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M. Shimizu et al. / Bioorg. Med. Chem. 16 (2008) 6949–6964
on silica gel (5 g), and the column was eluted with 5% AcOEt in
hexane to give 27a (61.6 mg, 81%, a mixture of two isomers in a
ca. 1:1 ratio).
(3H, d, J = 7.0 Hz, H-21), 3.40 (3H, s, OMe, overlapped with H-20),
4.17–4.34 (2H, m, CH2OH), 4.48 (1H, m, H-3), 4.69 (2H, s, OCH2O),
4.88 (1H, m, H-1), 5.61 (1H, m, H-16), 5.72 (1H, m, C@CH), 5.90
(1H, d, J = 11.0 Hz, H-7), 6.25 (1H, d, J = 11.0 Hz, H-6).
E-isomer: 1H NMR (CDCl3) d: 0.02–0.11 (12H, 4ꢁ Si-Me), 0.83,
0.93 (each 9H, s, 2ꢁ Si-t-Bu, overlapped with H-18, 26a, 27a),
1.43 (3H, d, J = 7.0 Hz, H-21), 2.82 (1H, m, H-9), 3.05 (1H, m, H-
10), 3.40 (3H, s, OMe, overlapped with H-20), 4.58 (1H, m, H-1),
4.691 (2H, s, OCH2O), 5.46 (1H, m, H-3), 5.62 (1H, m, H-16), 5.93
(1H, d, J = 11.4 Hz, H-7), 6.16 (1H, m, C@CH), 6.19 (1H, d,
J = 11.4 Hz, H-6), 10.19 (1H, d, J = 7.8 Hz, CHO). Z-isomer: 1H
NMR (CDCl3) d: 0.02–0.11 (12H, 4ꢁ Si-Me), 0.84, 0.93 (each 9H, s,
2ꢁ Si-t-Bu, overlapped with H-18, 26a, 27a), 1.43 (3H, d,
J = 7.0 Hz, H-21), 2.82 (1H, m, H-9), 3.02 (1H, m, H-10), 3.40 (3H,
s, OMe, overlapped with H-20), 4.694 (2H, s, OCH2O, overlapped
with H-3), 5.55 (1H, m, H-1), 5.62 (1H, m, H-16), 5.89 (1H, d,
J = 11.4 Hz, H-7), 6.16 (1H, m, C@CH), 6.31 (1H, d, J = 11.4 Hz, H-
6), 10.16 (1H, d, J = 7.7 Hz, CHO).
4.20. (20R)-1a-[(tert-Butyldimethylsilyl)oxy]-2-[2-(hydroxy)-
ethylidene]-16-ene-22-thia-25-[(methoxymethyl)oxy]-26,27-
dimethyl-19,24-dinorvitamin D3 tert-butyldimethylsilyl ether
(28b)
The same procedure as described above, but using NaBH4
(2.3 mg, 0.0608 mmol) and 27b (45.6 mg, 0.0610 mmol) gave 28b
(38.8 mg, 85%, a mixture of two isomers in a ca. 1:1 ratio).
E-isomer: 1H NMR (CDCl3) d: 0.01–0.10 (12H, 4ꢁ Si-Me), 0.73
(3H, s, H-18), 0.85, 0.92 (each 9H, s, 2ꢁ Si-t-Bu), 0.87 (6H, t,
J = 7.3 Hz, H-26a, 27a), 1.46 (3H, d, J = 7.0 Hz, H-21), 2.65 (2H, s,
H-23), 2.79 (1H, m, H-9), 2.88 (1H, dd, J = 12.8, 4.4 Hz, H-10),
3.32 (1H, q, J = 7.0 Hz, H-20), 3.41 (3H, s, OMe), 4.17–4.33 (2H,
m, CH2OH), 4.38 (1H, m, H-1), 4.69 (2H, s, OCH2O), 4.82 (1H, m,
H-3), 5.58 (1H, m, H-16), 5.72 (1H, m, C@CH), 5.94 (1H, d,
J = 11.1 Hz, H-7), 6.14 (1H, d, J = 11.0 Hz, H-6). Z-isomer: 1H
NMR (CDCl3) d: 0.01–0.10 (12H, 4ꢁ Si-Me), 0.72 (3H, s, H-18),
0.83, 0.93 (each 9H, s, 2ꢁ Si-t-Bu), 0.87 (6H, t, J = 7.3 Hz, H-26a,
27a), 1.46 (3H, d, J = 7.0 Hz, H-21), 2.65 (2H, s, H-23), 2.79 (1H,
m, H-9), 2.82 (1H, m, H-10), 3.32 (1H, q, J = 7.0 Hz, H-20), 3.41
(3H, s, OMe), 4.69 (2H, s, OCH2O), 4.17–4.33 (2H, m, CH2OH),
4.48 (1H, m, H-3), 4.87 (1H, m, H-1), 5.58 (1H, m, H-16), 5.72
(1H, m, C@CH), 5.90 (1H, d, J = 11.1 Hz, H-7), 6.25 (1H, d,
J = 11.1 Hz, H-6).
