Bergenin monohydrate from the rhizomae of Astilbe chinensis

The title compound, 4-methoxy-2-[(1S,2R,3S,4S,5R)-3,4,5,6-tetrahydro-3,4,5-tri­hydroxy-6-(hydroxy­methyl)-2H-­pyran-2-yl]-[alpha]-resorcylic acid [delta]-lactone monohydrate, C₁₄H₁₆O₉·H₂O, is a C-glucoside of 4-O-methylgallic acid which has antiasthmatic, antitussive, anti-inflammatory, antifungal, anti-HIV and antihepatotoxic activity. The mol­ecule is composed of three six-membered rings: an aromatic ring, a glucopyran­ose ring and an annellated [delta]-lactone ring. The glucopyran­ose ring exhibits only small deviations from an ideal chair conformation. The annellated [delta]-lactone ring possesses the expected half-chair conformation. There is one intra- and six intermolecular hydrogen bonds which form an extensive hydrogen-bonding network within the crystal.

S1. Comment

Bergenin has been isolated from the roots of Bergenia crassifolia (Hua et al., 1998), B. purpurascens and Casesalpinia digyna, from the bark of Corylopsis spicata and Mallotus japonicus (Yoshida et al., 1982), from the heartwood of Shorea leprosula and Macaranga peltatathe, and from the rhizhome of Astilbe chinensis (Sun et al., 2002). Pharmacological experiments have indicated that it possesses significant antiasthmatic, antitussive, anti-inflammatory, antifungal (Prithiviraj et al., 1997), in vitro anti-HIV (Piacente et al., 1996) and antihepatotoxic activity (Kim et al., 2000; Lim Kim Chung & Kim, 2000; Lim Kim Choi et al., 2000). The first structures of bergenin proposed by Tschitschibabin et al. (1929) and Shimokoriyama (1950) were revised independently by Hay & Haynes (1958) and Posternak & Dürr (1958). The structure of bergenin, which involves an aryl β-C-glucoside and an aryl δ-lactone ring, was unequivocally confirmed by synthesis of bergenin-type C-glucosylarenes (Frick & Schmidt, 1991) and an X-ray analysis of 3,4,8,10,11-penta-O-acetylbergenin (Frick et al., 1991). Meanwhile, the chemical structure of the natural product bergenin from plants was determined on the basis of two-dimensional NMR data (Zhou et al., 1999). The chemical structure of bergenin as the title monohydrate, (I), has now been confirmed by single-crystal X-ray diffraction analysis. \sch

The structure of (I), with the atom-numbering scheme, is shown in Fig. 1. The molecule is composed of three six-membered rings, viz. A (C5—C10, an aromatic ring), B (C1/O2/C3—C5/C10, an annellated δ-lactone ring) and C (C3—C4/C11—C13/O3, a glucopyranose ring). Ring B possesses the expected half-chair conformation, while ring C exhibits only small deviations from an ideal chair conformation. The B/C junction is trans fused. The hydroxyl and hydroxymethyl substituents at the other chiral centres (atoms C11, C12 and C13) adopt equatorial conformations with respect to the glucopyranose ring. The structure of (I) is consistent with the conformation found for 3,4,8,10,11-penta-O-acetylbergenin by Frick et al. (1991) through an X-ray analysis.

All hydroxyl groups, except for C6—OH, serve as simultaneous hydrogen-bond donors and acceptors (Table 2), resulting in one intra- and six intermolecular O—H···O hydrogen bonds. The intramolecular O—H···O hydrogen bond is formed between atom H4 of the C6 hydroxyl group and the O3 ring atom of the glucopyranose moiety. The water atom, O10, acts as an acceptor, with the O6 hydroxyl atom as donor, to form O6—H6O···O10 hydrogen bonds between the solvent and bergenin.

In the solid state, the screw-related molecules are linked by O7—H7O···O9, O8—H8O···O7 and O9—H9O···O6 hydrogen bonds, to form molecular chains along the a axis. The chain formation is further stabilized by the solvent water through O10—H10B···O1 and O10—H10A.·O8 hydrogen bonds.

