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

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Abstract

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).

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Acknowledgments

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.

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Authors and Affiliations

  1. Institute of Applied Synthetic Chemistry, Vienna University of Technology, 1060, Vienna, Austria

    Hannes Mikula, Dennis Svatunek, Philipp Skrinjar, Ernst Horkel, Christian Hametner & Johannes Fröhlich

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  1. Hannes Mikula
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  2. Dennis Svatunek
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  3. Philipp Skrinjar
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  4. Ernst Horkel
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  5. Christian Hametner
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Correspondence to Hannes Mikula.

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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 http://link.springer.de. (PDF 1798 kb)

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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). https://doi.org/10.1007/s00894-014-2181-0

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