The fungal metabolite austdiol

The title compound, (7R,8S)-7,8-di­hydroxy-3,7-di­methyl-6-oxo-7,8-di­hydro-6H-isochromene-5-carb­aldehyde, C₁₂H₁₂O₅, is a trans-vicinal diol. Of the two fused rings, which lie approximately in the same plane, the pyran ring is almost perfectly planar, while the cyclo­hexenone ring adopts a slightly distorted half-chair conformation. The crystal packing is dictated by two strong intermolecular O—H...O interactions, one involving hydroxy and keto groups, the other involving two hydroxy groups. Molecules are linked together through twofold axes, forming zigzag ribbons extended along the a axis.

S1. Comment

The fungal metabolite austdiol, (I), is the main toxic component of a mixture of substances produced in mouldy maize meal by cultures of <it>Aspergillus Ustus</it> (Steyn, 1973; Vleggaar <it> et al.</it>., 1974). Fungal secondary metabolites are important because of the wide range of biological activities which they can elicit (Paterson & Kemmelmeier, 1990). The effects can be beneficial (<it>e</it>.<it>g</it>. antibiotics) or detrimental (<it>e</it>.<it>g</it>. mycotoxins). Accurate knowledge of their molecular structure and properties is crucial in the search of new drugs, insecticides and herbicides, so they have been the object of increasing interest in recent decades (Paterson, 1986). In the 1970 s, austdiol was investigated by means of chemical and spectroscopic techniques (Vleggaar <it> et al.</it>., 1974; Steyn & Vleggaar, 1976), and the X-ray structure of its 5-bromo derivative (Engel & Kruger, 1976) was determined to verify the absolute configuration of the two stereocentres. Other physicochemical data, including UV absorbance and thin-layer chromatography retention indices, were achieved subsequently (Commission on Food Chemistry, 1982; Paterson, 1986; Frisvald & Thrane, 1987; Paterson & Kemmelmeier, 1990), and studies to elucidate the biosynthetic path that leads to austdiol were also performed (Colombo <it> et al.</it>., 1981, 1983). The core of austdiol has been recently found in the structures of four new fungi pigments (Wang <it> et al.</it>., 1997).

We report here the crystal structure of austdiol, (I), at room temperature as a preliminary step in the detailed investigation of its electrostatic properties [as in our previous study of another fungal metabolite, citrinin (Roversi <it> et al.</it>., 1996)] by X-ray diffraction at a temperature below 25 K. Fig. 1 shows the labelling scheme of the asymmetric unit of (I); the absolute configuration of the molecule was based on the known configuration of the 5-bromo derivative (Engel & Kruger, 1976). The six-membered ring of the cyclohexenone system has a distorted half-chair conformation, with puckering parameters (Cremer & Pople, 1975) Q = 0.457 (2) Å, θ = 125.0 (2)° and ϕ = 277.9 (3)° for the atom sequence C8a—C8—C7—C6—C5—C4a. Atoms C8 and C7 are 0.258 (4) and −0.441 (4) Å, respectively, from the mean plane defined by atoms C8a, C6, C5 and C4a, and the r.m.s. deviation of these latter four atoms from their plane is 0.016 Å. The pyran ring, defined by the atoms C4a—C4—C3—O2—C1—C8a, is almost perfectly planar, with deviations from the mean plane between −0.028 (1) (for C4a) and 0.022 (1) Å (for C8a). The only other 6,8a-dihydroisochromene whose structure has been deposited with the Cambridge Structural Database (Allen, 2002) is the 5-bromo derivative of austdiol (Engel & Kruger, 1976), that crystallizes with four independent molecules in the asymmetric unit. We have calculated the puckering parameters for the ring systems of the four molecules of this austdiol derivative, and found them very similar to those of the parent compound [Q = 0.45 (2) Å, θ = 124 (2)° and ϕ = 272 (4)° for the ciclohexenone ring (mean values); deviations from planarity are between −0.041 and 0.036 Å for the pyran ring]. In (I), the methyl substituent at C7 (7<it>R</it>) is oriented axially, while the two hydroxy groups at C7 and C8 (8<it>S</it>) are oriented equatorially, again in agreement with the orientation reported for the 5-bromo derivative. The molecule of austdiol is therefore nearly planar; the largest deviation is observed at the methyl C11 atom that is located 1.902 (3) Å from the plane through the ten atoms of the two fused rings.

