Journal of Chemical Crystallography

, Volume 40, Issue 7, pp 608–615 | Cite as

Refined Crystal Structure and Absolute Configuration of the Di-amino Acid Peptide Cyclo(l-Aspartyl-l-Aspartyl): Comparison with the DFT Calculated Structure

  • Rex A. Palmer
  • Brian S. Potter
  • Andrew P. Mendham
  • Trevor J. Dines
  • Babur Z. Chowdhry
Original Paper


The X-ray crystal structure of the di-amino acid peptide cyclo(l-Asp-l-Asp), C6H10N2O4, has been re-determined at 20 °C using CuKα radiation, λ = 1.54180 Å. The crystals are triclinic P1 with unit cell dimensions a = 5.0829(3), b = 5.0285(4), c = 18.8765(10) Å, α = 88.95(2)°, β = 83.72(2)°, γ = 74.79(2)°, unit cell volume 462.75(5) Å3, and Z = 2 independent molecules A and B per asymmetric unit. Final R indices [I > 2sigma(I)] are R1 = 0.0492, wR2 = 0.1039 for 2,540 independent reflections; R1 = 0.0686 and wR2 = 0.1112 for all 3,193 data; Goodness of Fit, S = 0.979, and the Flack x parameter = 0.1(3). In both molecules the overall shape of the diketopiperazine (DKP) ring displays an almost identical slightly distorted boat conformation with pseudo symmetry C2v (mm2). The two side chains of the cyclic peptide on opposite sides of both molecules differ in their conformations, one side being extended and the other coiled. The coiled chains are located away from the DKP ring plane while the extended chains lie approximately parallel to it. The crystal packing employs two strong hydrogen bonds, which traverse the entire crystal via translational repeats. The geometry of cyclo(l-Asp-l-Asp) derived from Ab initio calculations is compared with those of molecules A and B derived from the X-ray structure reported here. In this calculated model the DKP ring is in a pseudo twist boat conformation; both side chains are extended and lie approximately parallel to the DKP ring face as opposed to molecules A and B in the X-ray structure in each of which one side chain is approximately parallel and the other is folded away from the DKP ring face.

Graphical Abstract

Cyclic di-amino acid peptides are amongst the “simplest” peptide derivatives commonly found in nature and continue to be of long-standing interdisciplinary scientific interest with respect to potential pharmaceutical applications. Cyclo(l-Asp-l-Asp) is an example of a cyclic di-amino acid peptide, which has a six membered ring, and the amide linkage adopts a cis conformation. In contrast linear (l-Asp-l-Asp) is zwitterionic and has a single amide function which adopts the trans conformation. The synthesis and an X-ray structure of cyclo(l-Asp-l-Asp) have previously been reported, the latter being assigned the wrong absolute configuration. For the purposes of the present study, requiring precise molecular geometry, it was decided to carry out a re-determination of the crystal structure using a more complete measured set of independent intensities (94% against 36%) and correspondingly improved data/parameter ratio (3193/326 against 1215/369).


