title: DFT study of the Lewis acid mediated synthesis of 3-acyltetramic acids.
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.
authors.affiliation: Institute of Applied Synthetic Chemistry, Vienna University of Technology, 1060, Vienna, Austria, hannes.mikula@tuwien.ac.at.
authors.forename: Hannes
authors.initials: H
authors.lastname: Mikula
authors.forename: Dennis
authors.initials: D
authors.lastname: Svatunek
authors.forename: Philipp
authors.initials: P
authors.lastname: Skrinjar
authors.forename: Ernst
authors.initials: E
authors.lastname: Horkel
authors.forename: Christian
authors.initials: C
authors.lastname: Hametner
authors.forename: Johannes
authors.initials: J
authors.lastname: Fröhlich
mesh_terms: D000215:Acylation; D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000737:chemistry*; D002712:Chlorides / Q000737:chemistry*; D003198:Computer Simulation; D004735:Energy Transfer; D005663:Furans / Q000138:chemical synthesis*; D007536:Isomerism; D058116:Lewis Acids / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D012997:Solvents / Q000737:chemistry; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry*; D013720:Tenuazonic Acid / Q000138:chemical synthesis*
chemical_list: D017607:Aluminum Compounds; D002712:Chlorides; D005663:Furans; D058116:Lewis Acids; D012997:Solvents; D013388:Succinimides; C066006:3-acetyltetramic acid; D000077410:Aluminum Chloride; D013720:Tenuazonic Acid