A Highly Enantioselective Receptor for N-Protected Glutamate and Anomalous Solvent-Dependent Binding Properties

Abstract

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

The composite nanomaterials containing (R)‐thalidomide‐molecularly imprinted polymers as a recognition system for enantioselective‐controlled release and targeted drug delivery

“…Thalidomide was introduced in 1960s as a sedative and hypnotic drug for pregnant women. 12,13 In this current study, chiral recognition by a molecular bis(acrylamido)pyridine-based chirally imprinted polymer and its formation by a self-assembled process have been investigated. The drug has a stereocenter and it is used as a racemate with both the (S)-(2)-and (R)-(1)-enantiomers possessing biological effects for multiple myeloma and related plasma cell disorders in clinical practice.…”

“…In that case it was achieved by the copolymerization of different multifunctional monomers using the method of simultaneous multiple interactions with the template. 12,13 In this current study, chiral recognition by a molecular bis(acrylamido)pyridine-based chirally imprinted polymer and its formation by a self-assembled process have been investigated. A prepolymerized MIP formulation and the macromers were used to generate an engineered binding site complementary with the structure of the (R)-thalidomide that provided self-organization of the macromolecular multicomponent, resulting in the enhanced interfacial regions and surface interactions of the resultant nanoparticles.…”

An expedient synthesis of N-p-tosyl macrocycles containing two thiourea moieties from trisulfonamide and bisdithiocarbamate salts at room temperature in aqueous media

“…The continued interest in novel macrocyclic thiourea ligands stems from their applications in many areas of chemistry and biochemistry, including ion-selective electrodes and optodes, 2 their easy complexation of anions 3 and N-protected glutamate dianion, 4 and antimicrobial studies. 5 Our ongoing studies are concerned with the simple, convenient preparation of these macrocycles.…”

“…We have recently reported the synthesis of calix [4]crown-5-sulfonyl imidazolidinethione from calix [4]crown-5-monosulfonyldiamine and carbon disulfide by intramolecular cyclization at room temperature in water. 7 In our study of these N-sulfonyl macrocycles, we now report the synthesis of methylene-bridged cyclophane-thiones from trisulfonamide and activated bisdithiocarbamate salts by intermolecular cyclization at room temperature in water (Scheme 1).…”

Crystallographic, 1H NMR and CD studies of sterically strained thiourea anion receptors possessing two stereogenic centres

“…16 In our previous work, we have shown that to achieve effective enantioselective sensing of chiral anions, the receptors need to posses a minimum of two stereogenic centres. 17 This has also been demonstrated by other researchers, such as Kilburn et al, 18 Tucker et al 19 and James et al…”