Stereoselective construction of 2-oxindole fused spirocycle precursors /

Karahan, Seda
Recent literature on the bioactivity of isatin (indoline-2,3-dione) derivatives triggered organic chemists to make use of the unique potential of isatin in asymmetric organocatalytic synthesis. Due to extensive presence of 2-oxindole skeleton, especially spiro-fused cycles, in many natural products, they drew the special interest in the disciplines of medicinal chemistry and agrochemistry. Due to highly reactive prochiral carbonyl group, isatins are potent precursors for the synthesis of 3,3-disubstituted spirooxindoles. Direct nucleophilic addition to isatin-derived ketimines is one of the straightforward approaches leading to α-chiral amines which are frequent subunits of pharmaceuticals and agrochemicals besides being heterocycle precursors. In this respect, asymmetric organocatalytic synthesis offers facile and environmentally benign reaction process and selectivity as well. Remarkable advantages of cooperative activation of substrates via bifunctional organocatalysts bearing H-bond donor components such as urea, thiourea and squaramide are indispensable. Modulation of sterically encumbered units such as 1-adamantyl, 2-adamantyl and t-butyl in the structure of organocatalyst reveals distinct changes in stereoselectivity of the synthetic transformations. In this thesis study, we aimed to utilize new quinine-based squaramides in the asymmetric aza-Friedel-Crafts and Mannich reactions of isatin ketimines to obtain corresponding chiral 2-oxindoles with 1,3-aminonaphthol and 2-azidoethanamine functionalities, respectively. A new quinine-derived squaramide organocatalyst revealed excellent stereoselectivity up to >99% ee in aza-Friedel-Crafts reaction also up to 96% ee and 24:1 diastereomeric ratio in Mannich reaction of N-carbamate protected isatin ketimines. Additionally, representative examples of 1,4-naphthoxazepines, 1,2,3-triazoles and cyclic ureas were synthesized to demonstrate the synthetic potential of these novel chiral 3,3-disubstituted 2-oxindoles as being heterocycle precursors. Reaction scope, limitations and activation modes of organocatalysts were discussed in detail.


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Citation Formats
S. Karahan, “Stereoselective construction of 2-oxindole fused spirocycle precursors /,” Ph.D. - Doctoral Program, Middle East Technical University, 2019.