Three new monoterpene glucosides from Lamium amplexicaule

Article abstract of DOI:10.1002/hlca.200900158

Three new monoterpene glucosides, lamiuamplexosides A-C (1-3), along with thirteen known glucosides, were isolated from the whole plant of Lamium amplexicaule L. The structures of 1-3 were elucidated on the basis of spectroscopic, chemical, and physicoche

Full text of DOI:10.1002/hlca.200900158

Helvetica Chimica Acta – Vol. 92 (2009)
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Three New Monoterpene Glucosides from Lamium amplexicaule
by Masao Kikuchi*, Rie Onoguchi, and Yasunori Yaoita
Department of Molecular Structural Analysis, Tohoku Pharmaceutical University, 4-4-1 Komatsushima,
Aoba-ku, Sendai, Miyagi 981-8558, Japan
(phone: þ 81-22-2344181; fax: þ 81-22-2752013; e-mail: mkikuchi@tohoku-pharm.ac.jp)
Three new monoterpene glucosides, lamiuamplexosides A – C (1 – 3), along with thirteen known
glucosides, were isolated from the whole plant of Lamium amplexicaule L. The structures of 1 – 3 were
elucidated on the basis of spectroscopic, chemical, and physicochemical evidence.
Introduction. – The genus Lamium L. (Labiatae) comprises about 40 species of
annuals and perennials occurring from North Africa to Eurasia [1]. In a previous paper,
we reported the isolation and structural elucidation of iridoid glucosides and
phenylethanoid glucosides from the whole plant of L. purpureum L. [2]. As a part of
our continuing studies on the glucosides of the genus Lamium plants, we examined the
constituents of glucosides of L. amplexicaule L. There are reports of the isolation of
iridoid glucosides [3 – 8] and flavonoid glucosides [9] from this plant. Careful
reinvestigation of a MeOH extract of the whole plant of L. amplexicaule led to the
isolation of three new glucosides, lamiuamplexosides A – C1) (1 – 3, resp.), together
with the thirteen known glucosides 4 – 16. This article deals with the isolation and
structural elucidation of the new compounds.
Results and Discussion. – The whole plant of L. amplexicaule was extracted with
MeOH. The MeOH extract was partitioned between H2O and CHCl3, H2O and
AcOEt, and H2O and BuOH. The BuOH-soluble fraction was subjected to column
chromatography (silica gel and Sephadex LH-20) and prep. HPLC to afford a new
compound, named lamiuamplexoside A (1), and nine known compounds, 4, 6 – 8, 10 –
13, and 15. The H2O-soluble fraction was subjected to column chromatography (Diaion
HP-20 and silica gel) and prep. HPLC to afford two new compounds, named
lamiuamplexoside B (2) and lamiuamplexoside C (3), and four known compounds, 5, 9,
14, and 16.
Lamiuamplexoside A (1) was obtained as an amorphous powder. The molecular
formula of 1 was determined as C17H24O11 based on the positive-mode HR-FAB-MS
(m/z 405.1384 ([M þ H]þ)). Acid hydrolysis of 1 gave d-glucose, which was identified
by its retention time and optical rotation by means of chiral detection by HPLC. The
1H-NMR spectrum of 1 in CD3OD (Table 1) exhibited signals due to one Me (d(H)
1.23 (s)), two CH, one MeO (d(H) 3.73 (s)), and three CHꢀO groups (d(H) 3.19 (d,
1
)
Arbitrary atom numbering; for systematic names, see Exper. Part.
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 92 (2009)
J ¼ 3.2 Hz), 3.81 (dd, J ¼ 3.2, 1.2 Hz), and 5.69 (s)) and one C¼CꢀH moiety.
