Antifungal activity of morinol B derivatives of tetrahydropyran sesquilignan

Article abstract of DOI:10.1271/bbb.100422

The relationship between the structure of naturally occurring (7R,70R,8R,80R)-morinol B and its antifungal activity was examined. 3-Demethoxy morinol B showed much higher activity than the natural compound. The activity of the 4-butoxy-3-demethoxy derivative was higher than that of 3-demethoxy morinol B.

Full text of DOI:10.1271/bbb.100422

Biosci. Biotechnol. Biochem., 74 (10), 2071–2076, 2010
Antifungal Activity of Morinol B Derivatives of Tetrahydropyran Sesquilignan
y
Kenta MASUDA,1 Hisashi NISHIWAKI,1 Koichi AKIYAMA,3 Satoshi YAMAUCHI,1;2;
1;2
Masafumi MARUYAMA,1 Takuya SUGAHARA,1;2 and Taro KISHIDA
1Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
2South Ehime Fisheries Research Center, 1289-1 Funakoshi, Ainan, Ehime 798-4292, Japan
3Integrated Center for Sciences, Tarumi Station, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan
Received June 3, 2010; Accepted July 10, 2010; Online Publication, October 7, 2010
[doi:10.1271/bbb.100422]
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc/
The relationship between the structure of naturally
occurring (7R,70R,8R,80R)-morinol B and its antifungal
activity was examined. 3-Demethoxy morinol B showed
much higher activity than the natural compound. The
activity of the 4-butoxy-3-demethoxy derivative was
higher than that of 3-demethoxy morinol B.
hexane = 3/1) gave methyl ether derivative 3 (13 mg, 0.022 mmol,
20
81%) as a colorless oil, ½ꢀꢀD ¼ ꢁ30 (c 0.26, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.32 (1H, m), 1.48 (1H, m), 1.67 (1H, m), 1.82–1.98 (3H,
m), 3.24 (3H, s), 3.71 (1H, dd, J ¼ 11:5, 2.5 Hz), 3.77 (3H, s), 3.845
(3H, s), 3.853 (3H, s), 3.86 (3H, s), 3.90 (3H, s), 3.95 (3H, s), 3.98 (1H,
d, J ¼ 9:6 Hz), 4.46 (1H, d, J ¼ 11:5 Hz), 4.49 (1H, d, J ¼ 13:1 Hz),
5.64 (1H, m), 6.04 (1H, d, J ¼ 15:6 Hz), 6.67–6.69 (2H, m), 6.76 (1H,
d, J ¼ 8:7 Hz), 6.82–6.99 (6H, m). 13C-NMR (CDCl3) ꢁ: 30.9, 35.4,
38.3, 41.4, 55.7, 55.9, 56.8, 68.7, 82.3, 85.5, 108.4, 108.5, 108.9, 110.3,
110.7, 111.0, 118.6, 119.7, 120.3, 120.5, 128.6, 130.6, 131.0, 133.2,
133.7, 145.1, 148.2, 148.9, 149.4. EIMS m=z (%) 578 (Mþ, 98), 181
(100). HREIMS m=z Mþ: calcd. for C34H42O8, 578.2880; found,
578.2881.
Key words: morinol B; sesquilignan; antifungal activity
The sesquilignan, morinol B, has been isolated from a
Chinese herb as a mixture of enantiomers.1) Our
previous work determined its stereochemistry by a
synthetic study2) and then led to clarification of the
effect of the stereochemistry on the antifungal activity,
showing the highest activity of (7R,70R,8R,80R)-morinol
B (1) after a total of 16 stereoisomers had been
prepared.3) As the next step in this present study, the
derivatives of morinol B bearing (7R,70R,8R,80R) stereo-
chemistry were synthesized and their antifungal activ-
ities were examined to clarify the relationship between
the structure and antifungal activity, and to design
compounds having higher activity than the natural
product. The insectical,4) antimelanogenic,5) antiplasmo-
dial6) and anti-HIV activity,7) and the inhibition of
LPS-induced nitric oxide production8) by sesquilignans
have been reported. This is a first report on the structure-
antifungal activity relationship of sesquilignans.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[3-(3,4-dimethoxyphenyl)propan-1-yl]tetrahydropyran-5-yl}methanol
(4). A reaction mixture of (7R,8R,70R,80R)-morinol B (1) (16 mg,
0.028 mmol) and 5% Pd/C (52 mg) in EtOAc (5 ml) was stirred under
H2 gas (1 atm) at ambient temperature for 24 h before filtration. The
filtrate was concentrated. The residue was applied to silica gel column
chromatography (EtOAc/hexane = 4/1) to give dihydro-morinol B
20
(4) (13 mg, 0.023 mmol, 82%) as a colorless oil, ½ꢀꢀD ¼ ꢁ43 (c 0.21,
CHCl3). 1H-NMR (CDCl3) ꢁ: 0.85 (1H, m), 1.07 (1H, m), 1.17 (1H,
m), 1.26 (1H, m), 1.30–1.40 (2H, m), 1.82–1.94 (2H, m), 2.20 (1H, m),
2.34 (1H, m), 2.40 (1H, d, J ¼ 3:1 Hz), 3.70 (1H, dd, J ¼ 11:7,
2.5 Hz), 3.81–3.93 (1H, overlapped), 3.81 (3H, s), 3.83 (3H, s), 3.85
(3H, s), 3.88 (3H, s), 3.90 (3H, s), 3.93 (3H, s), 4.50 (1H, d,
J ¼ 11:7 Hz), 5.07 (1H, dd, J ¼ 9:1, 3.1 Hz), 6.46 (1H, dd, J ¼ 8:1,
1.8 Hz), 6.49 (1H, d, J ¼ 1:8 Hz), 6.70 (1H, d, J ¼ 8:1 Hz), 6.80 (1H,
d, J ¼ 8:2 Hz), 6.85 (1H, d, J ¼ 8:1 Hz), 6.88–6.92 (3H, m), 6.96 (1H,
d, J ¼ 1:7 Hz). 13C-NMR (CDCl3) ꢁ: 28.0, 31.6, 35.1, 35.2, 36.9, 41.4,
55.85, 55.92, 68.6, 73.9, 86.4, 109.0, 110.7, 110.8, 110.95, 111.0,
111.6, 119.0, 119.8, 120.0, 133.8, 134.9, 136.3, 147.0, 148.66, 148.74,
148.9, 149.4. EIMS m=z (%) 566 (Mþ, 100), 548 (52), 342 (71), 167
(52), 151 (82). HREIMS m=z Mþ: calcd. for C33H42O8, 566.2880;
found, 566.2880.
