Crystal structure of 5-[(benzoyloxy)methyl]-5,6-dihydroxy-4-oxocyclohex-2-en-1-yl benzoate

The crystal structure 5-[(benzoyloxy)methyl]-5,6-dihydroxy-4-oxocyclohex-2-en-1-yl benzoate a natural product from Pipers griffithii leaves known as zeylenone has been determined.


Chemical context
Zeylenone is a naturally occurring polyoxygenated cyclohexene derived from the shikimate pathway. It has been found in a few plant families such as Piperaceae and Annonaceae. The biological activity of zeylenone was reported as inducing apoptosis in the mitochondria of gastric cancer cells (Yang et al., 2018) and cervical carcinoma cells (Zhang et al., 2017). The absolute configuration of natural zeylenone was determined by CD spectroscopy to be (À)-zeylenone (Takeuchi et al., 2001).

Structural commentary
The molecular structure of the title compound (I) is shown in Fig. 1. It has three chiral centers at positions C1, C5 and C6 of the cyclohexanone ring. However, the absolute configuration (probably 1S, 5R and 6S) could not be deduced from the X-ray data because of the large standard deviation of the Flack parameter [0.0 (3)]. The two main substituents are methyl benzoate and benzoyloxy at positions C1 and C5, and positioned at the same side of the cyclohexenone ring. The dihedral angle between the methyl benzoate and benzoyloxy mean planes is 16.24 (10) , indicating that the rings are almost coplanar. The dihedral angle between the cyclohexenone ring and the methyl benzoate and benzoyloxy rings are 74.92 (9) and 69.23 (10) , respectively, indicating that the aromatic and cyclohexenone rings are almost perpendicular. The conformation of the cyclohexenone ring, the core structure of (À)zeylenone, is described as a half-chair based on the torsion angles H4-C4-C3-C2 [À178.7 (3) , almost planar] and C5-C6-C1-C2 [À60.65 (16) , perfectly staggered] and the puckering parameters [Q = 0.4989 (17) Å , = 130.8 (2) and È = 143.9 (3) ].

Computational calculations
The structure of the title compound was optimized using density functional theory (DFT) calculations at the M062X/6-31G(d) level using GAUSSIAN 09 (Frisch et al., 2016). The optimized structure was then used for the analysis of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) using the same level of theory in order to determine the reactivity of the compound via the energy gap. The DFT-optimized geometry was compared with the geometry obtained from the crystal structure using the molecular overlay module based on 50% steric and 50% electrostatic similarities in the Discovery Studio visualizer (Dassault, 2018), as shown in Fig. 4. The overlay similarity, which is calculated based on the steric and electrostatic overlaps, is high with a value of 0.86 and the r.m.s.d. of the heavy atoms (non-H atoms) is 0.67 Å . Geometrical parameters (i.e. bond lengths, bond angles and torsion angles) of the experimental and optimized structures are given in Table 2.
Finally, the molecular orbitals of zeylenone were calculated. The HOMO and LUMO plots are shown in Fig. 5. At the HOMO level, the orbitals are located on the phenyl ring of the methylene benzoate group and the orbitals are shifted to the cyclohexenone ring at the LUMO level. The energy gap (E HOMO À E LUMO ) is 7.61 eV. The large energy gap indicates the stability of the title compound.

Database survey
In the first reported total synthesis of zeylenone from shikimic acid, the absolute configuration was assigned as 1R, 5S, 6R. A circular dichroism study of the synthesized product gave (+)-    (15) O6 zeylenone (Liu et al., 2004). The first total synthesis of (À)zeylenone was also achieved from shikimic acid (Zhang et al., 2006). Similar structures to (À)-zeylenone are (À)-zeylenol and an alcohol form, (À)-zeylenone, from Piper cubeba (Taneja et al., 1991). The closest related structure is that of Cherrevenone, a polyoxygenated cyclohexene derivative from Uvaria cherrevensis. Here, the absolute configuration could again not be determined from the X-ray data, but was confirmed by an electronic circular dichroism analysis (CCDC refcode WOJLIT; Jaipetch et al., 2019).

Figure 5
The HOMO-LUMO plot for the title compound (I).