S. Feng et al. / Chinese Chemical Letters 25 (2014) 771–774
773
magnesium sulfate, and evaporated under reduced pressure at
0 8C. The product was purified on a chromatographic column
using silica gel with mixtures of ethyl acetate in hexane to give
apparatus equipped with a high-pressure mercury lamp at 0–5 8C
for about 1 h. The reaction progress was checked by HPLC (99.8%),
then evaporated under reduced pressure at 32 8C. The product was
purified on a chromatographic column using silica gel with
mixtures of ethyl acetate in hexane (1:1) to give 19.3 g of 1 as a
white solid (yield 92%).
4
4
0.3 g of 16 as light yellow oil (yield 78%).
2
0
1
1
6: ½
aꢂ
þ82:1 (c 1.0, CH
3 3
Cl); H NMR (400 MHz, CDCl ): d
D
ꢁ
0.00 (s, 3H), ꢁ0.06 (s, 3H), 0.48 (s, 3H), 0.82 (s, 9H), 0.72–0.97 (m,
2
0
1
2
2
2
H), 1.13 (d, 3H, J = 6 Hz), 1.17 (s, 3H), 1.18 (s, 3H), 1.19–1.27 (m,
H), 1.41–1.98 (m, 12H), 2.17–2.22(m, 1H) 2.39–2.42 (m, 1H),
.56–2.61 (m, 1H), 2.78–2.82 (m, 1H), 3.17–3.21 (m, 1H), 3.41–3.44
1: Mp: 122–124 8C;
½
a
ꢂ
þ37:9 (c 1.0, CH
3
Cl); H NMR
D
(400 MHz, DMSO-d ):
6
d 0.49 (s, 3H), 1.08 (s, 6H), 1.09 (d, 3H,
J = 1.6 Hz), 1.22–1.28 (m, 1H), 1.39–1.65 (m, 10H), 1.79–1.84 (m,
3H), 1.93–1.99 (m, 1H), 2.15–2.20 (m, 1H), 2.35–2.37 (m, 1H),
2.78–2.81 (m, 1H), 3.18–3.21 (m, 1H), 3.25–3.31 (m, 1H), 3.60(q,
1H, J = 7.6 Hz), 3.99–4.04 (m, 1H), 4.12(s, 1H), 4.18–4.21 (m, 1H),
4.54 (d, 1H, J = 4 Hz), 4.76 (s, 1H), 4.86 (d, 1H, J = 4.4 Hz), 5.23 (s,
(
m, 1H), 3.77–3.81 (m, 3H), 4.58 (s, 1H), 4.86 (s, 1H), 5.80 (d, 1H,
13
3
J = 11.2 Hz), 6.39 (d, 1H, J = 11.6 Hz); C NMR (100 MHz, CDCl ): d
ꢁ
4.7, ꢁ4.6, 12.7, 18.2, 18.8, 22.2, 23.2, 25.9(3C), 26.0, 28.8, 29.1,
2
7
9.4, 31.2, 35.2, 37.5, 39.6, 41.5, 44.7, 56.2, 57.1, 65.6, 69.4, 70.5,
13
9.0, 107.6, 116.5, 119.9, 136.5, 142.8, 150.0; MS (ESI) m/z: 517
1H), 5.99 (d, 1H, J = 11.2 Hz), 6.18 (d, 1H J = 11.2 Hz); C NMR
(100 MHz, DMSO-d ): 12.3, 19.1, 21.8, 22.9, 24.7, 28.3, 29.6, 29.7,
+
[
M+H] .
6
d
(1S),(3R)-3-tert-Butyldimethylsilyloxy-22-oxa-1,25-dihydroxy-
38.9, 43.1, 43.2, 44.1, 44.9, 55.5, 56.8, 64.3, 65.1, 68.2, 68.4, 76.7,
9
,10-secopregna-5,7(E),10(19)-triene (17): 16 (41.2 g, 80 mmol)
109.8, 117.8, 122.4, 135.9, 139.6, 149.5; MS (ESI) m/z: 441
+
was dissolved in methylene chloride (500 mL), and NMO (18.7 g,
60 mmol) and SeO (4.4 g, 40 mmol) were dissolved into the
[M+Na] ; HRMS (ESI) m/z calcd. for
C
26
H
42
O
4
:
441.2981
+
1
2
R
[M+Na] , found: 441.2945; t = 8.45 min.
reaction. The reaction mixture was warmed to reflux and stirred at
this temperature for 5 h. When the reaction was completed, the
mixture was treated with water (250 mL), the organic phase was
separated, and the aqueous residue was extracted with methylene
chloride (100 mL). The methylene chloride phase was dried over
anhydrous magnesium sulfate and filtered. The solvent was
evaporated under reduced pressure at 38 8C. The product was
purified on a chromatographic column using silica gel with
mixtures of ethyl acetate in hexane to give 20.4 g of 17 as colorless
oil (yield 48%).
3. Results and discussion
The synthetic strategy for the stereoselective synthesis of 1
starts from commercially available ergocalciferol. The route
involves modification of the side chain present in the ring vitamin
2
D precursor to a 1S-formylethyl group followed by elaboration of
the new side chain present in the particular target compound. The
synthesis the rest of the full vitamin D skeleton must be elaborated.
