Crystal structure of tetrahydroseselin, an angular pyranocoumarin

The title compound, tetrahydroseselin (THS), a hydrogenated product of the angular pyranocoumarin seselin, possesses photo-biological activity against different kinds of inflammatory skin diseases such as atopic dermatitis and pigment disorders like vitiligo and psoriasis.


Chemical context
The title molecule, tetrahydroseselin, a hydrogenated product of an angular pyranocoumarin, seselin, consists of three different kinds of fused rings: a central benzene ring, an outer pyrone ring and a pyrane ring with dimethyl substituents attached at C3. These pyranocoumarins have absorption bands in the near UV region resulting from the presence of conjugated double bonds in the enone system and exhibit photo-mutagenic and photo-carcinogenic properties (Appendino et al., 2004), which bind with the purine base of DNA in living cells to yield photo-adducts (Conforti et al., 2009). Based on this property, the molecules are used to treat numerous inflammatory skin diseases such as atopic dermatitis and pigment disorders like vitiligo and psoriasis, through exposure to UV radiation in photo dynamic therapy (PDT). Because of their strong ability to absorb UV radiation, these classes of molecules are utilized as photo-protective agents to prevent the absorption of harmful UV radiation by the skin, in the form of a variety of sun-screening lotions widely used in dermatological applications in the cosmetic and pharmaceutical industries (Chen et al., 2007(Chen et al., , 2009. Also, in vitro antiproliferative activity and in vivo photo-toxicity against numerous cancer cell lines, e.g. HL60 and A431, has been observed (Conconi et al., 1998). In addition, this class of coumarins have been successfully used in the treatment of inhibited proliferation in the human hepatocellular carcinoma cell line (March et al., 1993). Experimental results have shown that its photo-toxicity is extended via a Diels-Alder reaction to bind the double bond of a purine base of DNA in the living cell with the double bonds of coumarin to yield mono [(2 + 2) cycloaddition] and diadducts [(4 + 2) cycloaddition] (Conforti et al., 2009). As a part of our studies in this area, we are looking at the role of double bonds in the photo-biological activity of the aforesaid molecule. The crystal structure of the

Structural commentary
In the title compound, the three different fused rings comprising the molecule (Fig. 1), are the central benzene ring (C1/C5-C12), the outer pyrone ring (O2/C6-C7) and the dihydropyrane ring (O1/C1-C2), with dimethyl substituents attached at C3. The mean planes of these rings (O1/C1-C2 and O2/C6-C7) are inclined to the benzene plane by 6.20 (7) and 10.02 (8) , respectively. The angles between the mean plane of the benzene ring and the four planar atoms of each pyran ring (O1/C1-C2) and (O2/C6-C10) are 3.0 (1) (r.m.s. of the fitted atoms = 0.0092 Å ) and 2.6 (1) (r.m.s. of the fitted atoms = 0.0046 Å ), respectively. Both rings are in half-chair conformations and atoms C2, C3, C7 and C8 deviate by 0.282, 0.446, 0.241 and 0.687 Å , respectively, from the plane through the other four essentially planar atoms of the respective pyran rings. These distortions of the dihydropyran rings are probably the result of the ring flexibility and the presence of the methyl substituents. Experimental results from the title compound reveal that the photo-biological activity of the parent compound seselin has been diminished due to the formation of distorted half-chair conformations of the pyran rings on hydrogenation. The C6-C5-C1-O1 and C11-C10-C6-O2 torsion angles are almost the same viz. 178.44 (12) and 178.73 (14) , respectively, indicating that these rings are coplanar. The destruction of photo-biological activity and change of conformation of the pyran rings of the title molecule is considered to be due to the loss of the double bonds in seselin.

Supramolecular features
In the crystal, no formal hydrogen bonds are present but the molecules exhibit very weak intermolecular C-HÁ Á ÁO interactions; none of these, however, can be considered as hydrogen bonds. Examples are: aromatic C8-HÁ Á ÁO2 i (ring)   The molecular structure of title compound, showing the atomic labelling. with displacement ellipsoids drawn at the 50% probability level

Synthesis and crystallization
The title compound was isolated as a colourless solid substance from the methanol extract of T. stictocarpum (in the local dialect, it is known as Aajmoda) by means of column chromatography over SiO 2 gel by gradient elution with a binary mixed solvent system of hexane and ethyl acetate. It was purified by reverse phase high-pressure liquid chromatography (RP-HPLC) followed by crystallization to yield a colourless product. This compound was subjected to hydrogenation using Pd/C in a protic solvent (MeOH) at room temperature with continuous mechanical stirring overnight. The reaction product was worked up by the usual method to yield a crude product, which was was purified by column chromatography over SiO 2 gel with gradient solvent elution to yield the pure title compound. Suitable crystals for X-ray diffraction analysis were obtained after recrystallization (Â3) from ethyl acetate:hexane (1:4), by slow evaporation at room temperature. 1 H NMR data (CDCl 3 , 200 MHz): H 7.25 (d, 1H, J = 8.6 Hz, H-12), 6.68 (d, 1H, J = 8.6 Hz H-11), 2.40 (t, 1H, J = 6.6 Hz, H-4), 2.35 (t, 1H, J = 6.4 Hz, H-9), 2.26 (t, 2H, J = 6.4 Hz, H-8), 1.56 (t, 2H, J = 6.6 Hz, H-3), 1.50 (s, 3H, CH 3 , H-13), 1.54 (s, 3H, CH 3 , H-14).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. All H atoms were located in difference-Fourier maps and the positional coordinates of all except the methyl H atoms were allowed to refine, with U iso (H) = 1.2U eq (C). Those on methyl groups were allowed to ride with C-H = 0.96 Å and with U iso (H) = 1.2U eq (C).  Extinction correction: SHELXL97 (Sheldrick, 2008), Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.089 (5)