Antimicrobial Activity of Lignans
1807
Ar
Ar
O
O
Ar
Ar
Ar
Ar
7'
8'
7
8
HO
OH
9'
9
Secoisolariciresinol (SECO)
Dihydroguaiaretic acid (DGA) 7,7'-Dioxodihydroguaiaretic acid (ODGA)
Fig. 1. Butane Type of Lignans.
Ar, 4-hydroxy-3-methoxyphenyl
113.5, 116.8, 120.4, 127.3, 127.9, 128.5, 132.8, 136.0, 136.1, 137.1,
148.0, 149.8. Anal. Found: C, 70.67; H, 7.60%. Calcd. for C22H28O5:
C, 70.94; H 7.58%.
washed with brine, and dried (Na2SO4). Concentration gave crude
aldehyde. To an ice-cooled mixture of this crude aldehyde, 2-methyl-2-
butene (3.60 ml, 34.0 mmol), and NaH2PO4.2H2O (1.30 g, 8.33 mmol)
in tert-BuOH (50 ml) and H2O (1.5 ml) was added NaClO2 (2.30 g,
25.4 mmol). The reaction mixture was stirred at room temperature for
1 h, and then 6 M aq. HCl solution and CHCl3 were added. The organic
solution was separated, washed with H2O and brine, and dried
(Na2SO4). After concentration, the residue was dissolved in THF
(30 ml) and 6 M aq. HCl solution (30 ml). The reaction solution was
stirred at 50 ꢂC for 20 min, and then EtOAc and brine were added. The
organic solution was separated, washed with sat. aq. NaHCO3 solution
and brine, and dried (Na2SO4). Concentration followed by silica gel
(4S,5S)-5-(4-Benzyloxy-3-methoxyphenyl)-5-methoxymethoxy-4-(p-
toluenesulfonyloxy)methyl-1-pentene (4). To an ice-cooled solution of
3 (1.40 g, 3.76 mmol) and pyridine (1.20 ml, 14.8 mmol) in CH2Cl2
(5 ml) was added p-TsCl (1.40 g, 7.34 mmol). The resulting reaction
solution was stirred at room temperature for 20 h before additions of
H2O and CH2Cl2. The organic solution was separated, washed with 1 M
aq. HCl solution, sat. aq. NaHCO3, and brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc/
column chromatography (EtOAc/hexane = 1/2) gave
20
6
(2.64 g,
hexane = 1/3) gave 4 (1.98 g, 3.76 mmol, 100%) as colorless crystals,
20
mp 80–81 ꢂC ((iso-Pr)2O), ½ꢀꢁ
ꢀ55 (c 1.5, CHCl3). 1H NMR
8.45 mmol, 97%) as a colorless oil, ½ꢀꢁ
ꢀ17 (c 0.4, CHCl3).
D
D
1H NMR (CDCl3) ꢁ 1.16 (3H, d, J ¼ 6:5 Hz, CH3), 2.33 (1H, dd,
J ¼ 16:8, 10.9 Hz, 2-HH), 2.47 (1H, m, 3-H), 2.78 (1H, dd, J ¼ 16:8,
7.6 Hz, 2-HH), 3.90 (3H, s, OCH3), 4.86 (1H, d, J ¼ 8:7 Hz, 4-H), 5.16
(2H, s, OCH2Ph), 6.79 (1H, dd, J ¼ 8:2, 2.0 Hz, ArH), 6.86–6.88 (2H,
m, ArH), 7.31 (1H, d, J ¼ 7:1 Hz, ArH), 7.35–7.39 (2H, m, ArH), 7.43
(2H, d, J ¼ 7:1 Hz, ArH); 13C NMR (CDCl3) ꢁ 16.3, 37.4, 39.7, 56.1,
71.0, 88.3, 109.4, 113.6, 118.7, 127.17, 127.21, 127.9, 128.6, 130.6,
136.9, 148.6, 150.0, 176.1. EIMS m=z 312 (Mþ, 100), 91 (99);
HREIMS m=z 312.1361 (calcd for C19H20O4, 312.1362).