S2. Experimental

The rhizomes of A. chinensis were collected in Anji county, Zhejiang province, China, in August 2001. The plants were identified as A. chinensis (Maxim.) Franch. et Savat. by Professor Xiang-Ji Xue, College of Pharmaceutical Science, Zhejiang University. A voucher specimen (No. 200120) was deposited in the Laboratory of Nature and Biochemistry, Zhejiang University. The rhizomes of Astilbe Chinensis were dried in the dark, in a ventilated hood, and ground. The material (5.0 kg) was extracted with MeOH (3 × 25 l) at room temperature to give 366 g of extract. The MeOH extract was suspended in H₂O, and sequentially partitioned with petroleum ether and EtOAc. The EtOAc extract (90.9 g) was absorbed onto silica gel and chromatographied on a silica-gel column eluted successively with CHCl₃, CHCl₃/MeOH (9:1), CHCl₃/MeOH (4:1) and CHCl₃/MeOH (1:1), to yield five fractions. The third fraction was subjected to column chromatography on Sephadex LH-20 and eluted with MeOH to afford 15.342 g of the pure title compound, (I). Crystals suitable for X-ray structure analysis were obtained by slow evaporation from an MeOH/H₂O (1:1) solution at room temperature (m.p. 443–445 K But 413 K given in CIF data block). Spectroscopic analysis: ¹³C NMR (125 MHz, DMDO-d₆, δ, p.p.m): 163.3 (C1), 150.9 (C6), 148.1 (C7), 140.8 (C8), 118.1 (C5), 116.1 (C10), 109.7 (C9), 81.9 (C13), 80.0 (C3), 74.0 (C11), 72.4 (C4), 71.0 (C12), 61.3 (C14), 60.0 (C15).

S3. Refinement

After location of H atoms in difference density maps, all H atoms were geometrically fixed and allowed to ride on their attached atoms using SHELXL97 (Sheldrick, 1997) defaults. The structure was refined using the absolute stereochemistry established through chemical synthesis (Frick & Schmidt, 1991).

Computing details

Data collection: XSCANS (Siemens, 1994); cell refinement: XSCANS; data reduction: SHELXTL/PC (Siemens, 1991); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC; software used to prepare material for publication: SHELXTL/PC.

Figures

Fig. 1. A view of (I), with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

4-methoxy-2-[tetrahydro-3,4,5-trihydroxy-6-(hydroxymethyl) pyran-2-yl]-α-resorcylic acid δ-lactone monohydrate

Crystal data

C14H16O9·H2O	Dx = 1.542 Mg m^−3
Mr = 346.28	Melting point: 413(1) K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
a = 7.497 (1) Å	Cell parameters from 34 reflections
b = 13.930 (2) Å	θ = 3.2–14.7°
c = 14.282 (2) Å	µ = 0.13 mm^−1
V = 1491.5 (4) Å^3	T = 288 K
Z = 4	Prism, colourless
F(000) = 728	0.56 × 0.52 × 0.50 mm

Data collection

Siemens P4 diffractometer	Rint = 0.010
Radiation source: normal-focus sealed tube	θmax = 29.2°, θmin = 2.0°
Graphite monochromator	h = 0→10
ω scans	k = 0→19
2523 measured reflections	l = −1→19
2330 independent reflections	3 standard reflections every 97 reflections
1787 reflections with I > 2σ(I)	intensity decay: 3.5%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.036	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.088	w = 1/[σ^2(Fo^2) + (0.049P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 0.96	(Δ/σ)max < 0.001
2330 reflections	Δρmax = 0.27 e Å^−3
232 parameters	Δρmin = −0.19 e Å^−3
3 restraints	Extinction correction: SHELXL97 (Sheldrick, 1997), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0135 (19)

