S.-Q. Xu et al. / Bioorg. Med. Chem. 18 (2010) 7203–7211
7209
the residue was purified by using silica gel chromatography (petro-
leum ether–EtOAc, 3:1) to give product 5b (65 mg, 18%, petroleum
ether–EtOAc, 5:2, Rf 0.76) and product 5a (245 mg, 68%, petroleum
ether–EtOAc, 5:2, Rf 0.75) as white solids. Compound 5a, mp 263–
266 °C. Crystals suitable for single crystal X-ray diffraction were
grown from EtOH. 1H NMR d 0.96–1.11 (18H, m, 6 ꢂ –CH3 in cam-
phanoyl), 1.61–2.54 (8H, m, 4 ꢂ –CH2 in camphanoyl), 1.46 (3H, d,
J = 6.26 Hz, 20-CH3), 2.39 (3H, d, J = 1.18 Hz, 4-CH3), 4.51 (1H, m, 20-
CH), 5.15 (1H, m, 30-H), 6.13 (1H, d, J = 1.57 Hz, 3-H), 6.71 (1H, d,
J = 3.52 Hz, 40-H), 6.86 (1H, d, J = 8.99 Hz, 6-H), 7.54 (1H, d,
and the reaction mixture was filtered. The precipitate was recrys-
tallized from MeOH to afford 22 as a yellow solid (2.1 g, 81%),
mp 137–138 °C (lit.17 mp 138–139 °C).
4.11. 7-(But-3-yn-2-ylthio)-4-methyl-2-methylene-2H-
chromene (23)
Following the same procedure for the preparation of 16, except
under nitrogen, 23 was obtained from 22 as a white solid (yield,
75%): mp 124–126 °C. 1H NMR d 1.62 (3H, d, J = 6.65 Hz, 8-CH3),
2.42 (3H, d, J = 1.56 Hz, 4-CH3), 2.37 (1H, d, J = 1.35 Hz, –CCH),
4.04 (1H, m, 8-CH), 6.26 (1H, d, J = 1.17 Hz, 3-H), 7.43 (1H, d,
J = 2.35 Hz, 8-H), 7.32 (1H, dd, J1 = 8.60 Hz, J2 = 1.95 Hz, 6-H), 7.52
(1H, d, J = 8.60 Hz, 5-H). EI-MS m/z (%): 244 (M+, 50), 229 (base).
J = 8.99 Hz, 5-H). [
a
]
+28.9 (c 0.9, CH2Cl2). EI-MS m/z (%): 622
D
(M+, 8). Anal. Calcd for C34H38O11: C, 65.58; H, 6.15. Found: C,
65.44; H, 6.24.
Compound 5b, mp 237–239 °C. 1H NMR d 0.82 (3H, s, –CH3 in
camphanoyl), 1.04–1.12 (15H, m, –CH3 ꢂ 5 in camphanoyl), 1.64–
2.57 (8H, m, 4 ꢂ –CH2 in camphanoyl), 1.45 (3H, d, J = 6.26 Hz, 20-
CH3), 2.39 (3H, d, J = 1.17 Hz, 4-CH3), 4.62 (1H, m, 20-CH), 5.27 (1H,
m, 30-H), 6.11 (1H, d, J = 1.17 Hz, 3-H), 6.81 (1H, d, J = 3.52 Hz, 40-
H), 6.86 (1H, d, J = 8.61 Hz, 6-H), 7.54 (1H, d, J = 8.61 Hz, 5-H).
4.12. 10-Thia-20,4-dimethylseselin (24)
Following the same procedure for the preparation of 17, 24 was
obtained from 23 as a yellow solid (yield, 56%, estimated by 1H
NMR). The crude 24 was used directly in the preparation of 25
and 26.
[
a
]
ꢀ24.0 (c 1.0, CHCl3). EI-MS m/z (%): 622 (M+, 6). Anal. Calcd
D
for C34H38O11: C, 65.58; H, 6.15. Found: C, 65.37; H, 6.28.
