Revised absolute stereochemistry of rhodiolosides A-D, rhodiolol A and sachalinol A from Rhodiola rosea

Article abstract of DOI:10.1248/cpb.56.1047

The absolute stereochemistry of rhodiolosides A - D (1-4), four monoterpene glycosides from the roots of Rhodiola rosea, and their aglycones, rhodiolol A (5), (-)-rosiridol (6) and sachalinol A (7), were reinvestigated. It was found that the absolute configurations of C-4 in these compounds, previously assigned to be 4-R, should be revised to 4-S.

Full text of DOI:10.1248/cpb.56.1047

July 2008
Notes
Chem. Pharm. Bull. 56(7) 1047—1048 (2008)
1047
Revised Absolute Stereochemistry of Rhodiolosides A—D, Rhodiolol A
and Sachalinol A from Rhodiola rosea
Wei LI,a Deqiang DOU,b and Kazuo KOIKE*,a
a Faculty of Pharmaceutical Sciences, Toho University; 2–2–1 Miyama, Funabashi, Chiba 274–8510, Japan: and b College
of Pharmacy, Liaoning University of Traditional Chinese Medicine; 79 Chong-Shan East Road, Shenyang 110032, P. R.
China. Received March 19, 2008; accepted April 14, 2008; published online April 21, 2008
The absolute stereochemistry of rhodiolosides A—D (1—4), four monoterpene glycosides from the roots of
Rhodiola rosea, and their aglycones, rhodiolol A (5), (ꢀ)-rosiridol (6) and sachalinol A (7), were reinvestigated. It
was found that the absolute configurations of C-4 in these compounds, previously assigned to be 4-R, should be
revised to 4-S.
Key words Rhodiola rosea; Crassulaceae; monoterpene; glycoside; rhodioloside
We had reported four monoterpene glycosides, rhodiolo-
Enzymatic hydrolysis of rhodioloside A (1) by naringinase
sides A—D (1—4) from the roots of Rhodiola rosea L. afforded rhodiolol A (5). The 1,8-dipivaloyl ester (8) obtained
(Crassulaceae).1) The absolute these configurations of C-4 in by selective protection of the 1,8-primary alcohol of 5 with
compounds (1—4), and their aglycones, rhodiolol A (5), pivaloyl chloride, derived the (S)- and (R)-MTPA esters (9
(ꢀ)-rosiridol (6) and sachalinol A (7) had been assigned to and 10). As shown in Chart 2, the Dd values (dS–dR) indi-
be 4-R by application of the modified Mosher’s method or cated the 4-S configuration. Thus, the structure of rhodiolo-
direct comparison of the Optical Rotation values with the side A (1) was revised to (2E,6E,4S)-4,8-dihydroxy-3,7-
reported compounds. However, very recently, several glyco- dimethyl-2,6-octadienyl b-D-glucopyranoside, and its agly-
sides with (ꢀ)-rosiridol (6) as the aglycone were determined cone, rhodiolol A (5) to (2E,6E,4S)-4,8-dihydroxy-3,7-di-
to be 4-S configurations.2) This promoted us to reinvestigate methyl-2,6-octadiene.
the absolute stereochemistry of rhodiolosides A—D (1—4)
and their aglycones (5—7).
Enzymatic hydrolysis of rhodioloside B (2) and rhodiolo-
side C (3) by naringinase afforded (ꢀ)-rosiridol (6). The
1-pivaloyl ester of (ꢀ)-rosiridol (11) derived to the (S)- and
(R)-MTPA esters (12, 13). On the basis of the calculate val-
Results and Discussion
The absolute configurations of C-4 in rhodiolosides A—D ues of DdS–R, the absolute configuration of C-4 was deter-
(1—4) were determined by the following strategy. Firstly, the mined to be S. Thus, the structure of rhodioloside B (2) was
monoterpene glycosides were hydrolyzed enzymatically to revised to (2E,4S)-4-hydroxy-3,7-dimethyl-2,6-octadienyl a-
obtain the aglycones. Secondly, the primary hydroxyl groups D-glucopyranosyl(1→6)-b-D-glucopyranoside, rhodioloside
in the aglycones were selectively protected by pivaloylation. C (3) to (2E,4S)-4-hydroxy-3,7-dimethyl-2,6-octadienyl b-D-
Thirdly, the 4-hydroxyl group in the pivaloylated monoter- glucopyranosyl(1→3)-b-D-glucopyranoside, and (ꢀ)-rosiri-
penes was esterified with (R)- and (S)-a-methoxy-a-(trifluo- dol (6) to (2E,4S)-4-hydroxy-3,7-dimethyl-2,6-octadiene.
romethyl)-phenylacetyl (MTPA) chloride to obtain the 4-(S)-
As for rhodioloside D (4), its aglycone, sachalinol A (7)
and 4-(R)-MTPA esters. The absolute configuration of C-4 obtained by enzymatic hydrolysis, was selectively converted
was determined by observation of the Dd values (dS–dR) be- into its 1-pivaloyl ester (14) with pivaloyl chloride, following
tween the 4-(S)- and 4-(R)-MTPA esters.
derived to the (S)- and (R)-MTPA esters (15, 16). The Dd
values (dS–dR) shown in Chart 4, indicated the 4-S configura-
tion. Thus, the structure of rhodioloside D was revised to
Chart 2
Chart 3
Chart 1
∗ To whom correspondence should be addressed. e-mail: koike@phar.toho-u.ac.jp
© 2008 Pharmaceutical Society of Japan

