Designing Powerful Biindole-Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements

Among inherently chiral selectors of axial stereogenicity, usually re¬sulting in very good enantiodiscrimination performances, the biin¬dole-based family has the additional advantage of very easy functio¬nalization of the two nitrogen atoms with a variety of substituents with de¬si¬rable properties. Aiming to evaluate the possi¬bility of exploiting such feature to enhance the enantiodiscrimination ability of the arche¬ty¬pe structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2’-biindole atro¬pisomeric core conjugated to bithiophene wings enabling fast and re¬gular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl sub¬stituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the sele¬ctor series was compa-ratively evaluated in proof-of-concept chiral voltammetry experiments with a “benchmark” chiral ferrocenyl probe as well as with chiral non-steroidal anti-inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl << hydroxyethyl sequen¬ce of selector substituents, sup¬porting our assumption on the bene¬ficial role of an additional coor¬dination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.