Advertisement

Amino Acids

, Volume 50, Issue 12, pp 1759–1767 | Cite as

1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization

  • Cristiano BolchiEmail author
  • Gabriella Roda
  • Marco Pallavicini
Original Article
  • 239 Downloads

Abstract

Amino acid benzyl esters are very useful chiral synthons, whose enantiomeric purity needs to be carefully verified because of their susceptibility to easy racemization. Alternative to chiral HPLC, 1H NMR in the presence of a chiral solvating agent (CSA) can allow a more rapid and acceptably accurate determination of the enantiomeric composition, if explicit spectral non-equivalence of one or more protons of the analyte enantiomers is found. Here, we have studied the enantiodiscrimination of 13 amino acid benzyl esters by 1H NMR in the presence of (R)-Mosher acid and in different solvents proving that, for 5 of them (Ala, Pro, Glu, Met, Ser), efficient enantiodifferentiation can be achieved and ≤ 98% enatiomeric excesses accurately determined. Generally, as expectable, the best enantiodifferentiated proton was that on the amino acid stereogenic α-carbon, but also the spectral non-equivalence of methyl protons and of protons on the β-carbon and on the benzylic carbon could be exploited to distinguish the two enantiomers and to quantify the minor one. Structural feature favoring the amino acid ester enantiodiscrimination by the CSA seems to be low sterical hindrance at the amino acid β-carbon.

Keywords

Amino acid benzyl ester 1H NMR spectroscopy Mosher’s acid Chiral solvating agent (CSA) Enantiodiscrimination 

Notes

Acknowledgements

The authors thank Mrs Donatella Nava for her excellent technical assistance in measuring NMR spectra on a Bruker Avance spectrometer at 600 MHz.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

726_2018_2653_MOESM1_ESM.docx (741 kb)
Supplementary material 1 (DOCX 740 kb)

