Phy&dmis@y, Vol. 33, No. 2, pp. 389-392, 1993 Printed in GreatBritain.

0031-9422f93 $6.00+0.00 0 1993 Pergamon PressLtd

BUTENOLIDES

FROM SINOMENIUM

ACUTUM

HIDEAKI OTSUKA, AIKO ITO, NAOMI FUJIOKA, KEN ICHIRO KAWAMATA, RYOJI KASAI, KAZUO YAMASAKI* and TOMOHIROSATOH~

Institute of Pharma~uti~l sciences, Hiroshima University, School of Medicine, l-2-3 Kasumi, Mina~-Ku, Hiroshima 734, Japan; vhionogi Research L&oratories, Shionogi & Co., Ltd, Sag&, Fukushima-ku, Osaka 553, Japan
(Received

3 Sepre&er 1992)

Key Word Index-Sinomenium acutwn; Menispermaceae; butenolide; menisdaurilide; daurilide; dihydroaquilegiolide.

dihydromenis-

Abstract-From the rhizome of Sinomenium acutum, four closely related butenolides were isolated. Two of the butenolides were identified as menisdaurilide and aquilegiolide. The structures of the other two butenolides were decided to be (4R,6R)-2~ihydrome~isdau~lide and (4R,6~2-dihydroaquile~olide.

INTRODUCI-ION

RFMJLTSAND DISCUSSION

The rhizome and caulis of Sinomenium acutum Rehder et Wilson are registered in the Japanese Pharmacopoeia XII and are widely used in traditional Chinese prescriptions for medicines with diuretic, anti-allergic and anti-inflammatory properties. Many allcaloids, such as sinomeuine [ 11, disinomenine [2], sinactine [3], sinoactine [4], acutumine [S] and magnoflorine [6], as well as the lignan syringaresinol[7j have been isolated from S. ucutum. A unique cyanoglucoside, menisdau~n (S), has been isolated from Meniso ~a~icum which belongs to the same family [8].

The rhizome and caulis of S. ucutum yielded four compounds (l-4) along with sinomenine, acutumine, menisdaurin (S), liliodendrin and N-feruloyltyramine. The last five compounds were identified by H and 13C NMR spectroscopy. Sinomenine and acutumine (a unique chlorine-containing alkaloid) have already been isolated from this plant, whereas menisdaurin (s) has been isolated for the first time; however, it has been isolated from a closely related plant (see above) and two Zlex spp., Z. w~~gii [9] and I. ~~~li~ (incorrect structure proposed [lo], but later revised [ll]). Liliodend~n is a

OH

OH

OH

OH

on

*Author to whom ~~~~nden~

should be addressed. 389

H. OTSUKA

et al.

Fig. 1.

Ster~o~hemie~ view of molecular structure and absolute con~guration of compound 6 as determined by X-ray diffraction. based on the empirical rule of the CD trend for butenolide [16]. Menisdau~lide has also previously been isolated from Aquikgia atrata var. atrouiolacea [17] but the absolute stereochemistry was not determined. We have now determined the absolute stereochemistry of 1 by the XABS method [18] of X-ray analysis using the p-bromobenzoate derivative of 1 (6). As the latter compound was derived from 1 through mild acylation, it should retain the stereochemistry of 1. The assigned structure has 4S,6R stere~hemistry which is the opposite of the previously proposed structure [8] (Fig. 1). Compound 2 has the same molecular formula as 1 (CsHsO,) and its NMR data were very similar to those of 1, suggesting a diastereomeric correlation. The NMR data were identical to those of aquilegiolide isolated from A. &rata var. atroviolaceu [17]. However, previous assignments for the carbon signals of C-2, C-3 and C-7 should be corrected (Tables 1, 2).
100 MHz) 2 El738 164.4 112.24 121.45 64.3 38.0 77.0 139.q 173.7 3 174.0 35.8 43.3 67.4 25.0 81.6 113.4 176.0 4 175.4 34.1 41.6 66.4 23.8 80.9 112.6 176.3

