Simple synthesis of enantiomerically pure sauriols A and B

Article abstract of DOI:10.1271/bbb.60094

Sauriols A and B belong to a class of diarylbutane-lignans and exhibit antifeedant activity. We succeeded in the first synthesis of sauriols A and B by using a simple and efficient asymmetric dimerization of a cinnamic acid derivative as the key step.

Full text of DOI:10.1271/bbb.60094

Biosci. Biotechnol. Biochem., 70 (7), 1750–1753, 2006
Simple Synthesis of Enantiomerically Pure Sauriols A and B
y
1;2
Naoki MORI,1 Hidenori WATANABE,1; and Takeshi KITAHARA
1Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences,
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
2Laboratory of Natural Product Chemistry, Center for Basic Research, The Kitasato Institute,
5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received February 16, 2006; Accepted March 7, 2006; Online Publication, July 1, 2006
[doi:10.1271/bbb.60094]
6
7
6
7
9
9
Sauriols A and B belong to a class of diarylbutane-
lignans and exhibit antifeedant activity. We succeeded
in the first synthesis of sauriols A and B by using a
simple and efficient asymmetric dimerization of a
cinnamic acid derivative as the key step.
HO
HO
MeO
HO
5
8
5
8
1
2
1
2
4
4
7'
8'
7' 8'
1'
9'
9'
3
3
1'
MeO 6'
MeO 6'
2'
2'
3'
5'
5'
3'
HO
OMe
HO
OMe
4'
4'
Key words: sauriol A; sauriol B; lignan; antifeedant
OH
OH
Sauriol A (1)
Sauriol B (2)
Lignans are found in many plants and exhibit various
biological activities. Their diverse structures and activ-
ities have fascinated organic chemists and a large
number of compounds have been synthesized up to the
present.1) Sauriols A (1) and B (2), which belong to
diarylbutane-lignan, have been isolated from emergent
portions of the southeastern United States freshwater
angiosperm, Saururus cernuus L. (Saururaceae) and
exhibited crayfish antifeedant activity (Fig. 1).2) We
report here a short-step synthesis of 1 and 2 by
employing asymmetric dimerization of a cinnamic acid
derivative.
Fig. 1.
the racemate. To deoxygenate the two primary alcohols,
diol 5 was converted to dimesylate 6 and reduced with
LAH to afford 7 in a good yield. Partial demethylation
to 1 and 2 was accomplished by changing the reaction
temperature with BBr3. At 0 ꢀC, two methyl ethers of
each benzene ring were quickly cleaved (5 min) by
excess BBr3, and sauriol A (1) was obtained in a 78%
yield. On the other hand, selective demethylation to
sauriol B (2) was quite difficult, and it was found that
treating 7 with excess BBr3 overnight at ꢁ78 ꢀC gave
the best result. Although a major product was the 4,40-
O,O0-didemethylated compound (8, 51%), sauriol B (2)
was obtained in a 27% yield along with a small amount
of 1 (7%), all of which were easily separated by silica
Results and Discussion
We have recently reported a novel method for
asymmetric dimerization of a cinnamic acid derivative
(3 ! 4), which was much more efficient than the
known enzymatic transformation,3–5) and synthesis of
the furofuran lignans, yangambin and caruilignan A, was
achieved in a small number of steps.6) The synthesis of
sauriols A (1) and B (2) was considered to be possible
by reducing the two benzylic positions and two lactone
carbonyls of 4, with subsequent partial cleavage of the
methyl ethers (Scheme 1).
gel column chromatography. H-NMR, 13C-NMR and
1
mass spectra of synthesized sauriols A (1) and B (2)
agreed well with those of the natural compounds.
Although values for the specific rotation were smaller
than those reported for natural sauriols (sauriol A: ½ꢀꢂD
ꢁ23 (c 0.94, CHCl3), lit.2) ½ꢀꢂD ꢁ240 (c 0.03, CHCl3);
sauriol B: ½ꢀꢂD ꢁ36 (c 1.1, CHCl3), lit.2) ½ꢀꢂD ꢁ92 (c
0.13, CHCl3)), we think that our data are reasonable
judging from the magnitude of the specific rotation of
related compounds 5–7 (see the Experimental section).
As both sauriols A (1) and B (2) are unstable and
decomposed even on SiO2, some decomposed com-
pounds may have affected the specific rotation of the
natural compounds.
Dilactone 4 was converted to diol 5 by successive
hydrogenolysis of the lactone ring, methyl esterification
and reduction with LAH as reported previously.6)
Recrystallization of diol 5 enabled the enantiomeric
purity to be enhanced to 100% e.e. which was
1
determined by a comparison of the H-NMR spectrum
of the corresponding bis-(R)-MTPA ester with that of
y
To whom correspondence should be addressed. Tel: +81-3-5841-5119; Fax: +81-3-5841-8019; E-mail: ashuten@mail.ecc.u-tokyo.ac.jp

