C-Silylated Calix[4]Arene as a New Receptor for Aspartate in Polar Solvents

The development of synthetic receptors for a chosen substrate (host-guest chemistry) is a well-established area of research, and selective receptors have now been described for a whole range of substrates, from simple metal cations to polyfunctional molecules such as peptides, proteins, and carbohydrates [1, 2]. Carboxylic acids (or carboxylates) are a particularly common functional group in biological and synthetic organic molecules and have inspired the elaboration of a number of different approaches for their recognition. Binding sites have been developed both for simple carboxylic acids and for incorporation into sophisticated receptors for more complex carboxylic acid derivatives, both in polar and nonpolar solvents [3]. The development of synthetic receptors for enantioselective binding of L-glutamate and L-aspartate derivatives has been of particular interest because of the critical role of these amino acids in the central nervous system as excitatory transmitters. Several groups have successfully developed receptors to be able to bind a range of dicarboxylates [4–6]. Calixarenes have been widely studied as hosts and potential hosts for molecular recognition [7]. For example, the binding affinities between p-tert-butylcalix[4]arene-based dipodal and some aliphatic diacetates such as malonate, succinate, glutarate, adipate, pimelate, and suberate in CH3CN were studied by Singh et al. [8]. We have recently introduced a different type of substituted calix[4]arene derivatives, which have a multiple functional groups at the upper rim. These receptors can bind selective amino acids such as arginine and lysine in polar solvents [9]. The recognition of aspartitic acid derivatives such as N-benzyloxycarbonyl-Daspartate (NZDA) with the calix[4]arene derivatives with multiple silicon groups at the upper rim is investigated.


Introduction
The development of synthetic receptors for a chosen substrate (host-guest chemistry) is a well-established area of research, and selective receptors have now been described for a whole range of substrates, from simple metal cations to polyfunctional molecules such as peptides, proteins, and carbohydrates [1,2]. Carboxylic acids (or carboxylates) are a particularly common functional group in biological and synthetic organic molecules and have inspired the elaboration of a number of different approaches for their recognition. Binding sites have been developed both for simple carboxylic acids and for incorporation into sophisticated receptors for more complex carboxylic acid derivatives, both in polar and nonpolar solvents [3].
The development of synthetic receptors for enantioselective binding of L-glutamate and L-aspartate derivatives has been of particular interest because of the critical role of these amino acids in the central nervous system as excitatory transmitters. Several groups have successfully developed receptors to be able to bind a range of dicarboxylates [4][5][6].
Calixarenes have been widely studied as hosts and potential hosts for molecular recognition [7]. For example, the binding affinities between p-tert-butylcalix [4]arene-based dipodal and some aliphatic diacetates such as malonate, succinate, glutarate, adipate, pimelate, and suberate in CH 3 CN were studied by Singh et al. [8]. We have recently introduced a different type of substituted calix [4]arene derivatives, which have a multiple functional groups at the upper rim. These receptors can bind selective amino acids such as arginine and lysine in polar solvents [9]. The recognition of aspartitic acid derivatives such as N-benzyloxycarbonyl-Daspartate (NZDA) with the calix [4]arene derivatives with multiple silicon groups at the upper rim is investigated.

Results and Discussion
2.1. Synthesis. Disilylated calixarene, 6 and 7 were synthesized according to the following procedure ( Figure 1).
The tetrabromo derivative 4 and dibromo derivative 5 can be prepared with the NBS bromination and subsequently butylation [14]. After bromine-lithium exchange on 4 and 5 with Li powder proceeds smoothly, the phenyllithium intermediate is then efficiently trapped by trimethylsilyl chloride (TMSCl) that give the disilylated derivatives 6 and 7 [15,16].

Binding Experiments
The compounds 6 and 7 were selected for preliminary study of host-guest properties in chloroform and methanol (1 : 1) at 25 • C. To evaluate the binding ability of calix [4]arene 2 Organic Chemistry International  This indicates a strong interaction with an association constant 5 * 10 3 M −1 , and producing a sharply kinked titration curve ( Figure 2).
For the determination of complex stoichiometry between receptor 6/NZDA 8, we have used the job methods [17]. The resulting plot shows an approximate 1 : 1 stoichiometry ( Figure 3). Table 1 shows the binding constant and stoichiometry between NZDA 8 and aspartic acid 9 and different calix [4]arene receptors.
The results show that receptor 7 has a good affinity to the NZDA 8. (Table 1 entry 3), in comparison to the latter interaction, the association constant between receptors 6 and 8 decreases because of the steric effect of bromine groups at the upper rim of 6. The binding affinities of 6 and 7 for NZDA 8 are greater than the affinities of 6 and 7 for aspartic acid (Table 1 entry 2, 3 and 7, 8). The receptors 4 and 10, which have not silyl group at the upper rim, could bind aspartate and aspartic acid weaker than receptors 6 and 7. This may be due to the formation of hypercoordinate complexes between the guests and silylated host (6 and 7), (Figure 2). In the case of receptor 11, it is believed that the electrostatic interaction is the main interaction (Figure 4).   [4]arene(4) (0.25 g, 0.26 mmol) in dry THF (5 mL) was stirred under argon and cooled to −78 • C. Then butyllithium 1.6 M in hexane (0.033 g, 0.52 mmol) was added dropwise, and the mixture was stirred for 0.5 h at −78 • C, and 1.5 h at room temperature. Again the solution cooled to −65 • C and to the mixture was added dropwise trimethylchlorosilane. The result solution was stirred at room temperature for 12 h, and then the reaction mixture was refluxed for 2 h. The mixture was washed with 10 mL of saturated ammoniumchlorid. The organic layer was separated, dried over sodium sulfate, and the solvent was removed under reduced pressure. The purification of the residue by column chromatography (pet. ether/ethyl acetate, 99 : 1) gave 0.06 g (24%) of 6.   [4]arene 5 (0.38 g, 0.39 mmoL) in dry THF(10 mL) was added dropwise, and the mixture was stirred for 0.5 h at −78 • C. After warming to room temperature, the mixture was stirred at room temperature for 2 h. Then trimethylchlorosilane (0.8 mL, mmoL) was added dropwise to the mixture, and the reaction was continued for 12 h. After this time, the suspense dark precipitate was filtered. Then, the filtrate was heated to reflux for 1.5 h, and after cooling, the mixture was evaporated under reduced pressure. The residue is then dissolved in the minimum amount of CH 2 Cl 2 , and, to this solution, MeOH was dropwise added till further addition leads to turbidity and the obtained solution was let in −15 •

Conclusions
It is possible to recognize N-benzyloxycarbonyl-D-aspartate (NZDA) 8 with silylated calix [4]arene 6 and 7, in polar solvent. The investigation shows that the silyl groups at upper calix [4]arene have great effect on binding process. Since NZDA is very similar to NMDA, as a channel blocker, the further studies could lead to introducing these new generation receptors 6 and 7 for clinically favorable NMDA receptor.