Skip to main content
SpringerLink
Log in

Direct high-performance liquid chromatographic enantioseparation of free α-, β- and γ-aminophosphonic acids employing cinchona-based chiral zwitterionic ion exchangers

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

We report a chiral high-performance liquid chromatographic enantioseparation method for free α-aminophosphonic, β-aminophosphonic, and γ-aminophosphonic acids, aminohydroxyphosphonic acids, and aromatic aminophosphinic acids with different substitution patterns. Enantioseparation of these synthons was achieved by means of high-performance liquid chromatography on CHIRALPAK ZWIX(+) and ZWIX(-) (cinchona-based chiral zwitterionic ion exchangers) under polar organic chromatographic elution conditions. Mobile phase characteristics such as acid-to-base ratio, type of counterion, and solvent composition were systematically varied in order to investigate their effect on the separation performance and to achieve optimal separation conditions for the set of analytes. Under the optimized conditions, 32 of 37 racemic aminophosphonic acids studied reached baseline separation when we employed a single generic mass-spectrometry-compatible mobile phase, with reversal of the elution order when we used (+) and (-) versions of the chiral stationary phase.

New zwitterionic ion-exchangers can separate free amino phosphonic acids and a change from Chiralpak ZWIX(+) to ZWIX(-) allows reversal of enantiomer elution order

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Hudson HR, Kukhar VP (2000) Aminophosphonic and aminophosphinic acids: chemistry and biological activity. Wiley, New York

    Google Scholar 

  2. Mucha A, Kafarski P, Berlicki L (2011) Remarkable potential of the alpha-aminophosphonate/phosphinate structural motif in medicinal chemistry. J Med Chem 54(17):5955–5980. doi:10.1021/jm200587f

    Article  CAS  Google Scholar 

  3. Morphy JR, Beeley NRA, Boyce BA, Leonard J, Mason B, Millican A, Millar K, Oconnell JP, Porter J (1994) Potent and selective inhibitors of gelatinase-A. 2. Carboxylic and phosphonic acid-derivatives. Bioorg Med Chem Lett 4(23):2747–2752. doi:10.1016/S0960-894x(01)80588-6

    Article  CAS  Google Scholar 

  4. Kraicheva I, Bogomilova A, Tsacheva I, Momekov G, Troev K (2009) Synthesis, NMR characterization and in vitro antitumor evaluation of new aminophosphonic acid diesters. Eur J Med Chem 44(8):3363–3367. doi:10.1016/j.ejmech.2009.03.017

    Article  CAS  Google Scholar 

  5. Kafarski P, Lejczak B (1991) Biological activity of aminophosphonic acids. Phosphorus Sulfur 63(1–2):193–215. doi:10.1080/10426509108029443

    Article  CAS  Google Scholar 

  6. Grzywa R, Oleksyszyn J, Salvesen GS, Drag M (2010) Identification of very potent inhibitor of human aminopeptidase N (CD13). Bioorg Med Chem Lett 20(8):2497–2499. doi:10.1016/j.bmcl.2010.02.111

    Article  CAS  Google Scholar 

  7. Selvam C, Goudet C, Oueslati N, Pin JP, Acher FC (2007) L-(+)-2-Amino-4-thiophosphonobutyric acid (L-thioAP4), a new potent agonist of group III metabotropic glutamate receptors: increased distal acidity affords enhanced potency. J Med Chem 50(19):4656–4664. doi:10.1021/jm070400y

    Article  CAS  Google Scholar 

  8. Wallace EM, Moliterni JA, Moskal MA, Neubert AD, Marcopulos N, Stamford LB, Trapani AJ, Savage P, Chou M, Jeng AY (1998) Design and synthesis of potent, selective inhibitors of endothelin-converting enzyme. J Med Chem 41(9):1513–1523. doi:10.1021/jm970787c

