Synthetic Strategies to Vitamin D Analogues
J . Org. Chem., Vol. 64, No. 9, 1999 3205
s, C18-CH3), 1.16 (6 H, s, C26,27-2CH3), 2.90 (1 H, dd, H14, J )
12.8, 5.5 Hz), 3.31 (3 H, s, MeO), 4.68 (1 H, s, OCH2O), 5.50 (1
H, d, H16, J ) 5.7 Hz), 5.65 (2 H, t, H20, J ) 7.5 Hz), 6.85 (1 H,
br s, NH), 7.21-7.38 (5 H, m, Ar). 13C NMR: 19.1 (CH3), 23.5
(CH2), 24.2 (CH2), 26.2 (CH3), 26.3 (CH3), 28.2 (CH2), 29.0
(CH2), 36.5 (CH2), 40.5 (CH2), 41.4 (CH2), 49.7 (C), 54.9 (OCH3),
58.7 (CH), 76.0 (C), 77.0 (CH), 90.9 (OCH2O), 118.7 (2 CHd
Ar), 123.3 (CHdAr), 129.0 (CHd), 129.8 (2 CHdAr), 138.2 (Cd
Ar), 147.4 (Cd), 153.4 (NCdO), 210.2 (CdO). HRMS: calcd
for C26H37NO5 + Na 466.2569, found 466.2569.
addition of the ketone 27d (362 mg, 0.82 mmol) in THF (2 mL).
The resulting solution was stirred for 1 h and then allowed to
warm to -20 °C. After 3 h, the reaction mixture was quenched
with H2O. The mixture was extracted with Et2O, and the
combined organic fractions were washed with brine, dried,
filtered, and concentrated in vacuo. The residue was flash
chromatographed (1-50% EtOAc/hexanes) to give 198 mg of
12d [30%, Rf ) 0.68 (20% EtOAc/hexanes), white solid]. 1H
NMR: 0.07 (12 H, s, 2 Me2Si), 0.78 (3 H, s, C18-CH3), 0.88 (18
H, s, 2 t-BuSi), 1.18 (6 H, s, C26,27-2CH3), 2.85 (1 H, m, H14),
3.31 (3 H, s, MeO), 4.21 (1 H, m, H3), 4.38 (1 H, m, H1), 4.67
(2 H, s, OCH2O), 4.85 (1 H, br s, H19Z), 5.19 (1 H, br s, H19E),
5.48 (1 H, d, H16, J ) 5.1 Hz), 5.62 (1 H, t, H20 J ) 7.3 Hz),
6.03 and 6.27 (2 H, AB pattern, H6 and H7, J ) 11.0 Hz), 6.94
(1 H, br s, NH), 7.03 (1 H, m, Ar), 7.26-7.41 (4 H, Ar, m). 13C
NMR: -4.5 (SiCH3), -4.4 (SiCH3), 18.4 (CSi), 18.5 (CH3), 23.6
(CH2), 24.9 (CH2), 26.1 (CH3 tBu), 26.6 (CH3), 26.6 (CH3), 28.6
(CH2), 29.0 (CH2), 32.0 (CH2), 38.5 (CH2), 41.7 (CH2), 45.3
(CH2), 46.6 (CH2), 47.0 (C), 53.8 (CH), 55.2 (OCH3), 68.0 (CH),
72.7 (CH), 76.4 (C), 78.1 (CH), 91.4 (OCH2O), 112.1 (CH2d),
118.9 (2 CHdAr), 123.3 (CHdAr), 123.5 (CHd), 129.4 (2 CHd
Ar), 129.8 (CHd), 136.4 (Cd), 139.1 (CdAr), 139.6 (Cd), 148.7
(Cd), 149.8 (Cd), 154.2 (NCdO). HRMS: calcd for C47H77NO6-
Si2 + Na 830.5187, found 830.5168.
A similar procedure was used to prepare compound 32d
[99%, Rf ) 0.46 (40% EtOAc/hexanes), colorless oil].
