Crystal structure and hydrogen bonding in N-(1-deoxy-β-d-fructopyranos-1-yl)-2-aminoisobutyric acid

The asymmetric unit contains two conformationally unequal zwitterion molecules that differ in the intramolecular hydrogen-bonding patterns. The 2C5 β-fructopyranose conformation also dominates in the compound’s solution.

The title compound, alternatively called d-fructose-2-aminoisobutyric acid (FruAib), C 10 H 19 NO 7 , (I), crystallizes exclusively in the -pyranose form, with two conformationally non-equivalent molecules [(IA) and (IB)] in the asymmetric unit. In solution, FruAib establishes an equilibrium, with 75.6% of the population consisting of -pyranose, 10.4% -furanose, 10.1% -furanose, 3.0% -pyranose and <0.7% the acyclic forms. The carbohydrate ring in (I) has the normal 2 C 5 chair conformation and the amino acid portion is in the zwitterion form. Bond lengths and valence angles compare well with the average values from related pyranose structures. All carboxyl, hydroxy and ammonium groups are involved in hydrogen bonding and form a three-dimensional network of infinite chains that are connected through homodromic rings and short chains. Intramolecular hydrogen bonds bridge the amino acid and sugar portions in both molecules. A comparative Hirshfeld surfaces analysis of FruAib and four other sugar-amino acids suggests an increasing role of intramolecular heteroatom interactions in crystal structures with an increasing proportion of C-H bonds.

Chemical context
d-Fructose-amino acids are derivatives of fructosamine and represent the major fraction of the early Maillard reaction products which form non-enzymatically both in processed foods and in vivo . Naturally occurring d-fructose-amino acids act as intermediates in the formation of food aroma and colour, while elevated fructosamine content in humans has been linked to the development of diabetic complications and tissue damage. Synthetic fructosamine derivatives have been offered as lectin blockers and antioxidants that might stimulate immune system , be potentially useful in prevention of cancer metastasis , or neuroinflammation (Song et al., 2016). The chemical and biological reactivity of fructosamines stems from their structural instability. Thus, in solutions, fructosamine derivatives rapidly establish a equilibrium between several cyclic and acyclic forms (Kaufmann et al., 2016), as exemplified in Fig. 1 for the title compound. The acyclic tautomers, while present in minute (<1%) proportions, are responsible for chemical transformations of fructosamines in numerous redox, isomerization, or degradation reactions. The cyclic conformers are responsible for the carbohydrate recognition by proteins such as lectins, transporters or enzymes, and thus define a number of biological activities of fructosamines . ISSN 2056-9890 As a part of our structure-activity studies, we have prepared d-fructose-2-aminoisobutyric acid (FruAib), a structural analogue of an efficient blocker of galectins-1, À3 and À4, d-fructose-l-leucine (Mossine et al., 2008). In this work, we report on the molecular and crystal structure of FruAib, C 10 H 19 NO 7 (I), with an emphasis on hydrogen-bonding patterns in the structure. A comparative Hirshfeld surfaces analysis of FruAib and four other sugar-amino acids is also completed.

Structural commentary
Crystalline FruAib has two conformationally nonequivalent molecules, (IA) and (IB), in the asymmetric unit. The molecular structures and atomic numbering are shown in Figs. 2 and 3. The molecules may be considered as conjugates of a carbohydrate, 1-amino-1-deoxy-d-fructose, and an amino acid, 2-aminoisobutyric acid, which are joined through the common amino group. The -d-fructopyranose rings of the carbohy-drate portions in both (IA) and (IB) exist in the 2 C 5 chair conformation, with puckering parameters Q = 0.582 Å , q = 177.7 , and f = 224 for (IA) and Q =0.565 Å , q = 175.5 , and f = 268 for (IB). These parameters correspond to a conformation with the lowest energy possible for fructose Atomic numbering and displacement ellipsoids at the 50% probability level for molecule (IA). Intramolecular N-HÁ Á ÁO and O-HÁ Á ÁO interactions are shown as dotted lines.

