Novel cyanoglucosides from the leaves of hydrangea macrophylla

Article abstract of DOI:10.1002/hlca.201000314

Four non-cyanogenic cyanoglucosides including hydranitrilosides A ₁, A₂, B₁, and B₂ (1-4, resp.), together with a new phenolic glucoside, 3-hydroxy-4-methoxybenzoic acid 3-O-β-D-glucopyranoside (5), were isolated from the leaves of Hydrangea macrophylla. Their structures were determined on the basis of chemical and spectral evidence. Copyright

Full text of DOI:10.1002/hlca.201000314

Helvetica Chimica Acta – Vol. 94 (2011)
847
Novel Cyanoglucosides from the Leaves of Hydrangea macrophylla
by Zhi-Bin Wang, Hui-Yuan Gao, Chun-Juan Yang, Zhi Sun, and Li-Jun Wu*
#
School of Traditional Chinese Materia Medica 49 , Shenyang Pharmaceutical University, Wenhua Road
No. 103, Shenhe District, Shenyang 110016, P. R. China
(
phone: þ 86-24-23986481; e-mail: wulijun111@hotmail.com)
Four non-cyanogenic cyanoglucosides including hydranitrilosides A , A , B , and B (1 – 4, resp.),
1
2
1
2
together with a new phenolic glucoside, 3-hydroxy-4-methoxybenzoic acid 3-O-b-d-glucopyranoside (5),
were isolated from the leaves of Hydrangea macrophylla. Their structures were determined on the basis
of chemical and spectral evidence.
Introduction. – Hydrangea macrophylla (Thunb.) Ser, a member of Saxifragaceae
family, is widely cultivated in many countries including China and Japan. Hydrangea
dulcis folium, which is the fermented and dried leaves of H. macrophylla, is listed in the
Japanese Pharmacopoeia XV and extensively used in confectionery, drinks, and foods
as a sweetener [1]. Dihydroisocoumarins [2][3] and secoiridoid glycosides [4][5]
isolated from this plant have showed many pharmacological effects, such as antidiabetic
[
6], antiallergic, and antimicrobial activities [7].
Here, we report the isolation and structure elucidation of three new non-cyanogenic
cyanoglucosides, hydranitriloside A (1), hydranitriloside A (2), and hydranitriloside
1
2
B (3), a related derivative isolated for the first time as a new natural product,
1
hydrantriloside B (4) [8], and a new phenolic glucoside, 3-hydroxy-4-methoxybenzoic
2
acid 3-O-b-d-glucopyranoside (5) from the leaves of the plant.
Results and Discussion. – Compound 1 was obtained as white amorphous powder
and possessed a molecular formula C H NO , deduced from the HR-ESI-MS analysis
1
ꢀ
4
17
7
þ
(
[M þ Na] at m/z 334.0901; [M ꢀ H] at m/z 310.0929). The IR spectrum indicated the
ꢀ
1
ꢀ1
presence of OH (3380 cm ) and CN (2255 cm ) groups, and an aromatic ring (1608
ꢀ
2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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48
Helvetica Chimica Acta – Vol. 94 (2011)
ꢀ1
1
and 1518 cm ). The H-NMR (Table 1) spectrum indicated the presence of a CH
2
group (d(H) 3.75 (s)) bearing a CN group and an aromatic ring with an ABX-coupling
system (d(H) 7.17 (d, J ¼ 2.0, 1 H), 6.82 (d, J ¼ 8.2, 1 H), 6.89 (dd, J ¼ 8.2, 2.0, 1 H)).
The signal at d(H) 4.76 (d, J ¼ 7.6, 1 H) was assigned to an anomeric H-atom signal of
the sugar unit. The acid hydrolysis of 1 with aqueous HCl (1m) yielded d-glucose, which
13
was identified by HPLC analysis using an optical rotation detector [9]. The C-NMR
(
Table 2) spectrum showed 14 C-atom signals including those of a cyano C-atom at
d(C) 120.0 and six aromatic C-atoms at d(C) 148.2, 147.0, 124.3, 123.6, 118.8, and 117.6.