4.7. (20R,30S,40R)-20,4-Dimethyl-30,40-di-O-(ꢀ)-camphanoyl-(+)-
cis-khellactone (6)
4.13. 10-Thia-20,4-dimethyl-(+)-cis-khellactone (25) and (26)
Following the same procedure for the preparation of 18 and 19,
25 (yield 52%, mp 226–227 °C, CHCl3–MeOH, 80:1, Rf 0.14) and 26
(yield 16%, mp 242–243 °C, CHCl3–MeOH, 80:1, Rf 0.15) were ob-
tained from 24 as white solids. Compound 25. 1H NMR (DMSO) d
1.31 (3H, d, J = 6.25 Hz, 20-CH3), 2.38 (3H, s, 4-CH3), 3.47 (1H, m,
30-CH), 3.63 (1H, m, 20-CH), 5.07 (1H, m, 40-CH), 5.19 (1H, d,
J = 6.65 Hz, 30-OH), 5.44 (1H, d, J = 4.7 Hz, 40-OH), 6.30 (1H, d,
J = 1.18 Hz, 3-H), 7.06 (1H, d, J = 8.60 Hz, 6-H), 7.55 (1H, d,
J = 8.22 Hz, 5-H). EI-MS m/z (%): 278 (M+, 26). Compound 26. 1H
NMR (DMSO) d 1.50 (3H, d, J = 7.04 Hz, 20-CH3), 2.38 (3H, d,
J = 1.17 Hz, 4-CH3), 3.31 (1H, m, 30-CH), 3.97 (1H, m, 20-CH), 5.07
(1H, m, 40-CH), 5.14 (1H, d, J = 4.30 Hz, 30-OH), 5.32 (1H, d,
J = 5.48 Hz, 40-OH), 6.30 (1H, d, J = 1.18 Hz, 3-H), 7.08 (1H, d,
J = 8.22 Hz, 6-H), 7.55 (1H, d, J = 8.21 Hz, 5-H). EI-MS m/z (%): 278
(M+, 22).
Compound 19 (63 mg, 0.245 mmol) was acylated with (S)-
(ꢀ)camphanic chloride (171 mg, 0.78 mmol) in anhydrous CH2Cl2
(10 mL) in the presence of DMAP (150 mg, 1.23 mmol) for 0.5 h
at rt. After the removal of the solvent under reduced pressure,
the residue was submitted to silica gel chromatography separation
(CHCl3–CH3OH, 120:1) to afford product 6 as a white solid
(128 mg, 84%), mp >280 °C. 1H NMR d 0.98–1.11 (18H, m, CH3 ꢂ 6
in camphanoyl), 1.64–2.57 (8H, m, 4 ꢂ –CH2 in camphanoyl),
1.46 (3H, d, J = 6.60 Hz, 20-CH3), 2.39 (3H, d, J = 1.22 Hz, 4-CH3),
4.48 (1H, m, 20-CH), 5.63 (1H, m, 30-H), 6.12 (1H, d, J = 0.98 Hz, 3-
H), 6.73 (1H, d, J = 4.88 Hz, 40-H), 6.88 (1H, d, J = 8.79 Hz, 6-H),
7.51 (1H, d, J = 9.03 Hz, 5-H). [
a
]
