Isogentisin (1,3-di­hydroxy-7-methoxy­xanthone)

Evans, I.R.; Howard, J.A.K.; Šavikin-Fodulović, K.; Menković, N.

doi:10.1107/S1600536804019890

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 60| Part 9| September 2004| Pages o1557-o1559

https://doi.org/10.1107/S1600536804019890

Isogentisin (1,3-dihydroxy-7-methoxyxanthone)

Ivana Radosavljević Evans,^a ^* Judith A. K. Howard,^a Katarina Šavikin-Fodulović ^b and Nebojša Menković ^b

^aDepartment of Chemistry, University of Durham, South Road, Durham DH1 3LE, England, and ^bInstitute for Medicinal Plant Research, Tadeuša Košćuška 1, 11000 Belgrade, Serbia and Montenegro
^*Correspondence e-mail: ivana.radosavljevic@durham.ac.uk

(Received 3 August 2004; accepted 10 August 2004; online 21 August 2004)

The crystal structure of isogentisin, C₁₄H₁₀O₅, a natural product isolated from Gentiana lutea, has been determined. The phenolic ring system is essentially planar and the displacement of the methoxy substituent from the mean molecular plane is very small. The structure is stabilized by a one-dimensional chain of intermolecular hydrogen bonds.

Comment

Xanthone compounds commonly occur in several higher plant families, such as Gentianaceae, Guttiferae, Moraceae and Polygalaceae. The study of xanthones is interesting both from the chemosystematic and pharmacological point of view. Inhibition of Type A and Type B monoamine oxidases (MAO) by a number of xanthones has been observed (Suzuki et al., 1980 , 1981 ). Among the xanthones that have been tested, isogentisin revealed potent MAO inhibition (Suzuki et al., 1978 ). Four ethanolic extracts prepared from leaves, flowers and roots of Gentiana lutea were tested for antitubercular activity against Mycobacterium bovis (BCG-strain). The extract obtained from flowers showed strong inhibition at a concentration of 1000 µg ml⁻¹ and slight inhibition at 500 µg ml⁻¹. This activity increased during the various purification steps, which finally led to the isolation of the active compound isogentisin (Menković et al., 1999 ). Mutagenicity in the Ames test in Salmonella typhimurium was also shown for isogentisin (Morimoto et al., 1983 , Matsushima et al., 1985 ). Isogentisin was first isolated by Cannonica & Pelizzoni (1955 ). The present paper presents the first single-crystal X-ray analysis of isogentisin and confirms that the crystal structure correpsonds to 1,3-dihydroxy-7-methoxyxanthone, (I) (Fig. 1). The 1,3-dihydroxy-7-methoxyxanthone fragment is essentially planar, with the largest displacement within the phenolic ring system of 0.062 (3) Å for C1. The methyl group of the methoxy substituent lies close to the mean plane of the molecule, as shown by the torsion angle of C10—C9—O15—C19 of 5.2 (5)°.

The packing diagram for isogentisin is shown in Figs. 2 and 3. The crystal structure can be described in terms of parallel molecules stacked along the direction of the a crystallographic axis, with the normal to the plane forming an angle of about 20° relative to it, and an intermolecular separation of about 3.5 Å. Within a xanthone unit, an intramolecular hydrogen bond with a length of 1.91 Å exists between the hydroxyl H atom H7 and the O5 acceptor of an adjacent carbonyl group. In addition, the same carbonyl O atom participates in a one-dimensional intermolecular hydrogen bond with the hydroxyl group on a neighbouring molecule (O5—H5 = 1.997 Å). The hydrogen-bonding patterns are shown in Fig. 4.

Figure 1
The molecular structure of isogentisin and the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
One view of the packing diagram for isogentisin.

Figure 3
A second view of the packing diagram for isogentisin.

Figure 4
Hydrogen bonding in isogentisin.

Experimental

Isolation of isogentisin from Gentiana lutea was carried out following a procedure described previously (Menković, 1997 ; Menković et al., 1990).

Crystal data

C₁₄H₁₀O₅
M_r = 258.23
Triclinic, $[P\overline 1]$
a = 7.2287 (14) Å
b = 8.6286 (15) Å
c = 9.0370 (16) Å
α = 97.896 (5)°
β = 105.962 (6)°
γ = 97.698 (5)°
V = 528.00 (17) Å³
Z = 2
D_x = 1.611 Mg m⁻³
Mo Kα radiation
Cell parameters from 826 reflections
θ = 6.0–49.1°
μ = 0.12 mm⁻¹
T = 120 K
Needle, yellow
0.08 × 0.04 × 0.02 mm

