Four pyrrole derivatives used as building blocks in the synthesis of minor-groove binders

The title nitropyrrole-based compounds are intermediates used in the synthesis of modified DNA minor-groove binders. They are ethyl 4-nitro-1H-pyrrole-2-carboxylate, its derivative ethyl 4-nitro-1-(4-pentynyl)-1H-pyrrole-2-carboxylate, N-[3-(dimethylamino)propyl]-1-isopentyl-4-nitro-1H-pyrrole-2-carboxamide and 1-(3-azidopropyl)-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-N-[2-(morpholin-4-yl)ethyl]-1H-pyrrole-2-carboxamide.


Chemical context
Over the past two decades, the field of minor-groove binders (MGBs) has expanded vastly and now these compounds display a wide spectrum of biological activities, such as antibacterial, antifungal, antiparasitic and anticancer activities. A large number of structural modifications have been carried out on the original, naturally occurring compounds distamycin and netropsin, in order to optimize their biological activities (Lang et al., 2014). In addition to modifying the biological activities, structural changes have been made to the head group, tail group and the heterocyclic moieties in order to modulate their solubility, selectivity and the degree of binding to the minor groove of DNA (Alniss et al., 2014). We have recently turned to developing MGB-biotin hybrid molecules to be used as novel biochemical probes in order to determine the mechanism of action of MGBs. Structural information is important in this field, as intermolecular contacts are important for minor-groove binding and molecular conformation is relevant to structure-activity and model building (Chenoweth & Dervan, 2009). This paper details the crystal structures of a number of key building blocks that have facilitated this molecular probe development.

Figure 2
The molecular structure of compound (II), with the atom labelling and 50% probability displacement ellipsoids.

Figure 3
The molecular structure of compound (III), with the atom labelling and 50% probability displacement ellipsoids.

Figure 1
The molecular structure of compound (I), with the atom labelling and 50% probability displacement ellipsoids.

Figure 4
The molecular structure of compound (IV), with the atom labelling and 50% probability displacement ellipsoids.
The molecular structure of compound (III) is shown in Fig. 3. It has the same 4-nitro pyrrole core as compounds (I) and (II) but has an amide substituent rather than an ester, and the pyrrole N atom now bears an iso-pentyl fragment. The introduction of the basic tail group, in this case the dimethylaminopropyl moiety, is a crucial feature for biological activity in these MGBs. The nitro group is again coplanar with the pyrrole ring, with torsion angle O2-N2-C2-C1 = 179.34 (15) , but both the other substituents lie out of the plane of the pyrrole ring.
The final structure reported, compound (IV), is illustrated in Fig. 4. It is another example of a compound containing a moiety that can be functionalized with click chemistry, this time an azide. Here, there are two pyrrole rings present, one of which is a 4-nitro pyrrole as found in compounds (I), (II) and (III). As with the previous structures, the nitro group is essentially coplanar with the pyrrole ring [torsion angle O4-N6-C15-C14 = À2.8 (3) ] and this coplanarity extends to the second pyrrole ring and through both amide groups [torsion angles O3-C12-C13-N5, C12-N4-C10-C11 and O2-C7-C8-N3 are 3.1 (3), 5.5 (3) and À2.9 (3) , respectively]. The amide O atoms and the pyrrole N atoms are all mutually syn with respect to the molecular axis running through them.

Supramolecular features
In the crystal of (I), a primary hydrogen-bonding interaction is formed, as would be expected, between the N-H donor and the carbonyl acceptor. This gives a centrosymmetric R 2 2 (10) motif. A weaker secondary centrosymmetric R 2 2 (10) hydrogenbonding motif is also present; see Fig. 5 and Table 1. This is formed by a pyrrole C-H donor and an O atom of the nitro group. Both hydrogen-bonded ring motifs are approximately coplanar with molecular (I) and thus a two-dimensional supramolecular structure results with layers of molecules parallel to plane (101). Interactions between the layers are both through dipole-to-dipole contacts [nitro-to-carbonyl NÁ Á ÁC distance = 3.174 (4) Å ] and throughcontacts [closest C-to-C distance, C1Á Á ÁC4, is 3.304 (4) Å ]. The layered structure of (I) seems to be reflected in its crystal morphology. The samples were stacked thin plates. An approximately single sample was obtained by cutting -but some degree of nonsingle nature is reflected in the slightly high R factors and the higher than expected residual electron density.

Figure 5
The crystal packing of compound (I), viewed along the c axis. The intermolecular interactions (See Table 1) are shown as dashed lines. For clarity, only the H atoms involved in these interactions have been included.

Figure 6
The crystal packing of compound (II), viewed along the a axis. The intermolecular interactions (See Table 2) are shown as dashed lines. For clarity, only the H atoms involved in these interactions have been included.
dipole-dipole-type contacts involving the nitro group and, perhaps surprisingly, the carbonyl group is not involved in the intermolecular hydrogen bonding. There is a short intramolecular contact [O1Á Á ÁC8 = 2.925 (2), O1Á Á ÁH8A = 2.41 Å ] which may disfavour intermolecular bonding here.
In the crystal of (III), the amide N-H group can be described as acting as a bifurcated donor giving two hydrogen bonds (Table 3 and Fig. 7), forming a short contact with the amide C O group and a much longer contact to an O atom of a nitro group. These combine to give an R 4 2 (16) motif, shown in Fig. 7. The carbonyl group also makes an intramolecular C-H-to-O contact similar to that found in the structure of (II) [O3Á Á ÁC5 = 2.970 (2), O3Á Á ÁH5A = 2.40 Å ; see Table 4]; however, here, with a strong N-H hydrogen-bond donor available, this is not enough to prevent O3 taking part in other contacts. The structure of (III), composed of hydrogenbonded layers parallel to the bc plane, features no shortor dipole-dipole contacts.
In the crystal of (IV), there are two classical N-HÁ Á ÁO hydrogen bonds (Table 4 and Fig. 8) that involve both of the amide N-H groups, but surprisingly only one of the potential amide C O acceptors. The other acceptor O atom is O5 of the nitro group. These hydrogen bonds combine to give layers parallel to the bc plane. As with (II), the reason for the second amide carbonyl group not acting as a classical hydrogen-bond acceptor may lie with a short intramolecular contact [O3Á Á ÁC11 = 2.765 (3) Å , O3Á Á ÁH11 = 2.27 Å ; see Table 4].
The remaining shortest intermolecular contact involves the terminal N atom of the N 3 group. This forms a short contact with the methyl carbon C17 [N9Á Á ÁC17 ii 2.968 (3) Å ; symmetry code: (ii) = Àx + 1, Ày, Àz + 1) and these contacts form the primary bridges between the layers described above.

Figure 7
The crystal packing of compound (III), viewed along the a axis. The intermolecular interactions (See Table 3) are shown as dashed lines. For clarity, only the H atoms involved in these interactions have been included.

(I) Ethyl 4-nitro-1H-pyrrole-2-carboxylate
Special details Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq O1 0.6535 (2) 0.5757 (2) 0.6758 (3) 0.0334 (7)   Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq O1 0.67236 (15) −0.08852 (7) 0.29527 (11) 0.0320 (3)     where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.33 e Å −3 Δρ min = −0.27 e Å −3 Special details Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > 2σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.