One-Pot Cyclization to Large Peptidomimetic Macrocycles by In Situ-Generated β-Turn-Enforced Folding

Abstract

Macrocycles have been targets of extensive synthetic efforts for decades because of their potent molecular recognition and self-assembly capabilities. Yet, efficient syntheses of macrocyclic molecules via irreversible covalent bonds remain challenging. Here, we report an efficient approach to large peptidomimetic macrocycles by using the in situ-generated β-turn structural motifs afforded in the amidothiourea moieties from the early steps of the reaction of 2 molecules of bilateral amino acid-based acylhydrazine with 2 molecules of diisothiocyanate. Four chiral and achiral peptidomimetic large macrocycles were successfully synthesized in high yields of 45–63% in a feasible one-pot reaction under sub-molar concentration conditions and were purified by simple filtration. X-ray crystallographic characterization of three macrocycles reveals an important feature that their four β-turn structures, each maintained by four 10-membered intramolecular hydrogen bonds, alternatively network the four aromatic arms. This affords an interesting conformation switching mode upon anion binding. Binding of SO4 2– to 1L or 1D that contains 4 alanine residues (with the lowest steric hinderance among the macrocycles) leads to an inside-out structural change of the host macrocycle, as confirmed by the X-ray crystal structure of 1L-SO4 2– and 1D-SO4 2– complexes, accompanied by an inversion of the CD signals. On the basis of the strong sulfate affinity of the macrocycles, we succeeded in the removal of sulfate anions from water via a macrocycle-mediated liquid–liquid extraction method. Our synthetic protocol can be easily extended to other macrocycles of varying arms and/or chiral amino acid residues; thus, a variety of structurally and functionally diverse macrocycles are expected to be readily made.

A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions

“…This is largely a result of the well-known difficulty of achieving selective intramolecular coupling via end-to-end cyclization when preparing larger rings; while normal-sized ring (5–7-membered) cyclization reactions of the type 1 → 2 (Scheme A) are generally kinetically favorable, “easy” reactions, the analogous cyclization reactions to make larger ring products ( 3a → 4a ) are usually much more difficult, and are often plagued by competing intermolecular reactions (e.g., 3a → 5a , Scheme A) . High-dilution (or pseudohigh-dilution) approaches are routinely used to limit intermolecular reactions, but rarely prevent them completely, and can negatively impact the practicality and scalability of the synthesis …”

“…The synthesis of macrocycles and medium-sized rings can be challenging, especially on large scales. 6 This is largely a result of the well-known difficulty of achieving selective intramolecular coupling via end-to-end cyclization when preparing larger rings; while normal-sized ring (5–7-membered) cyclization reactions of the type 1 → 2 ( Scheme 1 A) are generally kinetically favorable, “easy” reactions, the analogous cyclization reactions to make larger ring products ( 3a → 4a ) are usually much more difficult, and are often plagued by competing intermolecular reactions (e.g., 3a → 5a , Scheme 1 A). 7 High-dilution (or pseudohigh-dilution) approaches are routinely used to limit intermolecular reactions, but rarely prevent them completely, and can negatively impact the practicality and scalability of the synthesis.…”

Supramolecular axial chirality in [N–I–N]+-type halogen bonded dimers

“…In contrast, the asymmetric packing of molecules oriented by noncovalent forces in the self-assembly exhibits chirality at the supramolecular scale, which correlates to the generation of versatile chiral nano/microarchitectures and other selfassemblies of diverse dimensions and sizes. 4 Compared to the synthetic chemistry that produces chiral molecules by asymmetric catalysis or resolution, the supramolecular protocol is efficient as it works by assembling chiral molecules or through symmetry breaking with subsequent chiral amplication. [5][6][7] The various noncovalent forces allow exible design and fabrication of chiral-assembled structures towards advanced functions and applications for asymmetric sensing, recognition, resolution, and chiroptical materials.…”

pH-Dependent phosphate separation using a tripodal hexaurea receptor

“…Liquid–liquid extraction (LLE) is a relatively fast and feasible methodology for anion separation that can be integrated with industry-available equipment compared to chemical precipitation/crystallization. 21–24 A few reports found that H 2 PO 4 − or HPO 4 2− could be separated from water with 80% efficiency using synthetic receptors via LLE. 25–28 Typically, these receptors were positively charged either through protonation or chelation with metals, thus facilitating strong binding affinity with phosphate.…”