5β(H)-austricin, a new guaianolide from Artemisia leucodes

Article abstract of DOI:10.1023/B:CONC.0000033927.92754.bd

A new sesquiterpene lactone 5β(H)-austricin was isolated from white wormwood (Artemisia leucodes Schrenk.). Its structure was established by chemical and spectral methods.

Full text of DOI:10.1023/B:CONC.0000033927.92754.bd

Chemistry of Natural Compounds, Vol. 40, No. 2, 2004
5
β(H)-AUSTRICIN, A NEW GUAIANOLIDE FROM Artemisia leucodes
N. A. Talzhanov, V. I. Yamovoi, A. T. Kulyyasov,
K. M. Turdybekov, and S. M. Adekenov
UDC 547.314+547.737
A new sesquiterpene lactone 5β(H)-austricin was isolated from white wormwood (Artemisia leucodes
Schrenk.). Its structure was established by chemical and spectral methods.
Key words: sesquiterpene lactones, 5β(H)-austricin, relactonization reaction.
The sesquiterpene lactonesaustricin (1)leucomisin, parishin C, anhydroaustricin, matricarin, and artelin were isolated
previously from flowerheads and leaves of Artemisia leucodes Schrenk. (white wormwood) [1-5]. In continuation of research
of lactones of the ethanol extract of the aerial part of this plant, we isolated from polar fractions a new sesquiterpene lactone
+
25
(2), C H O , M 262, mp 258-260°C (EtOAc), [α]
+147.06 (c 0.034, CHCl ).
3
15 18
4
D
The IR spectrum of 2 has absorption bands at 3287 (OH), 1793 (γ-lactone carbonyl), 1664 (α,β-unsaturated ketone),
-1
and 1627 and 1610 cm (double bonds).
The PMR spectra of 2 (Table 1) and austricin [1] are practically identical with the exception of the signal for H-6,
which appears as a doublet of doublets at 4.2 ppm with SSCC J = 4.0 and J = 7.0 Hz. Therefore, it can be assumed that
5,6
6,7
the pairs H-5—H-6 and H-6—H-7 are in cis-positions relative to each other. Therefore, 2 can be formulated as 8α-hydroxy-2-
oxo-5α,6α,7α,11β(H)-guai-1(10),3(4)-dien-6,12-olide, which has structure 2a.
O
O
OH
OH
5
7
6
H
H
O
O
O
O
1
2a
It should be noted that a similar difference in the spectra was described earlier for badkhysin and isobadkhysin [6, 7],
where relactonization by base led to isomerization of the C-5 proton with retention of configuration of the lactone ring.
The structure of 2 was refined by saponfying austricin. Hydrolysis of 1 by K CO solution (0.5 N) in CH OH with
2
3
3
subsequent acidification by HCl (0.5%) gave two products (2b and 3).
O
O
O
OH
OH
O
+
O
H
H
O
O
O
O
2b
3
1
Institute of Phytochemistry, Ministry of Education and Science of the Republic of Kazakhstan, 470032, Republic of
Kazakhstan, Karaganda, ul. M. Gazalieva, 4, fax (3212) 43 37 73, e-mail: arglabin@phyto.kz. Translated from Khimiya
Prirodnykh Soedinenii, No. 2, pp. 111-114, March-April, 2004. Original article submitted October 8, 2003.
0009-3130/04/4002-0129 ©2004 Plenum Publishing Corporation
129