(17E)-17(20)-E n e-25-[(m et h oxym et h yl)oxy]-16r-[p h e-
n ylca r ba m oyl)oxy]-21-n or vita m in D3 ter t-Bu tyld im eth -
ylsilyl Eth er (29). A solution of n-BuLi (2.1 M in hexane, 1.40
mL, 2.94 mmol) was added dropwise via syringe to a solution
of the phosphine oxide 28 (1.34 g, 2.97 mmol) in THF (30 mL)
at -78 °C. The resulting deep red solution was stirred for 1 h
followed by the slow addition of the ketone 27d (347 mg, 0.78
mmol) in THF (5 mL). The resulting solution was stirred for
3 h and then allowed to warm to -40 °C. After 2 h, the reaction
mixture was quenched with H2O. The mixture was extracted
with Et2O, and the combined organic fractions were washed
with brine, dried, filtered, and concentrated in vacuo. The
residue was flash chromatographed (1-50% EtOAc/hexanes)
to give 287 mg of 29 [54%, Rf ) 0.66 (20% EtOAc/hexanes),
white solid] and of phosphine 28. 1H NMR: 0.055 (3 H, s,
MeSi), 0.06 (3 H, s, MeSi), 0.80 (3 H, s, C18-CH3), 0.88 (9 H, s,
t-BuSi), 1.20 (6 H, s, C26,27-2CH3), 2.85 (1 H, m, H14), 3.29 (3
H, s, MeO), 4.82 (1 H, m, H3), 4.64 (2 H, s, OCH2O), 4.75 (1 H,
br s, H19Z), 5.01 (1 H, br s, H19E), 5.45 (1 H, d, H16, J ) 5.8 Hz),
5.60 (1 H, t, H20, J ) 7.5 Hz), 6.01 and 6.15 (2 H, AB pattern,
H6 and H7, J ) 11.4 Hz), 6.67 (1 H, br s, NH), 6.99-7.39 (5 H,
m, Ar). 13C NMR: -4.5 (SiCH3), 18.4 (CSi), 18.5 (CH3), 23.6
(CH2), 24.8 (CH2), 26.0 (CH3-26 and 27), 26.5 (CH3), 26.6 (CH3),
28.6 (CH2), 29.0 (CH2), 32.1 (CH2), 32.9 (CH2), 36.7 (CH2), 38.4
(CH2), 41.7 (CH2), 46.9 (CH2), 47.2 (C), 53.7 (CH), 55.2 (CH3),
70.9 (CH), 76.4 (C), 78.1 (CH), 91.4 (CH2), 112.5 (CH2d), 118.9
(2 CHdAr), 121.5 (CHd), 123.5 (CHdAr), 129.4 (CHd), 129.7
(CHdAr), 137.8 (CdAr), 139.4 (Cd), 139.8 (Cd), 146.1 (Cd),
149.6 (Cd), 154.2 (NCdO).
A similar procedure was used to prepare compound 13d
[26%, Rf ) 0.73 (20% EtOAc/hexanes), white solid].
(17E)-8â-[(ter t-Bu t yld im et h ylsilyl)oxy]-16r-[(2′,2′-d i-
m eth ylpr opan oyl)oxy]-25-[(m eth oxym eth yl)oxy]-des-A,B-
21-n or ch olest-17(20)-en e (8b). A solution of 8a (450 mg, 1.02
mmol) in Py (16 mL) was treated with DMAP (10 mg) and
pivaloyl chloride (0.63 mL, 5.1 mmol) at 0 °C. After 14 h, the
reaction was treated with aqueous HCl (10%). The mixture
was extracted with Et2O, and the combined organic layers were
washed sequentially with HCl (10%), H2O, and an aqueous
saturated solution of CuSO4 and H2O. The etheral extract was
dried, filtered, and concentrated in vacuo. Flash chromatog-
raphy (5% EtOAc/hexanes)afforded 514 mg of pure 8b [96%,
1
Rf ) 0.73 (20% EtOAc/hexanes), colorless oil]. H NMR: 0.01
and 0.02 (6 H, 2 s, Me2Si), 0.88 (9 H, s, t-BuSi), 1.11 (3 H, s,
C18-CH3), 1.18 (9 H, s, t-BuCO), 1.20 (6 H, s, C26,27-2CH3), 2.00-
2.23 (3 H, m, 2H22 and H14), 3.36 (3 H, s, MeO), 4.08 (1 H, m,
H8), 4.69 (2 H, s, OCH2O), 5.23 (1 H, dt, H20, J ) 7.6 Hz, 1.3
Hz), 5.47 (1H, dd, H16, J ) 6.3 Hz, 1.3 Hz). 13C NMR: -5.2
(SiCH3), -4.9 (SiCH3), 17.7 (CH2), 17.9 (CSi), 21.1 (CH3), 24.6
(CH2), 25.7 (CH3 tBuSi), 26.2 (CH3-26 and -27), 27.1 (CH3 Piv),
27.6 (CH2), 32.5 (CH2), 34.1 (CH2), 38.2 (CH2), 38.3 (C), 41.5
(CH2), 44.2 (C), 49.6 (CH), 55.0 (OCH3), 69.2 (CH), 75.4 (CH),
76.2 (C), 90.9 (OCH2O), 125.4 (CHd), 149.8 (Cd), 178.5 (Cd
(20S)-16-En e-25-[(m eth oxym eth yl)oxy]vita m in D3 ter t-
Bu tyld im eth ylsilyl Eth er (30). A solution of MeLi (1.5 M
in Et2O, 160 mL, 0.24 mmol) was added via syringe to a
suspension of CuBr (21 mg, 0.15 mmol) in Et2O (1 mL) at 0
°C. After 1 h, a solution of 29 (33 mg, 0.05 mmol) in Et2O (1
mL) was added, and the mixture was stirred at room temper-
ature for 5 h in the dark. The reaction was quenched with
aqueous NH4Cl, and the mixture was extracted with Et2O. The
combined ethereal layers were washed with a saturated
solution of NaHCO3, dried, and concentrated in vacuo. The
residue was flash chromatographed (3% EtOAc/hexanes) to
give 24 mg of 30 [89%, Rf ) 0.67 (20% EtOAc/hexanes), white
O). HRMS: calcd for
547.3775.
