Skip to main content

DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids


The synthesis of 3-acyltetramic acids by C-acylation of pyrrolidine-2,4-diones was studied by density functional theory (DFT). DFT was applied to the mycotoxin tenuazonic acid (TeA), an important representative of these bioactive natural compounds. Lewis acid mediated C-acylation in combination with previous pH-neutral domino N-acylation–Wittig cyclization can be used for the efficient preparation of 3-acyltetramic acids. Nevertheless, quite harsh conditions are still required to carry out this synthetic step, leading to unwanted isomerization of stereogenic centers in some cases. In the presented study, the reaction pathway for the C-acetylation of (5S,6S-5-s-butylpyrrolidine-2,4-dione was studied in terms of mechanism, solvent effects, and Lewis acid activation, in order to obtain an appropriate theoretical model for further investigations. Crucial steps were identified that showed rather high activation barriers and rationalized previously reported experimental discoveries. After in silico optimization, aluminum chlorides were found to be promising Lewis acids that promote the C-acylation of pyrrolidine-2,4-diones, whereas calculations performed in various organic solvents showed that the solvent had only a minor effect on the energy profiles of the considered mechanisms. This clearly indicates that further synthetic studies should focus on the Lewis-acidic mediator rather than other reaction parameters. Additionally, given the results obtained for different reaction routes, the stereochemistry of this C-acylation is discussed. It is assumed that the formation of Z-configured TeA is favored, in good agreement with our previous studies.

Lewis acid mediated synthesis of tetramic acids starting from pyrrolidine-2,4-diones (shown for tenuazonic acid).

This is a preview of subscription content, access via your institution.

Fig. 1a–b
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Scheme 6
Fig. 6
Scheme 7
Fig. 7
Scheme 8
Fig. 8


  1. Schobert R, Schlenk A (2008) Tetramic and tetronic acids: an update on new derivatives and biological aspects. Bioorg Med Chem 16:4203–4221

    Article  CAS  Google Scholar 

  2. Royles BJL (1995) Naturally occurring tetramic acids: structure, isolation, and synthesis. Chem Rev 95:1981–2001

    Article  CAS  Google Scholar 

  3. Rosett T, Sankhala RH, Stickings CE, Taylor MEU, Thomas R (1957) Studies in the biochemistry of micro-organisms—metabolites of Alternaria-tenuis auct—culture filtrate products. Biochem J 67:390–400

  4. Stickings CE (1959) Studies in the biochemistry of micro-organisms—metabolites of Alternaria tenuis auct—the structure of tenuazonic acid. Biochem J 72:332–340

  5. Meronuck RA, Steele JA, Mirocha CJ, Christensen CM (1972) Tenuazonic acid, a toxin produced by Alternaria alternata. Appl Microbiol 23:613–617

    CAS  Google Scholar 

  6. Aoki S, Higuchi K, Ye Y, Satari R, Kobayashi M (2000) Melophlins A and B, novel tetramic acids reversing the phenotype of RAS-transformed cells, from the marine sponge Melophlus sarassinorum. Tetrahedron 56:1833–1836

    Article  CAS  Google Scholar 

  7. Lin Z-J, Lu Z-Y, Zhu T-J, Fang Y-C, Gu Q-Q, Zhu W-M (2008) Penicillenols from Penicillium sp. GQ-7, an endophytic fungus associated with Aegiceras corniculatum. Chem Pharm Bull 56:217–221

    Article  CAS  Google Scholar 

  8. Höltzel A, Gänzle MG, Nicholson GJ, Hammes WP, Jung G (2000) The first low molecular weight antibiotic from lactic acid bacteria: reutericyclin, a new tetramic acid. Angew Chem Int Ed 39:2766–2768

    Article  Google Scholar 

  9. Lacey RN (1954) Derivatives of acetoacetic acid. α-Acetyltetramic acids. J Chem Soc 850–854.

  10. Kozikowski AP, Greco MN, Springer JP (1984) Total synthesis of the unique mycotoxin α-cyclopiazonic acid (αCA): an unusual dimethylzinc mediated replacement of a phenylthio substituent by a methyl group and a contrathermodynamic Raney nickel desulfurization reaction. J Am Chem Soc 106:6873–6874

    Article  CAS  Google Scholar 

  11. Harris SA, Fisher LV, Folkers K (1965) The synthesis of tenuazonic and congeneric tetramic acids. J Med Chem 8:478–482

    Article  CAS  Google Scholar 

  12. Böhme R, Jung G, Breitmaier E (2005) Synthesis of the antibiotic (R)-reutericyclin via Dieckmann condensation. Helv Chim Acta 88:2837–2841