    Article  CAS  Google Scholar 

  9. Beck J, Gharbi S, Herteg-Fernea A, Vercheval L, Bebrone C, Lassaux P, Zervosen A, Marchand-Brynaert J (2009) Aminophosphonic acids and aminobis(phosphonic acids) as potential inhibitors of penicillin-binding proteins. Eur J Org Chem 2009(1):85–97. doi:10.1002/ejoc.200800812

    Article  Google Scholar 

  10. Yang S, Gao X-W, Diao C-L, Song B-A, Jin L-H, Xu G-F, Zhang G-P, Wang W, Hu D-Y, Xue W, Zhou X, Lu P (2006) Synthesis and antifungal activity of novel chiral α-aminophosphonates containing fluorine moiety. Chin J Chem 24(11):1581–1588. doi:10.1002/cjoc.200690296

    Article  CAS  Google Scholar 

  11. Manning HC, Goebel T, Marx JN, Bornhop DJ (2002) Facile, efficient conjugation of a trifunctional lanthanide chelate to a peripheral benzodiazepine receptor ligand. Org Lett 4(7):1075–1078. doi:10.1021/ol017155b

    Article  CAS  Google Scholar 

  12. Hammerschmidt F, Hanbauer M (2000) Transformation of arylmethylamines into alpha-aminophosphonic acids via metalated phosphoramidates: rearrangement of partly configurationally stable N-phosphorylated alpha-aminocarbanions. J Org Chem 65(19):6121–6131. doi:10.1021/jo000585f

    Article  CAS  Google Scholar 

  13. Hammerschmidt F, Li Y-F (1994) Determination of absolute configuration of α-hydroxyphosphonates by 31P NMR spectroscopy of corresponding Mosher esters. Tetrahedron 50:10253–10264. doi:10.1016/s0040-4020(01)81758-0

    Article  CAS  Google Scholar 

  14. Hammerschmidt F, Wuggenig F (1999) Enzymes in organic chemistry. Part 9: chemo-enzymatic synthesis of phosphonic acid analogues of L-valine, L-leucine, L-isoleucine, L-methionine and L-α-aminobutyric acid of high enantiomeric excess. Tetrahedron-Asymmetry 10:1709–1721. doi:10.1016/s0957-4166(99)00152-4

    Article  CAS  Google Scholar 

  15. Schmidt U, Krause HW, Oehme G, Michalik M, Fischer C (1998) Enantioselective synthesis of α-aminophosphonic acid derivatives by hydrogenation. Chirality 10:564–572. doi:10.1002/(sici)1520-636x(1998)10:7<564::aid-chir3>3.0.co;2-2

    Article  CAS  Google Scholar 

  16. Woschek A, Lindner W, Hammerschmidt F (2003) Enzymes in organic chemistry, 11:[1] hydrolase-catalyzed resolution of α- and β-hydroxyphosphonates and synthesis of chiral, non-racemic β-aminophosphonic acids. Adv Synth Catal 345(12):1287–1298. doi:10.1002/adsc.200303135

    Article  CAS  Google Scholar 

  17. Wuggenig F, Schweifer A, Mereiter K, Hammerschmidt F (2011) Chemoenzymatic synthesis of phosphonic acid analogues of L-lysine, L-proline, L-ornithine, and L-pipecolic acid of 99 % ee – assignment of absolute configuration to (–)-proline. Eur J Org Chem 2011(10):1870–1879. doi:10.1002/ejoc.201001501

    Article  Google Scholar 

  18. Hammerschmidt F, Voellenkle H (1989) Absolute configuration of (2-amino-1-hydroxyethyl) phosphonic acid from Acanthamoeba castellanii (Neff). Preparation of phosphonic acid analogs of (+)- and (-)-serine. Liebigs Ann Chem 1989(6):577–583. doi:10.1002/jlac.1989198901101

  19. Fischer C, Schmidt U, Dwars T, Oehme G (1999) Enantiomeric resolution of derivatives of α-aminophosphonic and α-aminophosphinic acids by high-performance liquid chromatography and capillary electrophoresis. J Chromatogr A 845(1–2):273–283. doi:10.1016/s0021-9673(99)00487-2

