The synthesis of pharmacologically important oxindoles via the asymmetric aldol reaction of isatin and the investigation of the organocatalytic activity of new alicyclic β-amino acid derivatives

Tünde Faragó; Attila M Remete; István Szatmári; Rita Ambrus; Márta Palkó

doi:10.1039/d3ra03528j

The synthesis of pharmacologically important oxindoles via the asymmetric aldol reaction of isatin and the investigation of the organocatalytic activity of new alicyclic β-amino acid derivatives

RSC Adv. 2023 Jun 26;13(28):19356-19365. doi: 10.1039/d3ra03528j. eCollection 2023 Jun 22.

Authors

Tünde Faragó¹, Attila M Remete¹, István Szatmári^{1

2}, Rita Ambrus³, Márta Palkó¹

Affiliations

¹ Institute of Pharmaceutical Chemistry, University of Szeged Eötvös utca 6 Szeged H-6720 Hungary palko.marta@szte.hu.
² Stereochemistry Research Group, Eötvös Loránd Research Network, University of Szeged Eötvös u. 6 H-6720 Szeged Hungary.
³ Institute of Pharmaceutical Technology and Regulatory Affairs Faculty of Pharmacy, University of Szeged Eötvös utca 6 Szeged H-6720 Hungary.

Abstract

This work involves the synthesis and subsequent development of a number of novel organocatalysts generated from β-amino acids bearing diendo and diexo norbornene skeletons to improve their catalytic characteristics. The aldol reaction between isatin and acetone selected as the model reaction, was used to test and study enantioselectivities. The potential impact on enantioselectivity control regarding enantiomeric excess (ee%) was probed by varying the reaction parameters, such as additive, solvent, catalyst loading, temperature and substrate range. The corresponding 3-hydroxy-3-alkyl-2-oxindole derivetives were produced by organocatalyst 7 with good enantioselectivity up to 57% ee in the presence of LiOH. Substrate screening was used to investigate a number of substituted isatins with excellent findings up to 99% ee. Another aspect of this effort involved employing high-speed ball mill apparatus to conduct a mechanochemical study to make this model reaction more environmentally benign and sustainable.