4.18. (20R)-1a-[(tert-Butyldimethylsilyl)oxy]-2-[2-(formyl)-
ethylidene]-16-ene-22-thia-25-[(methoxymethyl)oxy]-26,27-
dimethyl-19,24-dinorvitamin D3 tert-butyldimethylsilyl ether
(27b)
The same procedure as described above, but using DIBAL-H
(103 lL, 0.103 mmol, 1.0 M solution in toluene) and 26b
(51.1 mg, 0.0686 mmol) gave 27b (45.6 mg, 89%, a mixture of
two isomers in a ca. 1:1 ratio).
E-isomer: 1H NMR (CDCl3) d: 0.02–0.10 (12H, 4ꢁ Si-Me), 0.73
(3H, s, H-18), 0.85, 0.93 (each 9H, s, 2ꢁ Si-t-Bu), 0.89 (6H, t,
J = 7.5 Hz, H-26a, 27a), 1.46 (3H, d, J = 7.0 Hz, H-21), 2.65 (2H, s,
H-23), 2.79 (1H, m, H-9), 3.05 (1H, m, H-10), 3.32 (1H, q,
J = 7.0 Hz, H-20), 3.41 (3H, s, OMe), 4.58 (1H, m, H-1), 4.69 (2H,
s, OCH2O), 5.46 (1H, m, H-3), 5.58 (1H, m, H-16), 5.94 (1H, d,
J = 11.2 Hz, H-7), 6.16 (1H, m, C@CH), 6.19 (1H, d, J = 11.2 Hz, H-
6), 10.19 (1H, d, J = 7.9 Hz, CHO). Z-isomer: 1H NMR (CDCl3) d:
0.02–0.11 (12H, 4ꢁ Si-Me), 0.72 (3H, s, H-18), 0.83, 0.93 (each
9H, s, 2ꢁ Si-t-Bu), 0.89 (6H, t, J = 7.5 Hz, H-26a, 27a), 1.47 (3H,
d, J = 7.0 Hz, H-21), 2.65 (2H, s, H-23), 2.79 (1H, m, H-9), 3.00
(1H, m, H-10), 3.32 (1H, q, J = 7.0 Hz, H-20), 3.41 (3H, s, OMe),
4.69 (2H, s, OCH2O, overlapped with H-3), 5.54 (1H, m, H-1),
5.58 (1H, m, H-16), 5.89 (1H, d, J = 11.2 Hz, H-7), 6.16 (1H, m,
C@CH), 6.31 (1H, d, J = 11.2 Hz, H-6), 10.16 (1H, d, J = 7.9 Hz,
CHO).
4.21. (20S)-1a,25-Dihydroxy-2-[2-(hydroxy)-ethylidene]-16-
ene-22-thia-26,27-dimethyl-19,24-dinorvitamin D3 (8a: E-
isomer; 9a: Z-isomer)
A
mixture of 28a (55.3 mg, 0.074 mmol), CSA (102.9 mg,
0.443 mmol) in MeOH (1 mL) was stirred for 1.5 h at ambient tem-
perature, poured into 5% NaHCO3, and extracted with AcOEt. The
organic phase was washed with brine, and dried over anhydrous
MgSO4. Removal of the solvent afforded the crude product, which
was purified by column chromatography on silica gel (3 g) with
2% MeOH in AcOEt to yield 8a and 9a (28.3 mg, 80%, as ca. 1:1 iso-
meric mixture). The compounds 8a and 9a were further purified by
HPLC [YMC-Pack ODS-AM SH-342-5, 20% H2O-MeOH, 8 mL/min] to
give 8a (11.8 mg) and 9a (11.5 mg).