Materials and Methods
NMR data were measured by a JNM-EX400 spectrometer, using
TMS as a standard (0 ppm). MS data were measured with a JMS-
MS700V spectrometer, and optical rotation values were evaluated with
a Horiba SEPA-200 instrument. The silica gel used was Wakogel
C-300 (Wako, 200–300 mesh).
(R)-(3,4-Dimethoxyphenyl)[(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-
3-(2-propen-1-yl)tetrahydropyran-5-yl]methanol (5). A solution of
(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-5-[(R)-(3,4-dimethoxyphenyl)
(triisopropylsilyloxy)methyl]-3-(2-propen-1-yl)tetrahydropyran2) (61
mg, 0.10 mmol) and n-Bu4NF (0.18 ml, 1 M in THF, 0.18 mmol) in
THF (3 ml) was stirred at room temperature for 1 h before additions of
sat. aq. NH4Cl solution and EtOAc. The organic solution was
separated, washed with sat. aq. CuSO4 solution, sat. aq. NaHCO3
solution, and brine, and dried (Na2SO4). Concentration followed
by silica gel column chromatography (EtOAc/hexane = 1/1) gave
allyl derivative 5 (39 mg, 0.091 mmol, 91%) as a colorless oil,
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[(E)-3-(3,4-dimethoxyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}methyl
20
acetate (2). Colorless oil, ½ꢀꢀD ¼ ꢁ23 (c 0.30, CHCl3). 1H-NMR
data agreed with those in the literature.1)
(2R,3R,5R)-2-(3,4-Dimethoxyphenyl)-5-[(R)-(3,4-dimethoxyphenyl)
(methoxy)methyl]-3-[(E)-3-(3,4-dimethoxyphenyl)-2-propen-1-yl]tetra-
hydropyran (3). To an ice-cooled suspension of NaH (17 mg, 60% oil
suspension, 0.43 mmol) in DMF (1 ml) was added a solution of
(7R,8R,70R,80R)-morinol B1) (15 mg, 0.027 mmol) in DMF (1 ml).
After the mixture was stirred at 0 ꢂC for 30 min, MeI (0.50 ml,
8.0 mmol) was added. The reaction mixture was stirred at room
temperature for 2 h, and then H2O and EtOAc were added. The organic
20
½ꢀꢀD ¼ ꢁ32 (c 0.77, CHCl3). 1H-NMR (CDCl3) ꢁ: 1.35 (1H, ddd,
J ¼ 12:4, 12.4, 5.1 Hz), 1.52–1.60 (2H, m), 1.80–2.00 (3H, m), 2.56
(1H, br. s), 3.70 (1H, dd, J ¼ 11:6, 2.5 Hz), 3.88 (3H, s), 3.89 (6H, s),
3.92 (3H, s), 3.95 (1H, d, J ¼ 10:0 Hz), 4.49 (1H, d, J ¼ 11:6 Hz), 4.80
y
To whom correspondence should be addressed. Tel: +81-89-946-9846; Fax: +81-89-977-4364; E-mail: syamauch@agr.ehime-u.ac.jp

2072
K. MASUDA et al.
(1H, d, J ¼ 17:1 Hz), 4.84 (1H, d, J ¼ 10:2 Hz), 5.03 (1H, d,
J ¼ 9:1 Hz), 5.45 (1H, m), 6.83–6.93 (6H, m). 13C-NMR (CDCl3) ꢁ:
31.3, 36.5, 37.3, 41.5, 55.9, 68.5, 73.6, 85.7, 109.1, 110.6, 110.8, 111.0,
116.4, 118.8, 119.8, 133.4, 135.4, 136.4, 148.5, 148.8, 148.9, 149.2.
EIMS m=z (%) 428 (Mþ, 100), 204 (99), 167 (98). HREIMS m=z Mþ:
calcd. for C25H32O6, 428.2199; found, 428.2200.
3.86 (3H, s), 3.88 (3H, s), 3.93 (3H, s), 3.99 (1H, d, J ¼ 9:9 Hz), 4.50
(1H, d, J ¼ 11:8 Hz), 5.10 (1H, d, J ¼ 8:2 Hz), 5.66 (1H, m), 6.06 (1H,
d, J ¼ 15:7 Hz), 6.66–6.70 (2H, m), 6.76 (1H, d, J ¼ 8:7 Hz), 6.85–
6.96 (3H, m), 7.18–7.32 (3H, m), 7.36–7.38 (2H, m). 13C-NMR
(CDCl3) ꢁ: 31.9, 35.6, 38.2, 41.6, 55.8, 55.9, 56.0, 68.6, 74.1, 85.9,
108.4, 110.5, 110.7, 111.1, 118.9, 119.9, 120.1, 125.5, 126.5, 127.7,
128.5, 128.6, 130.7, 131.2, 133.5, 143.8, 148.9, 149.0, 149.1. EIMS
m=z (%) 504 (Mþ, 54), 259 (100), 180 (64), 166 (87), 151 (70), 149
(96). HREIMS m=z Mþ: calcd. for C31H36O6, 504.2512; found,
504.2514.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[(E)-3-phenyl-2-propen-1-yl]tetrahydropyran-5-yl}methanol (6). Col-
20
orless oil, ½ꢀꢀD ¼ ꢁ60 (c 0.35, CHCl3). 1H-NMR (CDCl3) ꢁ: 1.40
(1H, ddd, J ¼ 12:2, 12.2, 5.1 Hz), 1.60–1.75 (2H, m), 1.89 (1H, m),
1.92–2.04 (2H, m), 2.47 (1H, br. s), 3.73 (1H, dd, J ¼ 11:7, 2.5 Hz),
3.78 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 3.93 (3H, s), 3.99 (1H, d,
J ¼ 9:8 Hz), 4.50 (1H, d, J ¼ 11:7 Hz), 5.06 (1H, d, J ¼ 9:2 Hz), 5.83
(1H, m), 6.14 (1H, d, J ¼ 15:8 Hz), 6.70 (1H, d, J ¼ 8:1 Hz), 6.80–
7.00 (5H, m), 7.12–7.19 (3H, m), 7.23–7.29 (2H, m). 13C-NMR
(CDCl3) ꢁ: 31.7, 35.5, 38.2, 41.7, 55.80, 55.84, 55.89, 55.92, 68.6,
73.7, 85.8, 108.8, 110.55, 110.60, 111.0, 118.9, 119.8, 125.8, 126.9,
127.5, 128.1, 128.4, 131.5, 133.4, 136.2, 137.4, 148.6, 148.9, 149.0,
149.3. EIMS m=z (%) 504 (Mþ, 100), 167 (69). HREIMS m=z Mþ:
calcd. for C31H36O6, 504.2512; found, 504.2514.
