Computational Investigation of A Chiral Catalyst for Asymmetric 1,3-Dipolar Cycloadditions Between Azomethine Ylide and Dipolarophile

Date

2023-8-17

Author

Ceylan, Melih Mustafa

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[3+2] cycloaddition reactions are important for the synthesis of 5-membered rings, especially heterocyclic compounds. Pyrrolidine derivatives can be obtained by reacting azomethine ylide and dipolarophile. Using a chiral ligand and a metal cation makes this reaction to work asymmetrically by forming a chiral pre-reactive complex. The aim of this study is to understand why the chiral ligand and Zn2+ lead to the reaction between azomethine ylide and dimethyl maleate undergoing an enantioselective reaction by forming a pyrrolidine derivative with high enantiomeric excess up to 90 %. After manual conformational search and QM calculations were utilized, we observed that it did not yield satisfactory results, we started to employ a protocol involving molecular dynamics (MD) for the conformational sampling for the metal complex. MD simulations were performed for pyrrolidine derivative product (neutral/deprotonated), chiral ligand (neutral/deprotonated) and transition metal complex of Zn2+ with deprotonated versions of them. Frames of the trajectories were clustered with unsupervised machine learning method, DBSCAN. A representative sample of each cluster was aimed to optimize with density functional theory, after parameters of clustering were tuned. We believe that the approach presented in this study offers a way to understand how chiral ligands influence enantioselectivity in reactions and suggests new possibilities for future research and enhancements.

Subject Keywords

asymmetic [3+2] cycloaddition, 1,3-dipolar cycloaddition, azomethine ylide, enantioselectivity, clustering, molecular simulations

URI

https://hdl.handle.net/11511/105586

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Graduate School of Natural and Applied Sciences, Thesis