4.19. (20S)-1
a
-[(tert-Butyldimethylsilyl)oxy]-2-[2-(hydroxy)-
8a (E-isomer): 1H NMR (CDCl3) d: 0.83 (3H, s, H-18), 0.866,
0.874 (each 3H, t, J = 7.4 Hz, H-26a, 27a), 1.43 (3H, d, J = 7.0 Hz,
H-21), 2.54, 2.58 (each 1H, d, J = 12.8 Hz, H-23), 2.79 (1H, m, H-
9), 3.16 (1H, dd, J = 12.6, 4.7 Hz, H-10), 3.43 (1H, q, J = 7.0 Hz, H-
20), 4.11 (1H, dd, J = 12.4, 5.3 Hz, CH2OH), 4.38 (2H, m, H-1,
CH2OH), 4.82 (1H, m, H-3), 5.64 (1H, m, H-16), 5.77 (1H, m, C@CH),
5.98 (1H, d, J = 11.2 Hz, H-7), 6.27 (1H, d, J = 11.2 Hz, H-6). MS m/z
(%): 476 (M+, 1), 458 (3), 440 (8), 422 (28), 404 (9), 342 (32), 324
(57), 306 (100). HRMS m/z: 476.2959 (Calcd for C28H44O4S:
ethylidene]-16-ene-22-thia-25-[(methoxymethyl)oxy]-26,27-
dimethyl-19,24-dinorvitamin D3 tert-butyldimethylsilyl ether
(28a)
To the stirred solution of 27a (60.1 mg, 0.080 mmol, ca. 1:1 iso-
meric mixture) in ethanol (EtOH, 1 mL) was added sodium borohy-
dride (NaBH4, 3.0 mg, 0.080 mmol) portionwise at 0 °C. After being
stirred for 1 h, the mixture was poured into ice water and extracted
with AcOEt. The organic layer was washed with brine, and dried
over anhydrous MgSO4. Solvent was removed in vacuo, and the
residue was purified by chromatography on silica gel (5 g) using
15% AcOEt in hexane to give 28a (59.3 mg, 98%, a mixture of two
isomers in a ca. 1:1 ratio).
476.2960). UV kmax (EtOH): 245 (e 31,600), 254 (e 35,800), 263 (e
24,100) nm. 9a (Z-isomer): 1H NMR (CDCl3) d: 0.85 (3H, s, H-18),
0.865, 0.873 (each 3H, t, J = 7.4 Hz, H-26a, 27a), 1.43 (3H, d,
J = 7.0 Hz, H-21), 2.54, 2.58 (each 1H, d, J = 12.9 Hz, H-23), 2.69
(1H, dd, J = 12.7, 4.7 Hz, H-4), 2.80 (1H, m, H-9), 2.88 (1H, dd,
J = 14.2, 4.0 Hz, H-10), 3.44 (1H, q, J = 7.0 Hz, H-20), 4.16 (1H, dd,
J = 12.5, 5.7 Hz, CH2OH), 4.36 (1H, dd, J = 12.5, 8.1 Hz, CH2OH),
4.45 (1H, m, H-3), 4.85 (1H, m, H-1), 5.64 (1H, m, H-16), 5.77
(1H, m, C@CH), 5.94 (1H, d, J = 11.2 Hz, H-7), 6.37 (1H, d,
J = 11.2 Hz, H-6). MS m/z (%): 476 (M+, 1), 458 (5), 440 (11), 422
(29), 404 (9), 342 (4), 324 (63), 306 (100). HRMS m/z: 476.2953
(Calcd for C28H44O4S: 476.2960). UV kmax (EtOH): 245, 254,
263 nm.
E-isomer: 1H NMR (CDCl3) d: 0.01–0.10 (12H, 4ꢁ Si-Me), 0.85,
0.91 (each 9H, s, 2ꢁ Si-t-Bu, overlapped with H-18, 26a, 27a),
1.42 (3H, d, J = 7.0 Hz, H-21), 3.40 (3H, s, OMe, overlapped with
H-20), 4.38 (1H, m, H-1), 4.69 (2H, s, OCH2O), 4.17–4.34 (2H, m,
CH2OH), 4.82 (1H, m, H-3), 5.61 (1H, m, H-16), 5.72 (1H, m, C@CH),
5.94 (1H, d, J = 11.0 Hz, H-7), 6.14 (1H, d, J = 11.0 Hz, H-6). Z-iso-
mer: 1H NMR (CDCl3) d: 0.01–0.10 (12H, 4ꢁ Si-Me), 0.82, 0.93
(each 9H, s, 2ꢁ Si-t-Bu, overlapped with H-18, 26a, 27a), 1.42