Trichodermin (4β-acet­oxy-12,13-epoxy­trichothec-9-ene)

Abstract

In the title natural product, C₁₇H₂₄O₄, which is a very potent inhibitor of protein synthesis in mammalian cells, the five-membered ring displays an envelope conformation, whereas the two six-membered rings show different conformations, viz. chair and half-chair.

Related literature

For related literature, see: Nielsen et al. (2005 ▶); Wei et al. (1974 ▶); Zhang et al. (2007 ▶). For details of ring puckering analysis, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

• C₁₇H₂₄O₄

• M _r = 292.36

• Orthorhombic,

• a = 7.0127 (3) Å

• b = 8.4102 (3) Å

• c = 26.2786 (10) Å

• V = 1549.86 (10) ų

• Z = 4

• Mo Kα radiation

• μ = 0.09 mm⁻¹

• T = 293 (2) K

• 0.41 × 0.40 × 0.37 mm

Data collection

• Rigaku R-AXIS RAPID IP diffractometer

• Absorption correction: none

• 14719 measured reflections

• 2046 independent reflections

• 1726 reflections with I > 2σ(I)

• R _int = 0.027

Refinement

• R[F ² > 2σ(F ²)] = 0.036

• wR(F ²) = 0.104

• S = 1.11

• 2046 reflections

• 195 parameters

• H-atom parameters constrained

• Δρ_max = 0.18 e Å⁻³

• Δρ_min = −0.13 e Å⁻³

Data collection: PROCESS-AUTO (Rigaku, 1998 ▶); cell refinement: PROCESS-AUTO; data reduction: CrystalStructure (Rigaku/MSC, 2002 ▶); program(s) used to solve structure: SIR92 (Altomare et al., 1993 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C14—H14a⋯O2	0.96	2.58	2.936 (3)	102

supplementary crystallographic information

Comment

Trichodermin is a member of the 4β-aceoxy-12,13-epoxytrichothecene family (Nielsen et al., 2005), which form a medically and economically important class of mycotoxins produced by fungi that spoil fruit and grain. Many studies (e.g. Wei et al., 1974) show that trichodermin is a very potent inhibitor of protein synthesis in mammalian cells.

The molecular structure of (I) is shown in Fig. 1. The molecule contains two six membered rings, one five membered ring and one three membered ring. The five membered ring displays an envelope conformation with atom C12 at the flap position 0.705 (3) Å out of the mean plane formed by the other four atoms.

The O1-containing six-membered ring displays a chair conformation. The typical C9?C10 double bond length of 1.325 (3)Å suggests that C9 and C10 atoms are sp² hybridized, which correlates with the larger C9—C10—C11 bond angle of 125.0 (2)° and C8—C9—C10 bond angle of 121.0 (2)° and a small C8—C9—C10—C11 torsion angle of 2.6 (3)°. A ring puckering analysis for the C9-containing six membered ring gave θ of 128.3 (2)° and φ of 206.9 (3)°, indicating a half-chair conformation (Cremer & Pople, 1975).

The C14-methyl group is attached to the bridgehead C5 atom and the small C14—C5—C12—O2 torsion angle of 38.4 (2)° allows a weak intramolecular C—H···O interaction (Table 1) to occur.

Experimental

For morphological identification (Zhang et al., 2007) cultures were grown on OA, PDA, and SNA media for 7–14 days at room temperature (293 K) under ambient daylight (Nielsen et al., 2005). Microscopic observations and measurements were made from slides mounted in water. For metabolite production, the strains were inoculated onto PDA media and incubated for 10 days at 298 K in the dark. Selected strains were also cultivated in liquid media placed in a rotary shaker at 120 rpm for 10 days at 298 K in the dark. After cultivation, the bottles were stored at 253 K until extraction.

Liquid cultures were extracted with petroleum ether. The upper phase was filtered and evaporated in vacuo. Samples were then redissolved in petroleum ether to crystallize the crude product. Colourless chunks of (I) were recrystalized from n-hexane.

Refinement

In the absence of significant anomalous scattering effects, Friedel pairs were merged; the absolute configuration was not determined.

The H atoms were geometrically placed (C—H = 0.93–0.98 Å) and refined as riding with U_iso(H) = 1.2U_eq(C) or 1.5U_eq(methyl C). The methyl group was allowed to rotate, but not to tip, to best fit the electron density.

Figures

Fig. 1.

The molecular structure of (I) with 30% displacement ellipsoids (arbitrary spheres for H atoms), dashed line indicates hydrogen bonding.