D
+111 (c 1.0, CH2Cl2). ESI-MS
m/z (%): 645 (M+Na+). Anal. Calcd for C34H38O11: C, 65.58; H,
6.15. Found: C, 65.56; H, 6.36.
4.8. O-4-Methyl-2-oxo-2H-chromen-7-yl dimethylcarbamothio-
ate (20)
4.14. (20S,30R,40R)-10-Thia-20,4-dimethyl-30,40-di-O-(ꢀ)-campha-
noyl-(+)-cis-khellactone (7a) and (20R,30S,40S)-10-thia-20,4-
dimethyl-30,40-di-O-(ꢀ)-camphanoyl-(+)-cis-khellactone (7b)
Compound 15 (4.4 g, 25 mmol), K2CO3 (7.6 g, 55 mmol), and
dimethylthiocarbamoyl chloride (6.18 g, 50 mmol) were dissolved
in DMF (45 mL). After stirring at 65–70 °C for 1 h, ice water
(300 mL) was added, and the precipitate was filtered and recrystal-
lized from EtOAc to afford 20 as a yellow solid (5.8 g, 88%), mp
214–216 °C (lit.17 mp 208–209 °C). 1H NMR 2.44 (3H, s, 4-CH3),
3.38 (3H, s, N-CH3), 3.47 (3H, s, N-CH3), 6.28 (1H, s, 3-H), 7.07
(1H, s, 8-H), 7.26 (1H, 6-H), 7.60 (1H, d, J = 8.18 Hz, 5-H).
Following the same procedure for the preparation of 5a and 5b,
7a (yield 42%, mp 175–177 °C) and 7b (yield 42%, mp 153–155 °C)
were obtained from 25 as yellow solids. The diastereoisomers (7a)
and (7b) were separated by semi-preparative isolation on Alltima
HP column with CH3CN–water 70:30. Compound 7a (HPLC,
CH3CN–water 70:30, Rf 0.49). 1H NMR d 0.95 (3H, s, –CH3 in cam-
phanoyl), 1.05–1.12 (15H, m, –CH3 ꢂ 5 in camphanoyl), 1.58–2.60
(8H, m, 4 ꢂ –CH2 in camphanoyl), 1.33 (3H, d, J = 6.6 Hz, 20-CH3),
2.38 (3H, 4-CH3), 3.85 (1H, m, 20-CH), 5.33 (1H, dd, J1 = 11.7 Hz,
J2 = 2.7 Hz, 30-H), 6.17 (1H, 3-H), 6.85 (1H, d, J = 3.0 Hz, 40-H),
4.9. S-4-Methyl-2oxo-2H-chromen-7-yl dimethylcarbamothio-
ate (21)
7.04 (1H, d, J = 8.4 Hz, 6-H), 7.46 (1H, d, J = 8.4 Hz, 5-H). [
ꢀ171.9 (c 0.70, CH2Cl2); HRMS (MALDI-DHB) calcd mass for
34H38O10S [M++Na] 661.2083, found 661.2085. Compound 7b
a]
D
Compound 20 (5.0 g, 19.0 mmol) was heated to 220–230 °C for
1 h. The crude product was recrystallized from EtOH to give 21 as a
yellow solid (4.2 g, 84%), mp 160–162 °C (lit.17 mp 159–160 °C).
C
(HPLC, CH3CN–water 70:30, Rf 0.39). 1H NMR d 0.75 (3H, s, –CH3
in camphanoyl), 1.05–1.12 (15H, m, –CH3 ꢂ 5 in camphanoyl),
1.58–2.60 (8H, m, 4 ꢂ –CH2 in camphanoyl), 1.34 (3H, d,
J = 6.65 Hz, 20-CH3), 2.38 (3H, d, J = 1.0 Hz, 4-CH3), 3.90 (1H, m,
20-CH), 5.42 (1H, dd, J1 = 11.4 Hz, J2 = 3.0 Hz, 30-H), 6.17 (1H, d,
J = 1.0 Hz, 3-H), 6.95 (1H, d, J = 3.0 Hz, 40-H), 7.04 (1H, d,
4.10. 4-Methyl-7-mercapto-2H-chromen-2-one (22)
Under nitrogen, compound 21 (3.6 g, 13.7 mmol) and potassium
hydroxide (2.34 g, 41.6 mmol) were dissolved in MeOH (800 mL).
The mixture was refluxed for 1.5 h with stirring. After cooling to
rt, the mixture was acidified with concentrated HCl, and MeOH
was removed under vacuum. Then ice water (400 mL) was added,
J = 8.7 Hz, 6-H), 7.46 (1H, d, J = 8.7 Hz, 5-H). [a] +135.6 (c 0.83,
D
CH2Cl2); HRMS (MALDI-DHB) calcd mass for C34H38O10S [M++Na]
661.2083, found 661.2086.