Crystal structure of 7,8,15,16,17-pentathiadispiro[5.2.59.36]heptadecane

A dispiro compound bearing two cyclohexyl moieties and a central sulfur-rich seven-membered ring was re-synthesized and newly crystallized. The modified synthetic procedure, the compound’s purification and characterization and the crystal structure – which is only the second of its kind – including non-classical hydrogen-bonding interactions are reported and discussed.


Chemical context
Cyclic polysulfides comprise a subgroup of pharmacologically interesting organosulfur compounds that -depending on constitution and conformation -have been shown to exert specific antibacterial, antifungal, allelopathic and cytotoxic activity (Davison & Sperry, 2017), as well as a plethora of H 2 Smediated effects relying on H 2 S formation (Szabo & Papapetropoulos, 2017). The benefits imparted by these compounds have led to the evolution of synthetic pathways in many natural products, as well as organoleptic detection mechanisms in organisms confronted by them, including the senses of smell and taste in humans. Thus, volatile organic polysulfanes are among the most odorous compounds in natural products, including meat (Zhao et al., 2019), plants (Liang et al., 2017), and algae (Block et al., 2017). In fungi, 1,2,4-trithiolane, 1,2,4,6-tetrathiepane, and 1,2,3,4,5,6-hexathiepane have been found to contribute to the unique aroma of shiitake (Lentnius edodes), but it is 1,2,3,5,6-pentathiepane (lenthionine) that combines the most potent biological (antibacterial, antifungal, and anti-coagulative) and sensory activity (Davison & Sperry, 2017). Structural characterizations of this type of compounds are rather rare. The very few reports available in the literature include the crystal structures of pentathiepanes featuring two vicinal carbon atoms (Sugihara et al., 1999). The conformational study of the title compound, 7,8,15,16,17-pentathiadispiro[5.2.5 9 .3 6 ]heptadecane (C 12 H 20 S 5 ), is supposed to aid in the elucidation of the mechanism of action by which naturally occurring and synthetic pentathiepanes exert potent activity (Behnisch-Cornwell et al., 2019) and to advance the application of lenthionine derivatives for medical and material purposes (Tanagi et al., 2019).

Structural commentary
The title compound 7,8,15,16,17-pentathiadispiro[5.2.5 9 .3 6 ]heptadecane, C 12 H 20 S 5 , crystallizes in the monoclinic space group P2 1 /c. The molecule constitutes the asymmetric unit while Z =4. The title compound consists of three rings in a corner-sharing juxtaposed arrangement (Fig. 1). The two outer cyclohexyl rings are both in a typical, rather unremarkable, chair conformation. They are connected to the central ring via spiro carbon atoms, which are tethered to each other by one S 2 and one S 3 moiety, thereby forming the central sevenmembered ring. Crystal structures of such heterocyclic rings bearing five sulfur atoms in groups of two and three plus two carbon atoms are extremely rare, with only one example being available to date (Mloston et al., 2002; refcode: MOSYOI in the CSD, version 5.40, March 2019; Groom et al., 2016). In MOSYOI, the cyclohexyl substituents of this structure are replaced by 2,2,4,4-tetramethylcyclobutan-1-one moieties. The arrangement of the seven atoms of the central ring appears to be quite inflexible, at least in the solid state, as emphasized by an overlay of the two structures ( Fig. 2), which shows distances of the overlayed atoms all well below 0.1 Å and an r.m.s. deviation of 0.0846 Å . Considering that the four-membered and heavily substituted rings in MOSYOI (Mloston et al., 2002) are much more strained than the cyclohexane rings in the title compound, the conserved conformation of the central ring points towards the observed arrangement being thermodynamically rather favorable. In the context of investigating these compounds as pharmaceutical leads, such highly conserved structural motives are quite beneficial. The mean planes of the two cyclohexane rings, calculated from the positions of the six carbon atoms (Mercury software; Macrae et al., 2006), enclose an angle of 21.96 (9) , i.e. the two rings are not coplanar. The angles between the plane calculated from the positions of all seven atoms of the central ring and both cyclohexane-derived planes are 82.90 (5) (C1 ! C6) and 76.79 (5) (C7 ! C12), which are both close to perpendicular. This is similar in MOSYOI, with the four-membered rings being nearly perpendicular to the central seven-membered ring. The sulfur-sulfur bond distances range from 2.026 (1) to 2.035 (1) Å , which is a little bit shorter than the sum of the covalent radii of 2.06 Å (Pyykkö & Atsumi, 2009). The shortest S-S distance is between the two sulfur atoms of the S 2 moiety, while the S 3 moiety is slightly unsymmetrical [2.028 (1) and 2.035 (1) Å ]. The shorter S-S bond in the S 3 moiety is the one that points towards a non-classical hydrogen-bonding contact (vide infra), implying that this interaction might influence the relative distances in the S 3 fragment. The angles involving central S atoms range from 105.16 (5) (around S1) to 106.89 (5) (around S3) while the S-C-S angles are slightly wider with 111.58 (7) (around C1) and 114.31 (7) (around C7), i.e. they are more and less acute, respectively, than the ideal tetrahedral angle.

