Structural revisions of blumenol C glucoside and byzantionoside B

Article abstract of DOI:10.1248/cpb.58.438

The absolute stereochemistry of blumenol C glucoside and byzantionoside B was revised here as (6R,9S)- and (6R,9R)-9-hydroxymegastigman-4-en-3-one 9-O-β-D-glucopyranosides, respectively, by modified Mosher's method. The empirical rules of ¹³C-NMR chemical shift to determine the absolute stereochemistry of C-9 of 9-hydroxymegastigmane 9-O-β-D-glucopyranoside were also discussed.

Full text of DOI:10.1248/cpb.58.438

438
Communications to the Editor
Chem. Pharm. Bull. 58(3) 438—441 (2010)
Vol. 58, No. 3
Structural Revisions of Blumenol
C Glucoside and Byzantionoside B
Katsuyoshi MATSUNAMI,a Hideaki OTSUKA,*,a and
b
Yoshio TAKEDA
a Department of Pharmacognosy, Graduate School of Biomedical
Sciences, Hiroshima University; 1–2–3 Kasumi, Minami-ku,
Hiroshima 734–8553, Japan: and b Faculty of Pharmacy, Yasuda
Women’s University; 6–13–1 Yasuhigashi, Asaminami-ku, Hiroshima
731–0153, Japan.
Fig. 1. Revised Structures of Blumenol C Glucoside (1) and Byzantiono-
side B (2)
Received December 9, 2009; accepted January 5, 2010; published
online January 7, 2010
The absolute stereochemistry of blumenol C glucoside and
byzantionoside B was revised here as (6R,9S)- and (6R,9R)-
9-hydroxymegastigman-4-en-3-one 9-O-b-D-glucopyranosides,
respectively, by modified Mosher’s method. The empirical rules
of 13C-NMR chemical shift to determine the absolute stereo-
chemistry of C-9 of 9-hydroxymegastigmane 9-O-b-D-glucopyra-
noside were also discussed.
Key words blumenol C glucoside; byzantionoside B; megastigmane
glucoside
Fig. 2. Modified Mosher’s Analysis for 1 and 2
Blumenol C was first isolated from the leaves of Podocar-
pus blumei in 1972.1) The absolute stereochemistry of blu- Thus, blumenol C glucoside (1) isn’t the glucoside of blu-
menol C was then determined as (6R,9R) by chemical con- menol C, but the glucoside of 9-epi-blumenol C in fact, and
version of related compound.2) Its glucoside, i.e. blumenol C in other word, byzantionoside B is the really glucoside of
glucoside (1), was then isolated from the aerial parts of blumenol C.
Epimedium grandiflorum var. thunbergianum and the struc-
Aasen et al. reported the specific optical rotation value of
ture was determined by comparison of the spectral data of its blumenol C as [a]D ꢀ54° (cꢁ0.22, CHCl3).2) Thus, blu-
aglycone, derived from enzymatic hydrolysis of 1, with those menol C glucoside (1) was first misidentified as a glucoside
of blumenol C.3) Recently, byzantionoside B (2) was isolated of blumenol C, probably due to the moderate positive optical
from the aerial parts of Stachys byzantina as the C-9 epimer rotation value of aglycone [[a]D22 ꢀ112.5° (cꢁ0.52,
of blumenol C glucoside.4) Modified Mosher’s method is CHCl3)].3) However, the aglycones (1a, 2a) prepared in this
widely used recently for determination of the absolute stereo- study from blumenol C glucoside (1) and byzantionoside B
chemistry of chiral secondary alcohol.5) In this study, the ab- (2) showed [a]D24 ꢀ80.5° (cꢁ0.32, CHCl3) and [a]D23 ꢀ46.3°
solute configurations of these compounds (1, 2) were reinves- (cꢁ0.08, CHCl3), respectively, suggesting that it was difficult
tigated by this reliable method.