Crystal data

C17H24O4	Dx = 1.253 Mg m−3
Mr = 292.36	Melting point = 319–320 K
Orthorhombic, P212121	Mo Kα radiation λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 9452 reflections
a = 7.0127 (3) Å	θ = 3.2–27.0º
b = 8.4102 (3) Å	µ = 0.09 mm−1
c = 26.2786 (10) Å	T = 293 (2) K
V = 1549.86 (10) Å3	Chunk, colorless
Z = 4	0.41 × 0.40 × 0.37 mm
F000 = 632.00

Data collection

Rigaku R-AXIS RAPID IP diffractometer	2046 independent reflections
Radiation source: fine-focus sealed tube	1726 reflections with I > 2σ(I)
Monochromator: graphite	Rint = 0.027
Detector resolution: 10.0 pixels mm-1	θmax = 27.4º
T = 291(2) K	θmin = 3.0º
ω scans	h = −9→9
Absorption correction: none	k = −9→10
14719 measured reflections	l = −34→33

Refinement

Refinement on F2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F2 > 2σ(F2)] = 0.036	w = 1/[σ2(Fo2) + (0.0625P)2 + 0.0793P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.104	(Δ/σ)max < 0.001
S = 1.11	Δρmax = 0.18 e Å−3
2046 reflections	Δρmin = −0.13 e Å−3
195 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.032 (3)
Secondary atom site location: difference Fourier map