Furthermore, one anomeric signal (d(H) 4.60 (d, J ¼ 8.1 Hz)) was recognized. The
coupling constant of an anomeric signal indicated that the glucosyl linkage is in b-
configuration. The 13C-NMR spectrum of 1 in CD3OD (Table 1) showed signals due
one O-bearing, quaternary, sp3-type C-atom (d(C) 77.8) and one C¼O group (d(C)
1
168.6). The H,1H-COSY data of 1 (Fig. 1) implied connectivities of HꢀC(5) to
HꢀC(6), of HꢀC(5) to HꢀC(9), and of HꢀC(6) to HꢀC(7). The HMBC spectrum
(Fig. 1) showed the correlations HꢀC(1)/C(3) and C(1’), HꢀC(3)/C(4), C(5), and
C(11), HꢀC(9)/C(1), Me(10)/C(7), C(8), and C(9), and MeO/C(11). According to
the molecular formula of 1, there were six degrees of unsaturation. One C¼O group,
one C¼CꢀH moiety, an iridoid skeleton, and one b-Glc unit accounted for five of
those. The remaining degree of unsaturation was assumed to be due to an epoxide ring
formed between C(6) and C(7), as inferred from the 13C-NMR data (d(C) 57.8 (C(6))

Helvetica Chimica Acta – Vol. 92 (2009)
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Table 1. 1H- and 13C-NMR (400 and 100 MHz, resp.) Data of Compound 11) in CD3OD. d in ppm,
J in Hz.
d(H)
d(C)
HꢀC(1)
HꢀC(3)
C(4)
HꢀC(5)
HꢀC(6)
HꢀC(7)
C(8)
HꢀC(9)
Me(10)
C(11)
HꢀC(1’)
HꢀC(2’)
HꢀC(3’)
HꢀC(4’)
HꢀC(5’)
CH2(6’)
MeOꢀC(11)
5.69 (s)
7.47 (s)
94.3
154.1
107.4
33.0
57.8
63.4
77.8
46.5
21.4
168.6
99.8
74.6
78.0
71.6
78.4
62.8
51.8
3.24 (dd, J ¼ 8.8, 1.2)
3.81 (dd, J ¼ 3.2, 1.2)
3.19 (d, J ¼ 3.2)
2.27 (d, J ¼ 8.8)
1.23 (s)
4.60 (d, J ¼ 8.1)
3.14 (dd, J ¼ 9.0, 8.1)
a
)
)
)
a
a
3.65 (dd, J ¼ 12.0, 5.6), 3.87 (dd, J ¼ 12.0, 2.0)
3.73 (s)
a) Overlapped by the solvent signal.
and 63.4 (C(7))) [10]. Therefore, the constitution of 1 was deduced. The relative
1
configuration of 1 was determined as follows. In the H-NMR spectrum, the coupling
constant (J ¼ 8.8 Hz) between HbꢀC(5) and HbꢀC(9) indicates the cis relationship of
these H-atoms, and that (J ¼ 1.2 Hz) between HbꢀC(5) and HaꢀC(6) indicates the
trans relationship of these H-atoms, i.e., b-orientation of the epoxide ring (Fig. 2) [11].
In an NOE experiment, irradiation of Me(10) enhanced the signals of HaꢀC(1)
(4.31%) and HaꢀC(7) (4.46%). These observations revealed that the b-d-glucopyr-
anosyloxy group at C(1) and the OH group at C(8) are on the same face (b) of the ring
system (Fig. 2). From these data, the structure of 1 was elucidated as rel-(1aR,1bR,5-
R,5aR,6S,6aR)-5-(b-d-glucopyranosyloxy)-1a,1b,5,5a,6,6a-hexahydro-6-hydroxy-6-meth-
yloxireno[3,4]cyclopenta[1,2-c]pyran-2-carboxylic acid methyl ester, the absolute
configuration of which remains to be established.
Fig. 1. 1H,1H-COSY (—) and HMBC (H ! C) of 11)

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Fig. 2. Selected coupling constant ( --- ! ) and NOEs ($) of 11)
Lamiuamplexoside B (2) was obtained as an amorphous powder. The molecular
formula of 2 was determined as C23H34O16 based on the positive-mode HR-FAB-MS
(m/z 589.1744 ([M þ Na]þ)). The 13C-NMR spectrum of 2 in CD3OD (Table 2) was
similar to that of 8-epikingiside (¼(1R,4aS,8S,8aS)-8-(b-d-glucopyranosyloxy)-
4,4a,8,8a-tetrahydro-1-methyl-3-oxo-1H,3H-pyrano[3,4-c]pyran-5-carboxylic
acid
methyl ester; 17) (see Table 2) [12][13], except for the presence of an additional
hexosyl moiety and a difference in the chemical shift of CH2(6’) (d(C) 70.8 (Dd ¼
þ8.0)) due to glucosylation [14]. Acid hydrolysis of 2 gave only d-glucose, as
1
described above for 1. In the H-NMR spectrum of 2 in CD3OD (Table 2), two
Table 2. 1H- and 13C-NMR (600 and 150 MHz, resp.) Data of Compounds 21), and 13C-NMR (150 MHz)
Data of Compound 171) in CD3OD. d in ppm, J in Hz.
