A P212121 polymorph of (+)-clusianone

The title compound, C33H42O4 [systematic name: (1S,5S,7R)-3-benzoyl-4-hydroxy-8,8-dimethyl-1,5,7-tris(3-methylbut-2-enyl)bicyclo[3.3.1]nona-3-ene-2,9-dione], has a central bicyclo[3.3.1]nonane-2,4,9-trione surrounded by tetraprenylated and benzoyl groups. The compound was recrystallized several times in methanol using both a slow evaporation method and with a crystal-seeding technique. This subsequently produced diffraction-quality crystals which crystallize in the orthorhombic space group P212121, in contrast to a previous report of a structure determination in the Pna21 space group [McCandlish et al. (1976 ▶). Acta Cryst. B32, 1793–1801]. The title compound has a melting point of 365–366 K, and a specific rotation [α]20 value of +51.94°. A strong intramolecular O—H⋯O hydrogen bond is noted. In the crystal, molecules are assembled in the ab plane by weak C—H⋯O interactions.


Comment
Clusianone is a polycyclic polyprenylated acylpholroglucinols (PPAP) isolated from the plants of the family Clusiaceae (Guttiferae) and has gained considerable interest from both the natural product and synthetic chemistry community due to its potential bioactivity. Clusianone, both naturally occurring and synthetic, exhibits anti-HIV (Piccinelli et al., 2005;Garnsey et al., 2011) and anti-cancer properties (Simpkins, 2013).
Clusianone was isolated from the roots of Clusia congestiflora and analysis of X-ray diffraction has firmly established the equatorial orientation of the 3-methyl-2-butenyl group at C-7 which crystallized in the Pna2 1 space group (McCandlish et al., 1976). Subsequent isolation of the compound from Clusia Sandiensis (Monache et al., 1991) and Clusia spiritu-santensis (de Oliveira et al., 1996) led to NMR studies of clusianone and its methyl derivative, respectively, but gave contradictory NMR data for clusianone. Unfortunately, due to the complexity of the data and the unavailability of authentic sample of clusianone, no report was made of the C7 stereochemistry. Santos and co-workers isolated 7-epiclusianone from Rheedia gardneriana and reported its NMR and X-ray crystal structure, showing the C7 exo isomerism (Santos et al., 1998;Santos et al., 2001). Thereafter, the absolute structure of (+)-7-epiclusianone possessing an axial C7-prenyl group while comparison to clusianone isolated from the roots of Clusia congestiflora (McCandlish et al., 1976) had the C7-prenyl group as equatorial. The title compound's epimer (+)-7-epiclusianone crystallized in space group of P2 1 2 1 2 1 (Santos et al., 1998).
To date, the absolute configuration of (+)-clusianone determined by X-ray crystallography at room temperature has been only confirmed by (McCandlish et al., 1976). Previously reported clusianone isolated from Clusia congestiflora crystallizes in the Pna2 1 space group. The crystal was obtained from a 95% ethanol solution (McCandlish et al.,1976).
However, the lack of the specific optical rotation of the clusianone isolated by McCandlish et al. (1976) indicates that further investigation might be required to discover the uncertainty in stereochemistry of this compound.
Herein, we report the clusianone with melting point 365-366 K and a specific rotation [α] 20 value of +51.94 °. We report (+)-clusianone to crystallize in the orthorhombic space group P2 1 2 1 2 1 , Fig. 1, when crystals were isolated from methanol solution. Intramolecular O-H···O hydrogen bonds are noted, Table 1. Supramolecular layers in the ab plane are stabilised by weak C-H···O interactions, Fig. 2. The different solvent used to crystallize the compound might be the reason for the polymorph occurance.

Isolation and crystallization
G. Parvifolia leaves were collected from trees in a reserved forest, Sungai Congkak, Selangor, Malaysia. The leaves (133 g) were dried, powdered and macerated with n-hexane (3 x 1.0 L) frequently over three days. Each maceration were supplementary materials sup-2 Acta Cryst. (2013). E69, o1799-o1800 filtered, evaporated and then dried using a rotary evaporator under reduced pressure at 40 °C. The hexane extract of the leaves (9.7 g) was then chromatographed on silica gel (70-230 mesh) and eluted with diethyl ether and evaporated. This fraction of the extract which contains a major portion of chlorophyll compounds was then mixed with silica gel:activated charcoal in proportion of 1:3:1, respectively, and placed in a column with a porous frit. The material was eluted with hexane (500 ml) followed by dichloromethane (500 ml) with the aid of vacuum pressure. To isolate the compound, the dichloromethane dried fractions (4.8 g) was further chromatographed on silica gel (70-230 mesh) and eluted with mixtures of cyclohexane/chloroform and chloroform/methanol of increasing polarity. A total of 122 fractions were collected in 20 ml vials and fractions from F51-F60 were crystallized via slow methanol evaporation. Growth of diffraction quality crystals were obtained through several recrystallizations in methanol using both slow evaporation method and crystal seeding technique over a period of 10 days. Yellow cubic crystals (119 mg) were obtained and the melting point was 365-366 K and the specific optical rotation [α] 20 was +51.94 °. The specific optical rotation was measured using an ADP-440 Perkin Elmer digital polarimeter using a sodium lamp at 589 nm. The melting point was recorded on Stuart's melting point apparatus SMP100. All the data analysis relevant to melting point, specific rotation and X-ray diffraction analysis were repeated three times to determine the reproducibility of the data and various parameters.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. The H atoms were all located in a difference map, but those attached to carbon atoms were repositioned geometrically. The H atoms were initially refined with soft restraints on the bond lengths and angles to regularize their geometry (C-H in the range 0.93-0.98 and O-H = 0.82 Å) and U iso (H) (in the range 1.2-1.5 times U eq of the parent atom), after which the positions were refined with riding constraints except the hydroxyl hydrogen which were refined freely (Cooper et al., 2010).