  13. Jones RCF, Begley MJ, Peterson GE, Sumaria S (1990) Acylation of pyrrolidine-2,4-diones: a synthesis of 3-acyltetramic acids. X-ray molecular structure of 3-[1-(difluoroboryloxy)ethylidene]-5-isopropyl-1-methyl-pyrrolidine-2,4-dione. J Chem Soc Perkin Trans 1:1959–1968

  14. Schobert R, Dietrich M, Mullen G, Urbina-Gonzalez J-M (2006) Phosphorus ylide based functionalizations of tetronic and tetramic acids. Synthesis 2006:3902–3914

    Article  Google Scholar 

  15. Biersack B, Diestel R, Jagusch C, Rapp G, Sasse F, Schobert R (2008) First syntheses of melophlins P, Q, and R, and effects of melophlins on the growth of microorganisms and tumor cells. Chem Biodivers 5:2423–2430

    Article  CAS  Google Scholar 

  16. Schobert R, Jagusch C, Melanophy C, Mullen G (2004) Synthesis and reactions of polymer-bound Ph3P=C=C=O: a quick route to tenuazonic acid and other optically pure 5-substituted tetramates. Org Biomol Chem 2:3524–3529

    Article  CAS  Google Scholar 

  17. Lohrey L, Marschik S, Cramer B, Humpf H-U (2012) Large-scale synthesis of isotopically labeled 13C2-tenuazonic acid and development of a rapid HPLC-MS/MS method for the analysis of tenuazonic acid in tomato and pepper products. J Agric Food Chem 61:114–120

    Article  Google Scholar 

  18. Stewart JP (2007) Optimization of parameters for semiempirical methods. V: Modification of NDDO approximations and application to 70 elements. J Mol Model 13:1173–1213

  19. Kohn W, Sham LJ (1965) Self-consistent equations including exchange and correlation effects. Phys Rev 140:A1133–A1138

    Article  Google Scholar 

  20. Parr RG, Yang W (1989) Density functional theory of atoms and molecules. Oxford University Press, London

    Google Scholar 

  21. Krishnan R, Binkley JS, Seeger R, Pople JA (1980) Self-consistent molecular orbital methods. A basis set for correlated wave functions. J Chem Phys 72:650–654

    Article  CAS  Google Scholar 

  22. Becke AD (1993) Density-functional thermochemistry. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  23. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, revision A.1. Gaussian Inc., Wallingford

  24. Tomasi J, Mennucci B, Cammi R (2005) Quantum mechanical continuum solvation models. Chem Rev 105:2999–3094

    Article  CAS  Google Scholar 

  25. Fukui K (1981) The path of chemical reactions—the IRC approach. Acc Chem Res 14:363–368. doi:10.1021/ar00072a001

  26. Glendening ED, Badenhoop JK, Reed AE, Carpenter JE, Bohmann JA, Morales CA, Weinhold F (2001) NBO 5.0. Theoretical Chemistry Institute, University of Wisconsin, Madison

  27. Schobert R, Jagusch C (2005) An expedient synthesis of 3-acyltetramic acids of the melophlin family from α-aminoesters and immobilized Ph3PCCO. Tetrahedron 61:2301–2307

    Article  CAS  Google Scholar 

  28. Marquardt U, Schmid D, Jung G (2000) Racemic synthesis of the new antibiotic tetramic acid reutericyclin. Synlett 2000:1131–1132

    Article  Google Scholar 

  29. Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 120:215–241

    Article  CAS  Google Scholar 

  30. Zhao Y, Truhlar DG (2008) Density functionals with broad applicability in chemistry. Acc Chem Res 41:157–167

    Article  CAS  Google Scholar 

  31. Mikula H, Horkel E, Hans P, Hametner C, Fröhlich J (2013) Structure and tautomerism of tenuazonic acid—a synergetic computational and spectroscopic approach. J Hazard Mater 250–251:308–317

Download references


The Theodor Körner Fonds (Vienna, Austria) is gratefully acknowledged for financial support. We thank Philipp Hans for his support at the beginning of this study.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Hannes Mikula.

Electronic supplementary material

Below is the link to the electronic supplementary material.


Supplementary tables and figures, visualization of all optimized geometries, calculated energies for all reaction pathways considered, animations of all transition states, and Cartesian coordinates of all relevant structures. The electronic supplementary material (ESM) is available free of charge to subscribers at (PDF 1798 kb)


(ZIP 34.6 mb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mikula, H., Svatunek, D., Skrinjar, P. et al. DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids. J Mol Model 20, 2181 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Density functional theory
  • Tenuazonic acid
  • Tetramic acids
  • C-acetylation
  • Pyrrolidine-2,4-diones