Other fungal metabolites showing structural similarities with austdiol are <it>N</it>-methylsclerotioramine, (II) (Whalley et al., 1976), that contains a N atom instead of the O atom in the heterocyclic ring, and citrinin, (III), extensively studied in our laboratory (Destro & Marsh, 1984; Destro, 1991; Roversi <it> et al.</it>., 1996). The molecules of both compounds are composed of two differently substituted fused six-membered rings, as in austdiol. Furthermore, the position of the double bonds in the fused rings is exactly the same in (I) and (II), while it differs in (III) (see <it>Scheme</it>). For this reason, the heterocyclic ring of (II) is essentially planar and the cyclohexenone ring adopts a distorted half-chair conformation, as in (I), while (III) has a planar cyclohexadienone ring [with its atoms at a distance from the mean plane of between −0.031 (1) and 0.017 (1) Å] and a dihydropyran ring with puckering coordinates [Q = 0.455 (2) Å, θ = 124.5 (3)° and ϕ = 270.7 (3)°] very similar to those reported above for the cyclohexenone ring of (I).

The exocyclic C3—C9 bond, linking the methyl C9 atom to the unsaturated system, is markedly shorter than the other methyl bond C11—C7 [1.486 (3) <it>versus</it> 1.512 (4) Å]. Our preliminary results at <it>T</it> = 20 K confirm the short value of the C3—C9 bond also at low temperature. This feature may be due to some kind of hyperconjugative interaction of this methyl group with the unsaturated system of (I), as observed for citrinin (Roversi <it> et al.</it>., 1996).

The geometric parameters of the hydrogen bonds are given in Table 2. Each molecule of (I) is joined head-to-head to two different molecules by O—H···O hydrogen bonds through twofold axes (Fig. 2). One dimer involves the hydroxy group at C7 of the parent molecule and the keto group of the other, while in the second dimer, the hydrogen bond is formed by two hydroxy groups. The overall pattern is that of zigzag one-dimensional ribbons extended along the <it>a</it> axis. Similar patterns are common in vicinal diols (Brock, 2002). Ribbons of (I) are piled up along the <it>c</it> axis; the angle between the normal to the molecular plane (defined by all the atoms of the two fused rings) and the <it>c</it> axis is 3.60 (3)°. The layers are related by screw axes, so that the methyl group at C7 points towards the aldehyde O atom of the molecule of an adjacent layer, making a weak C—H···O interaction (Table 2).

S2. Experimental

The title compound was obtained as described by Colombo et al. (1983). Pale orange crystals of (I) (decomposition 528 K) were obtained upon slow crystallization from MeOH–H₂O (95:5).

S3. Refinement

Due to the absence of significant anomalous scatterers in the title compound, the absolute configuration could not be determined. The absolute configuration of the model was assigned to match the configuration of the chiral centres known from the X-ray analysis of the 5-bromo derivative (Engel & Kruger, 1976). All H atoms were located from difference Fourier maps and then refined isotropically.

Computing details

Data collection: XSCANS (Siemens, 1991); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPIII (Burnett & Johnson, 1996); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The molecular structure of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. Packing diagram of (I), viewed down the c axis. Intermolecular O—H···O hydrogen bonds are shown as dashed lines.

(7R,8S)-7,8-dihydroxy-3,7-dimethyl-6-oxo-7,8-dihydro- 6H-isochromene-5-carbaldehyde

Crystal data

C12H12O5	Dx = 1.449 Mg m^−3 Dm = 1.451 Mg m^−3 Dm measured by flotation in CCl4/benzene solution
Mr = 236.22	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P21212	Cell parameters from 60 reflections
a = 8.448 (1) Å	θ = 2.1–12.4°
b = 19.938 (1) Å	µ = 0.11 mm^−1
c = 6.428 (1) Å	T = 290 K
V = 1082.7 (2) Å^3	Prism, pale orange
Z = 4	0.5 × 0.3 × 0.23 mm
F(000) = 496