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	0.0940 (2)	0.54515 (13)	0.70349 (13)	0.0474 (5)
O2	0.2351 (2)	0.46012 (10)	0.59816 (11)	0.0324 (4)
O3	0.6459 (2)	0.50246 (10)	0.46516 (10)	0.0264 (3)
O4	0.7915 (2)	0.66373 (12)	0.53087 (13)	0.0409 (5)
H4O	0.7938	0.6112	0.5050	0.049*
O5	0.7156 (2)	0.83886 (10)	0.60465 (12)	0.0326 (4)
O6	0.4244 (2)	0.86799 (11)	0.70672 (13)	0.0409 (5)
H6O	0.3372	0.8684	0.7414	0.049*
O7	0.2102 (2)	0.31910 (11)	0.45466 (12)	0.0303 (4)
H7O	0.1542	0.3601	0.4258	0.036*
O8	0.5575 (2)	0.25522 (10)	0.38740 (11)	0.0310 (4)
H8O	0.5946	0.2283	0.4346	0.037*
O9	0.9834 (2)	0.45263 (12)	0.37981 (13)	0.0386 (4)
H9O	0.9927	0.5076	0.3599	0.046*
C1	0.2193 (3)	0.54124 (16)	0.64929 (17)	0.0314 (5)
C3	0.3551 (3)	0.46160 (15)	0.51905 (15)	0.0244 (4)
H3	0.3044	0.5011	0.4689	0.029*
C4	0.5357 (3)	0.50095 (15)	0.54730 (14)	0.0234 (4)
H4	0.5896	0.4593	0.5949	0.028*
C5	0.5106 (3)	0.60018 (15)	0.58636 (15)	0.0238 (4)
C6	0.6355 (3)	0.67383 (15)	0.57784 (15)	0.0256 (5)
C7	0.6017 (3)	0.76364 (15)	0.61761 (16)	0.0271 (5)
C8	0.4457 (3)	0.77830 (15)	0.66983 (16)	0.0285 (5)
C9	0.3232 (3)	0.70564 (16)	0.68016 (16)	0.0299 (5)
H9	0.2206	0.7154	0.7154	0.036*
C10	0.3537 (3)	0.61736 (15)	0.63750 (16)	0.0257 (5)
C11	0.3756 (3)	0.35838 (15)	0.48548 (15)	0.0238 (4)
H11	0.4173	0.3198	0.5385	0.029*
C12	0.5171 (3)	0.35300 (14)	0.40864 (15)	0.0241 (4)
H12	0.4683	0.3830	0.3521	0.029*
C13	0.6891 (3)	0.40618 (14)	0.43521 (15)	0.0245 (5)
H13	0.7486	0.3720	0.4864	0.029*
C14	0.8144 (3)	0.41411 (17)	0.35295 (17)	0.0308 (5)
H14A	0.8317	0.3510	0.3256	0.037*
H14B	0.7613	0.4551	0.3056	0.037*
C15	0.8762 (4)	0.8319 (2)	0.6577 (2)	0.0574 (9)
H15A	0.8477	0.8258	0.7229	0.069*
H15B	0.9466	0.8887	0.6482	0.069*
H15C	0.9425	0.7767	0.6377	0.069*
O10	0.8437 (2)	0.39252 (13)	0.67747 (14)	0.0377 (4)
H10A	0.898 (3)	0.3449 (12)	0.660 (2)	0.064 (11)*
H10B	0.916 (3)	0.4374 (14)	0.685 (2)	0.072 (11)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0431 (10)	0.0396 (10)	0.0596 (11)	−0.0141 (9)	0.0279 (10)	−0.0178 (9)
O2	0.0320 (9)	0.0247 (8)	0.0405 (9)	−0.0081 (7)	0.0149 (8)	−0.0071 (7)
O3	0.0255 (8)	0.0202 (7)	0.0334 (8)	−0.0003 (6)	0.0074 (7)	−0.0026 (7)
O4	0.0311 (9)	0.0381 (10)	0.0535 (11)	−0.0112 (8)	0.0166 (9)	−0.0148 (9)
O5	0.0320 (8)	0.0250 (8)	0.0409 (9)	−0.0087 (7)	−0.0016 (8)	0.0028 (7)
O6	0.0415 (11)	0.0205 (7)	0.0607 (12)	−0.0008 (8)	0.0175 (10)	−0.0066 (8)
O7	0.0259 (8)	0.0239 (7)	0.0410 (9)	−0.0041 (7)	−0.0029 (8)	0.0003 (7)
O8	0.0339 (9)	0.0224 (7)	0.0368 (8)	0.0036 (7)	−0.0013 (8)	−0.0044 (7)
O9	0.0240 (8)	0.0306 (9)	0.0612 (11)	0.0008 (7)	0.0004 (9)	0.0101 (8)
C1	0.0302 (12)	0.0266 (11)	0.0373 (12)	−0.0047 (11)	0.0058 (11)	−0.0053 (10)
C3	0.0220 (10)	0.0216 (10)	0.0295 (11)	−0.0014 (9)	0.0037 (9)	0.0001 (9)
C4	0.0216 (10)	0.0218 (9)	0.0267 (10)	0.0004 (9)	0.0024 (9)	−0.0005 (9)
C5	0.0240 (10)	0.0225 (10)	0.0248 (10)	−0.0022 (9)	0.0002 (9)	−0.0015 (9)
C6	0.0229 (10)	0.0264 (11)	0.0274 (11)	−0.0016 (9)	0.0019 (9)	−0.0021 (9)
C7	0.0266 (11)	0.0226 (10)	0.0320 (11)	−0.0039 (9)	−0.0025 (10)	0.0027 (9)
C8	0.0291 (12)	0.0222 (10)	0.0341 (12)	0.0018 (10)	0.0023 (11)	−0.0016 (9)
C9	0.0285 (12)	0.0278 (11)	0.0334 (12)	−0.0003 (10)	0.0058 (11)	−0.0018 (10)
C10	0.0242 (11)	0.0215 (10)	0.0315 (11)	−0.0036 (9)	0.0030 (10)	−0.0011 (9)
C11	0.0229 (10)	0.0193 (9)	0.0291 (11)	−0.0009 (8)	−0.0012 (9)	0.0004 (9)
C12	0.0258 (11)	0.0194 (9)	0.0271 (10)	0.0008 (9)	−0.0023 (10)	0.0008 (8)
C13	0.0220 (10)	0.0208 (10)	0.0306 (11)	0.0039 (9)	−0.0013 (9)	0.0002 (9)
C14	0.0263 (12)	0.0318 (12)	0.0342 (12)	0.0009 (10)	0.0045 (10)	−0.0028 (10)
C15	0.0461 (18)	0.0574 (19)	0.069 (2)	−0.0238 (16)	−0.0226 (16)	0.0127 (16)
O10	0.0294 (9)	0.0332 (9)	0.0504 (11)	−0.0004 (8)	0.0042 (9)	0.0003 (9)