As shown in the Figure, the DQF-COSY experiment on 1 indicated the presence of
Table 1. 1H-NMR Data (at 600 MHz, d in ppm, J in Hz) of Compounds 1 – 4
1a
)
2 )
b
3a)
4a)
HꢀC(2) 7.17 (d, J ¼ 2.0)
HꢀC(3)
7.56 (d, J ¼ 2.0)
6.98 (d, J ¼ 2.1)
7.28 (d, J ¼ 8.5)
7.11 (d, J ¼ 8.5)
7.11 (d, J ¼ 8.5)
HꢀC(5) 6.82 (d, J ¼ 8.2)
6.91 (d, J ¼ 8.3)
7.16 (d, J ¼ 8.3)
HꢀC(6) 6.89 (dd, J ¼ 8.2, 2.0) 7.00 (dd, J ¼ 8.3, 2.0) 6.89 (dd, J ¼ 8.3, 2.1) 7.28 (d, J ¼ 8.5)
CH ꢀC(1) 3.75 (s)
3.81 (s)
3.71 (s)
3.83 (s)
3.86 (s)
3.82 (s)
2
MeO
HꢀC(1’) 4.76 (d, J ¼ 7.6)
5.61 (d, J ¼ 7.6)
4.90 (d, J ¼ 7.6)
4.90 (d, J ¼ 7.5)
HꢀC(2’) 3.48 (dd, J ¼ 8.9, 7.6) 4.27 – 4.32 (m)
HꢀC(3’) 3.45 (dd, J ¼ 8.9, 8.2) 4.27 – 4.32 (m)
3.49 (dd, J ¼ 8.9, 7.6) 3.46 (dd, J ¼ 8.9, 7.5)
3.45 (dd, J ¼ 8.9, 9.7) 3.40 – 3.45 (m)
HꢀC(4’) 3.39 – 3.43 (m)
HꢀC(5’) 3.37 – 3.41 (m)
4.27 – 4.32 (m)
4.01 – 4.05 (m)
3.39 – 3.43 (m)
3.37 – 3.41 (m)
3.36 – 3.42 (m)
3.36 – 3.42 (m)
CH (6’) 3.90 (dd, J ¼ 11.7, 2.0), 4.49 (dd, J ¼ 11.7, 2.0), 3.88 (dd, J ¼ 12.4, 1.9), 3.90 (dd, J ¼ 12.2, 2.0),
2
3.71 (dd, J ¼ 11.7, 4.8) 4.33 (dd, J ¼ 11.7, 4.8) 3.69 (dd, J ¼ 12.4, 4.8) 3.69 (dd, J ¼ 12.2, 5.1)
a) Recorded in CD OD. ) Recorded in C D N.
b
3
5
5
Table 2. 13C-NMR Data (at 150 MHz, d in ppm) of Compounds 1 – 4
1a
)
2a)
2 )
b
3a)
4a)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
124.3 (s)
118.8 (d)
147.0 (s)
148.2 (s)
117.6 (d)
123.6 (d)
22.9 (t)
125.0 (s)
118.0 (d)
148.2 (s)
150.6 (s)
114.0 (d)
123.5 (d)
23.0 (t)
119.9 (s)
56.8 (q)
102.7 (d)
74.9 (d)
77.9 (d)
71.3 (d)
78.3 (d)
62.5 (t)
123.9 (s)
116.7 (d)
148.2 (s)
149.8 (s)
113.5 (d)
121.9 (d)
22.8 (t)
119.1 (s)
56.2 (q)
102.3 (d)
74.9 (d)
78.5 (d)
71.2 (d)
78.8 (d)
62.4 (t)
126.9 (s)
113.6 (d)
151.2 (s)
147.6 (s)
118.3 (d)
121.1 (d)
23.1 (t)
119.8 (s)
56.8 (q)
102.7 (d)
74.9 (d)
77.7 (d)
71.3 (d)
78.2 (d)
62.5 (t)
126.0 (s)
130.3 (d)
118.4 (d)
158.8 (s)
118.4 (d)
130.3 (d)
22.8 (t)
CH ꢀC(1)
2
C(8)
MeO
C(1’)
C(2’)
C(3’)
C(4’)
C(5’)
C(6’)
120.0 (s)
119.9 (s)
104.3 (d)
74.9 (d)
77.6 (d)
71.3 (d)
78.4 (d)
62.4 (t)
102.3 (d)
74.9 (d)
78.0 (d)
71.4 (d)
78.2 (d)
62.6 (t)
a) Recorded in CD OD. ) Recorded in C D N.