to distinguish these epimers only by optical rotation values at
that time. Finally, it is noteworthy that there is a slight but
Results and Discussion
clear difference between 9-epi-blumenol C (1a) and blu-
1
Blumenol C glucoside (1) and byzantionoside B (2) were menol C (2a) for H2-7 in H-NMR spectra, i.e. 1.61 and
identified by comparison of the literature data at first (Tables 1.76 ppm for 1a, and 1.45 and 1.93 ppm for 2a. The compari-
1, 2).3,4) The aglycones (1a, 2a, respectively) were prepared son of chemical shifts of H2-7 also provides the important
by enzymatic hydrolysis of the glucosides. Their (R)- or (S)- criterion to distinguish each other (Table 2).
MTPA esters were then prepared by the conventional proce-
The above results arouse further interest that whether or
dure (1b and 1c from 1a, 2b and 2c from 2a, see Experimen- not there was some trend in NMR spectra between (9R) and
tal). The distribution patterns of DdS–R values for 1b and 1c, (9S)-O-b-D-glucopyranosides among related megastigmanes.
and 2b and 2c clearly demonstrated that 1 and 2 possess 9S It has been reported that the chemical shift at C-9 is indica-
and 9R configurations, respectively (Figs. 1, 2). In addition, tive for 9R (ca. 77 ppm) and 9S (ca. 74 ppm) configuration
the application of the b-D-glucosylation-induced shift-trend for D7,8-type of 9-hydroxymegastigmane 9-O-b-D-glucopyra-
rule6) also supported this result (Table 1). The absolute stere- noside.9,10) This rule seems to be applicable for most com-
ochemistry of C-6 was also confirmed by CD spectra. The pounds, however, in the case of staphylinoside I (dC-9
:
CD data of 1 and 2 were essentially identical to that of sedu- 76.3 ppm, 9S) that possessed 6-OMe, this rule does not work
moside H of which the absolute stereochemistry was deter- well for the determination of C-9 configuration.11) Therefore,
mined precisely by catalytic hydrogenation and application in this paper, this rule was also refined further by comparing
of CD octant rule, and also chemical conversion to related with the literature data (Fig. 3). The stereochemistry of these
compound.7,8) Therefore, the actual structures of 1 and 2 compounds was determined by the reliable methods, i.e.
must be (6R,9S)-9-hydroxymegastigman-4-en-3-one 9-O-b- modified Mosher’s method, b-D-glucosylation-induced shift-
D-glucopyranoside and (6R,9R)-9-hydroxymegastigman-4- trend rule, synthetic approach and chemical conversion.
en-3-one 9-O-b-D-glucopyranoside, respectively (Fig. 1).
The empirical rules observed here are as follows: The
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: hotsuka@hiroshima-u.ac.jp.

March 2010
439
Table 1. 13C-NMR Data for Blumenol C Glucoside (1) and Byzantionoside B (2) (150 MHZ)
1
1
1a
(CD3OD)
2
2
2a
(CD3OD)
C
(C5D5N)
(CD3OD)
(C5D5N)
(CD3OD)
1
2
3
4
5
6
7
8
9
10
11
12
13
1ꢄ
2ꢄ
3ꢄ
4ꢄ
5ꢄ
6ꢄ
36.4
37.4
48.2
202.4
125.6
169.8
52.7
26.7
37.5
77.7
22.0
29.1
27.5
25.0
104.1
75.4
78.3
71.8
77.9
62.9
37.4
48.3
202.2
125.6
169.7
52.6
27.5
39.9(ꢂ2.4)
68.9(ꢀ8.8)
23.5(ꢂ1.5)
29.1
36.3
37.4
48.2
202.5
125.5
170.1
52.5
26.9
37.9
75.7
19.9
29.1
27.6
25.0
102.3
75.3
78.3
72.0
78.0
63.1
37.4
48.2
202.3
125.5
169.7
52.5
47.8
198.4
125.4
165.2
51.3
25.7
36.7
76.0
22.0
28.7
27.1
24.3
104.2
75.4
78.7
71.9
78.4
63.0
47.8
198.4
125.4
165.2
51.2
26.0
37.1
74.2
19.9
28.8
27.1
24.3
102.4
75.3
78.7
72.1
78.4
63.2
27.3
39.9(ꢂ2.0)
68.6(ꢀ7.1)
23.6(ꢂ3.7)
29.1
27.5
24.8
27.4
24.9
Parenthesis is dglucoside-aglycone
.
