Sporidesmins are a diverse class of natural products containing molecules with one or two epidithiodioxopiperazine (ETP) rings that display a wide variety of biological activities (Waksman & Bugie, 1944
; Saito et al.
; Fujimoto et al.
; Gardiner et al.
; Li et al.
). While toxic to mammalian cells, studies have suggested that certain sporidesmins, namely bis-ETPs chetomin (Waksman & Bugie, 1944
) and chaetocin (Hauser et al.
), may possess anticancer activity due to their ability to suppress neovascularization (Waksman & Bugie, 1944
; Hauser et al.
; McInnes et al.
; Brewer et al.
; Kung et al.
). In order to understand better the chemistry and biology of the bridged bis-ETPs, diketopiperazines (1,4-piperazine-2,5-diones, DKPs) (Martins & Carvalho, 2007
) and bridged bis-DKP structures lacking a disulfide bridge must also be studied. Even in the absence of the disulfide bridge many compounds of this class exhibit a broad spectrum of interesting biological activity. Natural products, such as ditryptophenaline (Springer et al.
), WIN-64821,WIN-64745 (Barrow et al.
; Popp et al.
) and leptosin S (Yamada et al.
) incorporate a 3a,3a′-bispyrrolidinoindoline core with contiguous stereogenic quaternary carbons and display cytotoxicity in various cell lines. Perhaps the most interesting is a C
-symmetrical piperazine-2,5-dione (WIN-64821), which is a competitive substance-P antagonist against the human NK1 receptor at submicromolar concentrations (Barrow et al.
; Popp et al.
; Oleynek et al.
; Sedlock et al.
) and also serves as an antagonist of the cholecystokinin type-B receptor (Hiramoto et al.
). The title compound, (I), was synthesized as part of a wider project to develop new synthetic methods for the preparation of bridged bis-DKPs (Polaske et al.
). Unlike other model compounds, which we observed to crystallize consistently in one form only, this compound crystallizes as at least two polymorphic forms, obtained by different methods of crystallization. The molecular structures of the polymorphs are very different: one adopts a ‘C’ shape, (1), while the other adopts an ‘S’ shape, (2). The ‘S’-shaped polymorph also undergoes a reversible orthorhombic-to-monoclinic phase transition upon cooling (the ‘C’-shaped structure is insensitive to temperature).
The molecular structure of polymorph (1) is shown in Fig. 1. The ‘C’ shape is supported by weak distorted intra- and intermolecular C—H
O interactions (Table 1) and by Cl
Cl interactions (Fig. 2). The Cl1
[symmetry code: (i) x
− 1, y
− 1] distance is 3.445 (4) Å and the pertinent angles are C5—Cl1
= 143.9 (4)° and C22i
Cl1 = 168.9 (5)°. This is slightly longer than the mean Cl
Cl distance of 3.38 Å obtained by a search of the Cambridge Structural Database (CSD, Version 5.30 plus three updates; Allen, 2002
) for Cl
Cl contact distances between two Cl atoms (not including those reported structures with Cl
Cl interactions between dichloromethane and chloroform), yielding 774 hits. Two
(8) rings, one intermolecular and one intramolecular, are formed by C—H
O interactions. In all cases, the C—H
O interactions are weak, with poorly activated H atoms, long H
O distances and the motif is rather distorted. Nevertheless, these motifs represent the favorable arrangement of mildy electropositive and electronegative sites such as to maximize electrostatic interaction; they are not a direct cause of the ‘C’ shape, nor are they merely an effect of the shape.
The ‘C’-shaped molecular structure of polymorph (1), with displacement ellipsoids at the 30% probability level and H atoms omitted.
Table 1 Hydrogen-bond geometry (Å, °) for polymorph (1)
Figure 2 Weak C—HO (dotted blue lines in the electronic version of the paper) and ClCl (dotted green lines) link adjacent molecules of polymorph (1) into a chain. (In the electronic version of the paper, red dotted lines indicate (more ...)