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
C14	0.6512 (4)	0.9319 (2)	0.36688 (10)	0.0589 (6)
H14A	0.6793	1.0017	0.3390	0.088*
H14B	0.7086	0.9727	0.3974	0.088*
H14C	0.5156	0.9253	0.3714	0.088*
C7	0.4588 (3)	0.6081 (3)	0.39880 (9)	0.0533 (5)
H7A	0.3918	0.7071	0.4051	0.064*
H7B	0.4180	0.5680	0.3660	0.064*
C8	0.4061 (3)	0.4884 (3)	0.43987 (9)	0.0589 (6)
H8A	0.4140	0.5397	0.4729	0.071*
H8B	0.2752	0.4548	0.4348	0.071*
C13	0.4905 (3)	0.7268 (3)	0.27735 (9)	0.0641 (6)
H13A	0.4452	0.6423	0.2553	0.077*
H13B	0.3912	0.7860	0.2947	0.077*
O2	0.6596 (2)	0.81223 (19)	0.26194 (6)	0.0629 (4)
C15	0.7438 (4)	0.6934 (3)	0.45039 (7)	0.0564 (5)
H15A	0.6641	0.7780	0.4626	0.085*
H15B	0.8732	0.7299	0.4482	0.085*
H15C	0.7369	0.6051	0.4735	0.085*
C5	0.7308 (3)	0.7668 (2)	0.35565 (7)	0.0433 (4)
C18	1.1534 (4)	1.1714 (3)	0.34760 (9)	0.0627 (6)
H18A	1.2106	1.2347	0.3739	0.094*
H18B	1.0445	1.2262	0.3341	0.094*
H18C	1.2444	1.1536	0.3209	0.094*
C6	0.6749 (3)	0.6406 (2)	0.39726 (7)	0.0421 (4)
C12	0.6697 (3)	0.7020 (2)	0.30416 (7)	0.0465 (5)
C9	0.5325 (3)	0.3449 (2)	0.43982 (8)	0.0525 (5)
C16	0.4718 (4)	0.2079 (3)	0.47267 (9)	0.0676 (6)
H16A	0.5618	0.1226	0.4692	0.101*
H16B	0.3478	0.1721	0.4622	0.101*
H16C	0.4669	0.2415	0.5076	0.101*
O4	1.0964 (3)	0.9811 (2)	0.41353 (6)	0.0741 (5)
C17	1.0918 (3)	1.0153 (2)	0.36930 (9)	0.0506 (5)
O3	1.0281 (2)	0.91593 (16)	0.33263 (5)	0.0502 (4)
C4	0.9533 (3)	0.7633 (2)	0.34927 (8)	0.0440 (4)
H4	1.0141	0.7309	0.3812	0.053*
C11	0.7705 (3)	0.4800 (2)	0.38357 (7)	0.0419 (4)
H11	0.9069	0.4892	0.3911	0.050*
C10	0.6935 (3)	0.3431 (2)	0.41348 (8)	0.0486 (5)
H10	0.7641	0.2495	0.4136	0.058*
C2	0.8015 (3)	0.5625 (2)	0.29623 (7)	0.0461 (4)
H2	0.7955	0.5252	0.2609	0.055*
O1	0.7508 (2)	0.43802 (14)	0.33066 (5)	0.0462 (3)
C3	0.9936 (3)	0.6396 (2)	0.30725 (8)	0.0497 (5)
H3A	1.0438	0.6907	0.2770	0.060*
H3B	1.0849	0.5610	0.3189	0.060*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C14	0.0555 (13)	0.0392 (9)	0.0820 (14)	0.0064 (9)	0.0048 (11)	−0.0083 (10)
C7	0.0408 (11)	0.0516 (10)	0.0675 (13)	0.0032 (9)	0.0035 (10)	−0.0066 (10)
C8	0.0493 (12)	0.0608 (12)	0.0667 (13)	−0.0051 (11)	0.0101 (10)	−0.0109 (11)
C13	0.0542 (13)	0.0734 (14)	0.0648 (13)	0.0018 (12)	−0.0151 (11)	0.0026 (12)
O2	0.0649 (10)	0.0625 (9)	0.0612 (9)	0.0067 (8)	−0.0071 (8)	0.0092 (7)
C15	0.0640 (13)	0.0531 (10)	0.0520 (11)	−0.0085 (11)	0.0012 (10)	−0.0139 (9)
C5	0.0388 (9)	0.0374 (8)	0.0537 (10)	0.0026 (8)	−0.0021 (8)	−0.0079 (8)
C18	0.0740 (16)	0.0468 (11)	0.0672 (13)	−0.0104 (11)	0.0040 (12)	−0.0033 (10)
C6	0.0401 (10)	0.0383 (9)	0.0480 (10)	0.0012 (7)	−0.0008 (8)	−0.0095 (8)
C12	0.0442 (10)	0.0446 (10)	0.0508 (10)	0.0015 (8)	−0.0046 (9)	−0.0020 (8)
C9	0.0568 (12)	0.0509 (11)	0.0497 (10)	−0.0096 (10)	−0.0015 (10)	−0.0071 (9)
C16	0.0737 (16)	0.0677 (13)	0.0613 (13)	−0.0158 (13)	0.0082 (12)	0.0011 (11)
O4	0.1000 (14)	0.0670 (10)	0.0553 (9)	−0.0305 (10)	−0.0103 (9)	−0.0022 (8)
C17	0.0456 (11)	0.0478 (10)	0.0583 (12)	−0.0069 (9)	−0.0008 (9)	−0.0065 (9)
O3	0.0536 (8)	0.0426 (7)	0.0543 (8)	−0.0087 (6)	−0.0013 (6)	−0.0036 (6)
C4	0.0412 (10)	0.0386 (9)	0.0524 (10)	−0.0014 (8)	−0.0021 (8)	−0.0025 (8)
C11	0.0401 (10)	0.0399 (8)	0.0457 (10)	0.0007 (8)	−0.0017 (8)	−0.0067 (7)
C10	0.0531 (12)	0.0406 (9)	0.0521 (10)	−0.0014 (9)	−0.0032 (9)	−0.0061 (8)
C2	0.0498 (11)	0.0437 (9)	0.0447 (9)	0.0012 (9)	0.0008 (8)	−0.0087 (8)
O1	0.0520 (8)	0.0385 (6)	0.0481 (7)	−0.0008 (6)	−0.0003 (6)	−0.0100 (5)
C3	0.0452 (11)	0.0453 (10)	0.0586 (11)	0.0037 (8)	0.0051 (9)	−0.0071 (9)

Geometric parameters (Å, °)