C30H56O5Si + Na 547.3794, found
A similar procedure was used to prepare compound 9b [97%,
Rf ) 0.72 (20% EtOAc/hexanes), colorless oil].
1
(17E)-16r-[(2′,2′-Dim et h ylp r op a n oyl)oxy]-25-[(m et h -
oxymethyl)oxy]-des-A,B-21-norcholest-17(20)-en-8â-ol(34b).
A solution of TBAF (1 M in THF, 4.65 mL, 4.65 mmol) was
added via syringe to a solution of 8b (400 mg, 0.76 mmol) in
THF (1 mL). The resulting mixture was refluxed for 20 h, and
then a saturated solution of NaHCO3 was added. The aqueous
phase was extracted with Et2O. The combined organic extracts
were dried, filtered, and concentrated in vacuo. The residue
was flash chromatographed (15% EtOAc/hexanes) to afford 288
mg of 34b [92%, Rf ) 0.26 (30% EtOAc/hexanes), colorless oil].
1H NMR: 1.14 (3 H, s, C18-CH3), 1.17 (9 H, s, t-BuCO), 1.19 (6
H, s, C26,27-2CH3), 2.03-2.21 (3 H, m, 2H22 and H14), 3.34 (3
H, s, MeO), 4.16 (1 H, m, H8), 4.68 (2 H, s, OCH2O), 5.27 (1 H,
dt, H20, J ) 7.5 Hz, 1.3 Hz), 5.50 (1H, d, H16, J ) 6.4 Hz). 13C
NMR: 17.5 (CH2), 20.7 (CH3), 24.5 (CH2), 26.2 (CH3-26 and
27), 27.0 (CH3 Piv), 27.6 (CH2), 32.0 (CH2), 33.5 (CH2), 37.9
(CH2), 38.5 (C), 41.5 (CH2), 43.9 (C), 49.2 (CH), 55.0 (OCH3),
69.0 (CH), 75.1 (CH), 76.1 (C), 90.9 (OCH2O), 126.0 (CHd),
149.4 (Cd), 178.5 (CdO). HRMS: calcd for C24H42O5 + Na
433.2930, found 433.2938.
solid]. H NMR: 0.04 (3 H, s, MeSi), 0.05 (3 H, s, MeSi), 0.67
(3 H, s, C18-CH3), 0.87 (9 H, s, t-BuSi), 1.02 (3 H, d, C21-CH3,
J ) 6.9 Hz), 1.16 (6 H, s, C26,27-2CH3), 2.80 (1 H, dd, H14, J )
12.5, 4.4 Hz), 3.29 (3 H, s, MeO), 3.84 (1 H, m, H3), 4.63 (2 H,
s, OCH2O), 4.76 (1 H, d, H19Z, J ) 1.6 Hz), 5.01 (1 H, d, H19E
,
J ) 1.2 Hz), 5.30 (1 H, br s, H16), 6.09 and 6.16 (2 H, AB
pattern, H6 and H7, J ) 11.2 Hz). 13C NMR: -4.6 (SiCH3), -4.5
(SiCH3), 17.4 (CH3), 18.4 (CSi), 21.4 (CH3), 22.3 (CH2), 23.9
(CH2), 26.0 (CH3 tBu), 26.5 (CH3-26 and 27), 29.0 (CH2), 29.7
(CH2), 32.5 (CH), 32.9 (CH2), 35.8 (CH2), 36.7 (CH2), 38.1 (CH2),
42.3 (CH2), 47.1 (CH2), 50.5 (C), 55.1 (OCH3), 58.6 (CH), 70.8
(CH), 76.3 (C), 91.2 (OCH2O), 112.2 (CH2d), 118.0 (CHd),
120.6 (CHd), 121.8 (CHd), 138.8 (Cd), 141.4 (Cd), 146.0 (Cd
), 161.1 (Cd). HRMS: calcd for C35H60O3Si 556.4311, found
556.4298.
(17E)-1r-[(ter t-Bu t yld im et h ylsilyl)oxy]-17(20)-en -25-
[(m eth oxym eth yl)oxy]-16r-[(p h en ylca r ba m oyl)oxy]-21-
n or vita m in D3 ter t-Bu tyld im eth ylsilyl Eth er (12d ). A
solution of n-BuLi (2.15 M in hexanes, 1.1 mL, 2.36 mmol)
was added dropwise via syringe to a THF solution of the
phosphine oxide 7 (2.30 mmol, 2.30 mL, 1 M) at -78 °C. The
resulting reddish solution was stirred for 1 h followed by the
slow
A similar procedure was used to prepare compound 35b
[97%, Rf ) 0.27 (30% EtOAc/hexanes), colorless oil].