(R)-{(2R,3R,5R)-2-(3,4-Dimethoxyphenyl)-3-[(E)-3-(3,4-dimetho-
xyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}(3-methoxyphenyl)me-
20
thanol (11). Colorless oil, ½ꢀꢀD ¼ ꢁ42 (c 0.72, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.42 (1H, ddd, J ¼ 12:3, 12.3, 5.1 Hz), 1.66–1.74 (2H, m),
1.91 (1H, m), 1.95 (1H, m), 2.00 (1H, m), 2.66 (1H, br. s), 3.71 (1H,
dd, J ¼ 11:8, 2.6 Hz), 3.73 (3H, s), 3.86 (6H, s), 3.88 (3H, s), 3.92 (3H,
s), 3.98 (1H, d, J ¼ 9:9 Hz), 4.49 (1H, d, J ¼ 11:8 Hz), 5.06 (1H, d,
J ¼ 8:6 Hz), 5.68 (1H, m), 6.07 (1H, d, J ¼ 15:8 Hz), 6.67–6.70 (2H,
m), 6.73–6.81 (2H, m), 6.85–6.91 (2H, m), 6.93–6.96 (3H, m), 7.20
(1H, dd, J ¼ 8:0, 8.0 Hz). 13C-NMR (CDCl3) ꢁ: 31.8, 35.7, 38.2, 41.6,
55.2, 55.8, 55.9, 56.0, 68.6, 74.0, 85.9, 108.4, 110.7, 111.1, 111.8,
113.1, 118.8, 118.9, 119.9, 125.4, 129.4, 130.7, 131.2, 133.5, 145.5,
148.3, 148.85, 148.9, 149.0, 159.9. EIMS m=z (%) 534 (Mþ, 100), 180
(54). HREIMS m=z Mþ: calcd. for C32H38O7, 534.2617; found,
534.2618.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[(E)-3-(3-methoxyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}methanol
20
(7). Colorless oil, ½ꢀꢀD ¼ ꢁ44 (c 0.22, CHCl3). 1H-NMR (CDCl3)
ꢁ: 1.41 (1H, ddd, J ¼ 12:3, 12.3, 4.8 Hz), 1.51–1.77 (2H, m), 1.89 (1H,
m), 1.91–2.08 (2H, m), 2.42 (1H, br. s), 3.73 (1H, dd, J ¼ 12:2,
2.0 Hz), 3.78 (3H, s), 3.80 (3H, s), 3.84 (3H, s), 3.89 (3H, s), 3.94 (3H,
s), 3.99 (1H, d, J ¼ 9:8 Hz), 4.51 (1H, d, J ¼ 12:2 Hz), 5.07 (1H, d,
J ¼ 9:0 Hz), 5.84 (1H, m), 6.11 (1H, d, J ¼ 15:7 Hz), 6.60–6.77 (3H,
m), 6.81–6.97 (6H, m), 7.17 (1H, dd, J ¼ 7:9, 7.9 Hz). 13C-NMR
(CDCl3) ꢁ: 31.7, 35.5, 38.2, 41.7, 55.75, 55.82, 55.88, 55.90, 56.0,
68.6, 73.7, 85.8, 108.7, 110.6, 111.0, 111.4, 112.3, 118.5, 118.9, 119.8,
119.9, 127.8, 129.4, 131.4, 133.4, 136.2, 138.9, 148.6, 148.9, 149.4,
159.7. EIMS m=z (%) 534 (Mþ, 100), 167 (66). HREIMS m=z Mþ:
calcd. for C32H38O7, 534.2617; found, 534.2617.
(R)-{(2R,3R,5R)-2-(3,4-Dimethoxyphenyl)-3-[(E)-3-(3,4-dimetho-
xyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}(4-methoxyphenyl)me-
20
thanol (12). Colorless oil, ½ꢀꢀD ¼ ꢁ56 (c 0.50, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.39 (1H, ddd, J ¼ 12:3, 12.3, 4.9 Hz), 1.61–1.79 (3H, m),
1.91–2.01 (2H, m), 2.34 (1H, br. s), 3.67 (1H, dd, J ¼ 11:4, 2.6 Hz),
3.73 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 3.88 (3H, s), 3.93 (3H, s), 3.98
(1H, d, J ¼ 9:7 Hz), 4.49 (1H, d, J ¼ 11:4 Hz), 5.07 (1H, d,
J ¼ 8:8 Hz), 5.65 (1H, m), 6.06 (1H, d, J ¼ 15:7 Hz), 6.68–6.69 (2H,
m), 6.76 (1H, d, J ¼ 8:7 Hz), 6.83 (2H, d, J ¼ 8:6 Hz), 6.86–7.00 (3H,
m), 7.29 (2H, d, J ¼ 8:6 Hz). 13C-NMR (CDCl3) ꢁ: 31.8, 35.6, 38.2,
41.7, 55.2, 55.8, 55.9, 56.0, 68.7, 73.5, 85.8, 108.4, 110.6, 111.05,
111.08, 113.9, 118.8, 119.9, 125.6, 127.6, 130.7, 131.1, 133.6, 135.8,
148.3, 148.9, 148.95, 149.03, 159.2. EIMS m=z (%) 534 (Mþ, 100),
180 (64), 165 (60), 151 (62). HREIMS m=z Mþ: calcd. for C32H38O7,
534.2617; found, 534.2618.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[(E)-3-(4-methoxyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}methanol
20
(8). Colorless oil, ½ꢀꢀD ¼ ꢁ59 (c 0.23, CHCl3). 1H-NMR (CDCl3)
ꢁ: 14.0 (1H, ddd, J ¼ 12:3, 12.3, 5.0 Hz), 1.55–1.72 (2H, m), 1.85–2.05
(3H, m), 2.30–2.50 (1H, br.), 3.73 (1H, dd, J ¼ 11:8, 2.5 Hz), 3.78
(3H, s), 3.80 (3H, s), 3.86 (3H, s), 3.89 (3H, s), 3.93 (3H, s), 3.99 (1H,
d, J ¼ 9:9 Hz), 4.50 (1H, d, J ¼ 11:8 Hz), 5.05 (1H, d, J ¼ 9:0 Hz),
5.69 (1H, m), 6.08 (1H, d, J ¼ 15:9 Hz), 6.72 (1H, d, J ¼ 8:1 Hz), 6.79
(2H, d, J ¼ 8:8 Hz), 6.85–6.90 (3H, m), 6.93–6.95 (2H, m), 7.09 (2H,
d, J ¼ 8:8 Hz). 13C-NMR (CDCl3) ꢁ: 31.7, 35.5, 38.3, 41.7, 55.3,
55.81, 55.85, 55.92, 56.0, 68.6, 73.8, 85.8, 108.8, 110.6, 111.0, 113.6,
113.8, 118.9, 119.9, 125.2, 126.9, 130.3, 130.9, 133.5, 134.5, 136.3,
148.6, 149.0, 149.3, 158.7. EIMS m=z (%) 534 (Mþ, 100), 165 (76).