1048
Vol. 56, No. 7
400 MHz): d 5.54 (1H, tt, Jꢃ6.9, 1.0 Hz, H-2), 4.63 (2H, d, Jꢃ6.8 Hz, H2-
1), 3.94 (1H, t, Jꢃ6.5 Hz, H-4), 1.70 (3H, br s, H3-10), 1.61 (2H, m, H2-5),
1.51 (1H, m, Ha-6), 1.36 (1H, m, Hb-6), 1.18 (9H, s, H3-pivaloylꢁ3), 1.17
(3H, s, H3-8 or H3-9), 1.17 (3H, s, H3-8 or H3-9).
(S)- and (R)-MTPA Derivatives of 8, 11 and 14 A solution of 8
(1.0 mg) in dry pyridine (0.1 ml) was added (ꢀ)-MTPA chloride (10 ml) at
room temperature. After being stirred at room temperature for 4 h, the mix-
ture was evaporated to dryness and purified by RP-HPLC with 90% MeOH
to give (S)-MTPA ester 9 (1.2 mg). Using a similar procedure, treatment of 8
(1.0 mg) with (ꢂ)-MTPA chloride afforded (R)-MTPA ester 10 (1.3 mg).
(S)-MTPA ester 12 (0.6 mg) and (R)-MTPA ester 13 (0.9 mg) were obtained
from 11 (each 0.6 mg). (S)-MTPA ester 15 (1.2 mg) and (R)-MTPA ester 16
(1.1 mg) were obtained from 14 (each 1.0 mg).
Chart 4
(2E,4S)-4,7-dihydroxy-3,7-dimethyl-2-octenyl b-D-glucopy-
ranoside, and sachalinol A to (2E,4S)-4,7-dihydroxy-3,7-di-
methyl-2-octene.
As a conclusion, the absolute configurations of C-4 in rho-
diolosides A—D (1—4), rhodiolol A (5), (ꢀ)-rosiridol (6)
and sachalinol A (7) were all revised to 4-S.
(S)-MTPA Ester of 8 (9): 1H-NMR (CDCl3, 400 MHz): d 5.68 (1H, t,
Jꢃ6.7 Hz, H-2), 5.40 (1H, dd, Jꢃ7.7, 6.0 Hz, H-4), 5.25 (1H, d, Jꢃ6.7 Hz,
H-6), 4.63 (1H, dd, Jꢃ13.0, 6.7 Hz, H-1), 4.57 (1H, dd, Jꢃ13.0, 6.7 Hz, H-
1), 4.36 (2H, br s, H2-8), 2.50 (1H, m, H-5), 2.36 (1H, m, H-5), 1.72 (3H, s,
H3-10), 1.58 (3H, s, H3-9).
(R)-MTPA Ester of 8 (10): 1H-NMR (CDCl3, 400 MHz): d 5.60 (1H, t,
Jꢃ6.4 Hz, H-2), 5.38 (1H, t, Jꢃ5.5 Hz, H-4), 5.36 (1H, t, Jꢃ6.4 Hz, H-6),
4.59 (1H, dd, Jꢃ13.0, 6.4 Hz, H-1), 4.54 (1H, dd, Jꢃ13.0, 6.4 Hz, H-1), 4.42
(2H, br s, H2-8), 2.56 (1H, m, H-5), 2.40 (1H, m, H-5), 1.64 (3H, s, H3-9),
1.58 (3H, s, H3-10).
Experimental
General Experimental Procedures Optical rotations were measured
with a JASCO DIP-370 digital polarimeter in a 0.5-dm length cell. The H-
1
NMR spectra were measured with a JEOL ECP-500 spectrometer or JEOL
AL-400 spectrometer with TMS as the internal reference, and chemical
shifts are expressed in d (ppm). Diaion HP-20 resin (Mitsubishi Chemical
Corporation, Tokyo, Japan) and silica gel (silica Gel 60N, Kanto Chemical
Co., Inc., Tokyo, Japan) were used for column chromatography. Preparative
HPLC was performed using an ODS column (YMC-Pack Pro C18, 10 mm
i.d.ꢁ250 mm, YMC Co., Ltd., Kyoto, Japan).
1
(S)-MTPA Ester of 11 (12): H-NMR (CDCl3, 400 MHz): d 5.67 (1H, t,
Jꢃ6.5 Hz, H-2), 5.37 (1H, dd, Jꢃ7.6, 6.2 Hz, H-4), 4.92 (1H, t, Jꢃ7.3 Hz,
H-6), 4.63 (1H, dd, Jꢃ11.1, 6.5 Hz, H-1), 4.59 (1H, dd, Jꢃ11.1, 6.5 Hz, H-
1), 2.42 (1H, m, H-5), 2.28 (1H, m, H-5), 1.72 (3H, s, H3-10), 1.63 (3H, s,
H3-9), 1.54 (3H, s, H3-8).
1
