tyrosine and L-Dopa. For some substrates such as amino acids, resolution by the formation of diastereomers offers an attractive alternative. Among different methods in this case, crystallization-induced asymmetric transformation (CIAT) that is in situ racemization and selective crystallization of a reaction product can be a good choice. Using this method, preparation of L-Tyrosine and L-Dopa has been reported. In the synthetic route, racemic phenyl alanine methyl ester derivatives as versatile precursors were prepared by reducing azlactone derivatives with Mg in methanol as a reducing reagent and then in the resolution step (S)- enantiomer of L-Dopa (3,4-dihydroxyphenylalanine) and L-Tyrosine (4-hydroxyphenylalanine) were achieved via salt formation with (2R,3R)-tartaric acid in the presence of 5-nitro salicylaldehyde in good yield and high optical purity.


Main Subjects

1.   Deferrari G., Mannucci I., Garibotto G., Amino Acid Biosynthesis. Encyclopedia of life sciences (2010).

2.   Blaskovich M. A., Handbook on Syntheses of Amino Acids. General Routes to Amino Acids; Oxford University Press: New York, NY, USA. (2010).

3.   (a) Fernstrom J. D., Fernstrom M. H., Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J. Nutr 137: 1539–1547 (2007), (b) Goldstein D. S., Catecholamines 101. Clin. Auton. Res 20(6): 331–352 (2010).

4.   Perlman J. M., Volpe J. J., Amino Acids, Volpe's Neurology of the Newborn, 6nd Ed., Chapter 27, 763–792 (2018).

5.   (a) Gnegy M. E., Basic Neurochemistry, 8nd Ed., Principles of Molecular, Cellular, and Medical Neurobiology. Catecholamines, Chapter 14, 283–299 (2012), (b) Trevino L. A., Lorduy K., Natishyn M., Dougall A. L., Baum A., Catecholamines and Behavior, Encyclopedia of Human Behavior, 2nd Ed.,  434-440 (2012).

6.   (a) Lopez V. M., Decatur C. L., Daniel Stamer W., Lynch R. M., McKay B. S., L-DOPA Is an Endogenous Ligand for OA1. PLoS Biol 6: 236 (2008), (b) Stansley B. J., Yamamoto B. K., l-Dopa and Brain Serotonin System Dysfunction. Toxics 3(1): 75–88 (2015).

7.   (a) Koyanagi T., Katayama T., Suzuk H., Nakazawa H., Yokozeki K., Kumagai H. Hyperproduction of 3,4-Dihydroxyphenyl-L-alanine (L-Dopa) Using Erwinia herbicola Cells Carrying a Mutant Transcriptional Regulator TyrR. Biosci. Biotechnol. Biochem 73:1221-1223 (2009), (b) Contin M., Martinelli P., Pharmacokinetics of levodopa. J. Neuro 257(2): 253-261 (2010).

8.   Kim H. J., Jeon B. S., Jenner P., Hallmarks of Treatment Aspects: Parkinson's Disease Throughout Centuries Including l –Dopa. Int. Rev. Neurobiol 132: 295-343 (2017).

9.   Patil S. A., Apine O. A., Surwase S. N., Jadhav J. P., Biological sources of L-DOPA: An alternative approach. Advances in Parkinson’s disease 2: 81- 87 (2013).

10. Tao L., Xuan L., Comprehensive mass analysis for chemical processes, a case study on L-Dopa manufacture. Green Chem 16: 4241- 4256 (2014).

11. Reinhold D. F., Utne T., Abramson N. L., Process for L-dopa. U.S. Patent 4,716,246, Dec, 29 (1987).

12. (a) Chávez-Béjar M. I., Báez-Viveros J. L., Martínez A., Bolívar F., Gosset G., Biotechnological production of l-tyrosine and derived compounds. Process Biochem 47:1017-1026 (2012), (b) Grayson I., Kessler C., Modern applications of amino acids and dipeptides in pharmaceuticals and biopharmaceuticals. Chim. Oggi-Chem. Today 33: 48-51 (2015).

13.(a)     El-Mekabaty A., Erlenmeyer Azlactones: Synthesis, Reactions and Biological Activity. Int. J. Modern Org. Chem 2: 40-66 (2013), (b) Sharma N., Banerjee J., Shrestha N., Chaudhury D., A Review on Oxazolone, it’s Method of Synthesis and Biological Activity. Eur. J. Pharm. Sci 2: 964-987 (2015). (c) Bala S., Saini M., Kamboj S., Methods for synthesis of Oxazolones: A Review. Int.J. ChemTech Res 3: 1102-1118 (2011). (d) Rodrigues C. A. B., Martinho J. M. G., Afonso C. A. M., Synthesis of a Biologically Active Oxazol-5-(4H)-one via an Erlenmeyer −Plochl Reaction. J. Chem. Educ 92: 1543–1546 (2015).