HREIMS m=z Mþ: calcd. for C32H38O7, 534.2617; found, 534.2615.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-phenyltetrahydropyran-5-yl}methanol (13).
20
Colorless oil, ½ꢀꢀD ¼ ꢁ40 (c 0.23, CHCl3). 1H-NMR (CDCl3) ꢁ:
1.41 (1H, ddd, J ¼ 12:3, 12.3, 5.0 Hz), 1.62–1.72 (2H, m), 1.91–2.07
(3H, m), 2.58 (1H, br. s), 3.77–3.84 (1H, overlapped), 3.77 (3H, s),
3.83 (3H, s), 3.841 (3H, s), 3.843 (3H, s), 4.04 (1H, d, J ¼ 9:8 Hz),
4.51 (1H, d, J ¼ 11:8 Hz), 5.06 (1H, d, J ¼ 8:5 Hz), 5.65 (1H, m), 6.06
(1H, d, J ¼ 15:7 Hz), 6.66–6.72 (3H, m), 6.75 (1H, d, J ¼ 8:3 Hz),
6.86 (1H, dd, J ¼ 8:3, 1.8 Hz), 6.93 (1H, d, J ¼ 1:8 Hz), 7.29–7.42
(5H, m). 13C-NMR (CDCl3) ꢁ: 31.7, 35.5, 38.4, 41.8, 55.8, 55.86,
55.93, 68.6, 73.6, 86.0, 108.6, 109.1, 110.8, 111.2, 118.8, 118.9, 125.5,
127.4, 127.49, 127.54, 128.1, 128.47, 128.53, 131.2, 136.4, 141.0,
148.4, 148.6, 149.0. EIMS m=z (%) 504 (Mþ, 91), 298 (79), 279 (55),
178 (100), 167 (56), 151 (84). HREIMS m=z Mþ: calcd. for C31H36O6,
504.2512; found, 504.2515.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(3,4-dimethoxyphenyl)-3-
[(E)-3-(3,4,5-trimethoxyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}
20
methanol (9). Colorless oil, ½ꢀꢀD ¼ ꢁ45 (c 0.60, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.43 (1H, ddd, J ¼ 12:3, 12.3, 5.2 Hz), 1.63–1.75 (2H, m),
1.89 (1H, m), 1.93–2.05 (2H, m), 2.54 (1H, d, J ¼ 3:2 Hz), 3.77–3.92
(1H, overlapped), 3.77 (3H, s), 3.81 (3H, s), 3.82 (3H, s), 3.83 (3H, s),
3.86 (3H, s), 3.87 (3H, s), 3.92 (3H, s), 3.98 (1H, d, J ¼ 9:7 Hz), 4.49
(1H, d, J ¼ 11:7 Hz), 5.04 (1H, d, J ¼ 6:0 Hz), 5.73 (1H, m), 6.05 (1H,
d, J ¼ 15:7 Hz), 6.38 (2H, s), 6.69 (1H, d, J ¼ 8:2 Hz), 6.77–6.96 (2H,
m), 6.91–6.96 (3H, m). 13C-NMR (CDCl3) ꢁ: 31.9, 35.7, 38.4, 41.6,
55.8, 55.9, 56.0, 56.1, 68.6, 73.9, 85.9, 109.1, 110.8, 111.2, 118.9,
120.0, 126.9, 129.8, 130.0, 131.5, 132.3, 133.2, 133.6, 136.4, 137.5,
148.6, 149.0, 149.1, 149.4, 153.3. EIMS m=z (%) 594 (Mþ, 25), 576
(72), 151 (100). HREIMS m=z Mþ: calcd. for C34H42O9, 594.2829;
found, 594.2822.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(2-methoxyphenyl)tetrahydropyran-5-yl}me-
20
thanol (14). Colorless oil, ½ꢀꢀD ¼ ꢁ27 (c 0.55, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.48 (1H, ddd, J ¼ 12:3, 12.3, 4.9 Hz), 1.63–1.79 (3H, m),
1.92 (1H, m), 2.22 (1H, m), 2.69 (1H, br. s), 3.72 (1H, d, J ¼ 11:4 Hz),
3.79 (3H, s), 3.81 (3H, s), 3.84 (6H, s), 3.87 (3H, s), 4.49 (1H, d,
J ¼ 11:4 Hz), 4.57 (1H, d, J ¼ 9:9 Hz), 5.10 (1H, d, J ¼ 7:9 Hz), 5.69
(1H, m), 6.06 (1H, d, J ¼ 15:7 Hz), 6.65–6.76 (4H, m), 6.85–6.90 (2H,
m), 6.94 (1H, s), 7.03 (1H, dd, J ¼ 7:3, 7.1 Hz), 7.27 (1H, dd, J ¼ 7:9,
7.1 Hz), 7.48 (1H, d, J ¼ 7:3 Hz). 13C-NMR (CDCl3) ꢁ: 32.4, 35.5,
38.4, 41.8, 55.5, 55.8, 55.85, 55.87, 55.94, 68.8, 74.1, 108.6, 109.1,
110.7, 110.8, 111.2, 118.75, 118.81, 121.0, 126.2, 128.0, 128.9, 129.6,
130.8, 130.9, 136.7, 148.3, 148.5, 149.0, 149.3, 156.9. EIMS m=z (%)
534 (Mþ, 23), 309 (100). HREIMS m=z Mþ: calcd. for C32H38O7,
534.2617; found, 534.2623.