Table 2. 1H-NMR Data for Blumenol C Glucoside (1) and Byzantionoside B (2) (600 MHz)
C
2
1 (C5D5N)
1 (CD3OD)
1a (CD3OD)
2 (C5D5N)
2 (CD3OD)
2a (CD3OD)
2.08 (1H, d, 17)
2.49 (1H, d, 17)
5.89 (1H, s)
1.78 (1H, m)
1.75—1.89 (2H, m)
1.98 (1H, d, 17)
2.48 (1H, d, 17)
5.80 (1H, s)
1.97 (1H, m)
1.67 (1H, m)
1.81 (1H, m)
1.61 (1H, m)
1.68 (1H, m)
2.00 (1H, d, 17)
2.44 (1H, d, 17)
5.81 (1H, s)
1.99 (1H, m)
1.61 (1H, m)
1.76 (1H, m)
2.07 (1H, d, 17)
2.45 (1H, d, 17)
5.92 (1H, m)
1.77 (1H, m)
1.50 (1H, m)
1.94 (1H, m)
1.97 (1H, d, 17)
2.46 (1H, d, 17)
5.80 (1H, s)
1.99 (1H, m)
1.50 (1H, m)
1.98 (1H, m)
1.61 (1H, m)
1.68 (1H, m)
1.99 (1H, m)
2.44 (1H, d, 17)
5.81 (1H, s)
1.98 (1H, m)
1.45 (1H, m)
1.93 (1H, m)
1.51—1.55 (2H, m)
4
6
7
8
1.66—1.77 (2H, m)
1.51—1.56 (2H, m) 1.62 (1H, m)
1.76 (1H, m)
9
10
11
12
13
4.04 (1H, m)
1.37 (3H, d, 6)
0.93 (3H, s)
3.82 (1H, m)
1.25 (3H, d, 6)
1.02 (3H, s)
3.69 (1H, m)
1.16 (3H, d, 6)
1.02 (3H, s)
1.09 (3H, s)
2.04 (3H, d, 1)
4.06 (1H, m)
1.27 (3H, d, 6)
0.92 (3H, s)
3.88 (1H, m)
1.18 (3H, d, 6)
1.01 (3H, s)
3.69 (1H, m)
1.16 (3H, d, 6)
1.02 (3H, s)
1.09 (3H, s)
2.04 (3H, d, 1)
0.98 (3H, s)
1.09 (3H, s)
0.94 (3H, s)
1.09 (3H, s)
1.86 (3H, d, 1)
4.90 (1H, d, 8)
3.97 (1H, m)
4.19 (1H, m)
4.19 (1H, m)
3.94 (1H, m)
4.36 (1H, dd, 12, 5)
4.53 (1H, dd, 12, 2)
2.04 (3H, d, 1)
4.32 (1H, d, 8)
3.15 (1H, dd, 9, 8)
3.34 (1H, dd, 9, 9)
3.27 (1H, dd, 9, 9)
3.25 (1H, m)
1.86 (3H, d, 1)
4.89 (1H, d, 8)
3.99 (1H, dd, 9, 8)
4.25 (1H, dd, 9, 9)
4.20 (1H, dd, 9, 9)
3.95 (1H, m)
2.04 (3H, d, 1)
4.33 (1H, d, 8)
3.14 (1H, dd, 9, 8)
3.35 (1H, dd, 9, 9)
3.27 (1H, m)
3.26 (1H, m)
3.65 (1H, dd, 12, 5)
3.85 (1H, dd, 12, 2)
1ꢄ
2ꢄ
3ꢄ
4ꢄ
5ꢄ
6ꢄ
3.66 (1H, dd, 12, 5)
3.85 (1H, dd, 12, 2)
4.35 (1H, dd, 12, 5)
4.54 (1H, dd, 12, 2)
J in Hz. m: multiplet or overlapped. Chemical shift were determined by HH-COSY and HMQC.