Data collection

Bruker SMART 6000 diffractometer
ω scans
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ) T_min = 0.956, T_max = 1.000
4830 measured reflections
1866 independent reflections
783 reflections with I > 2σ(I)
R_int = 0.01
θ_max = 25.0°
h = −8 → 8
k = −10 → 10
l = −10 → 10

Refinement

Refinement on F²
R[F² > 2σ(F²)] = 0.034
wR(F²) = 0.117
S = 0.96
1858 reflections
172 parameters
H-atom parameters constrained
Weighting scheme: see text
(Δ/σ)_max = 0.001
Δρ_max = 0.69 e Å⁻³
Δρ_min = −0.59 e Å⁻³

Table 1
Selected geometric parameters (Å, °)

C1—C13	1.392 (4)
C1—C17	1.369 (4)
C2—C11	1.441 (4)
C2—C12	1.401 (4)
C2—C17	1.425 (4)
C3—C4	1.387 (4)
C3—C10	1.404 (4)
C3—C11	1.454 (4)
C4—O8	1.373 (4)
C4—C18	1.401 (4)
O5—C11	1.256 (4)
O6—C13	1.352 (4)
O7—C17	1.349 (4)
O8—C12	1.364 (3)
C9—C10	1.376 (4)
C9—C14	1.400 (5)
C9—O15	1.362 (4)
C12—C16	1.376 (4)
C13—C16	1.390 (4)
C14—C18	1.372 (4)
O15—C19	1.422 (4)

C13—C1—C17	119.9 (3)
C11—C2—C12	120.8 (3)
C11—C2—C17	122.4 (3)
C12—C2—C17	116.8 (3)
C4—C3—C10	118.7 (3)
C4—C3—C11	119.7 (3)
C10—C3—C11	121.6 (3)
C3—C4—O8	122.8 (3)
C3—C4—C18	121.4 (3)
O8—C4—C18	115.8 (3)
C4—O8—C12	119.4 (2)
C10—C9—C14	120.6 (3)
C10—C9—O15	125.2 (3)
C14—C9—O15	114.2 (3)
C3—C10—C9	120.0 (3)
C3—C11—C2	115.8 (3)
C3—C11—O5	122.0 (3)
C2—C11—O5	122.2 (3)
C2—C12—O8	121.5 (3)
C2—C12—C16	122.8 (3)
O8—C12—C16	115.7 (3)
C1—C13—O6	116.8 (3)
C1—C13—C16	121.1 (3)
O6—C13—C16	122.0 (3)
C9—C14—C18	120.2 (3)
C9—O15—C19	117.9 (2)
C13—C16—C12	118.4 (3)
C2—C17—C1	121.0 (3)
C2—C17—O7	120.8 (3)
C1—C17—O7	118.2 (3)
C4—C18—C14	119.1 (3)

Table 2
Hydrogen-bonding geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O6—H5⋯O5ⁱ	0.82	2.00	2.738 (3)	150
O7—H7⋯O5	0.82	1.91	2.634 (3)	147
Symmetry code: (i) x,y-1,z.

A Chebychev polynomial (Carruthers & Watkin, 1979 ; Prince, 1982 ) was used for the weighting scheme, with w = 1.0/[A₀T₀(x) + A₁T₁(x)… + A_n − 1]T_n − 1(x)] where A_i are the Chebychev coefficients listed below and x = F_calc/F_max; robust weighting (Prince, 1982): W = w[1 − (δF/6σF)²]², A_i are 1.96, 2.45 and 0.676. H atoms were positioned geometrically (C—H = 1.0 Å and O—H = 0.82 Å) and refined using a riding model, with U_iso(H) = 1.2U_eq(C) and 1.1U_eq(O).

Data collection: SMART (Bruker, 1999 ); cell refinement: SAINT (Bruker, 1999); data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003 ); molecular graphics: ATOMS (Shape Software, 2000 ); software used to prepare material for publication: CRYSTALS.

Supporting information

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S1600536804019890/fl6116sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S1600536804019890/fl6116Isup2.hkl

Computing details top

Data collection: SMART (Bruker, 1999); cell refinement: SAINT (Bruker, 1999); data reduction: SAINT (Bruker, 1999); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: CRYSTALS (Betteridge et al., 2003); molecular graphics: ATOMS (Shape Software, 2000); software used to prepare material for publication: CRYSTALS.