(R)-{(2R,3R,5R)-2-(3,4-Dimethoxyphenyl)-3-[(E)-3-(3,4-dimetho-
xyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}phenylmethanol (10).
20
Colorless oil, ½ꢀꢀD ¼ ꢁ36 (c 0.61, CHCl3). 1H-NMR (CDCl3) ꢁ:
1.42 (1H, ddd, J ¼ 12:3, 12.3, 5.0 Hz), 1.63–1.76 (2H, m), 1.94–2.00
(3H, m), 2.36 (1H, br. s), 3.70 (1H, dd, J ¼ 11:8, 2.3 Hz), 3.85 (3H, s),

Morinol B Derivatives
2073
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(3-methoxyphenyl)tetrahydropyran-5-yl}-
for 16 h before additions of H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4). Concentration
followed by silica gel column chromatography (EtOAc/hexane = 1/3)
gave diastereomerically pure phenol II (0.40 g, 0.74 mmol, 39%) as a
20
methanol (15). Colorless oil, ½ꢀꢀD ¼ ꢁ61 (c 0.12, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.41 (1H, ddd, J ¼ 12:3, 12.3, 4.9 Hz), 1.61–1.74 (2H, m),
1.89–2.00 (3H, m), 2.45 (1H, br. s), 3.72 (1H, dd, J ¼ 11:7, 2.5 Hz),
3.78 (3H, s), 3.84 (6H, s), 3.85 (6H, s), 4.02 (1H, d, J ¼ 9:7 Hz), 4.50
(1H, d, J ¼ 11:7 Hz), 5.06 (1H, d, J ¼ 8:8 Hz), 5.67 (1H, m), 6.07 (1H,
d, J ¼ 15:6 Hz), 6.68–6.70 (3H, m), 6.82–7.01 (6H, m), 7.31 (1H, dd,
J ¼ 7:9, 7.9 Hz). 13C-NMR (CDCl3) ꢁ: 31.6, 35.4, 38.2, 41.7, 55.3,
55.76, 55.81, 55.9, 68.5, 73.6, 85.9, 108.5, 108.9, 110.7, 111.1, 113.1,
113.4, 118.7, 118.9, 119.9, 125.4, 129.4, 130.6, 131.2, 136.3, 142.4,
148.3, 148.5, 148.9, 149.2, 159.7. EIMS m=z (%) 534 (Mþ, 100), 328
(64), 178 (57), 151 (74). HREIMS m=z Mþ: calcd. for C32H38O7,
534.2617; found, 534.2617.
20
colorless oil, ½ꢀꢀD ¼ þ7 (c 2, CHCl3). 1H-NMR (CDCl3) ꢁ: 0.93–
1.03 (21H, m), 1.21 (1H, ddd, J ¼ 12:3, 12.3, 4.3 Hz), 1.37 (1H, m),
1.49 (1H, m), 1.72–1.84 (3H, m), 3.67 (1H, dd, J ¼ 11:4, 2.4 Hz), 3.87
(6H, s), 3.92 (1H, d, J ¼ 9:6 Hz), 4.58 (1H, d, J ¼ 11:4 Hz), 4.75 (1H,
d, J ¼ 6:8 Hz), 4.78 (1H, d, J ¼ 9:7 Hz), 5.07 (1H, d, J ¼ 9:9 Hz), 5.37
(1H, m), 6.17 (1H, s), 6.72 (2H, d, J ¼ 8:5 Hz), 6.78 (1H, d,
J ¼ 8:1 Hz), 6.84 (1H, dd, J ¼ 8:1, 1.2 Hz), 6.91 (1H, d, J ¼ 1:2 Hz),
7.18 (2H, d, J ¼ 8:5 Hz). 13C-NMR (CDCl3) ꢁ: 12.6, 18.0, 18.1, 30.6,
36.4, 37.9, 43.7, 55.78, 55.84, 68.5, 73.9, 85.5, 109.7, 110.3, 115.3,
116.3, 119.5, 128.6, 133.0, 135.5, 137.1, 148.3, 148.9, 155.6. EIMS
m=z (%) 540 (Mþ, 6), 497 (96), 323 (100). HREIMS m=z Mþ: calcd.
for C33H48O5Si, 540.3271; found, 540.3273. Phenol II was converted
to 19 by the previously described method.2) 19: Colorless oil,
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(4-methoxyphenyl)tetrahydropyran-5-yl}-
20
½ꢀꢀD ¼ ꢁ49 (c 0.25, CHCl3). 1H-NMR (CDCl3) ꢁ: 1.42 (1H, ddd,
20
methanol (16). Colorless oil, ½ꢀꢀD ¼ ꢁ55 (c 0.20, CHCl3). 1H-NMR
J ¼ 12:3, 12.3, 6.1 Hz), 1.63–1.72 (2H, m), 1.91–1.97 (3H, m),
2.66 (1H, br. s), 3.78–3.86 (1H, overlapped), 3.78 (3H, s), 3.83 (3H, s),
3.86 (6H, s), 3.98 (1H, d, J ¼ 9:9 Hz), 4.54 (1H, d, J ¼ 11:3 Hz),
5.05 (1H, d, J ¼ 8:7 Hz), 5.68 (1H, m), 5.62–5.70 (1H, br.), 6.06
(1H, d, J ¼ 15:6 Hz), 6.70–6.80 (6H, m), 6.87 (1H, d, J ¼ 7:9 Hz),
6.93 (1H, s), 7.17–7.24 (2H, m). 13C-NMR (CDCl3) ꢁ: 31.8, 35.6,
38.3, 41.7, 55.8, 68.6, 73.7, 85.6, 108.6, 109.1, 110.8, 111.2,
115.4, 118.8, 118.9, 125.5, 128.8, 130.7, 131.1, 132.9, 136.3, 148.3,
148.5, 148.9, 149.3, 155.7. EIMS m=z (%) 520 (Mþ, 100), 314 (80),
151 (58). HREIMS m=z Mþ: calcd. for C31H36O7, 520.2461; found,
520.2461.
