Total Synthesis of Natural Lignan Lactones
purified by SiO2-column chromatography (hexane/EtOAc )
1/1) to give the desired product 13a (172 mg, 94%): colorless
1H); 13C NMR (100 MHz, CDCl3) δ 55.8, 56.0, 68.0, 101.2,
105.8, 106.0, 108.2, 110.5, 118.3, 118.5, 123.4, 128.4, 128.8,
133.1, 139.5, 139.6, 147.5, 147.6, 150.0, 151.8; IR (KBr) 1747,
1506 cm-1. 1H and 13C NMR spectral data were identical with
those reported.2s 16: colorless crystals; mp 217-219 °C (lit.6d
mp 218-220 °C);1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H),
4.08 (s, 3H), 5.22 (s, 2H), 6.08 (d, Jgem ) 1.2 Hz, 1H), 6.12 (d,
Jgem ) 1.2 Hz, 1H), 6.84 (d, J ) 7.6 Hz, 1H), 6.85 (s, 1H), 7.00
1
crystals; mp 192-196 °C; H NMR (400 MHz, CDCl3) δ 2.93
(brs, 1H, OH), 3.20 (brs, 1H, OH), 3.74 (s, 3H), 4.05 (s, 3H),
4.65 (s, 2H), 5.18 (s, 2H), 6.04 (d, Jgem ) 1.1 Hz, 1H), 6.09 (d,
Jgem ) 1.1 Hz, 1H), 6.72 (d, J ) 1.7 Hz, 1H), 6.73 (s, 1H) 6.74
(d, J ) 1.7 Hz, 1H), 6.94 (d, J ) 7.8 Hz, 1H), 7.63 (1H, s); 13
C
NMR (100 MHz, CDCl3) δ 55.7, 56.0, 61.0, 61.3, 101.2, 104.1,
106.3, 108.4, 110.6, 123.4, 126.4, 129.5, 130.7, 132.8, 134.4,
137.6, 147.1, 147.7, 150.0, 150.5; IR (KBr) 3331, 1507, 1262
cm-1; HRMS (ESI) calcd for C21H19ClO6 (M + Na+) 425.0768,
found 425.0767.
(d, J ) 7.6 Hz, 1H), 7.10 (s, 1H), 7.30 (s, 1H), 8.28 (s, 1H); 13
C
NMR (100 MHz, CDCl3) δ 55.9, 56.1, 69.5, 101.4, 104.0, 107.7,
109.0, 109.5, 121.4, 122.7, 124.2, 129.7, 129.9, 131.6, 131.9,
138.0, 147.7, 148.3, 150.1, 152.0, 171.6; IR (KBr) 3470, 1755,
1466 cm-1. 1H and 13C NMR spectral data were identical with
those reported.2s
4-(2-Bromo-3,4,5-trimethoxyphenyl)-1-chloro-6,7-meth-
ylenedioxynaphthalene-2,3-diyldimethanol (13b). Fol-
lowing the procedure for the preparation of 13b, the reaction
using tribromide 12b (450 mg, 0.706 mmol) gave diol 13b (296
Dehydrodesoxypodophyllotoxin (17) and 5′-methoxy-
retrochinensin (18). Following the procedure for the prepa-
ration of 15 and 16, the reaction of diol 14b (41 mg, 0.10 mmol)
gave the desired product 17 (10 mg, 26%) and 18 (29 mg, 74%).
17: colorless crystals; mp 268-271 °C (lit.14 mp 270-272 °C);
1H NMR(400 MHz, CDCl3) 3.84 (s, 6H), 3.97 (s, 3H), 5.38 (s,
2H), 6.09 (s, 2H), 6.55 (s, 2H), 7.12 (s, 1H), 7.21 (s, 1H), 7.70
(s, 1H); 13C NMR (100 MHz, CDCl3) 56.1, 61.0, 68.0, 101.8,
103.6, 103.7, 107.2, 118.7, 119.1, 130.3, 130.3, 134.6, 137.8,
139.8, 140.4, 148.7, 150.0, 153.0, 169.6; IR (KBr) 3449, 1769,
1464 cm-1. 1H and 13C NMR spectral data were identical with
those reported.2s 18: white powder; mp 295-298 °C (lit.14 mp
1
mg, 82%): colorless crystals; mp 169-172 °C; H NMR (400
MHz, CDCl3) δ 3.78 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.42 (d,
Jgem ) 12.0 Hz, 1H), 4.67 (d, Jgem ) 12.0 Hz, 1H), 5.02 (d, Jgem
) 12.8 Hz, 1H), 5.23 (d, Jgem ) 12.8 Hz, 1H), 6.02 (s, 2H), 6.52
(s, 1H), 6.64 (s, 1H), 7.69 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ 56.2, 60.9, 61.2, 61.3, 61.7, 101.7, 102.2, 103.1, 110.4, 110.7,
128.2, 130.0, 132.1, 133.5, 134.3, 134.7, 137.1, 142.7, 148.8,
149.1, 151.2, 153.0; IR (KBr) 3356, 1462, 1252 cm-1; HRMS
(ESI) calcd for C22H20BrClO7 (M + Na+) 532.9979, found
532.9952.
