Synthesis and crystal structure of (±)-Goniotamirenone C

Earlier we reported the isolation of Goniotamirenone C [6-(2-chloro-1-hydroxy-2-phenylethyl)-2H-pyran-2-one] from the leaf extracts of Goniothalamus tamirensis. Its gross structure was elucidated using NMR spectroscopic techniques and, on the basis of ECD calculations, the absolute configuration of this natural product was assigned as the syn isomer, (7S,8S)-Goniotamirenone C. In this paper we correct the structure of the natural product to the anti isomer from the semi-synthesis and single-crystal X-ray structure determination of (±)-Goniotamirenone C, which displays identical NMR spectroscopic data to the natural product.


Chemical context
Goniothalamus is one of the largest genera belonging to the Annonaceae family, which is distributed throughout tropical and subtropical areas. So far, over 160 species have been discovered globally (Saunders & Chalermglin, 2008) with 15 species found in Thailand (Soonthornchareonnon et al., 1999). Many species of Goniothalamus have been used as folk medicines for the treatment of common illnesses and as a tonic. Goniothalamus is well known as a rich source of styryllactones, with over 100 compounds isolated and identified (Meesakul et al., 2020;Jaidee et al., 2019, Bihud et al., 2019. However, chlorinated styryllactones are rarely reported in the Annonaceae family. To the best of our knowledge, only two compounds, Parvistone A and Goniotamirenone C, have been isolated and identified from Polyalthia parviflora (Liou et al., 2014) and Goniothalamus tamirensis (Meesakul et al., 2020), respectively. Styryllactones show interesting pharmacological activities, such as cytotoxic activity against several tumor cell lines (Lan et al., 2005;Tian et al., 2006;Prawat et al., 2012), antimycobacterial (Lekphrom et al., 2009;Prawat et al., 2012) and antiplasmodial activities (Lekphrom et al., 2009;Prawat et al., 2012). As a part of our continuing study of the phytochemistry of plants in the Annonaceae family, we report here the synthesis and crystal structure of (AE)-Goniotamirenone C. ISSN 2056-9890

Structural commentary
The title compound crystallizes in the space group P2 1 /n with Z 0 = 2. The centrosymmetric space group confirms the compound crystallizes as a racemic mixture. One molecule is ordered within the asymmetric unit and there is disorder of the other molecular site with occupancies of 0.846 (4) and 0.154 (4) (Fig. 1). The molecules have two stereogenic carbon centres and the ordered molecule has the configuration (7R,8S), in the asymmetric unit selected. The major occupancy component on the disordered site is of configuration (7S,8R) and the configuration of the minor component is (7R,8S). Thus the minor component of the disorder has the same configuration as the ordered molecule in the selected asymmetric unit. These assignments confirm the relative stereochemistry as anti and thus the structural assignment can be revised from our earlier work (Meesakul et al. 2020).
Each molecule adopts a staggered conformation about the bond between the stereocentres with chlorine and hydroxyl groups antiperiplanar (Table 1). The main conformational difference between molecules on the ordered site and the disordered site is the dihedral angle between the phenyl (C9X-C14X; where X takes no value for the ordered site and A and B for the disordered site) and pyran-2-one rings (O1X, C2X-C6X). This angle is only 5.88 (6) on the ordered site and 28.22 (18) and 27.7 (11) , respectively, for the major and minor occupancy molecules on the disordered site.

Supramolecular features
The molecules in the asymmetric unit are linked by hydrogen bonds between the hydroxyl groups as hydrogen-bond donors and the carbonyl groups of the lactones as hydrogen-bond acceptors. The hydrogen-bond metrics are presented in Table 2 and fall within standard values. These interactions link the molecules into chains running parallel to the [100] direction ( Fig. 2). For clarity, the interactions between the ordered molecule and the major component of the disorder are shown. These O-HÁ Á ÁO interactions are supported by C-HÁ Á ÁO C interactions within the chain. The chains stack, seemingly rather awkwardly, in the [001] direction (Fig. 3), presenting an interesting C5-H5Á Á ÁCl (2.70 Å ) inter-chain contact. The contents of the asymmetric unit with complete atom labelling of the ordered molecule and selected labelling of major and minor occupancy disordered molecules, for clarity. The minor occupancy molecule is shaded in pink. Displacement ellipsoids are plotted at the 50% probability level. Table 1 Selected torsion angles ( ).

Figure 2
A perspective view, with hydrogen bonds shown as dotted magenta lines, of a part of one chain that propagates along the [100] direction. Symmetry code: (i) À1 + x, +y, +z. Displacement ellipsoids are plotted at the 50% probability level.

Figure 3
A view along the [100] direction of the stacking of the hydrogen-bonded chains. Chains are coloured differently for clarity.
Compound 2 was ring-opened at 213 K using HCl in anhydrous diethyl ether solution, furnishing the desired compound as a colourless solid. Crystals suitable for analysis by single crystal X-ray diffraction grew from slow evaporation of a 1:4 dichloromethane:methanol solution.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The disorder was modelled by reference to a free variable and the refined disorder occupancies are 0.846 (4) and 0.154 (4). The bond distances and 1,3-non-bonded distances in the pyran-2-one and chlorohydrin parts of the minor disordered component were restrained to be the same as the corresponding distances in the ordered independent molecule, subject to s.u. values of 0.02 and 0.04 Å , respectively, while the phenyl group of this molecule was fitted as a regular hexagon and refined as free rotating group. Enhanced rigid bond restraints were applied to the pyran-2-one ring of the minor component. The anisotropic displacement parameters for the Cl atoms in the disordered molecules were constrained to be identical. H atoms bonded to C atoms were located in difference maps for the ordered independent molecule and the major component on the disordered site. All C-bound H atoms were placed in geometrically idealized positions with bond lengths of 0.95 Å (aromatic C-H) and 1.00 Å (aliphatic C-H), and refined using riding models with U iso (H) = 1.2U eq (C). H atoms attached to O were refined using riding models with U iso (H) = 1.5U eq (O) and as freely rotating idealized tetrahedral groups with bond lengths of 0.84 Å . Synthesis and crystal structure of (±)-Goniotamirenone C Pornphimol Meesakul, Christopher Richardson, Surat Laphookhieo and Stephen G. Pyne

Computing details
Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: ShelXT (Sheldrick, 2015b); program(s) used to refine structure: SHELXL (Sheldrick, 2015a); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). 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. Refinement. Approximately 15% of the opposite enantiomer crystallises about the same position as one of the two independent molecules in the asymmetric unit. This was modelled using PART instructions and by using the SAME command for the minor component to the appropriate ordered molecule and the RIGU restraint. The refinement settled well.