S. Tamura et al. / Bioorg. Med. Chem. 18 (2010) 5975–5980
5979
saturated NaCl and dried over MgSO4. Removal of the solvent from
the EtOAc extract under reduced pressure afforded crude diol
(59.5 mg). A solution of the crude diol (21.0 mg) in CH2Cl2 (1.5 mL)
(m/z): 325 (M+H)+. HR FAB-MS (m/z): calcd for C17H24O6+H:
325.1651, found: 325.1622.
was treated with n-butyryl chloride (31.0
lL, 0.30 mmol) in the
4.8. Preparation of bioisosteric analogs (2a–2c)
presence of i-Pr2NEt (65.0 L, 0.38 mmol) at 0 °C for 10 min. The
l
reaction mixture was poured into aqueous saturated NaCl, then
the whole was extracted with EtOAc. The EtOAc extract was succes-
sively washed with 5% HCl, aqueous saturated NaHCO3, and aqueous
saturated NaCl and dried over MgSO4. Removal of the solvent from
the EtOAc extract under reduced pressure gave a residue, which
was purified by column chromatography (SiO2 3 g, n-hexane/
EtOAc = 2:1) to furnish 9a (20.8 mg, 54% from 8a).
A solution of 9a (17.6 mg, 0.05 mmol) in C6H6 (3.3 mL) was trea-
ted with tert-butyl hydroperoxide (45.3 lL, 3.3 M in toluene,
0.15 mmol) in the presence of VO(acac)2 (1.3 mg, 0.005 mmol)
for 20 min. The reaction mixture was poured into aqueous satu-
rated NaHCO3, then the whole was extracted with EtOAc. The
EtOAc extract was washed with aqueous saturated NaCl and dried
over Na2SO4. Removal of the solvent from the EtOAc extract under
reduced pressure gave crude epoxide. To a solution of the crude
epoxide in C6H6 (3.3 mL) was added PPh3 (61.3 mg, 0.23 mmol),
A solution of the crude diol (26.0 mg) in CH2Cl2 (1.8 mL) was
treated with AcCl (26.5
lL, 0.38 mmol) in the presence of i-Pr2NEt
(82.8 L, 0.47 mmol) at 0 °C for 10 min. Work-up in the same man-
l
isovaleric acid (15.3
lL, 0.14 mmol), and diethyl azodicarboxylate
ner as preparation for 9a gave a residue, which was purified by col-
umn chromatography (SiO2 3 g, n-hexane/EtOAc = 2:1) to furnish
9c (21.1 mg, 48% from 8a).
Removal of the MOM group of 8b (48.0 mg, 0.17 mmol) was car-
ried out in the same manner as preparation for 9a gave a residue,
which was purified by column chromatography (SiO2 3 g, n-hex-
ane/EtOAc = 3:2) to afford secondary alcohol (25.6 mg). NaBH4
reduction of the alcohol (24.4 mg, 0.10 mmol) was conducted in
the same manner as preparation for 9a provided crude diol. A solu-
tion of the crude diol in CH2Cl2 (4.0 mL) was treated with AcCl
(106 L, 40% in toluene, 0.25 mmol) at 0 °C, then the reaction mix-
l
ture was stirred at rt for 15 min. Removal of the solvent from the
whole mixture under reduced pressure gave a residue, which
was purified by column chromatography (SiO2 2 g, n-hexane/
EtOAc = 3:1) to furnish 2a (15.8 mg, 70% from 9a).
Epoxidation of 9b (14.0 mg, 0.05 mmol) followed by Mitsunobu
inversion were carried out in the same manner as preparation for
2a gave a residue, which was purified by column chromatography
(SiO2 2 g, n-hexane/EtOAc = 7:3) to furnish 2b (13.5 mg, 71% from
9b). Epoxidation of 9c (16.1 mg, 0.05 mmol) was carried out in
the same manner as preparation for 2a gave crude epoxide. To a
solution of the crude epoxide in C6H6 (3.3 mL) was added PPh3
(70.2 lL, 0.90 mmol) in the presence of i-Pr2NEt (212 lL,
1.2 mmol) at 0 °C for 10 min. Work-up in the same manner as
preparation for 9a gave a residue, which was purified by column
chromatography (SiO2 3 g, n-hexane/EtOAc = 3:2) to furnish 9b
(22.8 mg, 50% from 8b).
(61.3 mg, 0.23 mmol), acetic acid (8.3
lL, 0.13 mmol), and diethyl
azodicarboxylate (106 L, 40% in toluene, 0.25 mmol) at 0 °C, then
l
the reaction mixture was stirred at rt for 10 min. Work-up in the
same manner as preparation for 2a gave a residue, which was puri-
fied by column chromatography (SiO2 2 g, n-hexane/EtOAc = 2:1)
to furnish 2c (12.4 mg, 65% from 9c).
