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A series of acyclic thiourea derivatives, designed to create a cleft with four hydrogen bond donors suitable for carboxylate recognition, have been prepared, and their ability to bind to N-protected amino acid carboxylate salts has been investigated. The crystal structure of one of the thioureas has been determined showing that it forms a hydrogen bonded centrosymmetric dimer in the solid-state, in a conformation appropriate for the desired binding of carboxylates. The thioureas show good discrimination between different amino acids and those thioureas incorporating chiral moieties show moderate enantioselectivity for a range of amino acid derivatives.

The development of enantioselective receptors continues to be a challenging endeavor for supramolecular chemists, and enantioselective recognition of biologically relevant molecules in competitive solvents is particularly demanding. [1] Although numerous receptors have been developed for dicarboxylic acids and dicarboxylates, [2] only a few enantioselective receptors for chiral dicarboxylic acids (in the neutral diprotonated form) have been described, [3] and very few examples of enantioselective receptors for chiral dicarboxylates have been reported. [4] We recently described an acyclic monothiourea receptor 1 a, which bound a range of N-protected amino acid carboxylate salts with modest enantioselectivity. [5] Building on this work, we have now prepared macrocyclic receptor 2, which features two thiourea moieties flanked by carboxypyridines and separated by a chiral diamine. The receptor was designed to produce a chiral pocket for dicarboxylates by forming up to eight hydrogen-bonding interactions with the carboxylate oxygen atoms and intramolecular hydrogen bonding with the pyridine unit to help preorganize [6] the receptor (Scheme 1). Binding measurements, by NMR titration and isothermal calorimetry, indicate that the macrocycle exhibits strong and highly enantioselective 1:1 binding of N-Boc-l-glutamate (as the dicarboxylate dianion) in relatively polar solvents (CH 3 CN, DMSO) and that complexation involves a large, favorable entropic contribution. Remarkably, however, no binding of N-Boc-glutamate by the macrocycle is observed in a less polar solvent (CDCl 3 ).The synthesis of receptor 2 was readily achieved by coupling acid 3 [5] with (S,S)-1,2-diphenylethylenediamine to give bisphthalimide 4 (Scheme 2). Removal of the phthalimide protecting groups and treatment of the resulting bisamine 5 with CS 2 and DCC produced the bis(isothiocyanate) 6. A further equivalent of bisamine 5 was added to bisisothiocyanate 6, in the presence of DMAP, by syringe pump over three hours to yield the macrocyclic bisthiourea 2 in 26 % yield.The 1 H NMR spectrum [7] of macrocycle 2 in CDCl 3 at room temperature is poorly resolved, with very broad signals for all protons, and resolution is not improved at higher temper- COMMUNICATIONS

Solvatation des Makrocyclus durch polare Lösungsmittel ermöglicht die starke Bindung eines N‐geschützten anregenden Aminosäureneurotransmitters. Während sich in CH3CN und DMSO mit hoher Enantioselektivität (und mit einer größeren entropischen Triebkraft zur Bindung) ein 1:1‐Komplex aus Makrocyclus und N‐Boc‐L‐glutamat (in Form des Dicarboxylatanions, siehe Grafik) bildet, beobachtet man keine Bindung im schwächer koordinierenden CDCl3.

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