(2E,4E,6E)-3-Methyl-7-(pyren-1-yl)octa-2,4,6-trienoic acid

The title compound, C25H20O2, was synthesized by a Wittig reaction between triphenyl[1-(pyren-1-yl)ethyl]phosphonium bromide and ethyl (2E,4E)-3-methyl-6-oxohexa-2,4-dienoate, in the presence of n-butyl lithium, followed by saponification. It was obtained pure in the all-trans configuration following crystallization from ethyl acetate. The asymmetric unit contains two independent molecules (A and B), which are arranged almost parallel to each other within the crystal structure. The triene chain is not coplanar with the pyrene ring system, forming dihedral angles of 52.8 (1) and 42.2 (1)° for molecules A and B, respectively. Intermolecular hydrogen bonds between the carboxyl groups of the molecules link them into centrosymmetric pairs, AA and BB, each with the R 2 2(8) graph-set motif.

The title compound, C 25 H 20 O 2 , was synthesized by a Wittig reaction between triphenyl[1-(pyren-1-yl)ethyl]phosphonium bromide and ethyl (2E,4E)-3-methyl-6-oxohexa-2,4-dienoate, in the presence of n-butyl lithium, followed by saponification. It was obtained pure in the all-trans configuration following crystallization from ethyl acetate. The asymmetric unit contains two independent molecules (A and B), which are arranged almost parallel to each other within the crystal structure. The triene chain is not coplanar with the pyrene ring system, forming dihedral angles of 52.8 (1) and 42.2 (1) for molecules A and B, respectively. Intermolecular hydrogen bonds between the carboxyl groups of the molecules link them into centrosymmetric pairs, AA and BB, each with the R 2 2 (8) graph-set motif. Mo K radiation = 0.08 mm À1 T = 100 K 0.21 Â 0.17 Â 0.14 mm
Data collection: CrysAlis CCD (Oxford Diffraction, 2008); cell refinement: CrysAlis RED (Oxford Diffraction, 2008); data reduction: CrysAlis RED; program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009) and Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX (Farrugia, 1999) and publCIF (Westrip, 2009). therapeutic efficacy to toxicity index and to provide better selectivities for various therapeutic applications. These analogs usually involve changes in the lipophilic part of the molecules and/or the tetraene chain. A well known such example is acitretin (2) which is currently the drug of choice for treating psoriasis and has been shown to exert its effect indirectly, that is not by binding to the retinoid receptors but by displacing ATRA from its cellular binding proteins (CRABPs) (Tian et al., 1997). Recently, the crystal structures of three polymorphic forms (I, II and III) of acitretin have been determined (Malpezzi et al., 2005) as well the crystal structures of the acitretin analog 3 (O-demethylated acitretin) and ATRA analog 4, in which the double bond adjacent to the ring is restricted within an aromatic ring, in complex with CRABP II (Chaudhuri et al., 1999). Both in the crystal structures of acitretin and its analog 3 the aromatic ring and the polyene chain are not coplanar but form dihedral angles of maximum 38.4° (forms I and II) and 60.8° (form III) and 56°, respectively, whereas in the crystal structure of ATRA analog 4, a charge/π-cloud interaction between the aromatic ring and Arg59 residue is identified (Chaudhuri et al., 1999) which might account for the somewhat stronger binding of 4 to CRABP II binding domain. We therefore considered of interest to combine structural features from the lipophilic parts of acitretin and ATRA analog 4.
Indeed, reduction of the commercially available 1-acetylpyrene (6) with NaBH 4 , followed by treatment of the thus obtained alcohol with Ph 3 P.HBr, provided the phosphonium salt (7) (Fig. 2). This salt was subjected to a Wittig reaction with the unsaturated aldehyde 8 (Meyer et al., 1978) using n-BuLi as the base to obtain ester 9 as a mixture of geometric isomers. Finally, saponification and recrystallization of the thus obtained acid from ethyl acetate provided the title compound (5).
Only the all-E isomers of compounds 8 and 9 are drawn in Figure 2.
We now wish to report the results of the X-ray crystallographic analysis of acitretin analog 5. Its asymmetric unit contains two symmetry-independent molecules (labelled A and B) which are arranged almost parallel to each other within the crystal structure and have their carboxylic ends pointing in the same direction (Fig. 3). Molecules A and B have an enantiomeric-type relationship and a least-squares fit of A (blue) and B (red) within the asymmetric unit is presented in Fig. 4. The pyrene ring system of the two independent molecules shows a planar arrangement; the r.m.s. deviation of the sixteen atoms consisting supplementary materials sup-2 this system is 0.042 Å and 0.019 Å for A and B, respectively. The triene chain of each molecule A and B forms with the corresponding pyrene system a dihedral angle of 52.8 (1)° and 42.2 (1)°, respectively.
The carboxylic moiety of each molecule forms strong intermolecular hydrogen bonds with a neighbouring centrosymmetric molecule (Table 1), thereby linking them into elongated AA and BB dimers located on crystallographic inversion centres; those interactions can be described by the classic graph-set motif of R 2 2 (8) (Bernstein et al., 1995). Similar centrosymmetric hydrogen-bonded dimers have also been observed in form II of acitretin (Malpezzi et al., 2005). The formation of such dimers excludes the possibility of the presence of specific supramolecular arrangements such as chains or layers. The packing of the dimers within the crystal structure is accomplished through normal van der Waals contacts.