Cyclic dipeptide Crystal structure Absolute configuration Ring geometry 


  1. 1.
    Prasad C (1995) Peptides 16:151CrossRefGoogle Scholar
  2. 2.
    Yang SW, Chan TM, Terracciano J, Loebenberg D, Chen DGD, Patel M, Gullo V, Pramanik B, Chu M (2004) J Antibiot 57:345Google Scholar
  3. 3.
    Szardenings AK, Burkoth TS, Lu HH, Tien DW, Campbell DA (1997) Tetrahedron 53:6573CrossRefGoogle Scholar
  4. 4.
    Szardenings AK, Harris D, Lam S, Shi LH, Tien DW, Yang YW, Patel DV, Navre M, Campbell DA (1998) J Med Chem 41:2194CrossRefGoogle Scholar
  5. 5.
    Hilton CW, Prasad C, Vo P, Mouton C (1992) J Clin Endocrin Met 75:375CrossRefGoogle Scholar
  6. 6.
    Gautschi M, Schmid JP, Peppard TL, Ryan TP, Tuorto RM, Yang XG (1997) J Agric Food Chem 45:3183CrossRefGoogle Scholar
  7. 7.
    Ginz M, Engelhardt UH (2000) J. Agric. Food Chem 48:3528CrossRefGoogle Scholar
  8. 8.
    Imamura M, Prasad C (2003) Peptides 24:445CrossRefGoogle Scholar
  9. 9.
    Campo VL, Martins MB, da Silva Carlos,CHTP, Carvalho I (2009) Tetrahedron 65:5343CrossRefGoogle Scholar
  10. 10.
    O’Reilly E, Lestini E, Balducci D, Paradisi F (2009) Tetrahedron Lett 50:1748CrossRefGoogle Scholar
  11. 11.
    Fischer PM (2003) J Pept Sci 9:9CrossRefGoogle Scholar
  12. 12.
    Schöllkopf U et al (1981) Angew Chem Int Ed Engl 20:798CrossRefGoogle Scholar
  13. 13.
    Strecker A (1854) Ann Chem Pharm 91:349CrossRefGoogle Scholar
  14. 14.
    Joshi KB, Verma S (2008) Tetrahedron Lett 49(27):4231CrossRefGoogle Scholar
  15. 15.
    Ruckle T, de Lavallaz P, Keller M, Dumy P, Mutter M (1999) Tetrahedron Lett 55:11281Google Scholar
  16. 16.
    Degeilh R, Marsh RE (1959) Acta Cryst 12:1007CrossRefGoogle Scholar
  17. 17.
    Fava GG, Belicchi M (1981) Acta Cryst B37:625Google Scholar
  18. 18.
    Mendham AP, Palmer R, Potter B, Dines TJ. Mithchell JC, Withnall R, Chowdhry BZ (2009) J Raman Spectrosc (In press: JRS-09-0183)Google Scholar
  19. 19.
    Davies DB, Khalad Md A (1975) J. Chem Soc Perkins Trans 2:187Google Scholar
  20. 20.
    Kopple KD, Narutis V (1981) Int J Pept Prot Res 18:33CrossRefGoogle Scholar
  21. 21.
    Bowman RL, Kellerman M, WCJr Johnson (1983) Biopolymers 22:1045CrossRefGoogle Scholar
  22. 22.
    Bettens FL, Bettens RPA, Brown RD, Godfrey PD (2000) J Am Chem Soc 122:5856CrossRefGoogle Scholar
  23. 23.
    Zhu Y, Tang M, Shi X, Zhao Y (2007) Int J. Quantum Chem 107:745CrossRefGoogle Scholar
  24. 24.
    Hirst JD, Persson BJ (1998) J Phys Chem A 102:7519CrossRefGoogle Scholar
  25. 25.
    Schapp J, Haas K, Sunkel K, Beck W (2003) Eur J Inorg Chem 20:3745CrossRefGoogle Scholar
  26. 26.
    Bergeron RJ, Phanstiel O, Yao GW, Weimar WR (1995) J Am Chem Soc 116:8479CrossRefGoogle Scholar
  27. 27.
    Tayhas G, Palmore R, McBride MT (1998) Chem Commun 145Google Scholar
  28. 28.
    Tayhas G, Palmore R, Luo TM, McBride MT, Picciotto EA, Reynoso-Paz M (1999) Chem. Materials 11:3315Google Scholar
  29. 29.
    Mendham AP, Dines TJ, Withnall R, Mitchell JC, Chowdhry BZ (2009) J Raman Spectrosc 40:1498CrossRefGoogle Scholar
  30. 30.
    Frisch MJ et al (1998) Gaussian 98, revision A.6. Gaussian, Inc., Pittsburgh PAGoogle Scholar
  31. 31.
    Becke AD AD (1993) J Chem Phys 98:5648CrossRefGoogle Scholar
  32. 32.
    Lee C, Yang W, Parr RG (1998) Phys Rev B 37:785CrossRefGoogle Scholar
  33. 33.
    Dunning TH Jr (1989) J Chem Phys 90:1007CrossRefGoogle Scholar
  34. 34.
    Enraf-Nonius CAD-4 Express ‘88 Software 1988. Enraf-Nonius, Delft HollandGoogle Scholar
  35. 35.
    North ACT, Philips DC, Mathews FS (1968) Acta Cryst A24:351Google Scholar
  36. 36.
    Sheldrick GM (1996) SHELXS-96 program for crystal structure determination. University of Göttingen, GermanyGoogle Scholar
  37. 37.
    Sheldrick GM (2008) Acta Cryst A64:112Google Scholar
  38. 38.
    Sheldrick GM (1997) SHELXL-97 program for crystal structure refinement. University of Göttingen, GermanyGoogle Scholar
  39. 39.
    Farrugia LJ (1998) WinGX: A Windows Program for Crystal Structure Analysis J Appl Cryst 32:837Google Scholar
  40. 40.
    Spek AL (1990) Acta Cryst A46:C34Google Scholar
  41. 41.
    Bruno IJ, Cole JC, Edgington PR, Kessler MK, Macrae CF, McCabe P, Pearson J, Taylor R (2002) Acta Cryst B58:389Google Scholar
  42. 42.
    Barnes CL (1997) J Appl Cryst 30:568 [Based on ORTEP-III (v 1.0.3) by Johnson CK, Burnett MN]Google Scholar
  43. 43.
    Merrit EA, Bacon DJ (1997) Meth Enzymol 277: 505. [Implemented in WinGX (qv) and generated by Ortep-3 for Windows]Google Scholar
  44. 44.
    Sayle R (1994) RASMOL, a molecular visualisation program. Glaxo Research and Development, UKGoogle Scholar
  45. 45.
    Flack HD (1983) Acta Cryst A39:876–881Google Scholar
  46. 46.
    Ladd MFC, Palmer RA (2003) Structure determination by X-ray crystallograph, 4th edn. NY, Klewer-Plenum, p 499Google Scholar
  47. 47.
    Ladd MFC and Palmer RA (2003) Structure Determination by X-ray Crystallography, 4th Edn. Klewer-Plenum, NY (Tables 7.24 and 7.25.)Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.School of Crystallography, Birkbeck CollegeUniversity of LondonLondonUK
  2. 2.Division of Electronic Engineering & PhysicsUniversity of DundeeDundeeUK
  3. 3.School of ScienceUniversity of Greenwich at MedwayKentUK

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