(CDCl3) ꢁ 1.83–1.92 (2H, m, 3-H2), 2.02 (1H, m, 4-H), 2.43 (3H, s,
CH3PhSO2), 3.27 (3H, s, OCH2OCH3), 3.85 (3H, s, OCH3), 4.11 (1H,
dd, J ¼ 9:3, 3.8 Hz, TsOCHH), 4.35 (1H, dd, J ¼ 9:3, 4.6 Hz,
TsOCHH), 4.40 (1H, d, J ¼ 6:6 Hz, OCHHOCH3), 4.42 (1H, d,
J ¼ 6:6 Hz, OCHHOCH3), 4.46 (1H, d, J ¼ 8:4 Hz, ArCH(OMOM)),
4.80 (1H, d, J ¼ 17:0 Hz, 1-HH), 4.87 (1H, d, J ¼ 10:3 Hz, 1-HH),
5.13 (2H, s, OCH2Ph), 5.48 (1H, m, 2-H), 6.70 (1H, dd, J ¼ 8:3,
1.8 Hz, ArH), 6.78 (1H, d, J ¼ 1:8 Hz, ArH), 6.81 (1H, d, J ¼ 8:3 Hz,
ArH), 7.27–7.37 (5H, m, ArH), 7.43 (2H, d, J ¼ 7:8 Hz, ArH), 7.78
(2H, d, J ¼ 8:3 Hz, ArH); 13C NMR (CDCl3) ꢁ 21.5, 31.2, 44.2, 55.8,
55.9, 68.6, 70.9, 76.5, 94.0, 110.6, 113.5, 117.5, 120.1, 127.2, 127.8,
127.9, 128.5, 129.7, 132.1, 132.9, 134.7, 134.8, 137.0, 144.6, 147.9,
149.7. Anal. Found: C, 65.95; H, 7.45%. Calcd. for C29H34O7S: C,
66.13; H 6.51%.
(2S,3R,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-2-[(R)-(4-benzyloxy-3-
methoxyphenyl)(triisopropylsilyloxy)methyl]-3-methyl-4-butanolide (7).
To a solution of KHMDS (25.0 ml, 0.5 M toluene solution, 12.5 mmol)
in THF (10 ml) was added 6 (2.60 g, 8.32 mmol) in THF (10 ml) at
ꢀ70 ꢂC. After stirring at ꢀ70 ꢂC for 10 min, a solution of 4-benzyloxy-
3-methoxybenzaldehyde (2.00 g, 8.26 mmol) in THF (10 ml) was
added. After the resulting reaction solution was stirred at ꢀ70 ꢂC for
1 h, sat. aq. NH4Cl solution and EtOAc were added. The organic
solution was separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chromatography (EtOAc/
hexane = 1/2) gave a mixture of erythro and threo aldol product (1/3,
4.49 g, 8.10 mmol, 97%). FABMS m=z 555 (ðM þ HÞþ, 4), 154 (100);
HRFABMS m=z 555.2383 (calcd for C34H35O7, 555.2382). To an ice-
cooled solution of a mixture of erythro and threo aldol product (5.00 g,
9.01 mmol) and 2,6-lutidine (1.50 ml, 12.9 mmol) in CH2Cl2 (50 ml)
was added TIPSOTf (2.90 ml, 10.8 mmol). After the reaction solution
was stirred at room temperature for 1 h, sat. aq. NaHCO3 solution was
added. The organic solution was separated, washed with sat. aq. CuSO4
solution and sat. aq. NaHCO3 solution, and dried (Na2SO4). Concen-
tration followed by silica gel column chromatography (EtAOc/
(4R,5S)-5-[(4-Benzyloxy-3-methoxyphenyl)(methoxymethoxy)methyl]-
4-methyl-1-pentene (5). To an ice-cooled suspension of LiAlH4
(0.77 g, 0.020 mol) in THF (40 ml) was added a solution of 4 (5.40 g,
0.010 mol) in THF (10 ml). The reaction mixture was stirred at room
temperature for 20 h. After additions of sat. aq. MgSO4 and K2CO3, the
mixture was stirred at room temperature for 30 min, and then the
mixture was filtered. The filtrate was concentrated, and then the residue
was applied to silica gel column chromatography (EtOAc/
hexane = 1/9) to give 5 (3.12 g, 0.0088 mol, 88%) as colorless
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crystals, mp 43–44 ꢂC (hexane), ½ꢀꢁ
ꢀ80 (c 0.4, CHCl3). 1H NMR
D
(CDCl3) ꢁ 1.00 (3H, d, J ¼ 6:5 Hz, CH3), 1.75 (1H, m, 4-H), 1.85 (1H,
m, 3-HH), 2.07 (1H, m, 3-HH), 3.37 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 4.31 (1H, d, J ¼ 7:0 Hz, 5-H), 4.48 (1H, d, J ¼ 6:7 Hz,
CH3OCHHO), 4.51 (1H, d, J ¼ 6:7 Hz, CH3OCHHO), 4.96 (1H, d,
J ¼ 16:7 Hz, 1-HH), 4.98 (1H, dd, J ¼ 10:2 Hz, 1-HH), 5.14 (2H, s,
OCH2Ph), 5.73 (1H, m, 2-H), 6.74 (1H, dd, J ¼ 8:2, 1.8 Hz, ArH),
6.82–6.84 (2H, m, ArH), 7.29 (1H, d, J ¼ 7:3 Hz, ArH), 7.32–7.38
(2H, m, ArH), 7.44 (2H, m, ArH); 13C NMR (CDCl3) ꢁ 15.3, 37.6,
39.6, 55.7, 56.0, 71.1, 81.5, 94.2, 110.8, 113.4, 116.1, 120.1, 127.3,
127.8, 128.5, 133.9, 137.0, 137.2, 147.6, 149.5. Anal. Found: C, 73.94;
H, 7.88%. Calcd. for C22H28O4: C, 74.12; H 7.92%.