Experimental
To an ice-cold solution of 1-acetylpyrene (0.73 g, 3 mmol) in MeOH/diglyme (3:7, 6 ml), NaBH 4 (0.29 g, 7.6 mmol) was added portionwise in 15 min. The resulting reaction mixture was stirred at this temperature for 45 min. Excess NaBH 4 was destroyed by adding icechips. The product was extracted with EtOAc, the organic layer was washed twice with H 2 O, dried over Na 2 SO 4 and evaporated to dryness to leave the corresponding alcohol (0.71 g, 96% yield) as a pale yellow solid and had R f (PhMe) 0.11. This alcohol was treated with Ph 3 P.HBr (2.0 g, 5.76 mmol) in MeCN/THF (7:3, 6 ml) at 80 o C for 12 h.
After evaporation of the solvents, trituration with Et 2 O and overnight refrigeration, the corresponding phosphonium salt 7 was obtained as pale yellow solid (1.35 g, 82%) and used as such without further purification into the following experiment.
A solution of phosphonium salt 7 (1.03 g, 1.8 mmol) in THF (1.5 ml) and DMPU (0.5 ml) was cooled at -10 o C and a 1.6 M solution of n-BuLi in hexanes (1.35 ml) was added dropwise. The resulting dark red solution was left to vigorously stirring over 30 min at this temperature. Then, temperature was set at -78 o C and aldehyde 8 (0.15 g, 0.9 mmol) was added.
The resulting reaction mixture was left to stir at -78 o C over 30 min and then to attain room temperature for 12 h. Excess n-BuLi was destroyed by careful addition of a 5% aqueous solution of NH 4 Cl to pH 7-8. The mixture was extracted with EtOAc, washed twice with H 2 O, dried over Na 2 SO 4 and evaporated to dryness. The corresponding unsaturated ester 9 (0.09 g, 25%) was obtained in oily form after f.c.c. purification using PhMe:Hex 7:3 as the eluent (R f 0.28) as an inseparable mixture of geometric isomers (all-E-9 ca 75% of the mixture). The thus obtained ester 9 (0.09 g, 0.22 mmol) was suspended in MeOH/DMSO (6:1, 0.7 ml) and saponified with an 8 N aqueous solution of NaOH (0.11 ml) at 70 o C for 3 h. After evaporation of MeOH, the oily residue was diluted with H 2 O and acidified with glacial acetic acid to pH 5. The product was extracted with EtOAc. The organic layers were combined and washed once with a saturated aqueous solution of NaCl and twice with H 2 O, dried over Na 2 SO 4 and evaporated to dryness to obtain the corresponding acid 5 (0.04 g, 85%) from which all-E-5 was obtained in 40% yield following crystallization from EtOAc. Recrystallization from EtOAc gave finally yellow crystals of all-trans-5 suitable for X-ray analysis; m.p. 517-518 K.

Refinement
The H atoms of the carboxylic acid groups were located in difference Fourier maps and their positions were refined with soft distance restraints along with U iso (H) equal to 1.5U eq of their parent atoms. The methine and aromatic H atoms were placed in geometrically idealized positions [C-H = 0.93 Å and U iso (H) = 1.2U eq (C)]; the remaining methyl H atoms were constrained to an ideal geometry [C-H = 0.96 Å and U iso (H) = 1.5U eq (C)], but were allowed to rotate freely about the supplementary materials sup-3 C-C bonds. Two low-angle reflections were omitted from the final cycles of refinement because their observed intensities were significantly lower than the calculated values, being apparently obscured by the beam stop. Fig. 1. Synthetic scheme, part 1.   (5) with the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. Hall symbol: -P 1 Mo Kα radiation, λ = 0.71073 Å a = 7.5751 (7) Å Cell parameters from 4369 reflections b = 8.5466 (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 > σ(F 2 ) is used only for calculating Rfactors(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.