    CAS  Google Scholar 

  20. Pirkle WH, Burke JA (1992) Separation of the enantiomers of the 3,5-dinitrobenzamide derivatives of α-amino phosphonates on four chiral stationary phases. J Chromatogr A 598(2):159–167. doi:10.1016/0021-9673(92)85044-T

    Article  CAS  Google Scholar 

  21. Pirkle WH, Jonathan Brice L, Caccamese S, Principato G, Failla S (1996) Facile separation of the enantiomers of diethyl N-(aryl)-1-amino-1-arylmethanephosphonates on a rationally designed chiral stationary phase. J Chromatogr A 721(2):241–246. doi:10.1016/0021-9673(95)00844-6

    Article  CAS  Google Scholar 

  22. Pirkle WH, Jonathan Brice L, Widlanski TS, Roestamadji J (1996) Resolution and determination of the enantiomeric purity and absolute configurations of α-aryl-α-hydroxymethanephosphonates. Tetrahedron-Asymmetry 7(8):2173–2176. doi:10.1016/0957-4166(96)00263-7

    Article  CAS  Google Scholar 

  23. Zarbl E, Lammerhofer M, Hammerschmidt F, Wuggenig F, Hanbauer M, Maier NM, Sajovic L, Lindner W (2000) Direct liquid chromatographic enantioseparation of chiral alpha- and beta-aminophosphonic acids employing quinine-derived chiral anion exchangers: determination of enantiomeric excess and verification of absolute configuration. Anal Chim Acta 404(2):169–177. doi:10.1016/s0003-2670(99)00700-x

    Article  CAS  Google Scholar 

  24. Lämmerhofer M, Hebenstreit D, Gavioli E, Lindner W, Mucha A, Kafarski P, Wieczorek P (2003) High-performance liquid chromatographic enantiomer separation and determination of absolute configurations of phosphinic acid analogues of dipeptides and their α-aminophosphinic acid precursors. Tetrahedron-Asymmetry 14(17):2557–2565. doi:10.1016/s0957-4166(03)00537-8

    Article  Google Scholar 

  25. Hoffmann CV, Reischl R, Maier NM, Lämmerhofer M, Lindner W (2009) Stationary phase-related investigations of quinine-based zwitterionic chiral stationary phases operated in anion-, cation-, and zwitterion-exchange modes. J Chromatogr A 1216(7):1147–1156. doi:10.1016/j.chroma.2008.12.045

    Article  CAS  Google Scholar 

  26. Hoffmann CV, Pell R, Lämmerhofer M, Lindner W (2008) Synergistic effects on enantioselectivity of zwitterionic chiral stationary phases for separations of chiral acids, bases, and amino acids by HPLC. Anal Chem 80(22):8780–8789. doi:10.1021/ac801384f

    Article  CAS  Google Scholar 

  27. Hoffmann CV, Reischl R, Maier NM, Lämmerhofer M, Lindner W (2009) Investigations of mobile phase contributions to enantioselective anion- and zwitterion-exchange modes on quinine-based zwitterionic chiral stationary phases. J Chromatogr A 1216(7):1157–1166. doi:10.1016/j.chroma.2008.12.044

    Article  CAS  Google Scholar 

  28. Pell R, Sić S, Lindner W (2012) Mechanistic investigations of cinchona alkaloid-based zwitterionic chiral stationary phases. J Chromatogr A. doi:10.1016/j.chroma.2012.08.006

    Google Scholar 

  29. Wernisch S, Lindner W (2012) Versatility of cinchona-based zwitterionic chiral stationary phases: enantiomer and diastereomer separations of non-protected oligopeptides utilizing a multi-modal chiral recognition mechanism. J Chromatogr A 1269:297–307. doi:10.1016/j.chroma.2012.06.094

    Article  CAS  Google Scholar 

  30. Hoffmann CV, Reischl R, Maier NM, Lammerhofer M, Lindner W (2009) Investigations of mobile phase contributions to enantioselective anion- and zwitterion-exchange modes on quinine-based zwitterionic chiral stationary phases. J Chromatogr A 1216(7):1157–1166. doi:10.1016/j.chroma.2008.12.044