chemical shift of C-8 is usually affected too large by the have 9R configuration.
structure and substitution pattern around six-membered ring
moiety. C-9 is also affected in a similar way but slightly. The
Experimental
General Experimental Procedures The spectral data was taken by
similar procedures described previously.18) The absolute configuration of
glucose was determined by HPLC analysis [JASCO OR-2090 plus: Optical
rotation detector, SHODEX Asahipak NH2P-50: Fꢁ4.5 mm, Lꢁ25 cm,
75% CH3CN aq., 1 ml/min].
13C chemical shifts of C-9, C-10 and Glc-1 are valuable to
distinguish the stereochemistry of C-9 in methanol-d4 (Figs.
3B, D). Especially, C-10 may be the most reliable to this pur-
pose because it locates far from other substituent. The stereo-
chemistry of C-6 may not affect the above empirical rule by
judging from the data of C-6 epimeric counterparts (Figs.
3A, C).
Several compounds published by ourselves should be re-
vised here as follows: salvionoside C12) and leeaoside13) must
have 9R configuration, and euodionosides F and G14) are of
9S configuration. Lauroside E15) that was quoted as a known
compound in our previous work16,17) should be corrected to
Blumenol C Glucoside (1): Amorphous powder; [a]D23 ꢀ49.0° (cꢁ2.15,
MeOH); IR nmax (film) cmꢂ1: 3399, 2963, 1650, 1377, 1258, 1161, 1076,
1035; UV lmax (MeOH) nm (log e): 238 (4.06) (cꢁ2.30ꢃ10ꢂ5 M, MeOH);
13C- and 1H-NMR (C5D5N and CD3OD): Tables 1 and 2; CD De (nm):
ꢀ0.63 (331), ꢀ4.25 (234) (cꢁ2.30ꢃ10ꢂ5 M, MeOH); HR-ESI-TOF-MS
(positive-ion mode) m/z: 395.2043 [MꢀNa]ꢀ (Calcd for C19H32O7Na:
395.2040).
Byzantionoside B (2): Amorphous powder; [a]D24 ꢀ27.0° (cꢁ0.21,
MeOH); IR nmax (film) cmꢂ1: 3399, 2964, 1645, 1377, 1255, 1160, 1076,
1036; UV lmax (MeOH) nm (log e): 239 (4.24) (cꢁ2.82ꢃ10ꢂ5 M, MeOH);

440
Vol. 58, No. 3
Fig. 3. 13C Chemical Shifts Nature for Related Compounds
(A, C) Structures and chemical shifts, (B) chemical shift feature for 9-hydroxymegastigmane 9-O-b-D-glucopyranosides possessing saturated C-7 to 10, (D) chemical shift fea-
ture for D7,8-type of 9-hydroxymegastigmane 9-O-b-D-glucopyranosides.
13C- and 1H-NMR (C5D5N and CD3OD): Tables 1 and 2; CD De (nm):
m, H2-8), 1.58 (1H, m, H-7a), 1.34 (1H, m, H-7b), 1.36 (3H, d, Jꢁ6 Hz, H3-
ꢀ0.68 (332), ꢀ2.53 (235) (cꢁ2.82ꢃ10ꢂ5 M, MeOH); HR-ESI-TOF-MS
10), 0.98 (3H, s, H3-11), 0.95 (3H, s, H3-12); HR-ESI-TOF-MS (positive-ion
(positive-ion mode) m/z: 395.2038 [MꢀNa]ꢀ (Calcd for C19H32O7Na:
395.2040).
mode) m/z: 449.1907 [MꢀNa]ꢀ (Calcd for C23H29O4F3Na: 449.1910).