TABLE 1. PMR Spectra of 2 and 3 (CDCl3, 0 = TMS, δ, ppm)
1H chemical shift (SSCC Hz)
Atom
2
3
H-3
H-5
6.12 m
3.45 br.d (J1 = 4.0)
6.10 q (J = 2.0)
-
H-6
4.20 dd (J1 = 7.0; J2 = 4.0)
1.97 ddd (J1 = 12.0; J2 = 10.5; J3 = 7.0)
4.58 ddd (J1 = 10.5; J2 = 10.0; J3 = 6.0)
2.47 dd (J1 = 19.0; J2 = 10.0)
3.27 dd (J1 = 19.0; J2 = 6.0)
2.60 dq (J1 = 12.0; J2 = 7.0)
1.40 d (J1 = 7.0)
5.81 d (J = 3.0)
H-7
2.74 ddd (J1 = 13.0; J2 = 10.0; J3 = 4.0)
4.34 ddd (J1 = 11.0; J2 = 10.0; J3 = 4.0)
3.07 dd (J1 = 19.0; J2 = 4.0)
2.86 dd (J1 = 19.0; J2 = 11.0)
2.58 dq (J1 = 13.0; J2 = 7.0)
1.38 d (J = 7.0)
H-8
H-9a
H-9b
H-11
H-13
H-14
H-15
2.27 s
2.43 s
2.13 s
2.13 s
C 14
O 1
C 2
C 9
C 10
C 6
O 2
C 8
C 1
C 3
C 12
C 5
C 7
C 4
C 15
O 3
C 11
C 13
Fig. 1. Crystal structure 3.
The main product was a colorless crystalline compound, C H O , mp 258-260 C (EtOAc). Comparison of spectral
15 18
4
data and the mixed melting point with an authentic sample showed that 2b was identical to 2, which we isolated previouslyfrom
white wormwood.
Therefore, sesquiterpene2isa newcompoundwith structure2b, 5β(H)-austricin(8α-hydroxy-2-oxo-7α,5β,6β,11β(H)-
guai-1(10),3(4)-dien-6,12-olide).
+
The second product was a colorless crystalline compound (3), C H O , mp 193-195°C (EtOAc), M 244.
15 16
3
The IR spectrum of 3 contains absorption bands at 1775 (γ-lactone carbonyl), 1689 (conjugated ketone of a five-
-1
membered ring), and 1623 and 1600 cm (double bonds). It should be noted that absorption bands typical of OH are absent.
The UV spectrum has an absorption maximum characteristic of a conjugated system: λ
244, 257, and 308 nm with
max
log 5.42, 5.41, and 4.79, respectively.
Table 1 lists the PMR spectrum, which lacks a signal characteristic of the C-5 proton. However, the signal of H-6 is
shifted by1.61 ppm to weak field. Obviously, this is due to the formation of an olefinic bond at C-6—C-5 as a result of opening
of the lactone ring by base and closure at C-8 after acidification.
Comparison of the IR, UV, mass, and PMR spectra of 3 with literature data [8] identified it as dehydroisoleucomisin,
which was prepared previously by hydrolysis of austricin.
130

TABLE 2. Bond Lengths (d, Å)
Bond
d
Bond
d
O1C2
C1C10
C1C5
C1C2
O2C12
O2C8
C2C3
O3C12
C3C4
C4C5
1.226 (6)
1.344 (8)
1.494 (7)
1.498 (8)
1.349 (7)
1.464 (7)
1.459 (9)
1.216 (7)
1.330 (8)
1.460 (6)
C4C15
C5C6
1.478 (8)
1.350 (7)
1.470 (7)
1.506 (8)
1.527 (8)
1.486 (9)
1.507 (9)
1.516 (8)
1.496 (8)
1.509 (10)
C6C7
C7C8
C7C11
C8C9
C9C10
C10C14
C11C12
C11C13
TABLE 3. Bond Angles (ω, deg)
Angle
ω
Angle
ω
C10C1C5
C10C1C2
C5C1C2
C12O2C8
O1C2C3
O1C2C1
C3C2C1
C4C3C2
C3C4C5
C3C4C15
C5C4C15
C6C5C4
C6C5C1
C4C5C1
C5C6C7
C6C7C8
131.0 (5)
124.4 (5)
104.5 (4)
109.2 (4)
125.1 (6)
128.2 (6)
106.6 (4)
111.2 (5)
110.4 (5)
127.0 (5)
122.5 (5)
123.3 (5)
129.4 (4)
107.2 (4)
125.7 (5)
113.7 (5)
C6C7C11
C8C7C11
O2C8C9
116.0 (5)
101.8 (4)
108.6 (5)
103.6 (5)
117.0 (6)
115.8 (5)
126.2 (5)
122.2 (6)
11.6 (5)
O2C8C7
C9C8C7
C8C9C10
C1C10C9
C1C10C14
C9C10C14
C12C11C13
C12C11C7
C13C11C7
O3C12O2
O3C12C11
O2C12C11
112.5 (6)
100.8 (5)
117.4 (6)
120.2 (5)
129.2 (6)
110.5 (5)
In view of the fact that the orientation of the C-11 methyl was not previouslydefined, we carried out an x-raystructural
analysis of 3. Figure 1 shows the molecular structure. The bond lengths are slightly shortened (Table 2) and the bond angles
(Table 3) are significantly distorted compared with the usual values [9]. The difference is from 0.9 (O2–C8–C9) to 15.5°
(C5–C1–C2).
The lactone ring is trans-fused tothe guaiane skeleton. The torsion angle H7–C7–C8–H8 is 180.0°. The conformation
7
of the lactone ring is almost an ideal envelope (∆C = 1.1°). Atom C-7 deviates from the plane of the remaining atoms
S
(coplanar within ±0.006 Å) by 0.58 Å. The seven-membered ring (C5,C6,C7,C8,C9,C10,C1) adopts a distorted 8-sofa
8
conformation (∆C = 12.9°) with deviations of C8, C9, and C14 from the plane of C5, C6, C7, C10, and C1, which are
S
coplanar within 0.007 Å, by -0.84, -0.22, and 0.27 Å, respectively. The five-membered ring (C1,C2,C3,C4,C5) is planar with
O1 and C15 also in this plane.
Our investigation and previous ones [10] confirmed that the orientation of the methyl group does not change as a result
of relactonization.
131