(CDCl3) ꢁ: 1.42 (1H, ddd, J ¼ 12:4, 12.4, 4.8 Hz), 1.60–1.72 (2H, m),
1.86–1.99 (2H, m), 2.02 (1H, m), 2.48 (1H, br. s), 3.71 (1H, dd,
J ¼ 11:6, 2.5 Hz), 3.79 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 3.85 (3H, s),
3.86 (3H, s), 4.00 (1H, d, J ¼ 10:0 Hz), 4.49 (1H, d, J ¼ 11:6 Hz), 5.07
(1H, d, J ¼ 9:0 Hz), 5.66 (1H, m), 6.06 (1H, d, J ¼ 15:8 Hz), 6.69–
6.72 (3H, m), 6.92 (2H, d, J ¼ 8:6 Hz), 6.82–6.92 (3H, m), 7.34 (2H, d,
J ¼ 8:6 Hz). 13C-NMR (CDCl3) ꢁ: 31.9, 35.6, 38.4, 41.7, 55.3, 55.8,
68.6, 73.7, 85.5, 108.5, 110.7, 111.0, 111.1, 113.6, 113.8, 118.7, 118.9,
125.6, 128.6, 130.7, 131.1, 133.2, 136.4, 148.3, 148.5, 148.9, 149.3,
159.4. EIMS m=z (%) 534 (Mþ, 100), 328 (93), 151 (71). HREIMS
m=z Mþ: calcd. for C32H38O7, 534.2617; found, 534.2617.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(4-ethoxyyphenyl)tetrahydropyran-5-yl}-
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(4-trifluoromethoxyphenyl)tetrahydropyran-
20
methanol (20). Colorless oil, ½ꢀꢀD ¼ ꢁ50 (c 0.39, CHCl3). 1H-NMR
20
5-yl}methanol (17). Colorless oil, ½ꢀꢀD ¼ ꢁ38 (c 0.68, CHCl3).
1H-NMR (CDCl3) ꢁ: 1.37 (1H, ddd, J ¼ 12:3, 12.3, 4.9 Hz), 1.63 (1H,
m), 1.71 (1H, m), 1.91–1.98 (3H, m), 2.38 (1H, br. s), 3.78–3.85 (1H,
overlapped), 3.78 (3H, s), 3.83 (3H, s), 3.845 (3H, s), 3.850 (3H, s),
4.06 (1H, d, J ¼ 9:8 Hz), 4.51 (1H, d, J ¼ 11:7 Hz), 5.04 (1H, d,
J ¼ 9:2 Hz), 5.65 (1H, m), 6.07 (1H, d, J ¼ 15:7 Hz), 6.68–6.71 (3H,
m), 6.76 (1H, d, J ¼ 8:2 Hz), 6.86 (1H, d, J ¼ 8:2 Hz), 6.93 (1H, s),
7.24 (2H, d, J ¼ 8:3 Hz), 7.44 (2H, d, J ¼ 8:3 Hz). 13C-NMR (CDCl3)
ꢁ: 31.5, 35.3, 38.5, 41.7, 55.8, 55.9, 56.0, 68.6, 73.5, 85.1, 108.7, 109.0,
110.8, 111.2, 118.8, 119.0, 120.1 (J ¼ 174:7 Hz), 121.0, 125.0, 128.9,
130.6, 131.5, 136.2, 139.8, 148.5, 148.7, 148.9, 149.0, 149.4. EIMS
m=z (%) 588 (Mþ, 40), 178 (93), 167 (100). HREIMS m=z Mþ: calcd.
for C32H35O7F3, 588.2335; found, 588.2337.
(CDCl3) ꢁ: 1.40–1.43 (1H, overlapped), 1.41 (3H, t, J ¼ 7:0 Hz), 1.65–
1.72 (2H, m), 1.89–1.98 (3H, m), 2.51 (1H, br. s), 3.72 (1H, d,
J ¼ 11:5 Hz), 3.78 (3H, s), 3.84 (3H, s), 3.85 (6H, s), 3.98 (1H, d,
J ¼ 10:3 Hz), 4.03 (2H, q, J ¼ 7:0 Hz), 4.49 (1H, d, J ¼ 11:5 Hz),
5.06 (1H, d, J ¼ 6:9 Hz), 5.66 (1H, m), 6.05 (1H, d, J ¼ 15:7 Hz),
6.69–6.77 (3H, m), 6.82–6.93 (3H, m), 6.90 (2H, d, J ¼ 8:4 Hz), 7.32
(2H, d, J ¼ 8:4 Hz). 13C-NMR (CDCl3) ꢁ: 14.9, 31.9, 35.6, 38.4, 41.7,
55.8, 63.4, 68.6, 73.7, 85.6, 108.5, 109.0, 110.7, 111.1, 114.4, 118.7,
118.9, 125.6, 128.6, 130.7, 131.0, 133.0, 136.4, 148.3, 148.5, 149.0,
149.3, 158.7. EIMS m=z (%) 548 (Mþ, 100), 342 (62), 177 (75), 151
(85). HREIMS m=z Mþ: calcd. for C33H40O7, 548.2774; found,
548.2775.
(R)-{(2R,3R,5R)-2-(4-Butoxyphenyl)-3-[(E)-3-(3,4-dimethoxyphen-
yl)-2-propen-1-yl]tetrahydropyran-5-yl}(3,4-dimethoxyphenyl)metha-
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-2-(4-ethylphenyl)-3-[(E)-3-
(3,4-dimethoxyphenyl)-2-propen-1-yl]tetrahydropyran-5-yl}methanol
20
nol (21). Colorless oil, ½ꢀꢀD ¼ ꢁ43 (c 0.30, CHCl3). 1H-NMR
20
(18). Colorless oil, ½ꢀꢀD ¼ ꢁ37 (c 0.50, CHCl3). 1H-NMR (CDCl3)
(CDCl3) ꢁ: 0.98 (3H, t, J ¼ 7:3 Hz), 1.42 (1H, ddd, J ¼ 12:3, 12.3,
4.8 Hz), 1.51 (2H, m), 1.62–1.75 (2H, m), 1.77 (2H, m), 1.85–2.10 (3H,
m), 2.56 (1H, br. s), 3.70 (1H, dd, J ¼ 11:6, 1.4 Hz), 3.78 (3H, s), 3.83
(3H, s), 3.85 (6H, s), 3.94–4.00 (3H, m), 4.48 (1H, d, J ¼ 11:6 Hz),
5.06 (1H, d, J ¼ 9:0 Hz), 5.66 (1H, m), 6.06 (1H, d, J ¼ 15:7 Hz),
6.69–6.77 (3H, m), 6.82–6.93 (5H, m), 7.31 (2H, d, J ¼ 8:6 Hz).