14. (a)Wong H. N. C., X u Z. L., Chang H. M., Lee C. M., A modified synthesis of beta-aryllactic acids. Synthesis 8: 793-797 (1992), (b) Johnson T. B., Bencis R., Hydantoins: Syntesise of 3- Methoxy-4- Hydroxy- Phenylalanine and 3,4-dimethoxyphenylalanine. J. Am. Chem. Soc 35: 1606-1617 (1913), (c) Lyubimov S. E., Petrovskii P. V.,  Rastorguev E. A., Davankov, V. A., Asymmetric hydrogenation of methyl (Z)-2-acetamido-3-(3,4-dimethoxyphenyl)acrylate catalyzed by Rh complexes with available amidophosphite ligands. Russ. Chem. Bull 59: 1761-1764 (2010), (d) Gillespie, H. B., Snyder, H. R., Hartman, W. W., Dickey, J. B., dl-β-Phenylalanine. Org. Synth 19: 67 (1939).

15. Youn I. K., Yon G. H., Pak C. S., Magnesium-Methanol as a Simple Convenient Reducing Agent for (a,β-unsaturated esters. Tetrahedron Lett 27: 2409-2410(1986).

16. Engel P. C., Paradisi F., Novel Enzymes for Biotransformation and Resolution of Alpha-Amino Acids. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering Comprehensive Natural Products II, 5: 71–90 (2010).

17. (a)  Davies S. G., Fletcher A. M., Frost A. B., Lee J. A., Roberts, P. M., Thomson J. E., Trading N and O: asymmetric syntheses of β-hydroxy-α-amino acids via α-hydroxy-β-amino esters. Tetrahedron 69: 8885-8898 (2013), (b) Davies S. G., Fletcher A. M., Greenaway C. J., Kennedy M. S., Mayer C., Roberts P. M., Thomson J. E., Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids. Tetrahedron 1-13 (2018).


18. (a) Anderson N. G., Developing Processes for Crystallization-Induced Asymmetric Transformation. Org. Process Res. Dev 10(3): 683–683 (2006), (b) Faigl F., Fogassy E., Nógrádi M., Pálovics E., Schindler J., Strategies in optical resolution: a practical guide. Tetrahedron: Asymmetry 19: 519-536 (2008), (c) García-Urdiales E., Alfonso I., Gotor V., Update 1 of: Enantioselective Enzymatic Desymmetrizations in Organic Synthesis. Chem. Rev 111: 110-180 (2011), (d) Yoshioka R., Racemization, Optical Resolution and Crystallization-Induced Asymmetric Transformation of Amino Acids and Pharmaceutical Intermediates. Top. Curr. Chem 269: 83–132 (2007).

19. Shiraiwa T., Shinjo K., Kurokawa H., Asymmetric Transformations of Proline and 2-Piperidinecarboxylic Acid via Formation of Salts with Optically Active Tartaric Acid. Bull. Chem. Soc. Jpn 64: 3251-3255 (1991).

20. Shiraiwa T., Shinjo K., Masui Y., Ohta A., Natsuyama H., Miyazaki H., Kurokawa H., Facile Production of D-Histidine by Asymmetric Transformation of L-Histidine. Bull. Chem. Soc. Jpn 64: 3741- 3742 (1991).

21. Maryanoff C. A., Scott L., Shah R. D., Villani Jr F. J. A., A crystallization-induced asymmetric transformation to prepare (R)-4-chlorophenylalanine methyl ester. Tetrahedron Asymmetry 9: 3247-3250 (1998).

22. Wei B. M., Jiang L. J., Zheng Y. P., Xu H. Q., Preparation of D-Phenylalanine by Asymmetric Transformation. Chin. Chem. Lett 15: 411-413 (2004).

23. Roper J. M., Bauer D. P., Synthesis of Phenylalanines in High Enantiomeric Excess via Enzymatic Resolution. Synthesis 12: 1041-1043 (1983), (b) Hughes, A. B., Ed. Amino Acids, Peptides and Proteins in Organic Chemistry: Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis; Wiley: Weinheim, (2011).

24. Ito A., Kohno T., Hosoi I., Hirayama J., Maeda K., Method of evaluating pharmacological effects of medicine. U.S. Patent 7, 404, 945 B2 (2008).

25. Schichl D. A., Enthaler S., Holla W., Riermeier T., Kragl U., Beller M., Dynamic Kinetic Resolution of α‐Amino Acid Esters in the Presence of Aldehydes. Publication cover image. Eur. J. Org. Chem 20: 3506-3512 (2008).

26. (a) Sakai K., Hirayama N., Tamura R., Novel Optical Resolution Technologies. Series Title: Topics in Current Chemistry; Series Volume: 269; Publisher: Springer-Verlag Berlin Heidelberg; Copyright Holder, 86-100 (2007), (b) Eggeling L., Sahm H., Amino Acid Production. Reference Module in Life Sciences (2017).