Supramolecular features
In the crystal packing all molecules are oriented along parallel lines, although turned/flipped alternately by roughly 180 around the molecules' approximate longitudinal axes through the three rings which rest on crystallographic glides in the ac planes. The crystallographic direction of these vectors approximates [401]. The crystal packing is stabilized by nonclassical hydrogen-bonding contacts between the central sulfur atom (S2) of the S 3 fragment as acceptor and a C-H of one cyclohexyl moiety (C6-H6B) as donor, pointing roughly into opposite directions and protruding along the c-axis direction (C6-H6BÁ Á ÁS2 i and S2Á Á ÁH6B ii -C6 ii ; symmetry codes: (i) x, 3 2 À y, 1 2 + z, (ii): x, 3 2 À y, À 1 2 + z) ( Fig. 3 and Table 1).

Synthesis and crystallization
The title compound was synthesized based on a modified literature procedure (Magnusson, 1959). A 20% aqueous solution of ammonium polysulfide (63.9 ml, 187 mmol) was cooled to 273 K and added dropwise over 10 min to stirred cyclohexanone (25.8 ml, 250 mmol) cooled to the same temperature, leading to a uniform mixture of yellow color.   The molecular structure of 7,8,15,16,17-pentathiadispiro[5.2.5 9 .3 6 ]heptadecane. Ellipsoids are shown at the 50% level.
Deviating from the reported procedure, addition of colloidal sulfur (4.0 g, 125 mmol), albeit quickly dissolving, leads to liquid-liquid phase separation and a change of color from yellow to green. After stirring for 24 h at 295 K, 100 ml of 10% aqueous acetic acid was added to the reaction mix, which then was extracted in 3 Â 50 ml of diethyl ether. The organic fractions were combined and washed with aqueous, saturated NaHCO 3 (1Â100 ml) and water (1Â100 ml), before being dried over Na 2 SO 4 . The solvent was reduced to 5 ml in vacuo and adsorbed onto isolute1 HM-N, prior to purification by flash chromatography (silica 60, 20-45 mm particle diameter, 5 cm column diameter, 50 cm column length, 15 ml min À1 ethyl acetate (0-25%) in n-hexane, detection by thin layer chromatography and fluorescence quenching at 254 nm). Recrystallization from 0.1 ml mg À1 methanol yielded colorless block-like crystals, the identity of which was confirmed by melting point determination (356.5 K). As a result of the lipophilic nature of the analyte, the purity and stability of the colorless product was accessible to supercritical fluid chromatography (stationary phase: Torus DIOL column, mobile phase: scCO 2 (A) and methanol containing 20 mM ammonium formate (B), isocratic mode (5% B), oven temperature: 313 K). Yield: 5.0 g (14%

Figure 3
Crystal & Cie, 2010); program(s) used to solve structure: SHELXT2018 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2006); software used to prepare material for publication: CIFTAB (Sheldrick, 2015). 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.