Enantioselective Alkylation of Substituted Oxindoles Mediated by Asymmetric Organocatalysis

Chirality plays a crucial role in drug discovery and development because the biological activity of a chiral compound can be significantly affected by its stereochemistry. Thus, enantioselective processes are continually developed to increase the synthetic efficiency. Among them, asymmetric organocatalysis is a recently defined route to the sustainable production of chiral compounds. In this work, organocatalytic procedures have been tested to initiate an alkylation reaction, resulting in a quaternary chiral centre at C3 of an oxindole scaffold. Molecules bearing the oxindole moiety with a chiral C3 have been shown to be common in various compounds extracted from plant sources and are characterized by high biological activity. Some examples are alkaloids. Therefore, developing an efficient enantioselective route for 3,3’-disubstituted oxindole framework is of high interest, especially in the pharmaceutical framework. During this project, conducted at the University of Zaragoza in the Herrera-OrganoCatalisis Asimétrica Group, various oxindole substrates, differing only in the protecting group bonded to the amine of the oxindole scaffold, have been synthesized by adapting synthetic processes used for similar compounds. Subsequently, a screening of different catalysts was conducted to determine the most effective reaction conditions. In particular, various squaramide derivatives have been used as bifunctional catalysts. A screening of diverse benzohydrol alkylating agents was previously carried out by the research group, leading to the identification of Michler's hydrol as the most appropriate reactive species since it offers high yields; thus, it has been chosen as alkylating agent in this work. Additionally, more oxindole derivatives have been tested as substrates. The catalytic procedure produced similar enantiomeric excesses for all the N-substituted substrates under the tested reaction conditions, underscoring the versatility of this methodology.