    Article  CAS  Google Scholar 

  31. Hoffmann CV, Reischl R, Maier NM, Lammerhofer M, Lindner W (2009) Stationary phase-related investigations of quinine-based zwitterionic chiral stationary phases operated in anion-, cation-, and zwitterion-exchange modes. J Chromatogr A 1216(7):1147–1156. doi:10.1016/j.chroma.2008.12.045

    Article  CAS  Google Scholar 

  32. Pell R, Sic S, Lindner W (2012) Mechanistic investigations of cinchona alkaloid-based zwitterionic chiral stationary phases. J Chromatogr A 1269:287–296. doi:10.1016/j.chroma.2012.08.006

    Article  CAS  Google Scholar 

  33. Pell R, Sić S, Lindner W (2012) Mechanistic investigations of cinchona alkaloid-based zwitterionic chiral stationary phases. J Chromatogr A 1269:287–296. doi:10.1016/j.chroma.2012.08.006

    Article  CAS  Google Scholar 

  34. Wernisch S, Pell R, Lindner W (2012) Increments to chiral recognition facilitating enantiomer separations of chiral acids, bases, and ampholytes using Cinchona-based zwitterion exchanger chiral stationary phases. J Sep Sci 35(13):1560–1572. doi:10.1002/jssc.201200103

    Article  CAS  Google Scholar 

  35. Lämmerhofer M, Lindner W (1996) Quinine and quinidine derivatives as chiral selectors I. Brush type chiral stationary phases for high-performance liquid chromatography based on cinchonan carbamates and their application as chiral anion exchangers. J Chromatogr A 741(1):33–48. doi:10.1016/0021-9673(96)00137-9

    Article  Google Scholar 

  36. Maier NM, Schefzick S, Lombardo GM, Feliz M, Rissanen K, Lindner W, Lipkowitz KB (2002) Elucidation of the chiral recognition mechanism of cinchona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino Acids. J Am Chem Soc 124(29):8611–8629. doi:10.1021/ja020203i

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was financially supported by the University of Vienna through the interdisciplinary doctoral program Initiativkolleg Functional Molecules (IK I041−N). We thank Jan Pícha (Institute of Organic Chemistry and Biochemistry, AS CR) and Friedrich Hammerschmidt (Institute of Organic Chemistry, University of Vienna) for providing several samples of APAs. We are further grateful to the Operational Program Research and Development for Innovations - European Regional Development Fund (project CZ.1.05/2.1.00/03.0058) and the project of Palacký University in Olomouc PRF_2012_020 for financial support.

Author information

Author notes

  1. Michal Kohout

    Present address: Department of Organic Chemistry, Institute of Chemical Technology, Technická 5, 16628, Prague, Czech Republic

  2. Pavla Macíková

    Present address: Regional Centre of Advanced Technologies and Materials, Department of Analytical Chemistry, Faculty of Science, Palacky University, 17. listopadu 1192/12, 77146, Olomouc, Czech Republic

Authors and Affiliations

  1. Department of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090, Vienna, Austria

    Andrea F. G. Gargano, Michal Kohout, Pavla Macíková & Wolfgang Lindner

  2. Institute of Pharmaceutical Sciences, University of Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    Michael Lämmerhofer

Authors
  1. Andrea F. G. Gargano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michal Kohout
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pavla Macíková
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Lämmerhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wolfgang Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michael Lämmerhofer or Wolfgang Lindner.

Additional information

Published in the topical collection Amino Acid Analysis with guest editor Toshimasa Toyo'oka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gargano, A.F.G., Kohout, M., Macíková, P. et al. Direct high-performance liquid chromatographic enantioseparation of free α-, β- and γ-aminophosphonic acids employing cinchona-based chiral zwitterionic ion exchangers. Anal Bioanal Chem 405, 8027–8038 (2013). https://doi.org/10.1007/s00216-013-6938-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-013-6938-6

Keywords

Search

Navigation