References

  1. Bada JL (1972) Kinetics of racemization of amino acids as a function of pH. J Am Chem Soc 94:1371–1373CrossRefGoogle Scholar
  2. Bergmeier SC, Cobas AA, Rapoport H (1993) Chirospecific synthesis of (1S,3R9-1-amino-3-(hydroxymethyl)cyclopentane, precursor of carbocyclic nucleoside synthesis. Dieckmann cyclization with an alpha-amino acid. J Org Chem 58:2369–2376CrossRefGoogle Scholar
  3. Bolchi C, Valoti E, Gotti C, Fasoli F, Ruggeri P, Fumagalli L, Binda M, Mucchietto V, Sciaccaluga M, Budriesi R, Fucile S, Pallavicini M (2015) Chemistry and pharmacology of a series of unichiral analogues of 2-(2-pyrrolidinyl)-1,4-benzodioxane, prolinol phenyl ether, and prolinol 3-pyridyl ether designed as alpha4beta2-nNicotinic acetylcholine receptor agonists. J Med Chem 58:6665–6677CrossRefGoogle Scholar
  4. Bolchi C, Bavo F, Pallavicini M (2017a) One-step preparation of enantiopure l- or d-amino acid benzyl esters avoiding the use of banned solvents. Amino Acids 49:965–974CrossRefGoogle Scholar
  5. Bolchi C, Bavo F, Pallavicini M (2017b) Phase diagrams to evaluate the opportunity for enantiomeric enrichment of some nonracemic mixtures of amino acid benzyl esters by crystallization as p-toluenesulfonate salts. Org Process Res Dev 21:1752–1757CrossRefGoogle Scholar
  6. Bolchi C, Bavo F, Regazzoni L, Pallavicini M (2018) Preparation of enantiopure methionine, arginine, tryptophan, and proline benzyl esters in gree ethers by Fischer-Speier reaction. Amino Acids.  https://doi.org/10.1007/s00726-018-2599-2 CrossRefPubMedGoogle Scholar
  7. Dale JA, Dull DL, Mosher HS (1969) alpha-Methoxy-alpha-trifluorophenylacetic acid, a versatile reagent for the determination of enantiomeric composition of alcohols and amines. J Org Chem 34:2543–2549CrossRefGoogle Scholar
  8. Dhaon MK, Olsen RK, Ramasamy K (1982) Esaterification of N-protected alpha-amino acids with alcohol/carbodiimide/4-(dimethylamino)pyridine. racemization of aspartic and glutamic acid derivatives. J Org Chem 47:1962–1965CrossRefGoogle Scholar
  9. Izumiya N, Makisumi S (1957) Synthesis of aminoacid benzyl ester p-toluenesulfonates. Nippon Kagaku Zasshi 78:662–664CrossRefGoogle Scholar
  10. Jobbins MO, Miller MJ (2014) Syntheses of hydroxamic acid-containing bicyclic beta-lactams via palladium-catalyzed oxidative amidation of alkenes. J Org Chem 79:1620–1625CrossRefGoogle Scholar
  11. Kozikowski AP, Liao Y, Tückmantel W, Wang S, Pshenichkin S, Surin A, Thomsen C, Wroblewski JT (1996) Synthesis and biology of the rigidified glutamate analogue, trans-2-carboxyazetidine-3-acetic (t-CAA). Bioorg Med Chem Lett 6:2559–2564CrossRefGoogle Scholar
  12. Lynch JK, Holladay MW, Ryther KB, Bai H, Hsiao C, Morton HE, Dickman DA, Arnold W, King SA (1998) Efficient asymmetric synthesis of ABT-594; a potent, orally effective analgesic. Tetrahedron Asymmetry 9:2791–2794CrossRefGoogle Scholar
  13. Manning JM (1970) Determination of d- and l-amino acid residues in peptides. Use of tritiated hydrochloric acid to correct for racemization during acid hydrolysis. J Am Chem Soc 92:7449–7454CrossRefGoogle Scholar
  14. Matsuo H, Kawazoe Y, Sato M, Ohnishi M, Tatsuno T (1967) Studies on the racemization of amino acids and their derivatives I. Chem Pharm Bull 15:391–398CrossRefGoogle Scholar
  15. Meiresonne T, Mangelinckx S, De Kimpe N (2012) Stereoselective synthesis of both enantiomers of trans-2-(diphenylmethylideneamino)cyclopropanecarboxylic acid using a chiral pool approach and their incorporation in dipeptides. Tetrahedron 68:9566–9571CrossRefGoogle Scholar
  16. Nemes A, Csóka T, Béni S, Farkas V, Rábai J, Szabó D (2015) Chiral recognition studies of α-(nonafluoro-tert-butoxy)carboxylic acids by NMR spectroscopy. J Org Chem 80:6267–6274CrossRefGoogle Scholar
  17. Parker D (1991) NMR determination of enantiomeric purity. Chem Rew 91:1441–1457CrossRefGoogle Scholar
  18. Pérez-Trujillo M, Monteagudo E, Parella T (2013) 13C NMR Spectroscopy for the differentiation of enantiomers using chiral solvating agents. Anal Chem 85:10887–10894CrossRefGoogle Scholar
  19. Rudolph J, Hannig F, Theis H, Wischnat R (2001) Highly efficient chiral-pool synthesis of (2S,4R9-4-hydroxyornithine. Org Lett 3:3153–3155CrossRefGoogle Scholar
  20. Sato M, Tatsuno T, Matsuo H (1970) Studies on the racemization of amino acids and their derivatives III. Chem Pharm Bull 18:1794–1798CrossRefGoogle Scholar
  21. Seco JM, Quiñoá E, Riguera R (2004) The assignment of absolute configuration by NMR. Chem Rev 104:17–118CrossRefGoogle Scholar
  22. Seco JM, Quiñoá E, Riguera R (2012) Assignment of the absolute configuration of polyfunctional compounds by NMR using chiral derivatizing agents. Chem Rev 112:4603–4641CrossRefGoogle Scholar
  23. Smith GG, Evans RC (1980) The effect of structure and conditions on the rate of racemization of free and bound amino acids. In: Hare PE, Hoering TC, King K Jr (eds) Biogeochemistry of amino acids. Wiley, New York, pp 257–282Google Scholar
  24. Smith GG, Sivakua T (1983) Mechanism of the racemization of amino acids. Kinetics of racemization of arylglycines. J Org Chem 48:627–634CrossRefGoogle Scholar
  25. Soicke A, Reuter C, Winter M, Neudörfl J, Schlörer N, Kühne R, Schmalz H (2014) Stereoselective synthesis of tricyclic diproline analogues that mimic a PPII helix: structural consequences of ring-size variation. Eur J Org Chem 2014:6467–6480CrossRefGoogle Scholar
  26. Wenzel TJ, Chisholm CD (2011) Assignment of absolute configuration using chiral reagents and NMR spectroscopy. Chirality 23:190–214CrossRefGoogle Scholar
  27. Zervas L, Winitz M, Greenstein JP (1957) Arginine peptides. I. Intermediates in the synthesis of N-terminal and C-terminal arginine peptides. J Org Chem 22:1515–1521CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Cristiano Bolchi
    • 1
    Email author
  • Gabriella Roda
    • 1
  • Marco Pallavicini
    • 1
  1. 1.Dipartimento di Scienze Farmaceutiche, Sezione “Pietro Pratesi”Università degli Studi di MilanoMilanItaly

Personalised recommendations