Compound 9a: colorless oil. ½a D24
ꢂ
15.2 (c 0.92, MeOH). IR mmax
(KBr) cmꢁ1: 3314, 1758(sh), 1735, 1668. 1H NMR (500 MHz, CDCl3)
d: 6.42 (1H, s, 3-H), 6.04 (1H, d, J = 6.4 Hz, 1-H), 5.43 (1H, dd, J = 1.8,
1.8 Hz, 10-Ha), 5.32 (1H, dd, J = 1.8, 1.8 Hz, 10-Hb), 4.62 (1H, d,
J = 12.1 Hz, 11-Ha), 4.50 (1H, dd, J = 6.1, 6.0 Hz, 7-H), 4.47 (1H, d,
J = 12.1 Hz, 11-Hb), 2.79 (1H, dd, J = 6.4, 6.2 Hz, 9-H), 2.70 (1H,
ddd, J = 6.2, 6.2, 6.2 Hz, 5-H), 2.34 (1H, ddd, J = 12.5, 6.2, 6.1 Hz,
6-Ha), 2.27–2.30 (2H, m, 1-OCOCH2CH(CH3)2, 2.28 (2H, t,
J = 7.6 Hz, 11-OCOCH2CH2CH3), 2.13 (1H, m, 1-OCOCH2CH(CH3)2),
1.67 (1H, ddd, J = 12.5, 6.2, 6.0 Hz, 6-Hb), 1.64 (2H, tq, J = 7.6,
7.3 Hz, 11-OCOCH2CH2CH3), 0.98 (3H, d, J = 6.6 Hz, 1-OCOCH2-
CH(CH3)2), 0.97 (3H, d, J = 6.6 Hz, 1-OCOCH2CH(CH3)2), 0.93 (3H,
t, J = 7.3 Hz 11-OCOCH2CH2CH3). FAB-MS (m/z): 353 (M+H)+. HR
FAB-MS (m/z): calcd for C19H28O6+H: 353.1964, found: 353.1940.
Compound 2a: colorless oil. ½a D24
ꢁ47.3 (c 0.48, MeOH). IR mmax
ꢂ
(KBr) cmꢁ1: 1760(sh), 1740, 1670. 1H NMR (500 MHz, CDCl3) d:
6.51 (1H, s, 3-H), 5.83 (1H, d, J = 5.5 Hz, 1-H), 4.95 (1H, dd, J = 6.2,
5.4 Hz, 7-H), 4.67 (1H, d, J = 12.2 Hz, 11-Ha), 4.47 (1H, d,
J = 12.2 Hz, 11-Hb), 3.05 (1H, d, J = 5.5 Hz, 10-Ha), 2.96 (1H, ddd,
J = 8.6, 7.3, 6.1 Hz, 5-H), 2.82 (1H, d, J = 5.5 Hz, 10-Hb), 2.71 (1H,
dd, J = 8.6, 5.5 Hz, 9-H), 2.31 (2H, t, J = 7.6 Hz, 11-OCOCH2-
CH2CH3), 2.25 (1H, ddd, J = 12.5, 6.2, 6.1 Hz, 6-Ha), 2.17–2.20 (4H,
m, 1-OCOCH2CH(CH3)2, 7-OCOCH2CH(CH3)2), 2.00–2.10 (2H, m,
1-OCOCH2CH(CH3)2, 7-OCOCH2CH(CH3)2), 2.01 (1H, ddd, J = 12.5,
7.3, 5.4 Hz, 6-Hb), 1.66 (2H, sext-like, J = ca. 7.5 Hz,
11-OCOCH2CH2CH3), 0.94–0.98 (15H, m, 1-OCOCH2CH(CH3)2,
7-OCOCH2CH(CH3)2, 11-OCOCH2CH2CH3). FAB-MS (m/z): 475
(M+Na)+. HR FAB-MS (m/z): calcd for C24H36O8+Na: 475.2308,
found: 475.2321.
Compound 9b: colorless oil. ½a D24
ꢂ
19.2 (c 1.0, MeOH). IR mmax
(KBr) cmꢁ1: 3327, 1758(sh), 1731, 1672. 1H NMR (500 MHz,
CDCl3) d: 6.43 (1H, s, 3-H), 6.00 (1H, d, J = 6.4 Hz, 1-H), 5.42
(1H, dd, J = 2.2, 2.0 Hz, 10-Ha), 5.32 (1H, dd, J = 2.2, 2.0 Hz, 10-
Hb), 4.62 (1H, d, J = 12.3 Hz, 11-Ha), 4.50 (1H, br dd, J = 6.8,
6.8 Hz, 7-H), 4.46 (1H, d, J = 12.3 Hz, 11-Hb), 2.79 (1H, dd,
J = 7.3, 6.4 Hz, 9-H), 2.69 (1H, ddd, J = 7.7, 7.3, 6.6 Hz, 5-H) 2.34
(1H, ddd, J = 13.4, 6.8, 6.6 Hz, 6-Ha), 2.15 (3H, s, 1-OAc), 2.06
(3H, s, 11-OAc), 1.70 (1H, ddd, J = 13.4, 7.7, 6.8 Hz, 6-Hb). FAB-
MS (m/z): 283 (M+H)+. HR FAB-MS (m/z): calcd for C14H18O6+H:
283.1182, found: 283.1172.