1
283-284 °C); H NMR (400 MHz, CDCl3) δ 3.86 (s, 6H), 3.96
1-(3,4-Methylenedioxyphenyl)-6,7-dimethoxynaphtha-
lene-2,3-diyldimethanol (14a). Diol 13a (48 mg, 0.12 mmol)
in HMPA (0.79 mL) and THF (1.0 mL) was added to a stirred
solution of SmI2 (0.1 M THF solution, 1.20 mmol, 12.0 mL) at
rt, followed by being stirred for 2 h. The mixture was poured
into ice and water, which was extracted twice with CHCl3. The
combined organic phase washed with water, 10% aqueous
KOH solution, 3% aqueous Na2S2O3 solution, and brine, dried
(Na2SO4), and concentrated. The obtained crude product was
purified by SiO2-column chromatography (hexane/EtOAc )
1/1) to give the desired product 14a (33 mg, 86%): colorless
(s, 3H), 5.22 (s, 2H), 6.10 (s, 2H), 6.54 (s, 2H), 7.11 (s, 1H),
7.32 (s, 1H), 8.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 56.3,
61.0, 69.4, 101.9, 102.1, 106.2, 121.6, 124.7, 131.2, 133.1, 133.2,
137.9, 138.2, 148.4, 150.5, 153.8, 171.4; IR (KBr) 3470, 1755,
1466 cm-1. 1H and 13C NMR spectral data were identical with
those reported.2s
3-(2,2-Dimethylpropanoyloxymethyl)-1-(3,4-methyl-
enedioxyphenyl)-6,7-dimethoxynaphthalen-2-ylmetha-
nol (20a) and 2-(2,2-Dimethylpropanoyloxymethyl)-1-
(3,4-methylenedioxyphenyl)-6,7-dimethoxynaphthalen-
3-ylmethanol (21a). A stirred suspension of diol 14a (16.0
mg, 0.043 mmol), Bu2SnO (11 mg) and, molecular sieves 4A
(431 mg) in toluene (4.3 mL) was refluxed for 2 h. After cooling
to 0-5 °C, and then 2,2-dimethylpropanoyl chloride (5.2 mg,
0.043 mmol) was added. After being stirred for 20 h, the
mixture was filtered off using Celite. Being washed with
CHCl3, and the organic phase was concentrated. The obtained
crude product was purified by SiO2-column chromatography
(hexane/EtOAc ) 3/1) to give the desired product 20a (12.6
mg, 64%) and its isomer 21a (3.2 mg, 16%). 20a: colorless
crystals; mp 87.5-89.5 °C; 1H NMR (300 MHz, CDCl3) δ 1.24
(s, 9H), 1.93 (brs, 1H, OH), 3.75 (s, 3H), 4.01 (s, 3H), 4.60 (s,
1
crystals; mp 181-186 °C; H NMR (400 MHz, CDCl3) δ 3.03
(brs, 1H, OH), 3.33 (brs, 1H, OH), 3.74 (s, 3H), 3.99 (s, 3H),
4.62 (s, 2H), 4.89 (s, 2H), 6.04 (d, Jgem ) 1.2 Hz, 1H), 6.09 (d,
Jgem ) 1.2 Hz, 1H), 6.74 (s, 1H), 6.76 (dd, J ) 7.8 Hz, 1.7 Hz,
1H), 6.81(d, J ) 1.7 Hz, 1H), 6.94 (d, J ) 7.8 Hz, 1H), 7.11 (s,
1H), 7.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.7, 55.9,
60.7, 65.3, 101.2, 105.9, 106.3, 108.3, 110.7, 123.4, 127.4, 128.6,
128.8, 132.5, 133.2, 135.7, 138.8, 146.9, 147.7, 149.6, 149.7;
IR (KBr) 3410, 1508, 1234 cm-1; HRMS (ESI) calcd for
C21H20O6 (M + Na+) 391.1158, found 391.1156.