diglucoside of syringaresinol and the aglycone has been isolated from S. acutu~. ~-Feruloyltyramine has been isolated from several plants such as Allium bakeri [12]. It is known to have some biological activities such as (i) inhibition of platelet aggregation [123, (ii) inhibition of pros~~andin and leucotriene biosynthesis [I33 and (iii) blocking sodium channels [14]. This compound might be responsible for the anti-inflammatory and/or anti-allergic properties of the crude drug [15]. Compound 1 has a molecular formula of CsHsO, (HR-MS). From the 13C and H NMR data, 1 was identified as menisdaurilide. A previous report [8] showed that the compound can be obtained by acid treatment of 5. The reported NMR data were essentially the same as ours, but some assignments (C-2, C-3, C-7 and H-2, H-3) should be revised based on the H-H and C-H COSY experiments (Tables 1,2). In the same report the absolute configuration of 1 was tentatively proposed

Table 1. C NMR spectral data of 1-d (CD,OD, C

1
166.3 120.4 146.1 67.3 41.1 80.1 111.5 176.0

1* 163.3 119.8 144.0 66.7 39.9 78.3 111.3 173.7

1 PI+ 163.4 111.1t 119.6t 66.6 39.8 78.3 144.1t 173.8

2$ 164.3 121.6 139.8 64.5 38.1 77.0 112.4 173.4

165.7 122.2 139.9 65.1 38.4 78.3 112.6 175.9

*In CDCI,. fin CDCI,, assignment should be corrected. $In (CD&CO. QIn (CD&CO, assignment should be corrected, Table 2. H NMR data for 1 and 2 (400 MHz, CD,OD)* 2 6 6.66 6.35 4.55 1.77 2.52 5.30 5.86 H 2 3 4 5a 5e 6 7 2 3 4 1

5a

se

H 2 3 4 5a 5e 6 7

6 6.63 6.43 4.58 1.69 2.96 4.94 5.86

*J in Hz 1: upper right part; 2: lower left part.

Butenolides from Sinomenium acutum Table 3. H NMR data for 3 and 4 (40 MHz, CD,OD)* 4
6

391

3 H 2a 2e 3a 3e 4 5a 5e 6 7 I 2a 2e 3a 3e 4 5a 5e 6 0.8 I 2.0

H 2a 2e 3a 3e 4 5a 5e 6 1

6 2.41 2.87 1.36 2.18 3.89 1.24 2.68 4.91 5.80

2.16 2.16 1.58 2.09 4.25 1.40 2.64 5.13 5.78

0.8 1.6

0.8

*.I in Hz; 3: upper right part; 4: lower left part.

The new compound 3 was assigned a molecular formula of C,H,,O, (HR-MS), which corresponded to the saturation of one double bond equivalent in 1 or 2. The 13C NMR spectrum of 3 was compared with that of 1. The two doublet sp carbon signals of C-2 and C-3 were shifted upfield to give two triplet sp3 carbon signals, and the remaining carbon signals appeared at the corresponding positions (Table 1). These results indicated that the double bond between C-2 and C-3 was reduced. The two large coupling constants (11.2 and 11.5 Hz) for H-4 (63.89) of 3 confirmed that the orientation of 4-OH was equatorial. H-6 (64.91) was axial as deduced from its large coupling constant (J= 11.5) with H-5 (axial). All of the NMR data supported the structure 3 (Table 3). Compound 4 has the same formula as 3 and the NMR data implied that 4 was the diastereomer of 3. A characteristic difference between the HNMR data of 4 and 3 was shown by the H-4 signal (64.25) which showed only small coupling constants (c 4 Hz), confirming the orientation of 4-OH to be axial (Tables l-3). The absolute configurations of Z-4 were decided from the CD data. Compound 1 showed the n---71* cotton effect, As -3.6 (223 nm), while 2-4 showed + 5.55 (223 run), - 5.40 (220 nm) and + 5.22 (215 nm), respectively. Since the absolute configuration of 1 was confirmed by X-ray analysis to be 6R, the other compounds, 2-4, should be 6S, 6R and 6S, respectively [lq. The other chiral carbon (C-4) should have essentially the same configuration based on the NMR data. In conclusion, the structures of 3 and 4 were decided to be those of (4R,6R)-2,3-dihydromenisdaurilide and (4R,6S)-2,3-dihydroaquilegiolide, respectively. It should be noted that since the order of priority of C-3 and C-5 was reversed due to the double bond at C-2, C-3 the 4s configuration of 1 and 2 corresponds to the 4R configuration of 3 and 4.
EXPERIMENTAL