2
17
d(H)
d(C)
d(C)
HꢀC(1)
HꢀC(3)
C(4)
5.48 (d, J ¼ 8.1)
7.58 (d, J ¼ 1.1)
96.9
154.5
109.4
28.3
34.9
175.0
75.9
41.9
96.2
154.4
109.5
28.1
34.6
174.7
75.7
41.8
21.7
168.3
100.6
74.6
HꢀC(5)
3.06 (ddd, J¼ 11.7, 7.0, 3.7)
CH2(6)
2.54 (dd, J ¼ 16.5, 11.7, Ha), 2.86 (dd, J ¼ 16.5, 3.7, Hb)
C(7)
HꢀC(8)
HꢀC(9)
Me(10)
4.53 (dq, J ¼ 7.7, 6.6)
2.13 (ddd, J ¼ 8.1, 7.7, 7.0)
1.51 (d, J ¼ 6.6)
21.9
C(11)
168.4
101.2
74.7
78.0
71.9
77.4
70.8
105.6
75.2
77.9
71.6
HꢀC(1’)
HꢀC(2’)
HꢀC(3’)
HꢀC(4’)
HꢀC(5’)
CH2(6’)
HꢀC(1’’)
HꢀC(2’’)
HꢀC(3’’)
HꢀC(4’’)
HꢀC(5’’)
CH2(6’’)
MeOꢀC(11)
4.70 (d, J ¼ 8.1)
3.16 (dd, J ¼ 9.2, 8.1)
a
)
)
)
78.4
71.6
77.8
62.8
a
a
3.72 (dd, J ¼ 11.7, 5.9), 4.20 (dd, J ¼ 11.7, 2.2)
4.30 (d, J ¼ 8.1)
3.18 (dd, J ¼ 9.2, 8.1)
a
)
)
)
a
a
78.0
62.8
52.0
3.65 (dd, J ¼ 11.7, 5.9), 3.86 (dd, J ¼ 11.5, 1.5)
3.72 (s)
52.0
a) Overlapped by the solvent signal.

Helvetica Chimica Acta – Vol. 92 (2009)
2067
anomeric signals (d(H) 4.30 (d, J ¼ 8.1 Hz) and 4.70 (d, J ¼ 8.1 Hz)) were recognized.
The coupling constants of the latter indicated that the glucosyl linkages are in b-
configuration. Consequently, the structure of 2 was elucidated as rel-(1R,4aS,8S,8aS)-8-
[(6-O-b-d-glucopyranosyl-b-d-glucopyranosyl)oxy]-4,4a,8,8a-tetrahydro-1-methyl-3-
oxo-1H,3H-pyrano[3,4-c]pyran-5-carboxylic acid methyl ester. The absolute config-
uration of 2 could not be determined yet.