b
3
5
5

Helvetica Chimica Acta – Vol. 94 (2011)
849
Figure. Key HBMC, DQF-COSY, and Dif-NOE correlations of 1, 3, and 5
partial structures indicated in bold lines, and, in the HMBC experiment, long-range
correlations were observed between the following H- and C-atoms: HꢀC(7) and C(1),
C(2), C(6), and C(8); HꢀC(1’) and C(3). In addition, the position of glucose was
confirmed by the observation of an NOE effect at d(H) 7.17 (HꢀC(2)) upon irradiation
of anomeric H-atom (d(H) 4.76 (HꢀC(1’))). On the basis of the above analysis, the
structure of hydranitriloside A (1) was established as (3,4-dihydroxyphenyl)acetoni-
1
trile 3-O-b-d-glucopyranoside.
Compound 2 was obtained as white amorphous powder, and the molecular formula
þ
was determined as C H NO on the basis of the HR-ESI-MS ([M þ Na] at m/z
15
19
7
ꢀ1
3
48.1058). The IR spectrum indicated the presence of OH (3380 cm ) and CN
ꢀ1
ꢀ1
1
(
2255 cm ) groups, and an aromatic ring (1608 and 1518 cm ). In the H-NMR
spectrum, the signals of aromatic H-atoms overlapped when CD OD was used as
3
solvent, and better resolution was achieved in C D N. The NMR data were very similar
5
5
to those of compound 1, with the exception of the presence of a MeO signal at d(H)
1
13
3
.71 in the H-NMR (Table 1) spectrum and at d(C) 56.2 in the C-NMR spectrum
(
Table 2). In the HMBC spectrum, the cross-peaks between HꢀC(7) and C(1), C(2),
C(6), and C(8); HꢀC(1’) and C(3); and MeO and C(4) were observed. The irradiation
of the MeO group (d(H) 3.71) resulted in an enhancement of the signal at d(H) 6.91
(
HꢀC(5)) in the difference NOE experiment. Therefore, compound hydranitriloside
A (2) was identified as (3-hydroxy-4-methoxyphenyl)acetonitrile 3-O-b-d-glucopyr-
2
anoside.
Compound 3 was obtained as white amorphous powder with a molecular formula of
þ
C H NO , deduced from the HR-ESI-MS ([M þ Na] at m/z 348.1061). The presence
15
19
7
ꢀ
1
ꢀ1
of OH (3400 cm ) and CN (2249 cm ) functions, and of an aromatic ring (1597 and
516 cm ) were suggested by its IR spectrum. The H- and C-NMR (Tables 1 and 2)
ꢀ1
1
13
1
spectra of 3 indicated the presence of a CH group (d(H) 3.83 (s)) bearing a CN group,
2
an aromatic ring with an ABX-coupling system (d(H) 7.16 (d, J ¼ 8.9, 1 H), 6.98 (d, J ¼
2
.1, 1 H), 6.89 (dd, J ¼ 8.9, 2.1, 1 H)), a MeO group (d(H) 3.86 (s)), an anomeric H-
atom (d(H) 4.90 (d, J ¼ 7.6)), and a CN C-atom (d(C) 119.1). The acid hydrolysis of 3
liberated d-glucose, which was identified by HPLC analysis [9]. In the difference-NOE
experiment, the irradiation of the MeO group (d(H) 3.86) resulted in an enhancement

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Helvetica Chimica Acta – Vol. 94 (2011)
of the signal at d(H) 6.98 (HꢀC(2)), which suggested that compound 3 was an isomer of
compound 2 with respect to the MeO position. The 2D-NMR data, including HMQC,
HMBC, and DQF-COSY experiments, indicated that in 3 the respective positions of
the MeO and glucopyranosyloxy substituents reversed, compared to 2. Thus,
compound 3, named hydranitriloside B , was elucidated as (4-hydroxy-3-methoxyphe-
1
nyl)acetonitrile 4-O-b-d-glucopyranoside.