Synthesis of Sauriols A and B
1751
OMe
OMe
OMe
CO2H
O
O
O
4
O
MeO
MeO
N
PbO2, TFA, CH2Cl2
H
H
MeO
(64% yield, >95% e.e.)
O
OMe
MeO
OMe
3
OMe
OMe
OMe
O
O
Sauriols A and B
4
H
H
MeO
MeO
X
OMe
X =
X =
H: Yangambin
OMe: Caruilignan A
Scheme 1.
O
O
Ar
Ar
OH
OH
Ar
OMs
OMs
a
ref. 6
H
H
Ar
O
Ar
Ar
6
O
4
5
OMe
OMe
OMe
Ar
b
Ar =
Ar
7
HO
HO
R1O
d
c
R2O
7
MeO
HO
MeO
OMe
R3O
OMe
OH
OR4
Sauriol A (1)
Sauriol B (2): 27%
(R1 = Me, R2, R3, R4 = H)
Sauriol A (1): 7%
(R1, R2, R3, R4 = H)
8: 51%
(R1, R3 = Me, R2, R4 = H)
Scheme 2. Reagents and conditions: a) MsCl, Et3N, CH2Cl2, 0 ꢀC, 2 h, 94%; b) LAH, THF, reflux, 2 h, 92%; c) BBr3 (9 eq.), CH2Cl2, 0 ꢀC, 5 min,
78%; d) BBr3 (9 eq.), CH2Cl2, ꢁ78 ꢀC, overnight.
In conclusion, we accomplished the first synthesis of
sauriols A (1) and B (2) in a small number of steps. The
yields of 1 and 2 starting from dilactone 4 were 50% in
6 steps and 17% in 6 steps, respectively. The usefulness
of our asymmetric dimerization of 3 for synthesizing
diarylbutane-lignans as well as furofuran lignans could
be shown through this synthesis.