Compound 2b: colorless oil. ½a D24
ꢁ56.9 (c 0.50, MeOH). IR mmax
ꢂ
(KBr) cmꢁ1: 1759(sh), 1738, 1671. 1H NMR (500 MHz, CDCl3) d:
6.52 (1H, s, 3-H), 5.82 (1H, d, J = 4.8 Hz, 1-H), 4.97 (1H, dd, J = 6.2,
5.4 Hz, 7-H), 4.65 (1H, d, J = 12.2 Hz, 11-Ha), 4.47 (1H, d,
J = 12.2 Hz, 11-Hb), 3.06 (1H, d, J = 4.9 Hz, 10-Ha), 2.98 (1H, ddd,
J = 8.5, 6.1, 6.1 Hz, 5-H), 2.82 (1H, d, J = 4.9 Hz, 10-Hb), 2.72 (1H,
dd, J = 8.5, 4.8 Hz, 9-H), 2.28 (1H, ddd, J = 13.4, 6.2, 6.1 Hz,
6-Ha), 2.18 (2H, d, J = 5.5 Hz, 7-OCOCH2CH(CH3)2), 2.08 (6H, s,
1-OAc, 11-OAc), 2.06 (1H, m, 7-OCOCH2CH(CH3)2), 1.99 (1H,
ddd, J = 13.4, 6.1, 5.4 Hz, 6-Hb), 0.95 (6H, d, J = 5.5 Hz,
7-OCOCH2CH(CH3)2). FAB-MS (m/z): 405 (M+Na)+. HR FAB-MS
(m/z): calcd for C19H26O8+Na: .405.1525, found: 405.1511.
Compound 9c: colorless oil. ½a D24
ꢂ
9.9 (c 0.90, MeOH). IR mmax
(KBr) cmꢁ1: 3311, 1759(sh), 1739, 1668. 1H NMR (500 MHz, CDCl3)
d: 6.42 (1H, s, 3-H), 6.03 (1H, d, J = 6.2 Hz, 1-H), 5.42 (1H, dd, J = 1.8,
1.8 Hz, 10-Ha), 5.32 (1H, dd, J = 1.8, 1.8 Hz, 10-Hb), 4.52 (1H, d,
J = 12.1 Hz, 11-Ha), 4.50 (1H, br dd, J = 6.2, 6.1 Hz, 7-H), 4.46 (1H,
d, J = 12.1 Hz, 11-Hb), 2.79 (1H, dd, J = 6.2, 6.2 Hz, 9-H), 2.70
(1H, ddd, J = 6.2, 6.2, 6.2 Hz, 5-H). 2.34 (1H, ddd, J = 13.1, 6.2,
6.2 Hz, 6-Ha), 2.27–2.30 (2H, m, 1-OCOCH2CH(CH3)2), 2.13 (1H,
m, 1-OCOCH2CH(CH3)2), 2.06 (3H, s, 11-OCOCH3), 1.71 (1H,
ddd, J = 13.1, 6.2, 6.1 Hz, 6-Hb), 0.98 (3H, d, J = 6.7 Hz, 1-OCOCH2-
CH(CH3)2), 0.97 (3H, d, J = 6.7 Hz, 1-OCOCH2CH(CH3)2). FAB-MS
Compound 2c: colorless oil. ½a D24
ꢁ50.0 (c 0.49, MeOH). IR mmax
ꢂ
(KBr) cmꢁ1: 1760(sh), 1741, 1671. 1H NMR (500 MHz, CDCl3) d:
6.52 (1H, s, 3-H), 5.84 (1H, d, J = 5.4 Hz, 1-H), 4.96 (1H, dd, J = 6.1,
5.5 Hz, 7-H), 4.64 (1H, d, J = 12.2 Hz, 11-Ha), 4.47 (1H, d,
J = 12.2 Hz, 11-Hb), 3.07 (1H, d, J = 4.9 Hz, 10-Ha), 2.96 (1H, ddd,
J = 8.5, 6.1, 6.1 Hz, 5-H), 2.82 (1H, d, J = 4.9 Hz, 10-Hb), 2.72 (1H,