Modular Introduction of endo‐Binding Sites in a Macrocyclic Cavity towards Selective Recognition of Neutral Azacycles

Abstract

Macrocycles with a functionalized interior, which is a general cavity feature of bioreceptors, are relatively hard to synthesize. Here we report a modular strategy to customize diverse endo-binding sites in the macrocycle cavity. Only two steps are needed. First, one V-shaped functional module bearing an embedded binding site and two 2,5-dimethoxyphenyls as reaction modules are connected. Then the condensation of the resulting monomer and paraformaldehyde directly produces the designed macrocycle. V-shaped monomers are deliberately used to guarantee the binding sites equatorially directing inward into the cavity and 2,5-dimethoxyphenyls standing axially as macrocycle sidewalls. More than a dozen endo-functionalized macrocyclic receptors have been constructed. Host-guest complexation studies show that macrocycle BP1-decorated interior OH moieties can strongly encapsulate neutral azacycles by forming inner hydrogen bonds, giving a high association constant of 4.59 × 10 4 M À 1 in non-polar media.

Recent advances in the synthesis and applications of macrocyclic arenes

“…7). [31][32][33][34] Interestingly, they found that the macrocyclization process could be modulated by changing the geometrical configurations of these monomers. Linear monomers tended to yield cyclic trimers and pentamers while V-shaped monomers produced cyclic dimers.…”

Pseudo[n]-pillar[5]arenes: Synthesis, Structures, and Host–Guest Binding Properties

“…Inspired by the synthetic strategies of P­[ n ]­s, researchers have synthesized new macrocycles from the reaction of different alkoxy-substituted aromatic monomers and paraformaldehyde. This led to the rapid discovery of series of macrocycles, including biphenyl­[ n ]­arenes, prism­[ n ]­arenes, rhombicarene, pagoda­[ n ]­arenes, saucer­[ n ]­arenes, leggero pillar[5]­arenes, octopus[3]­arenes, acridane­[ n ]­arenes, methylene-bridged naphthotubes, and others, − over the last five years. In addition, the modification at phenylene sites, , methylene bridge, , or upper/lower rims , of P­[ n ]­s resulted in pillar­[ n ]­arene­[ m ]­quinones, tiara­[ n ]­arenes, and others. − …”

Water-soluble terphen[3]arene macrocycle: a versatile reversal agent of neuromuscular blockers

“…Recently, our research group reported a series of novel supramolecular macrocycles, namely biphen[n]arenes and their extended analogues, which were constructed through the Friedel-Crafts alkylation reactions of oligophenyl monomers containing methoxy groups. [25][26][27][28][29][30] On account of this modular synthetic strategy, these macrocycles possess easily adjustable cavity sizes and readily introducible functional groups. In this study, we present the synthesis of a terphen [3]arene functionalised with sulfate groups, which has good water solubility and biocompatibility.…”