Geometric parameters (Å, º)

O1—C1	1.219 (3)	C4—H4	0.9800
O2—C1	1.351 (3)	C5—C6	1.395 (3)
O2—C3	1.444 (3)	C5—C10	1.404 (3)
O3—C4	1.435 (2)	C6—C7	1.397 (3)
O3—C13	1.444 (2)	C7—C8	1.402 (3)
O4—C6	1.356 (3)	C8—C9	1.374 (3)
O4—H4O	0.8200	C9—C10	1.391 (3)
O5—C7	1.365 (3)	C9—H9	0.9300
O5—C15	1.426 (3)	C11—C12	1.528 (3)
O6—C8	1.365 (3)	C11—H11	0.9800
O6—H6O	0.8200	C12—C13	1.535 (3)
O7—C11	1.425 (3)	C12—H12	0.9800
O7—H7O	0.8200	C13—C14	1.508 (3)
O8—C12	1.428 (2)	C13—H13	0.9800
O8—H8O	0.8200	C14—H14A	0.9700
O9—C14	1.428 (3)	C14—H14B	0.9700
O9—H9O	0.8200	C15—H15A	0.9600
C1—C10	1.473 (3)	C15—H15B	0.9600
C3—C4	1.516 (3)	C15—H15C	0.9600
C3—C11	1.523 (3)	O10—H10A	0.82 (2)
C3—H3	0.9800	O10—H10B	0.83 (2)
C4—C5	1.502 (3)
C1—O2—C3	117.75 (16)	C8—C9—H9	120.2
C4—O3—C13	110.94 (15)	C10—C9—H9	120.2
C6—O4—H4O	109.5	C9—C10—C5	121.1 (2)
C7—O5—C15	113.87 (19)	C9—C10—C1	118.3 (2)
C8—O6—H6O	109.5	C5—C10—C1	120.64 (19)
C11—O7—H7O	109.5	O7—C11—C3	111.83 (18)
C12—O8—H8O	109.5	O7—C11—C12	111.31 (16)
C14—O9—H9O	109.5	C3—C11—C12	110.01 (17)
O1—C1—O2	116.6 (2)	O7—C11—H11	107.8
O1—C1—C10	124.6 (2)	C3—C11—H11	107.8
O2—C1—C10	118.7 (2)	C12—C11—H11	107.8
O2—C3—C4	110.69 (16)	O8—C12—C11	110.28 (17)
O2—C3—C11	107.18 (16)	O8—C12—C13	109.57 (17)
C4—C3—C11	109.58 (17)	C11—C12—C13	112.45 (17)
O2—C3—H3	109.8	O8—C12—H12	108.1
C4—C3—H3	109.8	C11—C12—H12	108.1
C11—C3—H3	109.8	C13—C12—H12	108.1
O3—C4—C5	111.25 (16)	O3—C13—C14	107.58 (17)
O3—C4—C3	107.58 (16)	O3—C13—C12	109.48 (16)
C5—C4—C3	108.62 (17)	C14—C13—C12	111.48 (17)
O3—C4—H4	109.8	O3—C13—H13	109.4
C5—C4—H4	109.8	C14—C13—H13	109.4
C3—C4—H4	109.8	C12—C13—H13	109.4
C6—C5—C10	118.83 (19)	O9—C14—C13	111.77 (19)
C6—C5—C4	124.05 (19)	O9—C14—H14A	109.3
C10—C5—C4	117.07 (18)	C13—C14—H14A	109.3
O4—C6—C5	123.12 (19)	O9—C14—H14B	109.3
O4—C6—C7	116.79 (19)	C13—C14—H14B	109.3
C5—C6—C7	120.1 (2)	H14A—C14—H14B	107.9
O5—C7—C6	121.3 (2)	O5—C15—H15A	109.5
O5—C7—C8	118.85 (19)	O5—C15—H15B	109.5
C6—C7—C8	119.88 (19)	H15A—C15—H15B	109.5