6,7-Methylenedioxy1-(3,4,5-trimethoxyphenyl)naph-
thalene-2,3-diyldimethanol (14b). Following the procedure
for the preparation of 14a, the reaction using diol 13b (56 mg,
0.11 mmol) gave the desired product 14b (29 mg, 67%):
colorless crystals; mp 215-226 °C; 1H NMR (400 MHz, CDCl3)
δ 2.62 (brs, 1H), 2.64 (brs, 1H), 3.82 (s, 6H), 3.94 (s, 3H), 4.63
(s, 2H), 4.92 (s, 2H), 6.01 (s, 2H), 6.51 (s, 2H), 6.78 (s, 1H),
7.12 (s, 1H), 7.68 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 56.1,
60.7, 61.0, 65.2, 101.2, 103.6, 103.8, 107.3, 128.0, 129.8, 130.0,
133.2, 124.5, 135.9, 137.1, 139.8, 147.8, 148.0, 153.1; IR (KBr)
3355, 1460, 1236 cm-1; HRMS (ESI) calcd for C22H22O7 (M +
Na+) 421.1263, found 421.1254.
2H), 5.44 (s, 2H), 6.07 (d, Jgem ) 14.1 Hz, 1H), 6.08 (d, Jgem
)
14.1 Hz, 1H), 6.75 (s, 1H), 6.80 (dd, J ) 7.9 Hz, J ) 1.7 Hz,
1H), 6.84 (d, J ) 1.7 Hz, 1H), 6.95 (d, J ) 7.9 Hz, 1H), 7.13 (s,
1H), 7.76 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 27.2, 38.8, 55.7,
55.9, 59.9, 65.1, 101.2, 105.8, 106.3, 108.3, 110.7, 123.4, 127.7,
128.7, 128.7, 131.0, 132.3, 133.0, 138.8, 146.9, 147.6, 149.7,
149.8, 178.3; IR (KBr) 3484, 1723, 1507 cm-1; HRMS (ESI)
calcd for C26H28O7 (M+Na+) 475.1733, found 475.1728. 21a:
colorless crystals; mp 93.0-95.0 °C; 1H NMR (300 MHz, CDCl3)
δ 1.17 (s, 9H), 2.00 (brs, 1H, OH), 3.76, (s, 3H), 4.01 (s, 3H),
4.88 (s, 2H), 5.00 (d, Jgem ) 13.8 Hz, 1H), 5.04 (d, Jgem ) 13.8
Hz, 1H), 6.05 (d, Jgem ) 12.4 Hz, 1H), 6.06 (d, Jgem ) 12.4 Hz,
1H), 6.73 (dd, J ) 7.9, 1.7 Hz, 1H), 6.76 (d, J ) 1.7 Hz, 1H),
6.78 (s, 1H), 6.90 (d, J ) 7.9 Hz, 1H), 7.16 (s, 1H), 7.81 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 27.2, 38.7, 55.7, 55.9, 62.2,
63.7, 101.2, 105.8, 106.3, 108.2, 110.7, 123.5, 125.9, 127.5,
128.3, 129.4, 132.0, 136.1, 140.7, 147.0, 147.6, 149.6, 150.0,
178.1; IR (KBr) 3434, 1723, 1507 cm-1; HRMS (ESI) calcd for
C26H28O7 (M + Na+) 475.1733, found 475.1740.
Justicidin B (15) and Retrojusticidin B (16). A stirred
suspension of diol 14a (115 mg, 0.312 mmol) and Fetizon’s
reagent (Ag2CO3-Celite) (3.12 g) in benzene (50 mL) was
refluxed for 1.5 h with azeotropic removal of water using a
Dean-Stark apparatus. After cooling to rt, the mixture was
concentrated. The obtained crude product was purified by SiO2-
column chromatography (CHCl3/EtOAc ) 30/1) to give the
desired product 15 (15 mg, 13%) and 16 (90 mg, 79%). 15:
1
colorless crystals; mp 240-242 °C (lit.2a mp 241-243 °C); H
3-(2,2-Dimethylpropanoyloxymethyl)-6,7-methylene-
dioxy-1-(3,4,5-trimethoxyphenyl)naphthalene-2-ylmeth-
NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 4.07 (s, 3H), 5.40 (s,
2H), 6.06 (d, Jgem ) 1.5 Hz, 1H), 6.11 (d, Jgem ) 1.5 Hz, 1H),
6.84 (dd, J ) 8.1 Hz, J ) 1.7 Hz, 1H), 6.86 (d, J ) 1.7 Hz, 1H),
6.99 (d, J ) 8.1 Hz, 1H), 7.12 (s, 1H), 7.19 (s, 1H), 7.71 (s,
(14) Takano, S.; Otaki, S.; Ogawa, K. Tetrahedron Lett. 1985, 26,
1659.
J. Org. Chem, Vol. 70, No. 7, 2005 2677