Data collection

Siemens P4 diffractometer	Rint = 0.019
Radiation source: fine-focus sealed tube	θmax = 27.5°, θmin = 2.0°
Graphite monochromator	h = −10→10
2θ/ω scans	k = 0→25
6711 measured reflections	l = −8→8
1470 independent reflections	3 standard reflections every 97 reflections
1269 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.036	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.102	All H-atom parameters refined
S = 1.09	w = 1/[σ^2(Fo^2) + (0.066P)^2 + 0.0091P] where P = (Fo^2 + 2Fc^2)/3
1470 reflections	(Δ/σ)max = 0.001
202 parameters	Δρmax = 0.20 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.63584 (16)	0.24079 (7)	0.2545 (3)	0.0471 (4)
O2	0.03004 (16)	0.18916 (7)	0.2257 (3)	0.0420 (4)
O3	0.4960 (2)	0.43060 (8)	0.3096 (5)	0.0858 (8)
O4	0.21085 (19)	0.48240 (7)	0.2953 (4)	0.0563 (5)
O5	−0.05386 (16)	0.38911 (8)	0.2661 (4)	0.0580 (5)
C1	0.0107 (2)	0.25620 (10)	0.2526 (3)	0.0387 (4)
C3	0.1789 (2)	0.16363 (9)	0.2255 (4)	0.0396 (5)
C4	0.3066 (2)	0.20359 (9)	0.2405 (4)	0.0378 (4)
C4A	0.2913 (2)	0.27448 (9)	0.2595 (3)	0.0324 (4)
C5	0.4200 (2)	0.31856 (9)	0.2679 (3)	0.0367 (5)
C6	0.3927 (2)	0.38942 (10)	0.2736 (4)	0.0469 (5)
C7	0.2269 (2)	0.41612 (10)	0.2154 (4)	0.0417 (5)
C8	0.1033 (2)	0.37207 (10)	0.3222 (4)	0.0407 (5)
C8A	0.1314 (2)	0.29917 (9)	0.2728 (3)	0.0334 (4)
C9	0.1811 (4)	0.08944 (11)	0.2036 (6)	0.0556 (6)
C10	0.5850 (2)	0.29765 (11)	0.2647 (4)	0.0403 (5)
C11	0.2096 (3)	0.41641 (14)	−0.0188 (5)	0.0557 (6)
H1	−0.095 (3)	0.2686 (12)	0.240 (4)	0.052 (7)*
H4	0.413 (2)	0.1814 (10)	0.227 (4)	0.036 (6)*
H8	0.115 (2)	0.3780 (10)	0.482 (4)	0.038 (5)*
H9A	0.137 (5)	0.079 (2)	0.063 (8)	0.123 (16)*
H9B	0.282 (4)	0.0718 (15)	0.200 (5)	0.074 (9)*
H9C	0.123 (4)	0.0691 (15)	0.302 (5)	0.072 (9)*
H10	0.661 (3)	0.3347 (13)	0.259 (4)	0.055 (7)*
H11A	0.107 (4)	0.4372 (14)	−0.053 (5)	0.061 (8)*
H11B	0.207 (3)	0.3751 (14)	−0.071 (4)	0.059 (8)*
H11C	0.292 (4)	0.4403 (15)	−0.076 (5)	0.073 (10)*
H04	0.309 (4)	0.4977 (16)	0.303 (5)	0.068 (8)*
H05	−0.074 (4)	0.4323 (16)	0.287 (6)	0.080 (10)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0308 (7)	0.0453 (8)	0.0652 (10)	0.0076 (6)	−0.0014 (8)	0.0030 (8)
O2	0.0328 (7)	0.0330 (7)	0.0602 (9)	−0.0033 (5)	−0.0006 (7)	−0.0014 (7)
O3	0.0429 (9)	0.0382 (9)	0.176 (2)	−0.0082 (7)	−0.0270 (16)	−0.0076 (12)
O4	0.0412 (8)	0.0290 (7)	0.0987 (14)	0.0018 (6)	−0.0049 (9)	−0.0079 (8)
O5	0.0302 (7)	0.0361 (8)	0.1077 (15)	0.0060 (6)	−0.0020 (10)	−0.0039 (11)
C1	0.0287 (9)	0.0353 (9)	0.0521 (12)	0.0021 (7)	0.0000 (11)	0.0039 (10)
C3	0.0356 (9)	0.0344 (9)	0.0487 (12)	0.0023 (7)	0.0003 (10)	0.0010 (9)
C4	0.0310 (9)	0.0326 (8)	0.0497 (11)	0.0040 (7)	−0.0022 (10)	−0.0002 (9)
C4A	0.0291 (8)	0.0325 (8)	0.0355 (9)	0.0010 (7)	−0.0007 (8)	0.0022 (8)
C5	0.0266 (8)	0.0353 (9)	0.0482 (12)	0.0009 (7)	−0.0038 (9)	0.0025 (9)
C6	0.0309 (9)	0.0347 (10)	0.0752 (16)	−0.0031 (8)	−0.0034 (11)	0.0012 (11)
C7	0.0321 (9)	0.0291 (8)	0.0639 (14)	0.0029 (7)	−0.0021 (10)	0.0006 (9)
C8	0.0310 (9)	0.0334 (9)	0.0577 (13)	0.0018 (8)	0.0024 (9)	−0.0020 (10)
C8A	0.0291 (8)	0.0312 (8)	0.0400 (10)	0.0020 (7)	−0.0002 (9)	0.0021 (8)
C9	0.0544 (14)	0.0315 (10)	0.0809 (18)	0.0000 (10)	0.0012 (15)	−0.0025 (12)
C10	0.0283 (9)	0.0431 (10)	0.0495 (12)	−0.0011 (8)	−0.0034 (10)	0.0046 (11)
C11	0.0550 (16)	0.0435 (12)	0.0685 (16)	0.0022 (12)	0.0011 (13)	0.0132 (13)

