Crystal and mol­ecular structure of aflatrem

Bruno N Lenta; Jules Ngatchou; Patrice T Kenfack; Beate Neumann; Hans-Georg Stammler; Norbert Sewald

doi:10.1107/S2056989015019040

. 2015 Oct 17;71(Pt 11):o867–o868. doi: 10.1107/S2056989015019040

Crystal and molecular structure of aflatrem

Bruno N Lenta ^a,^*, Jules Ngatchou ^b, Patrice T Kenfack ^c, Beate Neumann ^d, Hans-Georg Stammler ^d, Norbert Sewald ^d

PMCID: PMC4645010 PMID: 26594569

Abstract

The crystal structure of the title compound, C₃₂H₃₉NO₄, confirms the absolute configuration of the seven chiral centres in the molecule. The molecule has a 1,1-dimethylprop-2-enyl substituent on the indole nucleus and this nucleus shares one edge with the five-membered ring which is, in turn, connected to a sequence of three edge-shared fused rings. The skeleton is completed by the 7,7-trimethyl-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one group connected to the terminal cyclohexene ring. The two cyclohexane rings adopt chair and half-chair conformations, while in the dioxabicyclo[3.2.1]oct-3-en-2-one unit, the six-membered ring has a half-chair conformation. The indole system of the molecule exhibits a tilt of 2.02 (1)° between its two rings. In the crystal, O—H⋯O hydrogen bonds connect molecules into chains along [010]. Weak N—H⋯π interactions connect these chains, forming sheets parallel to (10-1).

Keywords: crystal structure, aflatrem, indole-diterpenoid, fungal endophytes, Aspergillus species, N—H⋯Cg (indole), hydrogen bonding

Related literature

For background to indole diterpenoids from endophytes, see: Strobel & Daisy (2003 ▸); Munday-Finch et al. (1996 ▸); Gallagher et al. (1980a ▸,b ▸); Lenta et al. (2007 ▸); Phongpaichit et al. (2007 ▸). For studies of Aspergillus sp, see: Nicholson et al. (2009 ▸); Duran et al. (2006 ▸). For the pharmacological basis of the behavioural effects of this molecule, see: Tinao-Wooldridge et al. (1995 ▸). For the isolation of fungal endophytes from the stem of Symphonia globulifera, see: Petrini et al. (1992 ▸); Amin et al. (2014 ▸). For geometric details of indole compounds, see: Krishna et al. (1999 ▸). For circular dichroism experiments on the title compound, see: Sun et al. (2014 ▸). For information on the Cambridge Structural Database (CSD), see: Groom & Allen (2014 ▸). graphic file with name e-71-0o867-scheme1.jpg

Experimental

Crystal data

C₃₂H₃₉NO₄
M _r = 501.64
Monoclinic,
a = 12.8022 (5) Å
b = 6.4019 (2) Å
c = 15.9557 (6) Å
β = 98.821 (4)°
V = 1292.24 (9) Å³
Z = 2
Cu Kα radiation
μ = 0.66 mm⁻¹
T = 100 K
0.18 × 0.14 × 0.02 mm

Data collection

Agilent SuperNova Dual Source diffractometer with an Atlas detector
Absorption correction: gaussian (CrysAlis PRO; Agilent, 2013 ▸) T _min = 0.899, T _max = 1.000
19981 measured reflections
4585 independent reflections
4078 reflections with I > 2σ(I)
R _int = 0.050

Refinement

R[F ² > 2σ(F ²)] = 0.056
wR(F ²) = 0.150
S = 1.06
4585 reflections
341 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.35 e Å⁻³
Δρ_min = −0.23 e Å⁻³
Absolute structure: Flack x determined using 1671 quotients [(I ⁺)−(I ⁻)]/[(I ⁺)+(I ⁻)] (Parsons & Flack, 2004 ▸)
Absolute structure parameter: 0.09 (14)

Data collection: CrysAlis PRO (Agilent, 2013 ▸); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▸); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▸); molecular graphics: DIAMOND (Brandenburg, 1999 ▸); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009 ▸).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989015019040/lh5789sup1.cif

e-71-0o867-sup1.cif^{(28.4KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989015019040/lh5789Isup2.hkl

e-71-0o867-Isup2.hkl^{(150.9KB, hkl)}

Click here for additional data file.^{(1.6MB, tif)}

. DOI: 10.1107/S2056989015019040/lh5789fig1.tif

The molecular structure of aflatrem with the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Click here for additional data file.^{(1.8MB, tif)}

b x y z x y z x y z x y z . DOI: 10.1107/S2056989015019040/lh5789fig2.tif

Crystal packing of aflatrem showing O—H⋯O hydrogen-bonded (dashed lines) zigzag chains along the b axis in the (010) plane. Weak N—H⋯π interactions are also shown as dashed lines. Symmetry codes: (i) − x + 2, y − Inline graphic , −z + 2; (ii) −x + 1, y − , −z + 1; (iii) −x + 1, y + , −z + 1; (iv) −x + 2, y + , −z + 2.

