Crystal structure of limonoid TS3, isolated from Trichilia rubescens

The absolute configurations of the 10 asymmetric carbons involved in the structure of the title limonoid, TS3, have been confirmed by resonant scattering. The roles of the water molecules and the C—H⋯π interactions in the crystal packing are highlighted.

Limonoids are a prominent class of secondary metabolites found in plants of the Meliaceae and Rutaceae families. They are also well known for their wide range of bioactive compounds that exhibit antiplasmodial, antiviral, antitumoral, antibacterial and cytotoxic properties (Krief et al., 2004;Lange et al., 2016). Vilasinin is one of the limonoid classes, to which belongs the title compound (TS3), and all the compounds of the rubescin series have been isolated from Trichilia rubescens (Tontsa et al., 2013;Tsamo et al., 2016). Among the broad spectrum of biological properties exhibited by vilasinin derivatives, TS3 has been found to induce apoptosis in human hepatoma cell lines, to interfere with NFkB signaling and to enhance cAMP-regulated chloride conductance of cells expressing CFTR (cystic fibrosis transmembrane conductance regulator) (deCarvalho et al., 2002).
As a result of the structure-activity relationships existing between bioactive compounds from the same series and/or class (Bauer et al., 2001;Arië ns, 1986), it is important to fully characterize each bioactive molecule. The molecular structure of TS3 was previously elucidated by one-and two-dimensional NMR techniques in combination with high-resolution mass spectrometry (deCarvalho et al., 2002). However, the absolute ISSN 2056-9890 configurations of the asymmetric carbons involved in its structure were not reported, and to date, no work on the crystal structure of this molecule is known. Herein, we report the crystal structure of limonoid TS3 and the roles of the water molecules and the C-HÁ Á Á interactions involving the furan rings in the crystal packing.

Structural commentary
The asymmetric unit of the title compound contains one water molecule and two crystallographically independent molecules (1 and 2) of TS3, as illustrated in Fig. 1. The two molecules are very similar with an r.m.s. fit of 0.068 Å for the 31 non-H atoms (Fig. 2).
As previously reported, using one-and two-dimensional NMR techniques in combination with high-resolution mass spectroscopy studies (deCarvalho et al., 2002), the TS3 molecule consists of three six-membered rings (A, C and D), three five-membered rings (B, E and F), and two epoxide rings.

Figure 1
The molecular structure of the two independent molecules (1 and 2) of the title compound TS3 with the crystallographic labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms have been omitted for clarity.

Supramolecular features
There are a number of hydrogen-bonding acceptor atoms (ketone and epoxide functions) present in the structure of TS3, and details are given in Table 1. The water molecule of the asymmetric unit contributes significantly to the crystal packing via three weak hydrogen bonds ( Fig. 3 and Table 1). The individual molecules stack in columns along the b-axis direction, and within each column there are C-HÁ Á Á furan interactions present (Table 1), stabilizing the columnar structures. Molecules 1 (black in Fig. 3) are linked about a twofold screw axis, via O water -HÁ Á ÁO and C-HÁ Á ÁO water hydrogen bonds, forming helices propagating along the b-axis direction. Molecules 1 and 2 (red in Fig. 3) are linked by O water -HÁ Á ÁO hydrogen bonds (water is green in Fig. 3; see Table 1) and C-HÁ Á ÁO hydrogen bonds, so forming slabs lying parallel to the ab plane. There are no other significant intermolecular interactions present in the crystal structure.

Database survey
A search in the Cambridge Structural Database (CSD, Version 5.39, update May 2018; Groom et al., 2016) for the skeleton of TS3 gave no hits. The moieties having the rings E and F have been seen in three cytotoxic limonoids, viz. aphanastatine, amoorastatine and hydroxyl-12-ammorastatine (Arnoux & Pascard, 1980;Polonsky et al., 1978). This moiety is also involved in the structure of Munronin H (Yan et al. 2015) and Toosendanin (Xu & Zhang, 2011). A number of structures with the second moiety (the fused rings A, B and C), but having different substituents, are known. Most of these compounds are reported as hemisynthesis products, while TS3 was obtained from a natural source.

Extraction and crystallization
The title compound was isolated from the root bark of Trichilia rubescens. The extraction and the isolation proce-    Table 1; colour code: black = molecule 1, red = molecule 2, green = water molecule). For clarity, only the H atoms involved in hydrogen bonding have been included. Table 1 Hydrogen-bond geometry (Å , ).