1,3-dihydroxy-7-methoxyxanthone top

Crystal data top

C₁₄H₁₀O₅	Z = 2
M_r = 258.23	F(000) = 268
Triclinic, P1	D_x = 1.611 Mg m⁻³
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.2287 (14) Å	Cell parameters from 826 reflections
b = 8.6286 (15) Å	θ = 6.0–49.1°
c = 9.0370 (16) Å	µ = 0.12 mm⁻¹
α = 97.896 (5)°	T = 120 K
β = 105.962 (6)°	Needle, yellow
γ = 97.698 (5)°	0.08 × 0.04 × 0.02 mm
V = 528.00 (17) Å³

Data collection top

Bruker SMART 6000 diffractometer	783 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.01
ω scans	θ_max = 25.0°, θ_min = 2.4°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −8→8
T_min = 0.956, T_max = 1.000	k = −10→10
4830 measured reflections	l = −10→10
1866 independent reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.034	H-atom parameters not refined
wR(F²) = 0.117	Chebychev polynomial (Carruthers, 1979; Prince, 1982) w = 1.0/[A₀T₀(x) + A₁T₁(x) ··· + A_n-1]T_n-1(x)] where A_i are the Chebychev coefficients listed below and x = F /Fmax; robust weighting (Prince, 1982): W = w[1-(δF/6σF)²]², A_i are 1.96, 2.45 and 0.676
S = 0.96	(Δ/σ)_max = 0.001
1858 reflections	Δρ_max = 0.69 e Å⁻³
172 parameters	Δρ_min = −0.59 e Å⁻³
0 restraints

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.9594 (4)	0.1431 (4)	0.6659 (4)	0.0173
C2	1.1318 (5)	0.3728 (4)	0.8682 (4)	0.0177
C3	1.3211 (4)	0.5934 (3)	1.0799 (3)	0.0154
C4	1.3865 (5)	0.4805 (4)	1.1671 (3)	0.0181
O5	1.1236 (3)	0.6399 (3)	0.8389 (2)	0.0220
O6	0.9766 (3)	−0.1150 (2)	0.7128 (2)	0.0230
O7	0.9354 (3)	0.3977 (3)	0.6125 (3)	0.0235
O8	1.3262 (3)	0.3199 (2)	1.1131 (2)	0.0195
C9	1.5219 (5)	0.7988 (4)	1.2928 (4)	0.0179
C10	1.3905 (5)	0.7550 (4)	1.1453 (4)	0.0179
C11	1.1864 (5)	0.5423 (4)	0.9226 (4)	0.0184
C12	1.2023 (4)	0.2669 (4)	0.9653 (3)	0.0161
C13	1.0311 (5)	0.0431 (4)	0.7678 (4)	0.0178
C14	1.5887 (5)	0.6835 (4)	1.3786 (4)	0.0192
O15	1.6008 (3)	0.9514 (2)	1.3672 (2)	0.0216
C16	1.1517 (4)	0.1043 (4)	0.9191 (4)	0.0161
C17	1.0072 (4)	0.3046 (4)	0.7146 (4)	0.0168
C18	1.5215 (5)	0.5249 (4)	1.3170 (3)	0.0188
C19	1.5317 (5)	1.0763 (4)	1.2928 (4)	0.0231
H5	1.0557 (3)	−0.1619 (2)	0.7637 (2)	0.0250*
H7	0.9795 (3)	0.4911 (3)	0.6531 (3)	0.0250*
H1	1.6017 (5)	1.1812 (4)	1.3599 (4)	0.0265*
H3	1.5570 (5)	1.0684 (4)	1.1889 (4)	0.0265*
H2	1.3881 (5)	1.0671 (4)	1.2774 (4)	0.0265*
H4	1.3444 (5)	0.8384 (4)	1.0846 (4)	0.0220*
H6	0.8731 (4)	0.0971 (4)	0.5572 (4)	0.0199*
H8	1.2004 (4)	0.0320 (4)	0.9927 (4)	0.0200*
H10	1.6857 (5)	0.7167 (4)	1.4851 (4)	0.0225*
H9	1.5681 (5)	0.4422 (4)	1.3781 (3)	0.0233*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0143 (15)	0.0208 (16)	0.0146 (15)	0.0014 (12)	0.0026 (12)	0.0011 (12)
C2	0.0178 (17)	0.0183 (16)	0.0186 (16)	0.0025 (13)	0.0082 (13)	0.0038 (13)
C3	0.0128 (16)	0.0187 (16)	0.0184 (16)	0.0050 (12)	0.0089 (12)	0.0049 (12)
C4	0.0201 (17)	0.0165 (16)	0.0173 (16)	−0.0003 (13)	0.0078 (13)	0.0011 (12)
O5	0.0245 (13)	0.0198 (12)	0.0198 (12)	0.0046 (10)	0.0026 (10)	0.0052 (9)
O6	0.0278 (13)	0.0152 (12)	0.0220 (12)	0.0035 (9)	0.0016 (10)	0.0025 (9)
O7	0.0300 (13)	0.0159 (11)	0.0199 (11)	0.0037 (10)	−0.0006 (10)	0.0043 (9)
O8	0.0236 (12)	0.0165 (12)	0.0159 (11)	0.0014 (9)	0.0030 (9)	0.0024 (9)
C9	0.0158 (16)	0.0195 (16)	0.0174 (15)	0.0004 (13)	0.0070 (13)	−0.0008 (12)
C10	0.0166 (16)	0.0177 (16)	0.0208 (16)	0.0040 (12)	0.0071 (13)	0.0041 (12)
C11	0.0184 (16)	0.0215 (17)	0.0185 (16)	0.0051 (13)	0.0088 (13)	0.0064 (13)
C12	0.0145 (16)	0.0202 (16)	0.0157 (16)	0.0032 (12)	0.0076 (13)	0.0038 (12)
C13	0.0200 (17)	0.0145 (15)	0.0189 (16)	0.0013 (13)	0.0074 (13)	0.0012 (12)
C14	0.0172 (16)	0.0237 (17)	0.0153 (15)	0.0029 (13)	0.0042 (13)	0.0007 (12)
O15	0.0246 (13)	0.0154 (11)	0.0195 (12)	0.0037 (9)	0.0001 (10)	−0.0012 (9)
C16	0.0132 (15)	0.0171 (15)	0.0195 (15)	0.0030 (12)	0.0063 (13)	0.0048 (12)
C17	0.0154 (15)	0.0212 (17)	0.0172 (15)	0.0065 (13)	0.0075 (12)	0.0064 (12)
C18	0.0216 (17)	0.0217 (16)	0.0148 (15)	0.0042 (13)	0.0063 (13)	0.0074 (12)
C19	0.0252 (17)	0.0146 (16)	0.0266 (18)	0.0049 (13)	0.0028 (14)	0.0033 (13)