TABLE 4. Atomic Coordinates (× 104; for H, × 103)
Atom
x
y
z
Atom
x
y
z
O1
C1
2596 (9)
2845 (8)
2437 (8)
2581 (10)
2655 (7)
2287 (11)
2306 (8)
2672 (7)
2898 (7)
3299 (8)
2392 (9)
3261 (12)
3196 (8)
2662 (10)
2617 (9)
3797 (14)
-296 (2)
928 (3)
2604 (2)
1924 (2)
79 (2)
C14
C15
3646 (13)
2102 (10)
212 (6)
-355 (4)
2647 (4)
96 (3)
1316 (4)
3112 (3)
336 (2)
203 (3)
101 (2)
79 (2)
O2
C2
2127 (3)
461 (3)
H3
2520 (3)
-416 (2)
3003 (3)
3768 (2)
2101 (2)
1749 (2)
1080 (2)
723 (2)
751 (3)
1373 (3)
724 (3)
74 (3)
H6
270 (8)
301 (3)
252 (2)
183 (2)
68 (5)
O3
C3
3343 (3)
1087 (4)
1854 (3)
1826 (3)
2517 (3)
2527 (3)
1834 (4)
997 (4)
H7
457 (6)
H8
110 (6)
C4
H9A
H9B
H11
275 (13)
448 (11)
135 (7)
40 (4)
C5
101 (4)
336 (3)
453 (5)
426 (4)
394 (5)
299 (3)
252 (3)
302 (5)
64 (3)
C6
78 (2)
C7
H13A
H13B
H13C
H15A
H15B
H15C
317 (11)
388 (9)
49 (3)
C8
113 (3)
65 (4)
C9
513 (14)
103 (8)
C10
C11
C12
C13
566 (3)
299 (2)
351 (2)
312 (4)
3298 (4)
2966 (4)
4080 (5)
194 (6)
305 (12)
780 (3)
EXPERIMENTAL
Melting points were determined on a Boetius apparatus. IR spectra were recorded (in KBr disks) on an Avatar 360
instrument (Thermo Nicolet); UV spectra (EtOH solutions), on a Specord UV VIZ instrument. NMR spectra were recorded on
1
13
a DRX-500 spectrometer (Bruker) at working frequencies 500.13 MHz ( H) and 125.76 MHz ( C) in CDCl . High resolution
3
mass spectra (EI, 70 eV) were obtained in an MAT 8200 (Finnigan). Optical rotations were measured on a CM-2 polarimeter.
We used SiO (KSK) for column chromatography and Silufol plates for TLC with development by KMnO
2
4
solution (1%).
The aerial part of white wormwood was collected in 2000 year during budding (August) in the Moiyn-Kum desert
(Kazakhstan), dried in air, and ground.
20
Starting austricin (1) with mp 147-149°C, [ ]
+28° (c 0.1, CHCl ) was isolated as before [2].
3
D
Isolation of 5β(H)-Austricin (2). Raw material (A. leucodes Schrenk., 1 kg) was extracted twice with EtOH
(2 × 8 L) at 60°C. The combined EtOH extracts were filtered and evaporated in vacuum in a rotary evaporator. The resulting
dryextract (210 g) was treated with EtOH:H O (0.9 L, 2:1 byvol.), thoroughlymixed, and filtered to remove solids. The filtrate
2
was extracted with CHCl (3 × 0.2 L). The CHCl extracts were combined and evaporated to dryness. The resulting solid
3
3
(93 g) was chromatographed over SiO with elution by benzene and then benzene:ethylacetate (7:3). Polar fractions (74-101)
2
were combined and evaporated to dryness. The resulting solid (5 g) was repeatedly chromatographed over SiO (50 g) with
2
+
elution by benzene:ethylacetate (60:40) to isolate 2 (40 mg, 0.004%), C H O , M 262, mp 258-260°C (EtOAc),
15 18
4
25
[α]
+147.06 (c 0.034, CHCl ).
3
D
-1
UV spectrum (EtOH, λ , nm): 255 (log ε 5.29). IR spectrum (KBr, ν, cm ): 3287 (OH), 1793 (γ-lactone C=O), 1664
max
(C=O), and 1627 and 1610 (C=C).
13
C NMR spectrum (125.76 MHz, CDCl ): 196.46 (C-2), 177.65 (C-12), 168.16 (C-4), 145.16 (C-10), 135.61 (C-3),
3
128.41 (C-1), 73.96 (C-6), 51.64 (C-5), 45.44 (C-9), 42.75 (C-11), 19.70 (C-15), 16.64 (C-14), 14.32 (C-13).
Table 1 gives the PMR spectrum.
Saponification of 1. A solution of 1 (200 mg, 0.76 mmol) in MeOH (10 mL) at room temperature was treated with
K CO (1 mL, 1 M, 1 mmol) and stirred for 3 h. Then solvent was removed in vacuum. The solid was dissolved in EtOAc,
2
3
washed with HCl (0.5%) and water until the washings were neutral, and dried over Na SO . The solvent was removed in
2
4
vacuum. The solid was chromatographed (gradient elution by petroleum ether:ethylacetate, 100:0 → 50:50) to afford lactone
3 (0.07 g, 35%) and 2 (0.105 g, 52.2%).
132