hexane = 1/7) gave threo 7 (2.54 g, 3.57 mmol, 40%) as a colorless
20
oil, ½ꢀꢁ
þ7 (c 1, CHCl3). 1H NMR (CDCl3) ꢁ 1.01–1.09 (18H, m,
D
CH(CH3)2), 1.11 (3H, d, J ¼ 7:1 Hz, CH3), 1.31 (3H, m, CH(CH3)2),
2.52 (1H, m, 3-H), 3.20 (1H, dd, J ¼ 9:8, 6.6 Hz, 2-H), 3.86 (3H, s,
OCH3), 3.88 (3H, s, OCH3), 4.64 (1H, d, J ¼ 8:4 Hz, 4-H), 5.15 (2H, s,
OCH2Ph), 5.16 (2H, s, OCH2Ph), 5.29 (1H, d, J ¼ 6:6 Hz, ArCHOSi),
6.86–6.92 (3H, m, ArH), 6.94 (1H, dd, J ¼ 8:3, 1.9 Hz, ArH), 6.99
(1H, s, ArH), 7.00 (1H, s, ArH), 7.27–7.31 (2H, m, ArH), 7.33–7.38
(4H, m, ArH), 7.42–7.44 (4H, m, ArH); 13C NMR (CDCl3) ꢁ 11.9,
13.0, 17.8, 44.6, 55.9, 56.0, 58.3, 71.1, 82.1, 87.3, 109.98, 110.01,
110.4, 113.9, 114.1, 118.1, 118.9, 127.19, 127.22, 127.8, 128.5, 133.5,
134.8, 137.2, 147.6, 148.0, 149.6, 149.7, 172.6. Anal. Found: C, 72.91;
H, 7.64%. Calcd. for C43H54O7Si: C, 72.64; H 7.66%.
(3R,4S)-4-(4-Benzyloxy-3-methoxyphenyl)-3-methyl-4-butanolide (6).
A reaction solution of 5 (3.10 g, 8.70 mmol), NMO (1.20 g, 10.2
mmol), and OsO4 (2% aq. solution, 1.00 ml) in acetone (80 ml), tert-
BuOH (20 ml), and H2O (20 ml) was stirred at room temperature for
18 h under N2 gas, and then sat. aq. Na2S2O3 solution was added. After
concentration of the mixture, the residue was dissolved in EtOAc and
H2O. The organic solution was separated, washed with brine, and dried
(Na2SO4). Concentration gave crude glycol. A reaction mixture of this
crude glycol and NaIO4 (2.20 g, 10.3 mmol) in MeOH (50 ml) was
stirred at room temperature for 1 h before concentration. The residue
was dissolved in EtOAc and H2O. The organic solution was separated,
(1R,2R,3R,4S)-1,4-Bis(4-benzyloxy-3-methoxyphenyl)-2-hydroxy-
methyl-3-methyl-1,4-butanediol (8). To a solution of threo 7 (0.58 g,
0.82 mmol) in toluene (10 ml) was added DIBAL-H (1.20 ml, 1.0 M in
toluene, 1.20 mmol) at ꢀ70 ꢂC. After the reaction solution was stirred