During our research on the supramolecular chemistry of simple pseudopeptidic compounds [18-23], we screened the crystallization conditions of several different N-protected dipeptide sequences. Thus, we observed that when the Z-AF-OH dipeptide was placed in a MeOH solution containing an excess of 12 N HCl, large crystals appeared after very long time (several months). Surprisingly, the X-ray diffraction analysis of these crystals unambiguously showed that they contained the corresponding methyl ester dipeptide (Z-AF-OMe) most likely produced by the acid-catalyzed esterification of the initial carboxylic acid-terminated compound (Scheme 1).
Crystal Structure Determination
The molecular structure of the title compound, along with the atom-numbering scheme, is depicted in Figure 1. Bond lengths and angles are in the usual ranges. The uretane and amide moieties adopt a trans conformation with torsion angles O2-C3-N4-C5 = 178.9(3)° and C5-C6-N7-C8 = −174.8(3)°. The peptide units are essentially planar (r.m.s. deviation is 0.025Å for O2, C3, O31, N4, H4, C5 as well as for C5, C6, O61, N7, H7, C8) and enclose a dihedral angle of 71.89(19)°. Further characteristic torsion angles describing the backbone conformation are given in the following Table 1.
The crystal packing is stabilized by intermolecular N-H⋯O=C hydrogen bonds (Table 2). Those H-bonds involve the interaction of the amide hydrogen of the peptide bond with the carbonyl oxygen of the same group in a second molecule and that of the uretane hydrogen with the carbonyl oxygen of the uretane group in another molecule. Two molecules form an R22(12) ring (Figure 2) [24]. These entities are further connected to chains running along the a axis (Figure 3). Additional aryl-aryl contacts of the edge-to-face type between the phenyl groups of the Phe side chains and those of the Z groups are established along the c axis (Figure 3). The C15-H15⋯cog(C11,C12,C13,C14,C15,C16) distance is 3.021 Å.
As previously commented, it is interesting to note that a similar compound in which the ester methyl group of the title compound is substituted by an H atom (Z-AF-OH), has exactly the same molecular conformation [23]. A least-squares fit of the two molecules is shown in Figure 4. Besides, also in this case, a similar H-bonding network implicating the amide and uretane groups was found in the solid state. This H-bonding network is also responsible for the self-assembling of Z-AF-OH in solution [23] and resembles that observed in natural β-sheet peptidic motives [5-7]. In both cases—the Z-AF-OH and the Z-AF-OMe compounds—the assembly can be described as a straight parallel β-sheet [25], without any twist between the backbond strands along the H-bonding direction, often found in related N-protected dipeptides [26]. However, in the crystals of Z-AF-OH, we had observed additional intermolecular H bonding interactions between the carboxylic acids that are not possible in the methyl ester compound Z-AF-OMe. A further comparative study between the two crystals is shown in Figure 5. The relative disposition of the peptidic backbones is parallel in Z-AF-OMe while anti-parallel in Z-AF-OH, with respect to the N to C termini direction (see green arrows in Figure 5 A,B). This difference is due to the H-bonding interactions observed between the COOH groups of Z-AF-OH, which are obviously absent in the corresponding methyl ester. However, the same N-H⋯O=C interactions within the backbones are present in both structures. The absence of the H-bonds implicating COOH in the title compound (Z-AF-OMe) produced a shift between the planes of the backbone strands (Figure 5C) which were perfectly aligned in the case of the original Z-AF-OH compound (Figure 5D). Thus, the presence or absence of interactions along the peptidic backbone direction is reflected in the alignment of the strands and in their relative senses (parallel or antiparallel), while retaining essentially the same conformation of the dipeptide.