Dehydroisoleucomisin (3). mp 193-195°C (EtOAc), lit. mp 203-205°C.
-1
UV spectrum (EtOH, λ , nm): 244, 257, 308 (log ε 5.42, 5.41, 4.79, respectively. IR spectrum (KBr, ν, cm ): 1775
max
(γ-lactone C=O), 1689 (C=O), and 1623 and 1600 (C=C).
Table 1 gives the PMR spectrum.
X-ray Structure Analysis. Cell constants and intensities of 1283 independent reflections were measured on a Bruker
P4 diffractometer (Mo Kα, graphite monochromator, θ/2θ-scanning, 2θ < 50°). The crystals are orthorhombic: a = 7.3555(6),
3
3
b = 16.0139(18), c = 21.5122(19) Å, α = β = γ = 90.0°, V = 2533.9(4) Å , d
= 1.281 g/cm , Z = 8 (C H O ), space group
15 16 3
calc
C222 . The structure was solved by direct methods and refined by anisotropic full-matrix least squares methods for
1
nonhydrogen atoms. All H atoms except for H14a, H14b, and H14c were found in a difference synthesis and refined
14
isotropically. The H atoms of C H were fixed in two positions of different occupancy (0.4 and 0.6) owing to disorder. We
3
used 1002 reflections with I > 2σ(I) in the calculations. The final agreement factors were R = 0.0564 and R = 0.1713. The
w
structure was solved and refined using SHELXS-97 and SHELXL-97 programs. Table 4 contains the atomic coordinates.
ACKNOWLEDGMENTS
We thank coworkers of the N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian
Academy of Sciences, V. A. Raldugin, Yu. V. Gatilov, and M. M. Shakirov for help with the x-ray structure and spectral
analyses.
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