Click here for additional data file.^{(1.2MB, tif)}

b x y z x y z x y z x y z . DOI: 10.1107/S2056989015019040/lh5789fig3.tif

Crystal packing of aflatrem showing O—H⋯O hydrogen-bonded (dashed lines) zigzag chains along the b axis in the (001) plane. Weak N—H⋯π interactions are also shown as dashed lines. Symmetry codes: (i) −x + 2, y − Inline graphic , −z + 2; (ii) −x + 1, y − , −z + 1; (iii) −x + 1, y + , −z + 1 and (iv) −x + 2, y + , −z + 2.

CCDC reference: 1430332

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (, ).

Cg is the centroid of the C17C22 ring.

DHA	DH	HA	D A	DHA
O4H4O3ⁱ	0.82	2.03	2.757(3)	148
N1H1Cg ⁱⁱ	0.86	2.78	3.527(1)	146

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

The authors wish to acknowledge the Alexander von Humboldt Foundation for providing a fellowship to B. N. Lenta at Bielefeld University

supplementary crystallographic information

S1. Comment

The search of compounds from plant endophytes has been the subject of research interest (Strobel & Daisy 2003). They produce a plethora of substances with potential applications in agriculture, medicine, pharmaceutical and for industry (Petrini et al. 1992; Strobel & Daisy, 2003; Phongpaichit et al., 2007). We are interested in the isolation and the structural study of compounds produced by endophytes from Cameroonian medicinal plants with pharmacological properties (Lenta et al., 2007) and one of the compounds that we have isolated from the fungal endophyte of the stem of Symphonia globulifera was aflatrem. Some authors have identified the biosynthetic genes of this molecule in Aspergilius sp (Nicholson et al., 2009; Duran et al., 2006). We report herein the study of its molecular and crystal structure.

Aflatrem crystallizes in the non-centrosymmetric space group P2₁ and its asymmetric unit consists of a single molecule as shown in Figure 1. As known in the literature, the molecule has a 1,l-dimethyl-2-propenyl substituent on the indole nucleus at position C18 and this nucleus shares one edge with the 5-membered ring (A) belonging to a group of three fused rings like an anthracene system (see Fig.1). The two others rings (6-membered, B and C) also share one edge with the 7, 7-trimethyl-6,8- dioxabicyclo[3.2.1]oct-3-en-2-one group. All the bond distances observed in the compounds are in agreement with the bonds distance of the Cambridge Structural Database (CSD, Groom & Allen, 2014). In the indole ring system, a small tilt of 2.02 (1)° is observed between the 6 and 5-membered rings. This value as well as the values of the bond angles is near the values always obtained in the indole based compounds (Krishna et al., 1999). The ring A (C1/C16/C15/C14/C2) adopts a dihedral angle of 3.12 (1)° with the 5-membered ring of indole system. With the exception of the C1–C2–C14 angle (96.9 (1)°),the values of the bond angles in this ring are in the range between 100 and 112° and they are in good agreement with the ideal conformation for which the angle is 107°. The lower value observed could be favored by the chair conformation of the B ring which shares one edge (C2 and C14) with ring A. This conformation is close to the ideal chair conformation since the bond angles range from 107 to 113° compared to an ideal value of 109°. The ring C assumes a half-chair conformation. The bicyclo[3.2.1]oct-3-en-2-one system is composed by a 6-membered ring named D (C6/C10/C9/C8/C7/O1) sharing one edge (C6 –C7) with a 5-membered ring called E (O1/C7/C6/O2/C25). The carbon atoms of ring D lie in the same plane and the O1 atom is located at 0.80 (1) Å from this plane. This atom is also located at 0.656 (1) Å from the plane which contains the carbon atoms of ring E and the dihedral angle between the two planes is 69.07 (1)°. The methyl and hydroxyl groups linked to the fused ring give the absolute configuration of 1S,3R,6S,7S,11R,12S,13S determined by Cu KαX-radiation with the Flack parameter being refined to 0.09 (14) and this configuration is in agreement with the previous circular dichroism assignment reported by Sun et al. (2014).

The crystal packing of the aflatrem molecules is illustrated in Figs. 2 and 3. In the crystal, molecules are connected along the b axis via O—H···O hydrogen bonds. In addition, weak N—H···π(indole) interactions connect these chains forming planes parallel to (10-1). This N—H···π(indole) interaction is typical of indole-based molecules as reported by Krishna et al. (1999).

S2. Experimental

The isolation of fungal endophytes from the stem of Symphonia globulifera was carried out aat the University of Yaoundé 1 (Cameroon) and was based on the method described by Petrini et al. (1992). One of the fungi was identified to Aspergillus sp. according to the method described by Amin et al. (2014) and cultured in solid medium prepared from 1 kg of rice distributed in the glass flask (total capacity of 2.5 L) at a rate of 200 g of rice in 200 ml of distilled water. After one month of incubation at 301K in the same laboratory, the culture medium was extracted with EtOAc and the extract concentrated on a rotary evaporator under vacuum at a temperature of 313K to yield 20.1 g of extract. This extract was subjected to column chromatography (CC) over silica gel (0.023–0.20 mesh, Merck) and eluted with a gradient system of petroleum ether /ethyl acetate to afford aflatrem (7.5 mg). The colourless crystals obtained were sent to the Laboratory of Inorganic and Structural Chemistry at Bielefeld University (Germany) for X-ray diffraction measurements.