N-Acylamino Acid Amidothiourea: A Versatile Chiral Helical Building Block

Thioureas represent an important class of molecular frameworks, distinguished by their hydrogen-bonding capabilities. This feature has enabled the development of a variety of synthetic anion receptors and advanced molecular technologies with applications in analysis, catalysis, and therapeutics. Over the past three decades, our lab has focused on establishing N-acylamino acid amidothiourea platforms to revolutionize the thiourea-based supramolecular functionality, particularly in anion recognition, chirality transfer, spontaneous resolution, and macrocyclization synthesis. This Account highlights representative studies from our lab and describes our exploration of the relationship between N-acylamino acid amidothiourea conformation, folding, and emerging material properties.

The design of thiourea-based anion receptors usually involves enhancing the hydrogen-bonding propensity of the thioureido −NH proton(s). Conventional strategies employ electron-withdrawing groups to increase the acidity of −NH(s), although this risks deprotonation of −NH when they are too acidic or encounter highly basic anions. Our lab developed an alternative strategy for this goal that circumvents this limitation. By incorporating electron-donating amide groups to generate N-amidothioureas and exploiting molecular allostery to drive intramolecular charge transfer (ICT), we achieved a dramatic enhancement in anion binding affinity by orders of magnitude. The N-amidothioureas also serve as dynamic regulators of intramolecular chirality transfer via N–N bond conformational switching from twisted to planar states. Notably, N-acylamino acid amidothioureas exhibit a pronounced template effect due to the folded β-turn structure, enabling efficient macrocyclization syntheses that were previously unattainable. This breakthrough has facilitated the construction of macrocycle-based nanopores for transmembrane transport. Furthermore, by integrating intermolecular binding sites, we achieved helicity propagation of the helical β-turn structure through self-assembly, yielding supramolecular double helices with a linear CD-ee dependence. It presents a critical step toward spontaneous resolution for practical applications.

Given the expanding interest in thiourea and its derivatives, our chiral helical building blocks provide a versatile platform for advancing functional thiourea-based materials.