Compound 4 was obtained as white amorphous powder with a molecular formula of
þ
C H NO , on the basis of HR-ESI-MS ([M þ Na] at m/z 318.0956). The acid
14
17
6
1
13
hydrolysis of 4 liberated d-glucose [9]. The H- and C-NMR spectra indicated the
presence of a CH group (d(H) 3.82 (s)), an AA’BB’-coupling of an aromatic ring
2
(
d(H) 7.28 (d, J ¼ 8.5, 2 H), 7.11 (d, J ¼ 8.5, 2 H)), a b-d-glucopyranosyl anomeric H-
atom (d(H) 4.90 (d, J ¼ 7.5)), and a CN group (d(C) 119.9 (C(8))). Furthermore, long-
range correlations in the HMBC spectra were observed between the following H- and
C-atoms: HꢀC(7) and C(1), C(2), and C(8); and HꢀC(1’) and C(4). On the basis of
this evidence, the structure of 4 was determined as (4-hydroxyphenyl)acetonitrile 4-O-
b-d-glucopyranoside. This compound, for which we propose the name hydranitriloside
B , was previously synthesized by Helferich et al. in 1935 [8], and it is reported here for
2
the first time as a natural product.
Compound 5, obtained as white amorphous powder, was found to possess a
þ
molecular formula of C H O , as evidenced by the HR-ESI-MS ([M þ Na] at m/z
14
18
9
ꢀ
1
3
53.0851). The IR spectrum indicated the presence of OH (3380 cm ) and CO
1698 cm ) groups, a benzene ring (1605 and 1509 cm ), and an ether (1074 cm )
ꢀ1
ꢀ1
ꢀ1
(
1
function. The H-NMR spectrum (Table 3) showed signals assignable to a trisubstituted
aromatic system at d(H) 8.55 (d, J ¼ 2.0, 1 H), 7.02 (d, J ¼ 8.2, 1 H), and 8.11 (dd, J ¼
8
.2, 2.0, 1 H), of a MeO group at d(H) 3.73 (s), and of b-d-glucopyranosyl group at
1
3
d(H) 5.75 (d, J ¼ 7.2). The acid hydrolysis of 5 gave d-glucose [9]. The C-NMR
spectrum (Table 3) revealed 14 C-atom signals, including those of a CO C-atom (d(C)
Table 3. 1H- and 13C-NMR Data (at 600 and 150 MHz, resp., d in ppm, J in Hz) of Compound 5
d(H)a)
d(C)a)
d(C)b)
C(1)
123.9 (s)
117.5 (d)
147.3 (s)
153.7 (s)
111.9 (d)
125.2 (d)
168.8 (s)
55.9 (q)
102.5 (d)
74.8 (d)
78.3 (d)
70.9 (d)
78.7 (d)
62.1 (t)
124.0 (s)
119.2 (d)
147.4 (s)
155.1 (s)
112.6 (d)
126.7 (d)
170.0 (s)
56.6 (q)
102.7 (d)
74.9 (d)
77.9 (d)
71.1 (d)
78.1 (d)
62.3 (t)
HꢀC(2)
8.55 (d, J ¼ 2.0)
C(3)
C(4)
HꢀC(5)
HꢀC(6)
COOH
MeOꢀC(4)
HꢀC(1’)
HꢀC(2’)
HꢀC(3’)
HꢀC(4’)
HꢀC(5’)
7.02 (d, J ¼ 8.2)
8.11 (dd, J ¼ 8.2, 2.0)
3.73 (s)
5.75 (d, J ¼ 7.2)
4.29 – 4.34 (m)
4.29 – 4.34 (m)
4.29 – 4.34 (m)
4.02 – 4.06 (m)
4.46 (dd, J ¼ 12.4, 2.4), 4.35 (dd, J ¼ 12.4, 4.8)
CH (6’)
2
a) Recorded in C D N. ) Recorded in CD OD.
b
5
5
3

Helvetica Chimica Acta – Vol. 94 (2011)
851
168.8), a MeO group (d(C) 55.9), and six aromatic C-atoms (d(C) 123.9, 117.5, 147.3,
153.7, 111.9, and 125.2). In the HMBC spectrum, the cross-peaks were observed
between HꢀC(2), and C(1) and C(7); HꢀC(6), and C(1) and C(7); and HꢀC(1’) and
C(3). In addition, the irradiation of MeO (d(H) 3.73) resulted in an enhancement of
the signal at d(H) 7.02 (HꢀC(2)) in the difference NOE spectrum. Based on the above
evidence, compound 5 was established as 3-hydroxy-4-methoxybenzoic acid 3-O-b-d-
glucopyranoside.
