Cycloalkyl Groups as Building Blocks of Artificial Carbohydrate Receptors: Studies with Macrocycles Bearing Flexible Side-Arms

Abstract

The cyclopentyl group was expected to act as a building block for artificial carbohydrate receptors and to participate in van der Waals contacts with the carbohydrate substrate in a similar way as observed for the pyrrolidine ring of proline in the crystal structures of protein-carbohydrate complexes. Systematic binding studies with a series of 1,3,5-trisubstituted 2,4,6-triethylbenzenes bearing various cycloalkyl groups as recognition units provided indications of the involvement of these groups in the complexation process and showed the influence of the ring size on the receptor efficiency. Representatives of compounds that exhibit a macrocyclic backbone and flexible side arms were now chosen as further model systems to investigate whether the previously observed effects represent a general trend. Binding studies with these macrocycles towards β-D-glucopyranoside, an all-equatorial substituted carbohydrate substrate, included 1H NMR spectroscopic titrations and microcalorimetric investigations. The performed studies confirmed the previously observed tendency and showed that the compound bearing cyclohexyl groups displays the best binding properties.

Compounds Derived from 9,9‐Dialkylfluorenes: Syntheses, Crystal Structures and Initial Binding Studies (Part II)

“…The results of these initial binding experiments with a fluorene derivative contribute to our systematic studies on the molecular recognition of carbohydrates by various artificial receptor molecules. Within the scope of these systematic studies, we are developing acyclic [5,6] and macrocyclic [22a–d] receptor molecules that can both mimic the key protein‐carbohydrate interactions [23] and have a relatively simple structure to synthesize. Not only the X‐ray structural analyses of protein‐carbohydrate complexes, but also the crystal structures of complexes of artificial receptors with carbohydrates obtained in the course of our studies [24] served as a source of ideas for the design of new receptor structures.…”

Crystal structure and Hirshfeld surface analysis of 4,4′-dimethoxybiphenyl-3,3′,5,5′-tetracarboxylic acid dihydrate

“…Our studies on the molecular recognition of mono-and oligosaccharides with artificial receptors led to the development of various acyclic (Mazik, 2009(Mazik, , 2012 and macrocyclic (Lippe & Mazik, 2013, 2015Amrhein et al, 2016;Amrhein & Mazik, 2021;Leibiger et al, 2022) receptor architectures. Among the acyclic compounds, those with a central aromatic core carrying three or more functionalized side arms as recognition groups have proven to be effective carbohydrate receptors.…”

Low‐Symmetry Macrocycles and Cages for Carbohydrate Recognition

“…A 23‐fold increase in binding affinity was observed between the pyrrole‐based receptor containing CH 2 O Boc ( 8 , K a =3400 M −1 in CDCl 3 ) and that with the CH 2 NH Boc moiety in the flexible arms ( 7 , K a =79000 M −1 in CDCl 3 ). The synthesis of an efficient system 9 including benzene‐based bridge units and cyclohexyl groups in flexible side arms has been also achieved [43] . The nature of these units allowed the combination of hydrogen bonding, CH‐π interactions and Van der Waals contacts with the saccharides resulting in a good K a of 12500 M −1 compared to the receptor 6 bearing the CH 2 NH Boc moiety ( K a =4810 M −1 in CDCl 3 ).…”

“…The synthesis of an efficient system 9 including benzene-based bridge units and cyclohexyl groups in flexible side arms has been also achieved. [43] The nature of these units allowed the combination of hydrogen bonding, CH-π interactions and Van der Waals contacts with the saccharides resulting in a good K a of 12500 M À 1 compared to the receptor 6 bearing the CH 2 NHBoc moiety (K a = 4810 M À 1 in CDCl 3 ). The combination of these interactions in the recognition process was validated by 2D NMR investigations and molecular modeling.…”