A Simple Helical Macrocyclic Polyazapyridinophane as a Stereoselective Receptor of Biologically Important Dicarboxylates under Physiological Conditions

Abstract

The interaction of a synthetic enantiopure azamacrocyclic receptor (L) with biologically important chiral dicarboxylates (A, 1-7) has been studied by means of potentiometric titrations in 0.15 M NaCl aqueous solution in a wide pH range. This macrocycle forms strong complexes of the type [HnLA](n-2) (with n = 0-5). As a general trend, the binding is much tighter at basic or neutral pH than in acidic medium. Interestingly, nonprotected excitatory amino acids (Asp and Glu) are strongly bound even at acidic pH. Regarding selectivity, the receptor showed stereoselective binding toward those substrates bearing an H-bonding donor at Calpha, being S-selective in most of the cases, except for glutamic acid. Thus, L displayed an excellent enantioselectivity for (S)-malate dianion (KS/KR = 11.50 at pH 10.0 and KS/KR = 6.86 at pH 7.0) and exhibited moderate enantiopreference for (S,S)-tartrate (KSS/KRR = 3.01 at pH 10 and KSS/KRR = 1.70 at pH 7.0). For this last anion, a very good diastereopreference was also observed (KSS/KRS = 8.46 at pH 10 and KSS/KRS = 4.99 at pH 7.0). On the contrary, L is smoothly R-selective toward (R)-Glu (KR/KS = 3.22 at pH 10 and KR/KS = 2.05 at pH 7.0) due to its longer and more flexible molecular structure. The stereoselectivity of the corresponding complexes decreased when decreasing pH values. For the hydroxy derivatives, mass spectrometry also reflected the trends observed by potentiometry and confirmed the receptor:dicarboxylate 1:1 stoichiometry of the supramolecular complexes. Additional experimental techniques were used to study the most stereoselective example. Solution studies by NMR suggested a good geometrical complementarity between the malate dianion and the receptor, which showed a predominant helical conformation in solution. Besides, self-diffusion rates (PGSE) of the diastereomeric complexes with malate also agree with binding data. Circular dichroism was also used in this case at different pH values, showing a very good correlation between the helical content of the receptor and the stereoselectivity of the molecular recognition process.

Contact Ion Pairs on a Protonated Azamacrocycle: the Role of the Anion Basicity

“…As pointed out before, multiprotonated M, formed in water at neutral pH, does not exhibit any tendency to add monocarboxylate anions, although it is able to efficiently trap dicarboxylates of suitable geometry and electronic properties [20][21][22][23][24][25]. A reason for such a different behavior can be found in the large dehydration penalty to be paid by the charged species involved, which can be offset only by the establishment of multiple electrostatic interactions within the adduct, provided that it does not demand any significant structural distortion of the diprotonated acceptor.…”

“…Polyazamacrocycles, such as M (Figure 1), have been successfully employed as chiral solvating agent for monocarboxylic acids in CDCl 3 [18], but not in aqueous solutions because the strong solvation capability of water inhibits the formation of the corresponding noncovalent adducts. However, in water, macrocycle M can efficiently form noncovalent adducts with polycarboxylic acids, although the process is very sensitive to the state of charge of both components and, therefore, to the pH of the solution [19,20].…”

“…Indeed, the hexaazamacrocycle M is a very basic acceptor which, in water at neutral pH, can accommodate more than two protons onto their NH groups [20]. Under these conditions, multiprotonated M is able to form 1:1 complexes only with dicarboxylates having suitable geometry and electronic properties [20][21][22][23][24][25].…”

“…Under these conditions, multiprotonated M is able to form 1:1 complexes only with dicarboxylates having suitable geometry and electronic properties [20][21][22][23][24][25]. Its selectivity has been interpreted in terms of geometric and electronic requirements for multiple hydrogen bondings with the dicarboxylate anion, thereby the intuition that multiprotonated M can mimic the active center of polycarboxylate carrier proteins.…”

“…to our modifications of the procedures reported in the literature [20,26,27] (see Experimental Details and Scheme S1 in the Supplementary Material (SM) section).…”