1752
N. MORI et al.
Experimental
OCH3), 4.21 (2H, dd, J ¼ 4:2, 9.9 Hz, CHaOMs), 4.32
(2H, dd, J ¼ 5:7, 9.9 Hz, CHbOMs), 6.38 (4H, s, ArH).
13C-NMR ꢁ (CDCl3) ppm: 34.5, 37.4, 40.1, 56.1, 60.8,
69.1, 105.9, 134.2, 136.7, 153.4. Anal. Calcd. for
C26H38O12S2: C, 51.47; H, 6.31. Found: C, 51.34; H,
6.34.
Optical rotation values were recorded with a Jasco
DIP-1000 polarimeter. IR spectra were measured with
a Jasco FT/IR-230 spectrophotometer. 1H-NMR (300
MHz) and 13C-NMR (75 MHz) data were recorded with
a Jeol JNM AL300 instrument. Chemical shifts (ꢁ) are
referenced to the residual solvent peak as the internal
standard (CDCl3: ꢁH ¼ 7:26, ꢁC ¼ 77:0). Mass spectra
were recorded with a Jeol JMS-700T instrument.
Column chromatography was performed with Merck
silica gel 60 (0.060–0.200 mm). Melting point values are
uncorrected.
(2R,3R)-2,3-Dimethyl-1,4-bis(3,4,5-trimethoxyphen-
yl)butane (7). To a solution of 6 (74.8 mg, 0.123 mmol)
in THF (6 ml) was added LAH (20 mg, 0.527 mmol) at
0 ꢀC, and the mixture was refluxed for 2 h. After cooling
to 0 ꢀC, water and 3 N HCl were added, and the reaction
mixture was extracted with CHCl3. The organic layer
was dried with anhydrous magnesium sulfate and
concentrated in vacuo. The residue was chromatograph-
ed over silica gel. Elution with hexane/ethyl acetate
(3:1) gave 7 (47.5 mg, 92%). Recrystallization from
(R)-MTPA ester of racemic 5. To a solution of
racemic 5 (1 mg) in pyridine (2 drops) was added (S)-
MTPACl (1 drop). After stirring overnight, the reaction
mixture was diluted with ethyl acetate, and successively
washed with a diluted HCl solution, saturated NaHCO3
solution, water and brine. The organic layer was dried
with anhydrous magnesium sulfate and concentrated in
vacuo. 1H-NMR ꢁ (CDCl3) ppm: 1.97–2.79 (6H, m),
3.50 (6H, s), 3.72 (12/2H, s), 3.74 (12/2H, s), 3.81 (6/
2H, s), 3.82 (6/2H, s), 4.01 (2/2H, dd, J ¼ 5:7, 11.4
Hz), 4.16 (2/2H, dd, J ¼ 4:8, 11.4 Hz), 4.37 (2/2H, dd,
J ¼ 4:5, 11.4 Hz), 4.49 (2/2H, dd, J ¼ 4:8, 11.4 Hz),
6.16 (4/2H, s), 6.21 (4/2H, s), 7.35–7.48 (10H, m).
MeOH gave colorless needles.
22
Mp 116–118 ꢀC. ½ꢀꢂ
ꢁ33 (c 0.5, CHCl3). IR ꢂmax
D
(KBr) cmꢁ1: 2930, 1585, 1509, 1467, 1421, 1325, 1240,
1
1134, 997. H-NMR ꢁ (CDCl3) ppm: 0.86 (6H, d, J ¼
6:6 Hz, 2-CH3 and 3-CH3), 1.77 (2H, m, 2-H and 3-H),
2.42 (2H, dd, J ¼ 7:5, 13.5 Hz, 1-Ha and 4-Ha), 2.54
(2H, dd, J ¼ 7:5, 13.5 Hz, 1-Hb and 4-Hb), 3.80 (12H, s,
OCH3), 3.82 (6H, s, OCH3), 6.28 (4H, s, ArH). 13C-
NMR ꢁ (CDCl3) ppm: 13.8, 37.2, 41.7, 56.0, 60.8,
105.7, 135.9, 137.3, 152.9. Anal. Calcd. for C24H34O6:
C, 68.87; H, 8.19. Found: C, 69.36; H, 8.23.
(R)-MTPA ester of 5. To a solution of recrystallized
5 (1 mg) in pyridine (2 drops) was added (S)-MTPACl
(1 drop). After stirring for 2 days, the reaction mixture
was diluted with ethyl acetate, and successively washed
with a diluted HCl solution, saturated NaHCO3 solution,
water and brine. The organic layer was dried with an-
hydrous magnesium sulfate and concentrated in vacuo.
1H-NMR ꢁ (CDCl3) ppm: 2.01–2.13 (2H, m), 2.42–2.62
(4H, m), 3.50 (6H, s), 3.74 (12H, s), 3.81 (6H, s), 4.01
(2H, dd, J ¼ 5:7, 11.4 Hz), 4.49 (2H, dd, J ¼ 4:8, 11.4
Hz), 6.16 (4H, s), 7.35–7.48 (10H, m). Other peaks
corresponding to the diastereomer were not observed.
Sauriol A (1). To a solution of 7 (47.5 mg, 0.113
mmol) in CH2Cl2 (3 ml) was added BBr3 (1.0 M in
CH2Cl2, 1.0 ml, 1.0 mmol) at 0 ꢀC. After stirring for
5 min, the reaction mixture was poured into water and
extracted with CHCl3. The organic layer was dried with
anhydrous sodium sulfate and concentrated in vacuo.
The residue was chromatographed over silica gel.
Elution with hexane/ethyl acetate (2:1) gave 1 (32.1
mg, 78%) as an amorphous solid.
22
½ꢀꢂ
ꢁ23 (c 0.94, CHCl3), lit. ½ꢀꢂD ꢁ240 (c 0.03,
D
CHCl3). IR ꢂmax (CHCl3) cmꢁ1: 3556, 3022, 2962,
1
1618, 1518, 1466, 1304, 1238, 1201, 1097. H-NMR ꢁ
(2R,3R)-2,3-Bis(methanesulfonyloxymethyl)-1,4-bis(3,
4,5-trimethoxyphenyl)butane (6). To a solution of 56)
(58.9 mg, 0.131 mmol) and triethylamine (50 ml, 0.359
mmol) in CH2Cl2 (2 ml) was added MsCl (40 ml, 0.524
mmol) at 0 ꢀC. After stirring for 2 h, the reaction mixture
was poured into water and extracted with CHCl3. The
organic layer was dried with anhydrous magnesium
sulfate and concentrated in vacuo. The residue was
chromatographed over silica gel. Elution with hexane/
ethyl acetate (1:3) gave 6 (74.8 mg, 94%). Recrystalli-
(CDCl3) ppm: 0.81 (6H, d, J ¼ 6:6 Hz, 9-H and 90-H),
1.74 (2H, m, 8-H and 80-H), 2.35 (2H, dd, J ¼ 7:5,
13.5 Hz, 7-Ha and 70-Ha), 2.49 (2H, dd, J ¼ 7:2, 13.5
Hz, 7-Hb and 70-Hb), 3.81 (6H, s, OCH3), 5.25 (2H, br s,
ArOH), 5.29 (2H, br s, ArOH), 6.17 (2H, d, J ¼ 1:5 Hz,
ArH), 6.35 (2H, d, J ¼ 1:5 Hz, ArH). 13C-NMR ꢁ
(CDCl3) ppm: 13.8, 37.1, 41.2, 56.0, 103.8, 109.2,
130.3, 133.5, 143.4, 146.7. FAB-HRMS m=z: calcd. for
C20H27O6 ½M þ Hꢂþ, 363.1808; found, 163.1840.
zation from CH2Cl2/hexane gave colorless crystals.
25
Sauriol B (2). To a solution of 7 (30.0 mg, 0.072
mmol) in CH2Cl2 (1.5 ml) was added BBr3 (1.0 M in
CH2Cl2, 0.65 ml, 0.65 mmol) at ꢁ78 ꢀC. After stirring
overnight, the reaction mixture was poured into water
and extracted with CHCl3. The organic layer was dried
with anhydrous sodium sulfate and concentrated in
vacuo. The residue was chromatographed over silica gel.
Mp 162–165 ꢀC. ½ꢀꢂ
ꢁ15 (c 0.85, CHCl3). IR ꢂmax
D
(KBr) cmꢁ1: 2937, 2828, 1591, 1508, 1466, 1425, 1350,
1241, 1172, 1129, 959. 1H-NMR ꢁ (CDCl3) ppm: 2.27–
2.33 (2H, m, 2-H and 3-H), 2.59 (2H, dd, J ¼ 9:0, 13.8
Hz, 1-Ha and 4-Ha), 2.85 (2H, dd, J ¼ 5:7, 13.8 Hz, 1-
Hb and 4-Hb), 3.01 (6H, s, SO2CH3), 3.83 (18H, s,