Geometric parameters (Å, º) top

C1—C13	1.392 (4)	O8—C12	1.364 (3)
C1—C17	1.369 (4)	C9—C10	1.376 (4)
C1—H6	1.000	C9—C14	1.400 (5)
C2—C11	1.441 (4)	C9—O15	1.362 (4)
C2—C12	1.401 (4)	C10—H4	1.000
C2—C17	1.425 (4)	C12—C16	1.376 (4)
C3—C4	1.387 (4)	C13—C16	1.390 (4)
C3—C10	1.404 (4)	C14—C18	1.372 (4)
C3—C11	1.454 (4)	C14—H10	1.000
C4—O8	1.373 (4)	O15—C19	1.422 (4)
C4—C18	1.401 (4)	C16—H8	1.000
O5—C11	1.256 (4)	C18—H9	1.000
O6—C13	1.352 (4)	C19—H1	1.000
O6—H5	0.819	C19—H3	1.000
O7—C17	1.349 (4)	C19—H2	1.000
O7—H7	0.820

C13—C1—C17	119.9 (3)	C2—C12—C16	122.8 (3)
C13—C1—H6	120.0	O8—C12—C16	115.7 (3)
C17—C1—H6	120.0	C1—C13—O6	116.8 (3)
C11—C2—C12	120.8 (3)	C1—C13—C16	121.1 (3)
C11—C2—C17	122.4 (3)	O6—C13—C16	122.0 (3)
C12—C2—C17	116.8 (3)	C9—C14—C18	120.2 (3)
C4—C3—C10	118.7 (3)	C9—C14—H10	119.8
C4—C3—C11	119.7 (3)	C18—C14—H10	119.8
C10—C3—C11	121.6 (3)	C9—O15—C19	117.9 (2)
C3—C4—O8	122.8 (3)	C13—C16—C12	118.4 (3)
C3—C4—C18	121.4 (3)	C13—C16—H8	120.8
O8—C4—C18	115.8 (3)	C12—C16—H8	120.8
C13—O6—H5	109.4	C2—C17—C1	121.0 (3)
C17—O7—H7	109.0	C2—C17—O7	120.8 (3)
C4—O8—C12	119.4 (2)	C1—C17—O7	118.2 (3)
C10—C9—C14	120.6 (3)	C4—C18—C14	119.1 (3)
C10—C9—O15	125.2 (3)	C4—C18—H9	120.4
C14—C9—O15	114.2 (3)	C14—C18—H9	120.4
C3—C10—C9	120.0 (3)	O15—C19—H1	109.4
C3—C10—H4	120.0	O15—C19—H3	109.4
C9—C10—H4	120.0	H1—C19—H3	109.4
C3—C11—C2	115.8 (3)	O15—C19—H2	109.4
C3—C11—O5	122.0 (3)	H1—C19—H2	109.4
C2—C11—O5	122.2 (3)	H3—C19—H2	109.4
C2—C12—O8	121.5 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O6—H5···O5ⁱ	0.82	2.00	2.738 (3)	150
O7—H7···O5	0.82	1.91	2.634 (3)	147

Symmetry code: (i) x, y−1, z.

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