Lamiuamplexoside C (3) was obtained as an amorphous powder. The negative-
mode FAB-MS of 3 showed a quasimolecular ion at m/z 347 ([M ꢀ H]ꢀ). The 1H-NMR
spectrum of 3 in CD3OD (Table 3) exhibited signals due to two Me (d(H) 0.93 (d, J ¼
6.4 Hz) and 1.84 (d, J ¼ 1.2 Hz)), one CH, three CH2, and one CH2ꢀO group (d(H)
3.59 – 3.63 (m) and 3.91 – 3.95 (m)) and one C¼CꢀH moiety. Furthermore, one
anomeric signal (d(H) 4.24 (d, J ¼ 7.8 Hz)) was recognized. The coupling constant of
the latter indicated that the glucosyl linkage is in b-configuration. The 13C-NMR
spectrum of 3 in CD3OD (Table 3) showed signals due one b-Glc unit and one C¼O
1
group (d(C) 169.8). The H,1H-COSY data of 3 (Fig. 3) implied connectivities of
HꢀC(3) to CH2(4), of CH2(4) to CH2(5), of CH2(5) to HꢀC(6), of HꢀC(6) to
CH2(7), of HꢀC(6) to Me(10), and of CH2(7) to CH2(8). The HMBC spectrum
(Fig. 3) showed the correlations Me(9)/C(1), C(2), and C(3) and HꢀC(1’)/C(8). The
C¼C bond between C(2) and C(3) was (E)-configured, based on a NOESY cross-peak
between CH2(4) and Me(9) (Fig. 3). On enzymatic hydrolysis with cellulose and b-
glucosidase (ca. 3 :1), 3 yielded (2E,6S)-8-hydroxy-2,6-dimethyloct-2-enoic acid (3a)
[15] and d-glucose, which was identified as described above for 1. The absolute
configuration at C(6) of 3a was determined as (S) by comparison of the optical-
rotation values with those reported in the literature [15]. Thus, the structure of 3 was
elucidated as (2E,6S)-8-(b-d-glucopyranosyloxy)-2,6-dimethyloct-2-enoic acid. The
Table 3. 1H- and 13C-NMR (400 and 100 MHz, resp.) Data of Compound 31) in CD3OD. d in ppm,
J in Hz.
d(H)
d(C)
C(1)
C(2)
169.8
129.0
143.6
27.1
36.9
30.5
37.6
68.8
12.6
19.9
104.3
75.2
77.9
71.7
78.2
62.9
HꢀC(3)
CH2(4)
CH2(5)
HꢀC(6)
CH2(7)
CH2(8)
Me(9)
Me(10)
HꢀC(1’)
HꢀC(2’)
HꢀC(3’)
HꢀC(4’)
HꢀC(5’)
CH2(6’)
6.81 (ddq, J ¼ 7.6, 7.6, 1.2)
2.18 – 2.25 (m)
1.24 – 1.31 (m), 1.47 – 1.53 (m)
1.67 – 1.72 (m)
1.43 – 1.46 (m), 1.63 – 1.66 (m)
3.59 – 3.63 (m), 3.91 – 3.95 (m)
1.84 (d, J ¼ 1.2)
0.93 (d, J ¼ 6.4)
4.24 (d, J ¼ 7.8)
3.16 (dd, J ¼ 9.0, 7.8)
a
)
)
)
a
a
3.66 (dd, J ¼ 12.0, 5.4), 3.86 (dd, J ¼ 12.0, 2.0)
a) Overlapped by the solvent signal.

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Helvetica Chimica Acta – Vol. 92 (2009)
Fig. 3. 1H,1H-COSY (—), HMBC (H ! C), and NOESY ( --- ! )
Correlations of 31)
corresponding compound with (6R) configuration has been already reported from the
dried stems of Cistanche tubulosa (Schrenk) R. Wight (Orobanchaceae) [16].
In addition to the three new glucosides, the other thirteen known glucosides, 8-
deoxylamiol (4) [17], lamiol (5) [3], lamioside (6) [7], 6a-hydroxygeniposide (7) [18],
daphylloside (8) [19], asperuloside (9) [20], shanzhiside methyl ester (10) [7], barlerin
(11) [7], caryoptoside (12) [21], lamalbid (13) [7], 6b-hydroxyipolamide (14) [22],
phlorigidoside B (15) [23], and 5-hydroxy-8-epiloganin (16) [24], were identified on the
basis of their optical-rotation values and NMR and MS data. This is the first report of
compounds 4, 7, 8, 12, 14, 15, and 16 from L. amplexicaule.
Iridoid monoglucosides with COOMe or Me groups at C(4) are considered as
chemotaxonomic markers for Lamium species [1][25][26]. The co-occurrence of
lamiuamplexoside A (1) with shanzhiside methyl ester (10) and caryoptoside (12) in
this plant suggests that the former compound plays a role as a precursor for the
formation of the latter compounds [27]. Lamiuamplexoside B (2), with a gentiobiosyl
moiety, is the first secoiridoid diglucoside isolated from this genus. Also, lamiuam-
plexoside C (3) is the first acyclic monoterpenoid glucoside isolated from this genus.