13C-NMR (CDCl3) ꢁ: 13.8, 19.2, 31.3, 31.9, 35.6, 38.3, 41.7, 55.78,
55.82, 55.9, 67.7, 68.6, 73.7, 85.6, 108.6, 111.1, 114.4, 118.7, 118.8,
125.6, 128.5, 131.0, 132.9, 136.4, 148.3, 148.5, 149.3, 158.9. EIMS
m=z (%) 576 (Mþ, 31), 558 (100), 380 (57), 351 (53), 177 (98), 151
(78). HREIMS m=z Mþ: calcd. for C35H44O7, 576.3087; found,
576.3085.
ꢁ: 1.24 (3H, t, J ¼ 7:6 Hz), 1.42 (1H, ddd, J ¼ 12:2, 12.2, 5.2 Hz),
1.64–1.74 (2H, m), 1.88 (1H, m), 1.97 (1H, m), 2.08 (1H, m), 2.52 (1H,
br. s), 2.66 (2H, q, J ¼ 7:6 Hz), 3.71 (1H, dd, J ¼ 11:6, 2.6 Hz), 3.78
(3H, s), 3.83 (3H, s), 3.85 (6H, s), 4.01 (1H, d, J ¼ 9:9 Hz), 4.48 (1H,
d, J ¼ 11:6 Hz), 5.07 (1H, d, J ¼ 8:8 Hz), 5.69 (1H, m), 6.07 (1H, d,
J ¼ 15:7 Hz), 6.68–6.76 (4H, m), 6.87 (1H, dd, J ¼ 8:2, 1.8 Hz), 6.93
(1H, d, J ¼ 1:8 Hz), 7.20–7.22 (2H, m), 7.23–7.3 (2H, m). 13C-NMR
(CDCl3) ꢁ: 15.6, 28.6, 31.8, 35.5, 38.2, 41.7, 55.8, 55.87, 55.94, 68.6,
73.8, 85.8, 108.7, 109.1, 110.8, 111.2, 118.7, 118.9, 125.6, 127.4,
128.0, 130.7, 131.2, 136.4, 138.1, 144.1, 148.4, 148.5, 149.0, 149.3.
EIMS m=z (%) 532 (Mþ, 19), 514 (96), 307 (100). HREIMS m=z Mþ:
calcd. for C33H40O6, 532.2825; found, 532.2827.
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(4-hydroxyphenyl)tetrahydropyran-5-yl}-
methanol (19). To an ice-cooled solution of a diastereomeric mixture
of acetate I (1.58 g, 1.88 mmol), which was prepared by the previously
described method2) with modification, and Et3N (0.29 ml, 2.1 mmol) in
CH2Cl2 (5 ml) was added MsCl (0.16 ml, 2.1 mmol), and then the
reaction mixture was stirred at 0 ꢂC for 30 min before additions of H2O
and CH2Cl2. The organic solution was separated washed with sat. aq.
NaHCO3 solution, and dried (Na2SO4). Concentration gave a crude
mesylate. A reaction mixture of this crude mesylate and K2CO3
(2.60 g, 18.8 mmol) in MeOH (10 ml) was stirred at room temperature
(R)-(3,4-Dimethoxyphenyl){(2R,3R,5R)-3-[(E)-3-(3,4-dimethoxy-
phenyl)-2-propen-1-yl]-2-(4-isopropoxyphenyl)tetrahydropyran-5-yl}-
20
methanol (22). Colorless oil, ½ꢀꢀD ¼ ꢁ50 (c 0.46, CHCl3). 1H-NMR
(CDCl3) ꢁ: 1.33 (3H, d, J ¼ 5:9 Hz), 1.34 (3H, d, J ¼ 6:0 Hz), 1.41
(1H, ddd, J ¼ 12:3, 12.3, 3.7 Hz), 1.63–1.73 (2H, m), 1.89 (1H, m),
1.96 (1H, m), 2.04 (1H, m), 2.60 (1H, br. s), 3.77 (1H, dd, J ¼ 11:7,
2.7 Hz), 3.78 (3H, s), 3.83 (3H, s), 3.85 (6H, s), 3.98 (1H, d,
J ¼ 9:9 Hz), 4.49 (1H, d, J ¼ 11:7 Hz), 4.54 (1H, m), 5.06 (1H, d,
J ¼ 9:0 Hz), 5.67 (1H, m), 6.06 (1H, d, J ¼ 15:7 Hz), 6.67–6.77 (3H,
m), 6.84–6.94 (3H, m), 6.90 (2H, d, J ¼ 8:6 Hz), 7.31 (2H, d,
J ¼ 8:6 Hz). 13C-NMR (CDCl3) ꢁ: 22.05, 22.08, 31.9, 35.6, 38.3, 41.8,

2074
K. MASUDA et al.
Table 1. Growth Rate (% ꢃ ꢂ, n ¼ 3) of Alternaria alternata at 0.50 mM of the (7R,70R,8R,80R)-Morinol B Derivatives
The area of the mycelial colony was measured. Ar ¼ 3,4-dimethoxyphenyl
Compound
Structure
Compound
Structure
Growth %
Growth %
No.
No.
OH
H
OH
H3CO
H3CO
7"
H
Ar
1"
H3CO 3"
H3CO 4"
8
7
1'
7'
8"
8'
9
41 1.7
43 0.43
1
4'
OCH3
1
O
Ar
O
3'
OCH3
4
OCH3
H3CO
3
OH
OCH3
H
(7R,7'R,8R,8'R)-morinol B
Ar
10
40 3.2
O
Ar
OAc
H
OH
Ar
Ar
Ar
H
2
3
77 0.63
Ar
O
Ar
11
67 4.3
O
H
Ar
OCH3
H
OCH3
Ar
Ar
55 4.0
OH
O
Ar
Ar
12
72 6.2
OH
H
O
OCH3
Ar
Ar
4
5
6
42 1.4
OH
H
O
Ar
Ar
Ar
Ar
Ar
OH
13
45 1.7
H
O
Ar
77 9.2
OH
O
Ar
H
OH
H
H
14
39 3.3
O
Ar
38 + 1.0
O
O
OCH3
Ar
Ar
OH
H
OH
Ar
Ar
Ar
15
56 + 3.4
7
44 + 1.8
O
OCH3
OCH3
OH
OH
H
H
Ar
Ar
Ar
8
41 1.7
0
16
H3CO
O
Ar
O
H3CO
55.8, 55.9, 56.0, 68.6, 70.0, 73.7, 85.6, 108.7, 109.1, 110.8, 111.2,
115.9, 118.8, 118.9, 125.7, 128.6, 130.8, 131.1, 136.5, 148.4, 148.6,
149.0, 149.3, 157.7. EIMS m=z (%) 562 (Mþ, 70), 544 (100), 347 (75),
285 (69), 177 (98), 151 (98). HREIMS m=z Mþ: calcd. for C34H42O7,
562.2930; found, 562.2933.