Geometric parameters (Å, º)

O2—C3	1.357 (2)	C5—C10	1.455 (2)
O2—C1	1.358 (2)	C6—C7	1.544 (3)
O1—C10	1.214 (3)	C7—C11	1.512 (4)
O3—C6	1.221 (3)	C7—C8	1.528 (3)
O4—C7	1.424 (2)	C8—C8A	1.507 (3)
O4—H04	0.88 (3)	C8—H8	1.04 (2)
O5—C8	1.417 (2)	C8A—C1	1.338 (3)
O5—H05	0.89 (3)	C1—H1	0.93 (3)
C3—C4	1.345 (3)	C9—H9A	1.00 (5)
C3—C9	1.486 (3)	C9—H9B	0.92 (3)
C4—C4A	1.425 (2)	C9—H9C	0.90 (3)
C4—H4	1.00 (2)	C10—H10	0.98 (3)
C4A—C5	1.399 (2)	C11—H11A	0.99 (3)
C4A—C8A	1.441 (2)	C11—H11B	0.89 (3)
C5—C6	1.432 (3)	C11—H11C	0.92 (3)
C3—O2—C1	118.7 (2)	C8A—C8—C7	110.6 (2)
C7—O4—H04	105 (2)	O5—C8—H8	108 (1)
C8—O5—H05	112 (2)	C8A—C8—H8	108 (1)
C4—C3—O2	121.4 (2)	C7—C8—H8	108 (1)
C4—C3—C9	125.9 (2)	C1—C8A—C4A	119.3 (2)
O2—C3—C9	112.7 (2)	C1—C8A—C8	121.2 (2)
C3—C4—C4A	121.4 (2)	C4A—C8A—C8	119.3 (2)
C3—C4—H4	117 (1)	C8A—C1—O2	123.5 (2)
C4A—C4—H4	122 (1)	C8A—C1—H1	125 (2)
C5—C4A—C4	123.8 (2)	O2—C1—H1	111 (2)
C5—C4A—C8A	120.8 (2)	C3—C9—H9A	106 (2)
C4—C4A—C8A	115.4 (2)	C3—C9—H9B	113 (2)
C4A—C5—C6	119.7 (2)	H9A—C9—H9B	104 (3)
C4A—C5—C10	124.3 (2)	C3—C9—H9C	112 (2)
C6—C5—C10	115.9 (2)	H9A—C9—H9C	110 (3)
O3—C6—C5	123.6 (2)	H9B—C9—H9C	111 (3)
O3—C6—C7	117.6 (2)	O1—C10—C5	127.4 (2)
C5—C6—C7	118.7 (2)	O1—C10—H10	118 (2)
O4—C7—C11	110.3 (2)	C5—C10—H10	114 (2)
O4—C7—C8	107.8 (2)	C7—C11—H11A	108 (2)
C11—C7—C8	112.5 (2)	C7—C11—H11B	112 (2)
O4—C7—C6	108.6 (2)	H11A—C11—H11B	107 (2)
C11—C7—C6	109.3 (2)	C7—C11—H11C	109 (2)
C8—C7—C6	108.2 (2)	H11A—C11—H11C	111 (2)
O5—C8—C8A	109.0 (2)	H11B—C11—H11C	110 (3)
O5—C8—C7	112.8 (2)
