Date

2022-12-14

Author

Karaçal, Duygu

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Indoline-2,3-dione, commonly known as isatin, is a well-known natural product and has excellent potential to be used as an electrophile and nucleophile, making them valuable building blocks in organic synthesis. They are recognized as core structures in various bioactive molecules and pharmaceutical compounds, and the highly reactive C-3 carbonyl group of isatins makes them more applicable in organic synthesis. The reactions of the C-3 carbonyl group of isatins are mostly by nucleophilic additions and spiroannulation, resulting in the formation of C-3 substituted oxindoles. Specifically, 3-aminooxindole and heterocyclic spiro oxindole moiety have been encountered as the core structure of many architecturally complex natural products due to their highly pronounced pharmaceutical activities. In literature, several methods exist for the enantioselective formation of an amine at the C-3 position of oxindoles. Moreover, there are a few reports for the enantioselective spiro oxindole formation. In this thesis study, in the first part, we aimed to synthesize C-3 substituted aminooxindoles by Mannich reaction of N-alkoxy carbonyl ketimines and acetylacetone in the presence of chiral quinine-based bifunctional organocatalysts developed in our research group with high enantioselectivity. 2-Adamantyl substituted squaramide bifunctional organocatalyst revealed excellent enantioselectivity and yielded up to 99% and 98%, respectively. From this methodology, in the second part of this thesis, we aimed to construct a stereoselective spirocyclic oxindole moiety at the C-3 position by Knoevenagel condensation and then Michael addition/cyclization reaction of isatins with ethyl cyanoacetate and 1,3-dicarbonyl compounds in the presence of chiral bifunctional organocatalysts. As in the Mannich reaction, 2-adamantyl squaramide-based bifunctional organocatalyst revealed the highest selectivity and yield as 99% ee and 98% yield, respectively. Optimization studies, reaction scope, and the activation modes of organocatalysts were discussed in detail.

Subject Keywords

Asymmetric synthesis, Bifunctional organocatalysis, Squaramide, Isatin, Ketimine, 2-oxindole, Spirooxindole

URI

https://hdl.handle.net/11511/101273

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Graduate School of Natural and Applied Sciences, Thesis