Dendritic Pillar[6]Arenes with Fixed Planar Chirality for Stereoselective Inclusions in Water: A Case of Facile Differentiation of Cocaine Adulterants, Levamisole and Dexamisole

Dendritic pillar[6]arenes encompass a new class of cavitands with planar chirality, unique binding pockets, and great water solubility. These easily accessible hosts permit differentiating racemic dexamisole from levamisole as known cocaine adulterants. Dendritic pillar[6]arenes can now be used for stereoselective recognition, chemosensing, and sequestration of a broad range of chiral drugs.

Abstract

We describe the preparation, conformational dynamics, and stereoselective recognition characteristics of water-soluble pillar[6]arenes pS–2 ¹²⁻ and pR–2 ¹²⁻. These two novel and diastereomeric cavitands comprise a 2,5-bis(ethoxy)pillar[6]arene core with one of six phenylene ring conjugated to two hexaanionic dendrons. Each dendron includes an (S)−glutamic acid amidated with two tris-carboxylic Behera's amines. Cavitands pS–2 ¹²⁻ and pR–2 ¹²⁻ were obtained in six synthetic steps and resolved by column chromatography. The results of ¹H NMR and circular dichroism spectroscopic measurements are in line with pS/pR–2 ¹²⁻ having unidirectional orientation of alkoxy substituents (i.e., planar chirality) and no observable interconversion for, at least, 2 weeks. Computational studies supported with ¹H DOSY NMR measurements revealed that sufficiently bulky dendrons require high activation energy to pass through the pillararene's cylindrical cavity therefore inhibiting rotation of the phenylene holding them. With the unique and chiral binding pocket, pS–2 ¹²⁻ (pR–2 ¹²⁻) formed inclusion complexes with cocaine adulterants levamisole and dexamisole (K _d > mM), with their racemic mixture showing separate ¹H NMR spectroscopic resonances. In this way, dendritic pillar[6]arenes can be used as chiral shift reagents for determining enantiopurity of pharmaceuticals but also for examining a variety of chiral recognition processes, sensing of chiral molecules, and stereoselective sequestrations in aqueous media.

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