Results and Discussions
The (7R,70R,8R,80R)-morinol B derivatives were
synthesized by the previously described method.2) The
antifungal activities of the derivatives were initially
examined by using phytopathogenic fungus Alternaria
alternata at 0.50 mM (Table 1). To check the role of the
benzylic hydroxy group in the activity, acetate 2 and
methyl ether 3 were examined. The activities of these
derivatives were slightly weaker than that of natural
product 1. On the other hand, the activity level of olefin
reductive derivative 4 was same as that of 1. These facts
indicate that the benzylic hydroxy group was important
for the higher activity and that the 700–800 double bond of
Organisms. The phytopathogenic fungi, Colletotrichum lagenarium
race 2.1, Bipolaris oryzae race 1.1, Fusarium solani race 3.3, and
Alternaria alternata race 1.1, had been isolated from a farm at
Ehime University and were kindly presented by Dr. Ohguchi. Each
fungus was cultured on potato dextrose agar (PDA, Sigma-Aldrich,
Canada).
Antifungal assay. The antimicrobial assay was performed by the
same method as that described in the literature.9)

Morinol B Derivatives
2075
OTIPS
OAc
OTIPS
OH
H
OCH3
OCH3
8
7
1) MsCl, Et3N/CH2Cl2
0oC, 30 min
OCH3
OCH3
19
2) K2CO3/MeOH
r.t., 16 h
O
TBDPSO
39%, 2 steps
HO
II
I
Scheme 1. Preparation of the Intermediate for the Synthesis of 19.
Table 2. Growth Rate (% ꢃ ꢂ, n ¼ 3) of Alternaria alternata at 3.9 mM of 3-Demethoxy (7R,70R,8R,80R)-Morinol B Derivatives
The area of the mycelial colony was measured. Ar ¼ 3,4-dimethoxyphenyl
Compound
Structure
Compound
Structure
Growth %
Growth %
No.
No.
OH
OH
H
H
Ar
Ar
Ar
Ar
Ar
57 3.2
20
16
74 0.97
O
O
O
H3CO
OH
H
OH
H
Ar
Ar
Ar
50 1.8
21
17
73 2.8
72 3.8
77 2.5
O
H
O
O
F3CO
OH
OH
H
Ar
Ar
77 4.4
22
Ar
Ar
Ar
18
O
O
O
OH
H
Ar
19
O
HO
the cinnamyl structure was not important for the activity.
Derivative 5 lacking the benzene ring at the 100–600
positions resulted in a decrease in the activity. This fact
suggests that this benzene ring was important, however,
the methoxy groups on this 700-phenyl ring of 1 did not
play an important role in the activity, because the
activities of phenyl derivative 6, 300-methoxy derivative
7, and 400-methoxy derivative 8 were same as that of 1.
Since the 300,400,500-trimethoxy derivative 9 also showed
same level of activity as that of 1, the increase of
methoxy group on the 700-phenyl group did not affect the
activity. In respect of the substituents on the 70 phenyl
group, derivative 10 lacking two methoxy groups
showed the same level of activity as that of 1, although
the activities of derivatives 11 and 12 lacking one
methoxy group were weaker. In the case of the
substituents on the 7-phenyl group, 4-methoxy deriva-
tive 16 showed the highest activity, whose growth rate
was 0% at 0.50 mM. Although the activities of derivative
13 lacking substituents, 2-methoxy derivative 14, and
3-methoxy derivative 15 were at almost the same level
as that of 1, these activity levels were weaker than that
of 4-methoxy derivative 16. It could be assumed that the
3-methoxy group of morinol B reduced the activity.
In the next step, the 3-demethoxy derivatives, which
had a different substituent at the 4 position of 16, were
synthesized and their activities were examined to
elucidate the important factor at the 4 position. 4-
Hydroxy derivative 19 was synthesized from a diaster-
eomeric mixture of hydroxy acetate I, which had been
prepared by the previously described method2) with
modification. The treatment of I with mesyl chloride and
triethylamine, and then by K2CO3 in MeOH gave phenol
II as a single isomer (Scheme 1). The coupling constant
at the 7 position was 9.6 Hz, showing diaxial stereo-
chemistry between the 7 and 8 positions. The tert-
butyldiphenylsilyl ether in this reaction was cleaved in
the presence of the secondary tri-isopropylsilyl ether.
Phenol II was converted to 19 by the previously
described method.2)
The antifungal activities of the 3-demethoxy deriva-
tives at 3.9 mM are shown in Table 2. 4-Methoxy
derivative 16 showed 74% growth rate. 4-Hydroxy
derivative 19, 4-trifluoromethoxy derivative 17, and
4-ethyl derivative 18 showed the same levels of activity
as that of 16. These facts indicate that hydrophilic and
electron withdrawing groups and the oxygen atom at the
4 position did not affect the activity. On the other hand,

2076
K. MASUDA et al.
the longer alkoxy derivative at the 4 position increased
the activity. Thus, the activities of 4-ethoxy derivative
20 and 4-butoxy derivative 21 were higher than that of
16. However, the activity of bulky 4-isopropoxy
derivative 22 was the same as that of 16. 4-Butoxy
derivative 21 showed the highest activity in this study,
having higher activity than that of thiabendazol (71%
of growth rate at 3.9 mM). A linear and longer alkoxy
group was necessary at the 4 position of morinol B for
this higher activity. Derivative 21 did not show the
antifungal activity against the other phytopathogenic
fungi, Colletotrichum lagenarium, Bipolaris oryzae, and
Fusarium solani.
was effective against Alternaria alternata at the same
level as that of sesquilignan morinol B and its deriva-
tives. Some morinol B derivatives showed higher
antifungal activity than that of the butane type of lignan.
Acknowledgments
We measured the 400 MHz NMR and MS data at
INCS of Ehime University. We are grateful to Marutomo
Co. for financial support.
References
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