rhizome and caulis of Sinomenium acutum Rehder et Wilson) was obtained from Kojima Kampo Co. Ltd (Osaka). The plant was originally collected from the Tokushima prefecture, Japan. Extraction and isolation. The sliced rhizome and caulis (10 kg) were extracted at room temp. with hexane, EtOAc and MeOH, successively. The MeOH extract (715 g) was chromatographed on a column of Diaion HP-20 (Mitsubishi Kasei Co. Ltd, Tokyo) by eluting successively with 20,40, 60, 80; 100% MeOH, CHCl,-MeOH (3:7) and CHCl,. From the 20% MeOH eluent, liliodendrine (mp 270 from MeOH, 469 mg) [ 191 was crystallized. The 40% MeOH eluent was sepd by CC on silica gel (CHCl,-MeOH) to give menisdaurin (5, 520 mg) [S], sinomenine (2.2 g) [19] and a mixt. of menisdaurilide congeners (509 mg), which was further sepd by CC on silica gel (CHCI,) and HPLC on ODS (8% MeOH) to give l(141 mg), 2 (8 mg), 3 (5 mg) and 4 (4 mg). The 60% MeOH eluent was sepd by CC on silica gel (benzene, CHCl,, MeOH) to afford acutumine (588 mg) [S] and N-feruloyltyramine (575 mg) [ 121. Menisdaurin (5). Needles from MeOH, mp 174-175 (ref. [8] 175-176), [a]; -212 (MeOH; ~1.00) (ref. [S] - 185 at 15 in the same solvent and at the same concn). Menisdaurilide (1). Needles from MeOH, mp 109-l 11 (ref. [S] 113), [a]; -27.3 (MeOH; ~0.307) (ref. [S] -31.4). UV lkfH (log E) nm: 256 (4.16) {ref. [S] 256 (4.24)); EIMS: m/z 152.0470 (CsHsO, requires 152.0473), 134 [M-HaO]+; IR ~2; cm-: 3462 (OH), 1717 (C=O), 1638; ORD (MeOH; cO.O1,21): [41J03 0, [+12s4 +242O, C$;, (&Ml247 -164W Cdl212 -3480, CD: A.5265 O, h223 -3.6 (MeOH; cO.OOlk H and 13CN~R:Z~bles 1, 2. Aquilegiolide (2). Needles from MeOH, mp 95-97 (ref. [17] 96-98), ORD (MeOH; ~0.005, 21): [4]325 0,
+4200~~412300&1209 Cdl 276 -5m&+12610~~~1249 - 2500, EIMS: m/z 152.0516 (CsHsO, requires 152.0473),

Mps: uncorr.; H and 13C NMR (CDCl,, TMS as int. standard): 400 and 100 MHz, respectively. Plant material. The crude drug, Sinomenium stem (registered name in Japanese Pharmacopoeia XII for

134 [M-HzO]+; CD: A&265 -28.8, As246 0, A&223 +5.55 (MeOH, ~0.001); H and 13CNMR: Tables 1, 2. Compound 3. Oil, EIMS: m/z 154.0621 (CsH,,03 requires 154.0629), 136 [M-H,O]+; ORD (MeOH; ~0.01, [r$]z14 0, CD: AEzi#J -5.40, 21) C41227 -10600, (MeOH; ~0.001); H and 13CNMR: Tables 1, 3.