We are grateful to Mr. S. Satoh and Mr. T. Matsuki for NMR and MS measurements.
Experimental Part
General. Column chromatography (CC): silica gel (SiO2; 70 – 230 mesh; Merck), Diaion HP-20
(250 – 300 mm; Mitsubishi Chemical Corporation), and Sephadex LH-20 (18 – 111 mm; GE Healthcare
Bio-Sciences AB). HPLC: CCPM pump (Tosoh), UV-8020 UV/VIS detector (Tosoh), and Jasco-OR-
2090 plus chiral detector; tR in min. Optical rotations: Jasco-DIP-360 digital polarimeter. UV Spectra:
Beckman-DU-64 spectrophotometer; lmax (log e) in nm. NMR Spectra: Jeol-JNM-LA 600 (1H at 600 and
13C at 150 MHz) and Jeol-JNM-LA 400 (1H at 400 and 13C at 100 MHz) spectrometers; chemical shifts d
in ppm rel. to Me4Si, J in Hz. FAB-MS: Jeol-JMS-DX-303 mass spectrometer; glycerol as matrix; in m/z.
Plant Material. The whole plants of Lamium amplexicaule were collected in Sendai City, Miyagi
Prefecture, Japan, in April 2007. Avoucher specimen (LA-2007-01) was deposited with the Laboratory of
Molecular Structural Analysis, Tohoku Pharmaceutical University.
Extraction and Isolation. The fresh whole plants (including roots, stems, leaves, and flowers) of
Lamium amplexicaule (900 g) were extracted three times (14 d each time) with MeOH (3 l) at r.t. The
MeOH extract was filtered and concentrated, and the residue (21.0 g) was suspended in H2O (1 l). This
suspension was extracted with CHCl3 (3 ꢁ 1 l), AcOEt (3 ꢁ 1 l), and BuOH (3 ꢁ 1 l).

Helvetica Chimica Acta – Vol. 92 (2009)
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The BuOH-soluble fraction was concentrated to afford a residue (8.0 g), which was subjected to CC
(SiO2, CHCl3/MeOH/H2O 30 :10 :1): Fractions 1 – 16 (by TLC). Fr. 3, on prep. HPLC (TSKgel-ODS-
120T column (300 ꢁ 7.8 mm, 10 mm; Tosoh), MeOH/H2O 1:2, 1.5 ml/min) gave 8 (10.0 mg, tR 22.8), 15
(0.4 mg, tR 30.4), and 11 (23.3 mg, tR 40.0). Fr. 4 was purified by CC (Sephadex LH-20, MeOH/H2O 1:1):
6 (28.9 mg). Fr. 6, on prep. HPLC (TSKgel-Amide-80 column (300 ꢁ 7.8 mm, 10 mm; Tosoh), MeCN/
H2O 9 :1, 1.5 ml/min) gave 1 (2.6 mg, tR 26.0), 4 (3.1 mg, tR 35.6), 10 (8.1 mg, tR 37.4), and 7/12 (tR 39.6).
The mixture 7/12, on prep. HPLC (TSKgel-ODS-120T column (300 ꢁ 7.8 mm, 10 mm; Tosoh), MeOH/
H2O 1:2, 1.5 ml/min) gave 7 (0.3 mg, tR 9.0) and 12 (0.7 mg, tR 12.8). Fr. 9 was purified by CC (Sephadex
LH-20, MeOH/H2O 1:1) to afford 13 (52.6 mg).
The H2O-soluble fraction was passed through a Diaion HP-20 column, and the adsorbed material
was eluted with H2O and MeOH. The MeOH eluate was concentrated to afford a residue (2.1 g), which
was subjected to CC (SiO2, CHCl3/MeOH/H2O 30 :10 :1): Fractions 1 – 14 (by TLC). Fr. 2, on prep.