C3—O2—C1—C8A	2.1 (3)	C5—C6—C7—C8	44.3 (3)
C1—O2—C3—C4	−3.5 (3)	O4—C7—C8—O5	67.3 (2)
C1—O2—C3—C9	177.6 (2)	C11—C7—C8—O5	−54.5 (3)
O2—C3—C4—C4A	0.7 (3)	C6—C7—C8—O5	−175.4 (2)
C9—C3—C4—C4A	179.5 (3)	O4—C7—C8—C8A	−170.3 (2)
C3—C4—C4A—C5	−177.6 (2)	C11—C7—C8—C8A	67.8 (2)
C3—C4—C4A—C8A	3.3 (3)	C6—C7—C8—C8A	−53.0 (2)
C4—C4A—C5—C6	176.0 (2)	O2—C1—C8A—C4A	2.0 (3)
C8A—C4A—C5—C6	−4.9 (3)	O2—C1—C8A—C8	−174.2 (2)
C4—C4A—C5—C10	−1.9 (4)	C5—C4A—C8A—C1	176.3 (2)
C8A—C4A—C5—C10	177.2 (2)	C4—C4A—C8A—C1	−4.5 (3)
C4A—C5—C6—O3	169.6 (3)	C5—C4A—C8A—C8	−7.4 (3)
C10—C5—C6—O3	−12.4 (4)	C4—C4A—C8A—C8	171.8 (2)
C4A—C5—C6—C7	−15.1 (3)	O5—C8—C8A—C1	−21.3 (3)
C10—C5—C6—C7	162.9 (2)	C7—C8—C8A—C1	−145.9 (2)
O3—C6—C7—O4	−23.3 (3)	O5—C8—C8A—C4A	162.5 (2)
C5—C6—C7—O4	161.1 (2)	C7—C8—C8A—C4A	37.9 (3)
O3—C6—C7—C11	97.0 (3)	C4A—C5—C10—O1	0.0 (4)
C5—C6—C7—C11	−78.5 (3)	C6—C5—C10—O1	−177.9 (2)
O3—C6—C7—C8	−140.1 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C4—H4···O1	1.00 (2)	2.23 (2)	2.880 (2)	121 (2)
C10—H10···O3	0.98 (2)	2.39 (2)	2.770 (2)	103 (1)
O4—H04···O3	0.88 (3)	2.07 (3)	2.623 (2)	119 (2)
O4—H04···O3^i	0.88 (3)	2.18 (3)	3.025 (2)	159 (2)
O5—H05···O4^ii	0.89 (3)	2.06 (3)	2.891 (2)	156 (3)
C10—H10···O5^iii	0.98 (2)	2.64 (2)	3.555 (2)	155 (2)
C1—H1···O1^iv	0.93 (2)	2.34 (2)	3.182 (2)	150 (1)
C9—H9A···O3^v	1.00 (5)	2.68 (4)	3.672 (4)	172 (3)
C11—H11B···O1^v	0.89 (2)	2.66 (2)	3.537 (2)	167 (2)

Symmetry codes: (i) −x+1, −y+1, z; (ii) −x, −y+1, z; (iii) x+1, y, z; (iv) x−1, y, z; (v) x−1/2, −y+1/2, −z.