5-Amino-1-(2′,3′-O-isopropylidene-d-ribityl)-1H-imidazole-4-carboxamide: a crystal structure with Z′ = 4

The title compound crystallizes in the monoclinic space group P21, with four crystallographically independent molecules, having a very similar conformation, in the asymmetric unit. The cluster of independent molecules has approximate non-crystallographic C 2 point symmetry.

5-Amino-1-(2 0 0 0 ,3 0 0 0 -O-isopropylidene-D-ribityl)-1Himidazole-4-carboxamide: a crystal structure with Z 0 0 0 = 4 Vincenzo Piccialli, a * Nicola Borbone, b Giorgia Oliviero, b  The title compound, C 12 H 20 N 4 O 5 , crystallizes in the monoclinic space group P2 1 , with four crystallographically independent molecules in the asymmetric unit. The four molecules have a very similar conformation that is basically determined by the formation of two intramolecular hydrogen bonds between the amino NH 2 donors and the carbonyl and ring O-atom acceptors, forming, respectively, R(6) and R(7) ring motifs.. In the crystal, intermolecular hydrogen bonding leads to the formation of R 2 2 (10) ring patterns, involving one amide CONH 2 donor and an imidazole N-atom acceptor. The cluster of the four independent molecules has approximate non-crystallographic C 2 point symmetry. The structural analysis also shows that during the synthesis of the title compound, the reductive cleavage of the d-ribose ring of the inosine precursor proceeds stereoselectively, with retention of configuration.

Chemical context
Our group has long been involved into the synthesis of new heterocyclic compounds ;  including novel bioactive nucleoside and nucleotide analogues (Galeone et al., 2002). The latter are synthetic compounds that have been developed to mimic their natural counterparts (Jordheim, et al., 2013). Several nucleoside and nucleotide analogues have been approved by the FDA for viral and cancer diseases and others have entered clinical trials. Therefore, the synthesis of new nucleoside analogues with potential biological activities (D'Atri et al., 2012) continues to be a keen research field. Recent efforts from our group in this field have been directed to the synthesis of sugar and/or base-modified nucleosides (D'Errico et al., 2012a;de Champdorè et al., 2004) and nucleotides, mixing the principles of combinatorial chemistry with those of high-throughput screening. Within this framework, we have pioneered the development of a synthetic solid-phase strategy (Oliviero et al., , 2008(Oliviero et al., , 2010aD'Errico et al., 2011D'Errico et al., , 2015 that has also allowed us to synthesize N-1 alkyl inosines and 5aminoimidazole-4-carboxamide riboside (AICAR) analogues (D'Errico et al., 2012b), starting from cheap inosine. AICAR is a purine biosynthetic precursor that acts as a modulator of a number of biological properties. Once in the cells, AICAR is 5 0 -phosphorylated to ZMP, a mimic of adenosine 5 0 -monophosphate (AMP). The direct binding of ZMP to an allosteric site of AMPK causes its phosphorylation and activation by a cellular kinase, resulting in a series of important metabolic events, including the inhibition of the basal and insulinstimulated glucose uptake, the inhibition of lipid synthesis and the activation of certain ATP-generating processes such as glycolysis and fatty acid oxidation. Nevertheless, AICAR is far from being a good drug lead-compound because it has a short half-life in cells and is not strictly specific for the AMPK enzyme. The discovery of the antiviral activity of acyclovir and acyclic nucleoside phosphonates has suggested that the replacement of the furanose ring with a hydroxylated alkyl chain could induce new biological activities. Based on these precedents, we have recently reported the synthesis of a small collection of 5-aminoimidazole-4-carboxamides carrying a dribityl chain at the N1-imidazole position, including the title compound .