(R)-MTPA Ester of 11 (13): H-NMR (CDCl3, 400 MHz): d 5.59 (1H, t,
Enzymatic Hydrolysis of 1, 2, 3 and 4 A solution of 1 (7.0 mg) in
0.1 M acetate buffer (pH 4.0, 1.0 ml) was treated with naringinase (Sigma
Chemical Co., 2 units), and then the reaction mixture was stirred at 40 °C for
12 h. The reaction mixture was passed through a Diaion HP-20 column, and
washed with H2O and MeOH. The MeOH fraction was chromatographed
over a silica gel column to give rhodiolol A (5, 2.8 mg, eluted with
CHCl3–MeOH, 92 : 8). Through a similar procedure, enzymatic hydrolysis
of 2 (8.0 mg), 3 (7.1 mg) and 4 (9.9 mg) was carried out to afford (ꢀ)-rosili-
dol (6, 1.9 mg from 2; 0.5 mg from 3, eluted with CHCl3–MeOH, 94 : 6) and
sachalinol A (7, 3.7 mg, eluted with CHCl3–MeOH, 9 : 1). The Optical Rota-
Jꢃ6.6 Hz, H-2), 5.33 (1H, dd, Jꢃ7.9, 5.7 Hz, H-4), 5.04 (1H, t, Jꢃ7.2 Hz,
H-6), 4.60 (1H, dd, Jꢃ11.0, 5.5 Hz, H-1), 4.55 (1H, dd, Jꢃ11.0, 5.5 Hz, H-
1), 2.49 (1H, m, H-5), 2.32 (1H, m, H-5), 1.70 (3H, s, H3-9), 1.60 (3H, s,
H3-8), 1.60 (3H, s, H3-10).
1
(S)-MTPA Ester of 14 (15): H-NMR (CDCl3, 500 MHz): d 5.67 (1H, t,
Jꢃ6.4 Hz, H-2), 5.37 (1H, dd, Jꢃ7.2, 6.2 Hz, H-4), 4.63 (1H, dd, Jꢃ13.0,
6.4 Hz, H-1), 4.57 (1H, dd, Jꢃ13.0, 6.4 Hz, H-1), 1.75 (2H, m, H2-5), 1.70
(3H, br s, H3-10), 1.28 (2H, m, H2-6), 1.14 (3H, s, H3-8 or H3-9), 1.12 (3H,
s, H3-8 or H3-9).
1
(R)-MTPA Ester of 14 (16): H-NMR (CDCl3, 500 MHz): d 5.59 (1H, t,
1
tion values and the H-NMR data of 5, 6 and 7 were identical with those in
Jꢃ6.9 Hz, H-2), 5.34 (1H, t, Jꢃ6.9 Hz, H-4), 4.59 (1H, dd, Jꢃ11.5, 6.2 Hz,
H-1), 4.55 (1H, dd, Jꢃ11.5, 6.2 Hz, H-1), 1.80 (2H, m, H2-5), 1.57 (3H, br s,
H3-10), 1.38 (2H, m, H2-6), 1.19 (3H, s, H3-8 or H3-9), 1.19 (3H, s, H3-8 or
H3-9).
literature.1)
Pivaloylation of 5, 6 and 7 A solution of 5 (2.1 mg) in dry pyridine
(1.0 ml) was treated with pivaloyl chloride (13 ml), and the mixture was
stirred at room temperature for 12 h. After addition of H2O (1 ml), the mix-
ture was extracted with EtOAc (2 mlꢁ3), dried over Na2SO4, and purified
with silica gel column chromatography to give the pivaloyl ester 8 (3.7 mg,
eluted with CHCl3). Through a similar procedure, pivaloylation of 6 (1.9 mg)
afforded the pivaloyl ester 11 (1.3 mg, eluted with CHCl3), and pivaloylation
Acknowledgements We thank Professor Masayuki Yoshikawa (Kyoto
Pharmaceutical University) for invaluable advice.
References
of
7 (3.7 mg) afforded the pivaloyl ester 14 (2.9 mg, eluted with
1) Ma G., Li W., Dou D., Chang X., Bai H., Satou T., Li J., Sun D., Kang
T., Nikaido T., Koike K., Chem. Pharm. Bull., 54, 1229—1233 (2006).
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56, 695—700 (2008).
CHCl3–MeOH, 96 : 4). The Optical Rotation values and the 1H-NMR data of
8 and 11 were identical with those in literature.1)
Compound 14: [a]D20 ꢂ5.5° (cꢃ0.29, MeOH). 1H-NMR (CDCl3,