Figure 3
Atomic numbering and displacement ellipsoids at the 50% probability level for molecule (IB). Intramolecular N-HÁ Á ÁO and O-HÁ Á ÁO interactions are shown as dotted lines.

Figure 1
Equilibrium in aqueous solution of (I), at 293 K and pH 6. Table 1 Hydrogen-bond geometry (Å , ).  (French et al., 1997), with (IB) providing a better fit. The bond distances and the valence angles are close to the average values for a number of crystalline pyranose structures (Jeffrey & Taylor, 1980). In the solution of FruAib, the -d-pyranose anomer dominates the equilibrium, at 76.6%, as follows from the 13 C NMR spectrum ( Fig. 1, Supporting Table S1). In the 1 H NMR spectrum of the major anomer (see Section 5), the vicinal proton-proton coupling constants J 3,4 = 9.8 Hz and J 4,5 = 3.4 Hz indicate H4 is in the trans disposition to H3 and in the gauche disposition to H5. Hence, the predominant conformation of FruAib in solution is the 2 C 5 -d-fructopyranose, as well.
The amino acid portions of both (IA) and (IB) are in the zwitterion form with a positively charged tetrahedral secondary ammonium nitrogen and a negatively charged deprotonated carboxyl group. Each molecule has three intramolecular interactions (Table 1), two of which bridge the carboxylate, ammonium, and the carbohydrate portions of the molecules. The intramolecular hydrogen-bonding patterns differ in the molecules. Thus, in (IB), the string of short heteroatom contacts stretches from O4B through O7B and can be denoted in terms of the S 3 2 (5) pattern descriptor. In (IA), the intramolecular hydrogen bonding is fragmented between the shorter zwitterionic bridge O7AÁ Á ÁH1NAÁ Á ÁO6A [the S 2 1 (3) pattern] and the O2A-HÁ Á ÁO3A contact. In the 1 H NMR spectrum of FruAib (see Section 5), the two protons attached to C1 produce two distinct signals at 3.297 and 3.210 ppm, with J 1A,1B = À12.7 Hz. The inequality of these protons indicates restricted rotation around the C1-C2 and C1-C7 bonds, thus suggesting that the intramolecular hydrogen bonds retain the structure in solution (Mossine et al., 1994). There are non-equivalences in carboxylate C-O distances that are observed in both molecules and which could be attributed to unequal participation of the oxygen atoms in hydrogen bonding. In (IA), O8A is involved in a three-center hydrogen-bonding interaction, with HÁ Á ÁO8A distances of 1.79 and 1.98 Å , while for the O7A interaction, the distances are 1.91 and 2.30 Å (Table 1), which explains the elongation of the C8A-O8A bond (1.260 Å ), as compared to the C8A-O7A distance (1.249 Å ). Similar considerations can be applied to (IB), where O7B is involved in two short heteroatom contacts and O8B participates in only one (Table 1), hence the difference in the C8B-O7B (1.263 Å ) and C8B-O8B (1.241 Å ) bond lengths.

Supramolecular features
FruAib crystallizes in the triclinic space group P1, with two non-equivalent molecules per unit cell. The molecular packing of (I) features infinite chains of hydrogen bonds spiralling along the a axis ( The molecular packing in (I). Color code for crystallographic axes: red Àa, green Àb, blue Àc. Hydrogen bonds are shown as cyan dotted lines.

Figure 5
Hydrogen-bond patterns in the crystal structure of (I). Table 2 Suspected C-HÁ Á ÁO contacts (Å , ) in (I). x + 1, y À 1, z are depicted in Fig. 5 and include the main infinite chain pattern C 5 5 (12); in the crystal, these infinite chains are connected through homodromic rings [R 4 4 (8)] and short chains [D 1 2 (5) and D (4)]. Thus, hydrogen bonds form a threedimensional network of short heteroatomic contacts throughout the crystal of (I). In addition, there are a number of close C-HÁ Á ÁO contacts that may qualify as weak hydrogen bonds (Table 2). Interestingly, molecule (IA) provides most of donors for these contacts.