O6—C8—C9	123.7 (2)	O5—C15—H15C	109.5
O6—C8—C7	115.9 (2)	H15A—C15—H15C	109.5
C9—C8—C7	120.5 (2)	H15B—C15—H15C	109.5
C8—C9—C10	119.6 (2)	H10A—O10—H10B	109 (2)
C3—O2—C1—O1	166.0 (2)	O6—C8—C9—C10	178.0 (2)
C3—O2—C1—C10	−15.0 (3)	C7—C8—C9—C10	−0.7 (4)
C1—O2—C3—C4	50.0 (3)	C8—C9—C10—C5	2.0 (3)
C1—O2—C3—C11	169.4 (2)	C8—C9—C10—C1	−179.5 (2)
C13—O3—C4—C5	172.40 (17)	C6—C5—C10—C9	−0.8 (3)
C13—O3—C4—C3	−68.8 (2)	C4—C5—C10—C9	176.8 (2)
O2—C3—C4—O3	−178.63 (16)	C6—C5—C10—C1	−179.2 (2)
C11—C3—C4—O3	63.4 (2)	C4—C5—C10—C1	−1.6 (3)
O2—C3—C4—C5	−58.1 (2)	O1—C1—C10—C9	−10.0 (4)
C11—C3—C4—C5	−176.11 (17)	O2—C1—C10—C9	171.1 (2)
O3—C4—C5—C6	−29.5 (3)	O1—C1—C10—C5	168.5 (2)
C3—C4—C5—C6	−147.8 (2)	O2—C1—C10—C5	−10.4 (3)
O3—C4—C5—C10	153.01 (17)	O2—C3—C11—O7	62.0 (2)
C3—C4—C5—C10	34.8 (2)	C4—C3—C11—O7	−177.78 (17)
C10—C5—C6—O4	179.2 (2)	O2—C3—C11—C12	−173.71 (16)
C4—C5—C6—O4	1.8 (3)	C4—C3—C11—C12	−53.5 (2)
C10—C5—C6—C7	−1.7 (3)	O7—C11—C12—O8	−64.7 (2)
C4—C5—C6—C7	−179.1 (2)	C3—C11—C12—O8	170.75 (18)
C15—O5—C7—C6	−74.6 (3)	O7—C11—C12—C13	172.67 (16)
C15—O5—C7—C8	107.2 (3)	C3—C11—C12—C13	48.1 (2)
O4—C6—C7—O5	3.9 (3)	C4—O3—C13—C14	−176.29 (17)
C5—C6—C7—O5	−175.3 (2)	C4—O3—C13—C12	62.4 (2)
O4—C6—C7—C8	−177.9 (2)	O8—C12—C13—O3	−174.63 (16)
C5—C6—C7—C8	3.0 (3)	C11—C12—C13—O3	−51.6 (2)
O5—C7—C8—O6	−2.3 (3)	O8—C12—C13—C14	66.5 (2)
C6—C7—C8—O6	179.5 (2)	C11—C12—C13—C14	−170.53 (18)
O5—C7—C8—C9	176.5 (2)	O3—C13—C14—O9	67.3 (2)
C6—C7—C8—C9	−1.7 (3)	C12—C13—C14—O9	−172.68 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4O···O3	0.82	1.96	2.668 (2)	144
O6—H6O···O10^i	0.82	1.81	2.625 (2)	169
O7—H7O···O9^ii	0.82	1.93	2.737 (2)	167
O8—H8O···O7^iii	0.82	1.92	2.733 (2)	171
O9—H9O···O6^iv	0.82	2.04	2.823 (2)	159
O10—H10B···O1^v	0.83 (2)	2.03 (2)	2.860 (3)	179 (4)
O10—H10A···O8^iii	0.83 (2)	1.95 (2)	2.768 (2)	171 (3)

Symmetry codes: (i) −x+1, y+1/2, −z+3/2; (ii) x−1, y, z; (iii) x+1/2, −y+1/2, −z+1; (iv) x+1/2, −y+3/2, −z+1; (v) x+1, y, z.