(6R,9S)-9-hydroxymegastigman-4-en-3-one (S)-MTPA ester (1c): Amor-
phous powder; 1H-NMR (CDCl3, 600 MHz) dH: 7.53—7.51 (2H, m, aro-
matic protons), 7.42—7.38 (3H, m, aromatic protons), 5.83 (1H, s, H-4),
5.10 (1H, m, H-9), 3.51 (3H, br s, OMe), 2.29 (1H, d, Jꢁ17 Hz, H-2a), 2.04
(1H, d, Jꢁ17 Hz, H-2b), 1.93 (3H, d, Jꢁ1 Hz, H3-13), 1.85 (1H, br t,
Jꢁ5 Hz, H-6), 1.78—1.68 (2H, m, H2-8), 1.71 (1H, m, H-7a), 1.50 (1H, m,
H-7b), 1.29 (3H, d, Jꢁ6 Hz, H3-10), 1.01 (6H, s, H3-11, H3-12); HR-
ESI-TOF-MS (positive-ion mode) m/z: 449.1914 [MꢀNa]ꢀ (Calcd for
C23H29O4F3Na: 449.1910). (6R,9R)-9-hydroxymegastigman-4-en-3-one (R)-
MTPA ester (2b): Amorphous powder; 1H-NMR (CDCl3, 600 MHz) dH:
7.54—7.51 (2H, m, aromatic protons), 7.43—7.38 (3H, m, aromatic pro-
tons), 5.83 (1H, s, H-4), 5.09 (1H, m, H-9), 3.51 (3H, br s, OMe), 2.27 (1H,
d, Jꢁ17 Hz, H-2a), 2.02 (1H, d, Jꢁ17 Hz, H-2b), 1.94 (3H, d, Jꢁ1 Hz, H3-
13), 1.77 (2H, m, H2-8), 1.77—1.68 (1H, m, H-6), 1.68 (1H, m, H-7a), 1.41
(1H, m, H-7b), 1.30 (3H, d, Jꢁ6 Hz, H3-10), 1.01 (3H, s, H3-12), 1.00 (3H,
s, H3-11); HR-ESI-TOF-MS (positive-ion mode) m/z: 449.1904 [MꢀNa]ꢀ
(Calcd for C23H29O4F3Na: 449.1910). (6R,9R)-9-hydroxymegastigman-4-en-
3-one (S)-MTPA ester (2c): Amorphous powder; 1H-NMR (CDCl3,
600 MHz) dH: 7.56—7.51 (2H, m, aromatic protons), 7.43—7.38 (3H, m,
aromatic protons), 5.80 (1H, s, H-4), 5.10 (1H, m, H-9), 3.58 (3H, br s,
OMe), 2.18 (1H, d, Jꢁ17 Hz, H-2a), 1.96 (1H, d, Jꢁ17 Hz, H-2b), 1.87 (3H,
d, Jꢁ1 Hz, H3-13), 1.72 (2H, m, H2-8), 1.72—1.61 (1H, m, H-6), 1.61 (1H,
m, H-7a), 1.30 (1H, m, H-7b), 1.36 (3H, d, Jꢁ6 Hz, H3-10), 0.92 (3H, s, H3-
11), 0.97 (3H, s, H3-12); HR-ESI-TOF-MS (positive-ion mode) m/z:
449.1905 [MꢀNa]ꢀ (Calcd for C23H29O4F3Na: 449.1910).
Enzymatic Hydrolysis Blumenol C glucoside (1) and byzantionoside B
(2) were hydrolyzed with b-glucosidase. The aglycone and glucose was sep-
arated by TLC (CHCl3 : MeOH : H2O, 15 : 6 : 1, Rf values, 1: 0.63, aglycone
(1a): 0.81, 2: 0.67, aglycone (2a): 0.87, and glucose: 0.15). The absolute
configuration of glucose was determined to be D-series by HPLC analysis.