Synthesis of Sauriols A and B
1753
Elution with MeOH/CHCl3 (100:1) gave 2 (7.4 mg,
27%) as an amorphous solid, 1 (2.0 mg, 7%) and 8 (14.4
References
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Lindquist, N., Two antifeedant lignans from the fresh-
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mg, 51%).
27
½ꢀꢂ
ꢁ36 (c 1.1, CHCl3), lit. ½ꢀꢂD ꢁ92 (c 0.13,
D
CHCl3). IR ꢂmax (CHCl3) cmꢁ1: 3548, 2962, 1618,
1516, 1464, 1304, 1213, 1117. 1H-NMR ꢁ (CDCl3) ppm:
0.83 (6H, d, J ¼ 6:6 Hz, 9-H and 90-H), 1.65–1.77 (2H,
m, 8-H and 80-H), 2.34–2.52 (4H, m, 7-H and 70-H), 3.79
(3H, s, OCH3), 3.83 (6H, s, OCH3), 5.22 (2H, br s,
ArOH), 5.35 (1H, s, ArOH), 6.14 (1H, d, J ¼ 1:8 Hz,
ArH), 6.28 (2H, s, ArH), 6.35 (1H, d, J ¼ 1:8 Hz, ArH).
13C-NMR ꢁ (CDCl3) ppm: 13.9, 37.2, 41.3, 41.5, 56.0,
56.2, 103.7, 105.5, 109.2, 130.2, 132.5, 132.7, 133.5,
143.4, 146.6, 146.7. FAB-HRMS m=z: calcd. for
C21H29O6 ½M þ Hꢂþ, 377.1964; found, 377.1951.
americanol
A and isoamericanol A by horseradish
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Acknowledgments
We sincerely thank Ms. Hiroko Naito for elemental
analyses. This work was supported by grant-aid for
scientific research [C-2, No. 14560081] from the Japa-
nese Ministry of Education, Culture, Sports, Science and
Technology.