The molecular structure of the polymorph determined at room temperature, (2rt), is shown in Fig. 3. The ‘S’-shaped molecule has crystallographic twofold rotational symmetry and as with polymorph (1) the crystal packing is dominated by an extensive network of weak intermolecular C—H
O interactions (Table 2) with all O atoms acting as bifurcated ‘acceptors’ although as in the case of polymorph (1) the geometry of the interactions and the poorly acidic nature of each donor H atom are indicative of very weak hydrogen bonding. In this structure, but here the Cl1
[symmetry code: (i) 2 − x
, 1 − y
] distance, at 3.319 (1) Å, is shorter than that observed in (1). The arrangement of C—H
O interactions is difficult to visualize with one simple diagram; contacts from the discrete crystallographically unique molecule touch eight adjacent molecules but do not form small cyclic motifs as in (1) and this is most easily seen by considering a perspective c
-axis plot (Fig. 4). In Fig. 4, the discrete unique molecule is shown at the centre of the plot and hydrogen-bonding contacts have been expanded to show all eight acceptor molecules.
Figure 3 The ‘S’-shaped molecular structure of room-temperature polymorph (2rt), with displacement ellipsoids at the 30% probability level and H atoms omitted. [Symmetry code (twofold rotation): (i) −x + 1, − (more ...)
Table 2 Hydrogen-bond geometry (Å, °) for polymorph (2rt)
Figure 4 A perspective c-axis plot of part of the crystal packing of room-temperature polymorph (2rt). The discrete unique molecule in the centre of the plot (colored red in the electronic version of the paper) is surrounded by eight hydrogen-bonding (more ...)
The structural behavior of polymorph (2) was first noted by comparison of experimental X-ray powder diffraction patterns, which were measured at room temperature, with calculated X-ray powder diffraction patterns based on a low-temperature (100 K) single-crystal structure. The two did not match and it was then that a room-temperature single-crystal analysis was carried out. Although we have not carried out a systematic variable-temperature study of this compound, flash cooling to 100 K produces a single-crystal structure, (2lt), with some striking differences when compared with (2rt). The compound undergoes an orthorhombic-to-monoclinic phase transition; the obvious effect of this reduction in symmetry is loss of the twofold axis and consequently loss of crystallographically imposed symmetry on the discrete molecule (Fig. 5). Although the molecule retains an ‘S’ shape, the two piperazinedione rings are able to twist further away from the central benzene ring. In (2lt), the torsion angles about the methylene linker are 109.9 (3) (C2—C8—C9—C14) and 94.2 (4)° (C13—C12—C15—C16), whereas in (2rt) the equivalent torsion angle is 76.0 (3)°. This reduction in symmetry also causes the onset of nonmerohedral twinning in the monoclinic structure; this is typical behavior in such situations. The crystal packing of (2lt) is not significantly different from that of (2rt) except that the twisting of the piperazinedione rings causes a change in the weak hydrogen-bonding geometry (Table 3), resulting in shorter H
O distances. For example, in (2rt), the approximate distance between H2 and O1i
[symmetry code: (i)
, 1 − z
] is approximately 2.81 Å; in (2lt) the equivalent distance, H2
[symmetry code: (vi) −x
, 1 − z
] is approximately 2.56 Å. The Cl1
[symmetry code: (ii) x
− 1] distance in (2lt) is the shortest of all three structures at 3.2414 (11) Å. This behaviour of polymorph (2) was found to be reversible and the crystal suffered no physical defects (e.g.
cracking) as a result of the phase change.
The ‘S’-shaped molecular structure of low-temperature polymorph (2lt), with displacement ellipsoids at the 30% probability level and H atoms omitted.
Table 3 Hydrogen-bond geometry (Å, °) for polymorph (2lt)
In summary, two polymorphs of the title compound have been identified. Both polymorphs differ entirely in their molecular conformation and consequently in the crystal packing. ‘C’-shaped monoclinic polymorph (1) is insensitive to temperature change; ‘S’-shaped polymorph (2) is orthorhombic at room temperature but forms a monoclinic nonmerohedrally twinned structure when flash cooled to 100 K. The weak inter- and intramolecular interactions in (1) are more conducive to retaining the ‘C’ shape as is and probably prevent such temperature-induced behavior.