Non-cyanogenic glucosides are less common than their cyanogenic counterparts.
They represent a small group of compounds comprising ca. 30 representatives with a
scattered distribution in plants [10]. While their function in plants is not fully
understood, they possess some interesting bioactivities. For example, they were found
to enhance the antibiotic activity of rifampicin, tetracycline, and ampicillin against the
Gram-positive and Gram-negative bacteria, and also to enhance the absorption of
drugs, vitamins, and nutrients through the gastrointestinal membrane and increase their
bioavailability [11].
To our knowledge, this is the first report on the presence of non-cyanogenic
cyanoglucosides in the genus Hydrangea.
Experimental Part
General. Column chromatography (CC): normal-phase CC: silica gel (SiO ; 200 – 300 mesh;
2
Qingdao Marine Chemical Inc., P. R. China); reversed-phase (RP) silica-gel CC: ODS (100 – 200 mesh;
Fuji Silysia Chemical, Ltd., Japan). HPLC pump and detector: Shimadzu LC10AT and RID-6A
(
2
refractive index detector), HPLC column: ODS-A (C-18, 10 mm ꢁ 25 cm, 5 mm, YMC), flow rate:
ꢀ1
.5 ml/min. IR Spectra: Shimadzu FTIR-8100 spectrometer; KBr discs; in cm . NMR Spectra: JNM-
ECA600 spectrometer; TMS as internal standard, d in ppm, J in Hz. HR-ESI-MS: Bruker micromass Q-
Tof mass spectrometer; in m/z.
Plant Material. The dried leaves of H. macrophylla were collected from Shizhu, Sichuan Province,
P. R. China, in May 2009, and identified by associate Prof. Jincai Lu of School of Traditional Chinese
Materia Medica of Shenyang Pharmaceutical University, P. R. China. A voucher specimen (HM 090505)
was deposited with the Department of Natural Products Chemistry, Shenyang Pharmaceutical
University, Shenyang, P. R. China.
Extraction and Isolation. The dried leaves of H. macrophylla (2.0 kg) were extracted with MeOH
(
3 ꢁ 8 l) for 3 h at 808 and evaporated in vacuo. The extract (452 g, 22.2%) was dissolved in H O (5 l) and
2
partitioned into AcOEt/H O 1:1 (v/v) for three times, and removal of the solvent in vacuo yielded an
2
AcOEt-soluble fraction (103.5 g, 4.3%) and an aq. phase. The aq. phase (5 l) was further extracted with
BuOH (3 ꢁ 5 l) to give a BuOH-soluble fraction (125.5 g, 6.5%) and an H O-soluble fraction. The
2
BuOH-soluble fraction was subjected to CC (SiO ; CHCl /MeOH/H O) to give six fractions, Frs. 1 – 6.
2
3
2
Compound 1 (7.1 mg, 0.000355%) was obtained from Fr. 5 after CC (ODS; MeOH/H O 1:9 ! 3 :7) and
2
HPLC (MeOH/H O 15 :85; t 11.5 min). Fr. 3 was separated by HPLC (MeOH/H O 20 :80) to give
2
R
2
compounds 2 (7.5 mg, 0.000375%; t 7.4 min) and 3 (26.6 mg, 0.001330%; t 10.4 min). Fr. 2 was separated
R
R
by CC (ODS; MeOH/H O 1:9 ! 3 :7) and HPLC (MeOH/H O 12 :88) to afford compounds 4 (5.1 mg,
2
2
0
.000255%; tR 14.5 min) and 5 (220.3 mg, 0.011015%; t 20.5 min).
R
Acid Hydrolysis of 1 – 5. A soln. of 1 – 5 (each 2.0 mg) in 1m HCl (1.0 ml) was heated under reflux for
ꢀ
3
h. After cooling, each mixture was neutralized with Amberlite IRA-400 (OH form, Alfa Aesar, USA)
and filtered, and the soln. was partitioned with AcOEt to give two layers. The aq. layer was evaporated
and then subjected to HPLC analysis using NH column (4.6 mm ꢁ 25 cm, Tokyo Kasei Co., Ltd., Japan)
2
and an optical-rotation detector (Shodex OR-2, Showa Denko Co., Ltd., Japan). d-Glucose were
confirmed by comparison of the tR with that of the authentic sample (NICPBP, P. R. China; mobile
phase: MeCN/H O 85 :15 (v/v); flow rate: 0.8 ml/min; t 12.8 min (d-glucose, positive optical rotation)).
