Diethyl trans-2,5-bis­(4-methoxy­benzyl­sulfan­yl)-1,4-dimethyl-3,6-dioxopiperazine-2,5-carboxyl­ate

Nathan W Polaske; Gary S Nichol; Bogdan Olenyuk

doi:10.1107/S1600536809022211

. 2009 Jun 17;65(Pt 7):o1583–o1584. doi: 10.1107/S1600536809022211

Diethyl trans-2,5-bis(4-methoxybenzylsulfanyl)-1,4-dimethyl-3,6-dioxopiperazine-2,5-carboxylate

Nathan W Polaske ^a, Gary S Nichol ^a,^*, Bogdan Olenyuk ^a,^‡

PMCID: PMC2969498 PMID: 21582859

Abstract

The title compound, C₂₈H₃₄N₂O₈S₂, was synthesized as part of a project to develop synthetic routes to analogues of sporidesmins, a class of secondary metabolite produced by the filamentous fungi Chaetomium and Pithomyces sp. The complete molecule is generated by crystallographic inversion symmetry: the methoxy group is essentially coplanar with the benzene ring to which it is bonded, a mean plane fitted through the non-H atoms of the aromatic ring and the methoxy group having an r.m.s. deviation of 0.0140 Å. Similarly, the ester group is also essentially planar (r.m.s. deviation of a plane fitted through all non-H atoms is 0.0101 Å). There is only one independent C—H⋯O interaction, which links together adjacent molecules into a two-dimensional sheet in the bc plane.

Related literature

For background information on the biological activity of sporidesmins, see: Fujimoto et al. (2004 ▶); Gardiner et al. (2005 ▶); Li et al. (2006 ▶); Saito et al. (1988 ▶); Waksman & Bugie (1944 ▶). For a discussion on the anti-cancer activity of these compounds, see: Brewer et al. (1978 ▶); Hauser et al. (1970 ▶); Kung et al. (2004 ▶); McInnes et al. (1976 ▶); Waksman & Bugie (1944 ▶). For related crystal structures, see: Isaka et al. (2005 ▶), Dubey et al. (2009 ▶); Polaske et al. (2009 ▶). For synthetic details, see: Hino & Sato (1974 ▶); Kawamura et al. (1975 ▶).

Experimental

Crystal data

C₂₈H₃₄N₂O₈S₂
M _r = 590.69
Monoclinic,
a = 11.290 (2) Å
b = 8.2259 (16) Å
c = 16.593 (3) Å
β = 109.704 (3)°
V = 1450.9 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.24 mm⁻¹
T = 150 K
0.32 × 0.30 × 0.10 mm

Data collection

Bruker SMART 1000 CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.919, T _max = 0.987
11556 measured reflections
3522 independent reflections
2778 reflections with I > 2σ(I)
R _int = 0.028

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.092
S = 1.03
3522 reflections
184 parameters
H-atom parameters constrained
Δρ_max = 0.38 e Å⁻³
Δρ_min = −0.24 e Å⁻³

Data collection: SMART (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXTL, publCIF (Westrip, 2009 ▶) and local programs.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809022211/fj2226sup1.cif

e-65-o1583-sup1.cif^{(18.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809022211/fj2226Isup2.hkl

e-65-o1583-Isup2.hkl^{(172.7KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C5—H5⋯O4ⁱ	0.95	2.43	3.2647 (19)	147

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Symmetry code: (i) Inline graphic .

Acknowledgments

We thank the US National Science Foundation (CHE-0748838 & CHE-9610347) for support.

supplementary crystallographic information

Comment

Sporidesmins are an interesting class of secondary metabolites produced by the filamentous fungi Chaetomium and Pithomyces sp. This diverse class of natural products contains molecules with one or two epidithiodioxopiperazine rings that display a wide variety of biological activities (Waksman & Bugie, 1944; Saito et al., 1988; Fujimoto et al., 2004; Gardiner et al., 2005; Li et al., 2006). While toxic to mammalian cells, recent studies have suggested that certain sporidesmins may possess anticancer activity due to their ability to suppress neovascularization (Waksman & Bugie, 1944; Hauser et al., 1970; McInnes et al., 1976; Brewer et al., 1978; Kung et al., 2004). In the process of developing synthetic methodologies towards the synthesis of sporidesmin natural products, we came across a number of sulfenylated 2,5-piperazinediones whose structures could not be determined with confidence by NMR spectroscopy. Single crystal X-ray diffraction was found to be the only method available capable of unambiguously identifying the structures of these molecules. Herein we report the structure of the title compound (I).

The stucture of (I) is shown in Figure 1. Molecular dimensions are unexceptional and the compound crystallizes with crystallographic inversion symmetry in an extended conformation composed of essentially planar components. The methoxy group is essentially coplanar with the benzene ring to which it is bonded and a mean plane fitted through the non-hydrogen atoms of the aromatic ring and the methoxy group has an r.m.s. deviation of 0.0140 Å. Similarly the ester moiety is also essentially planar (r.m.s. deviation of a plane fitted through all non-hydrogen atoms is 0.0101 Å). The crystal packing has few notable intermolecular interactions; there is only one C–H···O interaction (plus an equivalent related by inversion symmetry) which links together adjacent molecules into a thick two-dimensional sheet in the bc plane.

Experimental

To a dry flask equipped with a stir bar was added 1,4-dimethyl-3,6-diethoxycarbonyl-2,5-piperazinedione (Hino & Sato, 1974) (144 mg, 0.50 mmol), (DHQD)₂PYR (88 mg, 0.10 mmol) and N-(4-methoxybenzylthio)succinimide (Kawamura et al., 1975) (504 mg, 2.0 mmol). The compounds were then dried under vacuum for 15 minutes, followed by the addition of CH₂Cl₂ (2.25 ml). The mixture was allowed to stir at room temperature for 5 days. Once complete, the reaction was quenched with 1M KHSO₄ (3 ml) and extracted with CH₂Cl₂ (3 x 15 ml). The organic extracts were combined, dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, hexane:CH₂Cl₂:EtOAc (5:4:1)) followed by recrystallization from ethanol yielded colorless prisms (236 mg, 80% yield). LRMS (FAB, [M+H]+) found 591.36, C₂₈H₃₅N₂O₈S₂ requires 591.18.