(6R,9S)-9-hydroxymegastigman-4-en-3-one, 9-epi-blumenol C (1a): gummy
syrup; [a]D24 ꢀ80.5° (cꢁ0.32, CHCl3); IR nmax (film) cmꢂ1: 3416, 2964,
1658, 1374, 1255, 1126; UV lmax (MeOH) nm (log e): 239 (4.14); 13C- and
1H-NMR (CD3OD): Tables 1 and 2; CD De (nm): ꢀ1.65 (333), ꢀ2.54 (242)
(cꢁ2.14ꢃ10ꢂ5 M, MeOH); HR-ESI-TOF-MS (positive-ion mode) m/z:
233.1510 [MꢀNa]ꢀ (Calcd for C13H22O2Na: 233.1512). (6R,9R)-9-hydrox-
ymegastigman-4-en-3-one, blumenol C (2a): gummy syrup; [a]D23 ꢀ46.3°
(cꢁ0.08, CHCl3); IR nmax (film) cmꢂ1: 3423, 2963, 1658, 1372, 1292, 1256,
1126; UV lmax (MeOH) nm (log e): 239 (3.83) (cꢁ3.16ꢃ10ꢂ5 M, MeOH);
13C- and 1H-NMR (CD3OD): Tables 1 and 2; CD De (nm): ꢀ0.61 (327),
ꢀ2.75 (231) (cꢁ2.14ꢃ10ꢂ5 M, MeOH); HR-ESI-TOF-MS (positive-ion
mode) m/z: 233.1509 [MꢀNa]ꢀ (Calcd for C13H22O2Na: 233.1512).
Preparation of (R)- and (S)-MTPA Esters MTPA esters were prepared
from 1a and 2a by the procedure described previously.18) (6R,9S)-9-hydroxy-
megastigman-4-en-3-one (R)-MTPA ester (1b): Amorphous powder; 1H-
NMR (CDCl3, 600 MHz) dH: 7.54—7.51 (2H, m, aromatic protons), 7.41—
7.37 (3H, m, aromatic protons), 5.78 (1H, s, H-4), 5.12 (1H, m, H-9), 3.57
(3H, br s, OMe), 2.24 (1H, d, Jꢁ17 Hz, H-2a), 2.00 (1H, d, Jꢁ17 Hz, H-2b),
1.85 (3H, d, Jꢁ1 Hz, H3-13), 1.77 (1H, br t, Jꢁ5 Hz, H-6), 1.73—1.62 (2H,

March 2010
441
Acknowledgments This research was supported by Grant-in Aid for
tochemistry, 69, 1586—1596 (2008).
Scientific Research (C) (No. 20590103), the Research Foundation for Phar- 15) Marino S., Borbone N., Zollo F., Ianaro A., Meglio P., Iorizzi M., J.
maceutical Sciences, and Takeda Science Foundation. We are also grateful
for the use of NMR, UV and MS spectrometers at Research Center for Mol-
ecular Medicine, the Analysis Center of Life Science, and the Natural Sci-
Agric. Food Chem., 52, 7525—7531 (2004).
16) Sueyoshi E., Liu H., Matsunami K., Otsuka H., Shinzato T., Aramoto
M., Takeda Y., Phytochemistry, 67, 2483—2493 (2006).
ence Center for Basic Research and Development (N-BARD), Hiroshima 17) Matsunami K., Takamori I., Shinzato T., Aramoto M., Kondo K.,
University.
Otsuka H., Takeda Y., Chem. Pharm. Bull., 54, 1403—1407 (2006).
18) Matsunami K., Otsuka H., Kondo K., Shinzato K., Kawahata M.,
Yamaguchi K., Takeda Y., Phytochemistry, 70, 1277—1285 (2009).
19) Morikawa T., Zhang Y., Nakamura S., Matsuda H., Muraoka O.,
Yoshikawa M., Chem. Pharm. Bull., 55, 435—441 (2007).
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