Systematic Dissection of an Aminopyrrolic Cage Receptor for β-Glucopyranosides Reveals the Essentials for Effective Recognition

• Published in: Chemistry : a European journal Vol. 20; no. 20; pp. 6081 - 6091
• Main Authors: Francesconi, Oscar, Gentili, Matteo, Nativi, Cristina, Ardá, Ana, Cañada, F. Javier, Jiménez-Barbero, Jesús, Roelens, Stefano
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 12.05.2014; WILEY‐VCH Verlag
• Subjects: Amines - chemistry; carbohydrates; Glucosides - chemistry; Hydrogen Bonding; hydrogen bonds; Magnetic Resonance Spectroscopy; Models, Molecular; molecular recognition; Pyrroles - chemistry; receptors; structure elucidation; carbohydrates; molecular recognition; structure elucidation; receptors; hydrogen bonds
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201400365

A set of structures designed for the recognition of glucosides has been obtained by systematically destructuring a tripodal aminopyrrolic cage receptor that selectively recognizes octyl‐β‐D‐glucopyranoside (OctβGlc). NMR spectroscopy and isothermal titration calorimetry binding measurements showed that cleavage of one pillar of the cage was beneficial to the binding properties of the receptor, as long as two residual amino groups of the cleaved pillar were present. Removal of these two residual amino groups produced a dramatic loss of affinity for OctβGlc of the resulting monocyclic analogue of the parent cage receptor. A significant improvement in the binding ability was achieved by replacing one pillar with two aminopyrrolic hydrogen‐bonding arms, despite the loss of a preorganized structure. In contrast to the cage receptor, recognition of OctβGlc was observed, even in a competitive medium (30 % DMF in chloroform). Structural studies in solution, carried out through NMR spectroscopy and molecular modeling calculations, led to the elucidation of the 3D binding modes of the side‐armed monocyclic receptors; this highlighted the key role of the amino groups and demonstrated the occurrence of a rotaxane‐like complex, which featured the octyl chain of the glucoside threaded through the macrocyclic ring. Comfort is paramount! A set of structures designed for the recognition of glucosides has been obtained by systematically destructuring a tripodal aminopyrrolic cage receptor. A β‐glucoside is more effectively recognized by an adaptive cleft than by a preorganized cage, if a more comfortable fit can be achieved (see picture).