HPLC (TSKgel-ODS-120T column (300 ꢁ 7.8 mm, 10 mm; Tosoh), MeOH/H2O 1:4, 1.5 ml/min) gave 9
(2.4 mg, tR 28.7). Fr. 4, on prep. HPLC (TSKgel-ODS-120T column (300 ꢁ 7.8 mm, 10 mm; Tosoh),
MeOH/H2O 1:3, 1.5 ml/min) gave 5 (1.0 mg, tR 14.0), 14 (4.8 mg, tR 16.4), 2 (1.0 mg, tR 15.4), and 16
(1.1 mg, tR 21.8). Fr. 10, on prep. HPLC (TSKgel-ODS-120T column (300 ꢁ 7.8 mm, 10 mm; Tosoh),
MeOH/H2O 1:3, 1.0 ml/min) gave 3 (2.3 mg, tR 12.2).
Lamiuamplexoside A (¼ rel-(1aR,1bR,5R,5aR,6S,6aR)-5-(b-d-Glucopyranosyloxy)-1a,1b,5,5a,6,6a-
hexahydro-6-hydroxy-6-methyloxireno[3,4]cyclopenta[1,2-c]pyran-2-carboxylic Acid Methyl Ester; 1):
Amorphous powder. [a]2D5 ¼ ꢀ75.3 (c ¼ 0.26, MeOH). UV (MeOH): 231 (3.9). 1H- and 13C-NMR:
Table 1. FAB-MS (pos.): 405 ([M þ H]þ). HR-FAB-MS (pos.): 405.1384 ([M þ H]þ, C17H25O1þ1 ; calc.
405.1397).
Lamiuamplexoside B (¼ rel-(1R,4aS,8S,8aS)-8-[(6-O-b-d-Glucopyranosyl-b-d-glucopyranosyl)-
oxy]-4,4a,8,8a-tetrahydro-1-methyl-3-oxo-1H,3H-pyrano[3,4-c]pyran-5-carboxylic Acid Methyl Ester;
1
2): Amorphous powder. [a]1D9 ¼ ꢀ58.2 (c ¼ 0.10, MeOH). UV (MeOH): 231 (3.9). H- and 13C-NMR:
Table 2. FAB-MS (pos.): 589 ([M þ Na]þ). HR-FAB-MS (pos.): 589.1744 ([M þ Na]þ, C23H34NaOþ16
;
calc. 589.1744).
Lamiuamplexoside C (¼(2E,6S)-8-(b-d-Glucopyranosyloxy)-2,6-dimethyloct-2-enoic Acid; 3):
Amorphous powder. [a]2D2 ¼ ꢀ19.5 (c ¼ 0.23, MeOH). 1H- and 13C-NMR: Table 3. FAB-MS (neg.): 347
([M ꢀ H]ꢀ).
Acid Hydrolysis of 1 and 2. Each of the compounds 1 and 2 (ca. 0.3 mg) was refluxed with 5% HCl
soln. for 5 h. The mixture was neutralized with Ag2CO3 and filtered. The soln. was concentrated and dried
to give a sugar fraction. The sugar fraction was analyzed by HPLC (Shodex-SUGAR-KS-801 column
(300 ꢁ 8.0 mm; Showa Denko), H2O, 1.0 ml/min, chiral detection): tR 7.5 (d-glucose, pos. optical
rotation).
Enzymatic Hydrolysis of 3. Compound 3 (2.3 mg) was treated with cellulase (from Aspergillus niger,
0.39 units/mg; Sigma Chemical Corporation; 3.0 mg) and b-glucosidase (from almond, 5.5 units/mg;
Sigma Chemical Corporation; 1.0 mg) in an AcOH/AcONa buffer soln. (0.02m, pH 4.6; 5.0 ml). The
mixture was stirred at 378 for 3 d, then extracted with an equal amount of AcOEt (3ꢁ), and the AcOEt
layer was concentrated. The residue was dried to give the aglycone 3a, which was identified as (2E,6S)-8-
hydroxy-2,6-dimethyloct-2-enoic acid by the optical-rotation value ([a]2D0 ¼ ꢀ10.0 (c ¼ 0.10, MeOH))
and 1H-NMR data [15]. The sugar fraction, obtained by concentration of the aq. layer, was analyzed by
HPLC (Shodex-SUGAR-KS-801 column (300 ꢁ 8.0 mm; Showa Denko), H2O, 1.0 ml/min, chiral
detection): tR 7.5 (d-glucose, pos. optical rotation).
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Received May 4, 2009