Database survey
Search of SciFinder, Google Scholar, and the Cambridge Structural Database (Groom et al., 2016) by both structure and chemical names revealed no previous structural description of d-fructose-2-aminoisobutyric acid: thus the compound appears to be novel. The d-fructosamine portion of the molecule is more interesting for a structure comparison survey due to its conformational instability and practical significance to food and health sciences. The most closely related structures are d-fructose-glycine (FruGly, CCDC 1307697; Mossine et al., 1995) and d-fructose-l-proline (FruPro, CCDC 628806, 628807, 631528;Tarnawski, Ś lepokura et al., 2007). These d-fructose-amino acids crystallize in the 2 C 5 -pyranose conformations and exist as zwitterions as well, with the intramolecular hydrogen bonding that necessarily involves the amino acid carboxylate, the ammonium group and one hydroxy group donated by the carbohydrate moiety. However, none of these structures features the involvement of the pyranose ring O6 in the intramolecular hydrogen bonding found in (IA). On the other hand, (IB) is structurally close to both FruGly (Mossine et al., 1995) and FruPro (Tarnawski, Ś lepokura et al., 2007). In the molecules, the conformations around the C1-C2 bond are trans-gauche, with respective values of the N-C1-C2-O6 torsion angle falling into the 165-177 range and are stabilized with the similar intramolecular hydrogen-bonding pattern O3Á Á ÁH1NÁ Á ÁO7.
A compendium of structures close to (I) is presented in Table 3. In addition to FruPro and FruGly, two structures isomeric to FruGly were included: d-galactose-glycine (GalGly, CCDC123625; Mossine et al., 1996) and d-glucoseglycine (GlcGly, CCDC123624; Mossine et al., 1996). In sugar-amino acids, as demonstrated in Table 3, an increase in the proportion of C-H bonds leads to an increase in number of intramolecular hydrogen bonds. Such tendency towards the 'internalization' of hydrogen bonding was also noticed as a result of a comparative analysis of the 'fingerprint plots' based Two-dimensional fingerprint plots produced for the Hirshfeld surfaces of (IA) and (IB). The full plots for (IA) and (IB) are shown in (a) and (b), respectively. Contributions to the plots from the HÁ Á ÁH contacts are shown in (c) and (d) and the contributions from the OÁ Á ÁH/HÁ Á ÁO contacts are depicted in (e) and (f).

Table 3
Hydrogen bonding and contributions of the OÁ Á ÁH/HÁ Á ÁO contacts to the Hirshfeld surfaces of sugar-amino acids.
There is an obvious trend towards decrease in the proportion of intermolecular OÁ Á ÁH contacts as the number of the C-H bonds in the structure increases, although a total number of hydrogen-bonds per molecule increases as well.

Synthesis and crystallization
2-Aminoisobutyric acid (2.1 g, 0.02 mol), d-glucose (9 g, 0.05 mol), and sodium acetate (0.82 g, 0.01 mol) were dissolved in 100 ml of a methanol/glycerol (3:1) mixture and refluxed for 3 h. The reaction progress was monitored by TLC on silica. The reaction mixture was diluted with 900 ml of water and passed through a column charged with 80 ml of Amberlite IRN-77 (H + -form). The target compound was then eluted with 0.2 M pyridine, and fractions containing pure FruAib were pooled and evaporated. The residue was redissolved in 100 ml of water, decolorized with 0.5 g of charcoal and evaporated to a syrup. The latter was dissolved in 30 ml of ethanol and made nearly cloudy with dropwise addition of acetone. Crystallization occurred within a week at room temperature. Yield 2.0 g (38%, based on starting Aib ; J 1A,1B = À12.7; J 3,4 = 9.8; J 4,5 = 3.4; J 5,6A = 1.3; J 6A,6B = À12.9.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1A 0.4852 (