2
R

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Helvetica Chimica Acta – Vol. 94 (2011)
Hydranitriloside A (¼ [3-(b-d-Glucopyranosyloxy)-4-hydroxyphenyl]acetonitrile; 1). White amor-
1
2
5
phous powder (MeOH). [a]
D
¼ ꢀ66.0 (c ¼ 2.3, MeOH). UV (MeOH): 204 (4.62), 224 (4.10), 279
1
(
3.70). IR (KBr): 3380, 2924, 2255, 1609, 1518, 1439, 1287, 1236, 1075, 897, 804. H-NMR (600 MHz,
1
3
þ
CD OD): Table 1. C-NMR (150 MHz, CD OD): Table 2. HR-ESI-MS: 334.0901 ([M þ Na] ,
3
3
þ
ꢀ
ꢀ
C H NNaO
7
; calc. 334.0903); 310.0929 ([M ꢀ H] , C H NO
7
; calc. 310.0927).
1
4
17
14 16
Hydranitriloside A (¼ [3-(b-d-Glucopyranosyloxy)-4-methoxyphenyl]acetonitrile; 2). White amor-
2
2
5
phous powder (MeOH). [a] ¼ ꢀ75.0 (c ¼ 2.5, MeOH). UV (MeOH): 205 (4.65), 227 (4.18), 278
D
1
(
3.64). IR (KBr): 3380, 2919, 2251, 1595, 1518, 1458, 1267, 1233, 1080, 897, 806. H-NMR (600 MHz,
1
3
þ
C D N): Table 1. C-NMR (150 MHz, C D N): Table 2. HR-ESI-MS: 348.1058 ([M þ Na] ,
5
5
5
5
þ
7
C H NNaO ; calc. 348.1059).
15
19
Hydranitriloside B (¼ [4-(b-d-Glucopyranosyloxy)-3-methoxyphenyl]acetonitrile; 3). White amor-
1
2
5
phous powder (MeOH). [a] ¼ ꢀ65.1 (c ¼ 8.3, MeOH). UV (MeOH): 205 (4.64), 227 (4.13), 278
D
1
(
3.66). IR (KBr): 3400, 2923, 2249, 1597, 1516, 1425, 1267, 1229, 1076, 895, 804. H-NMR (600 MHz,
1
3
þ
CD OD): Table 1. C-NMR (150 MHz, CD OD): Table 2. HR-ESI-MS: 348.1061 ([M þ Na] ,
3
3
þ
7
C H NNaO ; calc. 348.1059).
15
19
Hydranitriloside B (¼ [4-(b-d-Glucopyranosyloxy)phenyl]acetonitrile; 4). White amorphous pow-
2
1
13
der (MeOH). H-NMR (600 MHz, CD OD): Table 1. C-NMR (150 MHz, CD OD): Table 2. HR-ESI-
3
3
þ
þ
6
MS: 318.0956 ([M þ Na] , C H NNaO ; calc. 318.0954).
14
17
3
-(b-d-Glucopyranosyloxy)-4-methoxybenzoic Acid (5). White amorphous powder (MeOH).
2
5
[
2
a]
D
¼ ꢀ68.0 (c ¼ 2.3, MeOH). UV (MeOH): 217 (4.46), 255 (4.15), 285 (3.77). IR (KBr): 3380,
1 13
930, 1698, 1605, 1522, 1509, 1437, 1281, 1219, 1075, 891, 828. H- and C-NMR (600 and 150 MHz, resp.,
þ
þ
9
ꢀ
C D N): Table 3. HR-ESI-MS: 353.0851 ([M þ Na] , C H NaO ; calc. 353.0849); 329.0873 ([M ꢀ H] ,
5
5
14 18
ꢀ
C H O
9
; calc. 329.0873).
1
4
17
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[
[
[
[
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Received August 18, 2010