Structural commentary
The asymmetric unit of the title compound contains four independent molecules with identical configuration (Z 0 = 4). The molecular structure of one molecule (A) is shown in Fig. 1 as an example. The molecular conformation is basically determined by the formation of two intramolecular hydrogen bonds (Table 1) between the amino NH 2 donors and, respectively, the carbonyl (O5) and the ring (O1) acceptors, which form, respectively, R(6) and R(7) ring motifs. The formation of the intramolecular hydrogen bonds is possible because of the pyramidal geometry of the N atom; the sums of valence angles around atoms N3A, N3B, N3C and N3D are, respectively, 336, 339, 334  A view of the molecular structure of one of the four crystallographically independent molecules (A) of the title compound. Displacement ellipsoids are drawn at the 30% probability level. Intramolecular hydrogen bonds are represented by dashed lines (see Table 1).
The title compound was obtained starting from commercial 2 0 ,3 0 -O-isopropylidene inosine (compound 1 of Fig. 2) through a synthetic route involving four steps. In the first step [(i) of Fig. 2], the ribose ring is opened by reductive cleavage of the C1 0 -O4 0 bond of 2 0 ,3 0 -O-isopropylidene inosine. The configuration of atom C4 0 (C6A in Fig. 1) in the title compound is R and this confirms the stereoselectivity of the reductive ribose opening.
The four independent molecules have a similar conformation. This can be inferred from Fig. 3, in which they are overlayed, and from Table 2 in which some parameters of the Hirshfeld surface of the four molecules are presented (Spackman & McKinnon, 2002).

Supramolecular features
In the crystal of the title compound, the cluster of the four crystallographically independent molecules (A, B, C, D) has approximate non-crystallographic C 2 point symmetry, around a direction parallel to b/2 + c, see Fig. 4a. Actually, the presence of non-crystallographic, local symmetry, is not uncommon in high Z 0 structures (Brock, 2016). Molecules are held in the crystal through a complex pattern of hydrogen bonds (Table 1). In particular, the independent molecules A and C are hydrogen bonded through an R 2 2 (10) ring pattern, involving one amido CONH 2 donor and the imidazole N acceptor (Table 1 and Fig. 4b). An analogous pattern is formed between molecules B and D. As is evident from Fig. 4a, in the cluster of four independent molecules, the pair of molecules (A and C) that are bonded through the R 2 2 (10) ring pattern produce a hollow in which the methyl groups of the other pair (B and D) are fitted.

Hirshfeld surface analysis
In order to assess possible packing differences involving the four independent molecules, we have examined their Hirshfeld surfaces (Spackman & McKinnon, 2002). The Hirshfeld fingerprint plots of the four independent molecules are illustrated in Fig. 5. The fingerprint plot is a graphical twodimensional map that indicates the distribution of the interactions for a single molecule in the crystal (Spackman & McKinnon, 2002). In the plot, for each point of the Hirshfeld surface enveloping the molecule in the crystal, the distance d i to the nearest atom inside the surface and the distance d e to the nearest atom outside the surface are reported. The colour of each point in the plot is related to the abundance of that interaction, from blue (low) to green (high) to red (very high). A distinctive feature of each plot of Fig Overlay of the four crystallographically independent molecules (A, B, C and D) of the title compound, viewed in two different orientations. Table 2 Parameters (Å 2 , Å 3 ) of the Hirshfeld surface of the four crystallographically independent molecules A, B, C and D).    Table 1). (b) The pair of independent molecules, A and B, with indication of some hydrogen-bonding patterns (dashed lines; see Table 1).
plots and symmetrically disposed with respect to the diagonal. They correspond to the strong hydrogen bonds present in the crystal packing. Another common feature is the sting along the diagonal, at d i = d e = 1.05 Å , which reflects points on the Hirshfeld surface that involve nearly head-to-head HÁ Á ÁH contacts. Although none of the four plots of Fig. 5 is superimposable on the others, they all look very similar, thus indicating that the packing around each molecule is similar.

Synthesis and crystallization
The title compound, was synthesized starting from 2 0 ,3 0 -Oisopropylidene inosine (1 in Fig. 1), as described recently (D'Errico et al., 2013). In particular, compound 3 (0.18 mmol) was dissolved in DMF (2.0 ml) and then ethylene diamine (EDA, 3.6 mmol) was added. The mixture was stirred at 323 K for 16 h (TLC monitoring: CHCl 3 /MeOH, 8:2) and then the solvents were removed under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with increasing amounts of MeOH in CHCl 3 (from 0 to 10%). The fractions containing the title compound were collected and solvents evaporated under reduced pressure. The obtained pale-yellow amorphous solid (71% yield) was dissolved in the minimal amount of CH 3 OH and left to slowly evaporate at 277 K, to give pale-yellow prismatic crystals.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The H atoms bonded to O and N atoms were located in difference Fourier maps and their coordinates were refined. The C-bound H atoms were included in calculated positions and refined as riding atoms: with C-H = 0.96-0.98 Å . For all H atoms, U iso = 1.2U eq of the carrier atom was assumed (1.5 in the case of the H atoms of methyl groups).     Data collection: COLLECT (Nonius, 1999); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: WinGX (Farrugia, 2012).

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.