Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to (E)-3-(2-oxo2-(pyren-1-yl)ethylidene)indolin-2-ones: A combined experimental and theoretical study

Functionalized oxindoles and pyrrolizidines form the central structural framework for numerous natural products with extensive biological and pharmacological applications. The requirement for high regio- and stereoselectivity is the main obstacle in the synthesis of such five-membered heterocycles. Multicomponent cycloaddition reactions often provide an efficient and straightforward approach for the preparation of specific regio- and stereoisomers. In this article, the regio- and stereochemistry of the polar [3 + 2]-cycloaddition (32CA) reaction of azomethine ylides prepared by the reaction of isatin derivatives and L-proline with a series of (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones was investigated by experimental and theoretical methods. Among the isatin and (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives, a remarkable inversion of regioselectivity was observed in the 32CA reaction of azomethine ylide generated by the reaction of L-proline and 5-chloroisatin or N-methyl-5chloroisatin with (E)-5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one. The regio- and stereochemical assignment of the structures of the cycloaddition products was determined by one- and two-dimensional (1D&2D) homonuclear and heteronuclear correlation nuclear magnetic resonance spectroscopy. The molecular mechanism as well as the regio- and stereoselectivity of the cycloaddition were investigated by means of global and local reactivity indices and a density functional theory (DFT) and explained in detail on the basis of the transition state stabilities of the reactants.

Automated summary

Functionalized oxindoles and pyrrolizidines are central in the synthesis of many natural products, but achieving high regio- and stereoselectivity is a challenge. This study investigates the regio- and stereochemistry of a specific cycloaddition reaction using experimental and theoretical methods. The research reveals a significant inversion of regioselectivity in certain reactions.