O1—C2	1.429 (2)	C15—H15B	0.9600
O1—C11	1.441 (2)	C15—H15C	0.9600
O2—C12	1.447 (2)	C5—C12	1.521 (3)
O2—C13	1.444 (3)	C5—C4	1.569 (3)
O3—C4	1.454 (2)	C5—C6	1.574 (3)
O3—C17	1.351 (2)	C18—C17	1.496 (3)
O4—C17	1.198 (3)	C18—H18A	0.9600
C9—C10	1.325 (3)	C18—H18B	0.9600
C14—C5	1.526 (2)	C18—H18C	0.9600
C14—H14A	0.9600	C6—C11	1.550 (2)
C14—H14B	0.9600	C12—C2	1.508 (3)
C14—H14C	0.9600	C9—C16	1.501 (3)
C7—C8	1.522 (3)	C16—H16A	0.9600
C7—C6	1.540 (3)	C16—H16B	0.9600
C7—H7A	0.9700	C16—H16C	0.9600
C7—H7B	0.9700	C4—C3	1.543 (3)
C8—C9	1.497 (3)	C4—H4	0.9800
C8—H8A	0.9700	C11—C10	1.495 (3)
C8—H8B	0.9700	C11—H11	0.9800
C13—C12	1.456 (3)	C10—H10	0.9300
C13—H13A	0.9700	C2—C3	1.523 (3)
C13—H13B	0.9700	C2—H2	0.9800
C15—C6	1.543 (3)	C3—H3A	0.9700
C15—H15A	0.9600	C3—H3B	0.9700
C5—C14—H14A	109.5	C11—C6—C5	108.57 (14)
C5—C14—H14B	109.5	O2—C12—C13	59.67 (13)
H14A—C14—H14B	109.5	O2—C12—C2	114.98 (16)
C5—C14—H14C	109.5	C13—C12—C2	125.02 (19)
H14A—C14—H14C	109.5	O2—C12—C5	117.80 (16)
H14B—C14—H14C	109.5	C13—C12—C5	128.51 (19)
C8—C7—C6	112.00 (18)	C2—C12—C5	103.23 (15)
C8—C7—H7A	109.2	C10—C9—C8	120.9 (2)
C6—C7—H7A	109.2	C10—C9—C16	122.2 (2)
C8—C7—H7B	109.2	C8—C9—C16	116.76 (19)
C6—C7—H7B	109.2	C9—C16—H16A	109.5
H7A—C7—H7B	107.9	C9—C16—H16B	109.5
C9—C8—C7	112.90 (18)	H16A—C16—H16B	109.5
C9—C8—H8A	109.0	C9—C16—H16C	109.5
C7—C8—H8A	109.0	H16A—C16—H16C	109.5
C9—C8—H8B	109.0	H16B—C16—H16C	109.5
C7—C8—H8B	109.0	O4—C17—O3	123.5 (2)
H8A—C8—H8B	107.8	O4—C17—C18	125.0 (2)
O2—C13—C12	59.88 (13)	O3—C17—C18	111.50 (19)
O2—C13—H13A	117.8	C17—O3—C4	116.79 (15)
C12—C13—H13A	117.8	O3—C4—C3	108.30 (15)
O2—C13—H13B	117.8	O3—C4—C5	111.98 (16)
C12—C13—H13B	117.8	C3—C4—C5	105.74 (16)
H13A—C13—H13B	114.9	O3—C4—H4	110.2
C13—O2—C12	60.45 (13)	C3—C4—H4	110.2
C6—C15—H15A	109.5	C5—C4—H4	110.2
C6—C15—H15B	109.5	O1—C11—C10	106.50 (15)
H15A—C15—H15B	109.5	O1—C11—C6	113.33 (15)
C6—C15—H15C	109.5	C10—C11—C6	113.11 (15)
H15A—C15—H15C	109.5	O1—C11—H11	107.9
H15B—C15—H15C	109.5	C10—C11—H11	107.9
C12—C5—C14	113.27 (18)	C6—C11—H11	107.9
C12—C5—C4	100.28 (16)	C9—C10—C11	125.0 (2)
C14—C5—C4	113.68 (16)	C9—C10—H10	117.5
C12—C5—C6	107.84 (15)	C11—C10—H10	117.5
C14—C5—C6	112.86 (16)	O1—C2—C12	109.28 (15)
C4—C5—C6	108.03 (16)	O1—C2—C3	114.30 (16)
C17—C18—H18A	109.5	C12—C2—C3	100.66 (14)
C17—C18—H18B	109.5	O1—C2—H2	110.7
H18A—C18—H18B	109.5	C12—C2—H2	110.7
C17—C18—H18C	109.5	C3—C2—H2	110.7
H18A—C18—H18C	109.5	C2—O1—C11	114.05 (13)
H18B—C18—H18C	109.5	C2—C3—C4	105.12 (15)
C7—C6—C15	109.60 (17)	C2—C3—H3A	110.7
C7—C6—C11	106.10 (16)	C4—C3—H3A	110.7
C15—C6—C11	108.99 (17)	C2—C3—H3B	110.7
C7—C6—C5	112.52 (16)	C4—C3—H3B	110.7
C15—C6—C5	110.89 (15)	H3A—C3—H3B	108.8

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
C14—H14a···O2	0.96	2.58	2.936 (3)	102