We knew oxygen and light will destroy the sensitive triene system.
2
0
1
0
1
7: ½
0.01 (s, 6H), 0.46 (s, 3H), 0.83 (s, 9H), 1.12 (d, 3H, J = 6 Hz), 1.16 (s,
H), 1.17 (s, 3H), 1.18–1.27 (m, 2H), 1.42–1.97 (m, 14H), 2.31–2.37
m, 1H), 2.43–2.47 (m, 1H), 2.77–2.81 (m, 1H), 3.16–3.20 (m, 1H),
.41–3.44 (m, 1H), 3.75–3.80 (m, 2H), 4.11–4.14 (m, 1H), 4.41–4.44
m, 1H), 4.88 (s, 1H), 4.99 (s, 1H), 5.78 (d, 1H, J = 11.6 Hz), 6.42 (d,
a
ꢂ
þ159:3 (c 1.0, CH
3
Cl); H NMR (400 MHz, CDCl
3
):
d
The synthesis of 11 or 11 employed a modification of Calverley’s
D
ꢁ
procedure and the new side chain in question [12].
3
In our present work (Scheme 2), the hydroxyl group in ring A of
ergocalciferol was protected with a TBS group with TBSCl and
imidazole in dichloromethane. Due to the instability of the triene
(
3
(
moiety of the vitamin D nucleus, we prepared epimeric SO
2
13
0
1
1
4
1
H, J = 11.6 Hz); C NMR (100 MHz, CDCl
8.1, 18.8, 22.2, 23.2, 25.9(3C), 26.0, 28.9, 29.1, 29.4, 37.0, 39.6,
1.5, 42.9, 44.8, 56.2, 57.1, 65.6, 66.8, 70.5, 70.6, 79.0, 107.7, 116.6,
3
):
d
ꢁ4.8, ꢁ4.7, 12.6,
adducts 10 or 10 through Diels–Alder reaction by bubbling SO
2
gas
into the dual-solvent system of water and dichloromethane (1:4)
at room temperature. Then the resulting sulfone was ozonized in
dichloromethane with pyridine at ꢁ65 8C to give the aldehydes 11
+
22.2, 134.6, 143.3, 153.1; MS (ESI) m/z: 555 [M+Na] .
0
1
(S),(3R)-1,3,25-Trihydroxy-9,10-secopregna-5,7(E),10(19)-tri-
ene (18): 17 (26.6 g, 50 mmol) and tetrabutyl ammonium fluoride
19.5 g, 75 mmol) were dissolved in THF (270 mL), and the reaction
or 11 . In each of the above reactions, the mixture was washed with
water, the aqueous layer was extracted with dichloromethane, and
the combined organic phase was dried over anhydrous magnesium
sulfate, filtered, and concentrated to afford colorless or light yellow
oils. An oxygenation procedure was taken to produce isomers 12
(
mixture was refluxed for 8 h. After cooling to room temperature
the organic layer was evaporated under reduced pressure at 40 8C.
The residue was dissolved in ethyl acetate (150 mL), transferred to
a separatory funnel, and washed with water (80 mL) and saturated
sodium chloride solution (80 mL). The ethyl acetate phase was
dried over anhydrous magnesium sulfate and filtered, and the
evaporation afforded the crude oil carbinol 18. The product was
purified on a chromatographic column using silica gel with
mixtures of ethyl acetate in hexane to give 18.0 g of 18 as a
colorless oil (yield 86%).
0
0
and 12 [13]. Although the methyl ketone reduction of 12 or 12
treated with NaBH could yield 13, the products were isomers with
4
the undesired R type as the major part [14]. In order to obtain the
desired 20(S)-alcohol 13 or 13 with high purity, an asymmetric
synthetic strategy was employed. 13 or 13 was introduced by the
0
0
(R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 12
0
or 12 using borane tetrahydrofuran complex (1 mol/L THF) as the
2
reducing agent [15]. After the extrusion of SO , the important
2
D
0
1
1
8: ½
aꢂ
þ168:2 (c 1.0, MeOH); H NMR (400 MHz, CDCl
3
):
d
intermediate 20(S)-alcohol 14 was afforded. Due to the fact that
the epoxide exhibits high reactivity toward primary and secondary
alcohols under Williamson conditions to give the corresponding
ether, 3-(bromomethyl)-2,2-dimethyloxirane was chosen as the
alkylating agent to react with the secondary alcohol 14 to afford
the epoxy-ether 15, which subsequently reacted with the boron
reagents to give tertiary alcohol 16 as the major product [16].
Alcohol 16 was produced in one pot from 14 with lithium sec-
butylborohydride(L-Selectride) in THF at room temperature [17].
16 was oxidized at C1 position with selenium dioxide and N-
methylmorpholine-N-oxide (NMO) under reflux in methylene
chloride to produce 17 [18]. The subsequent desilylation of 17 with
tetrabutylammonium fluoride yielded 18 in THF. Triplet-sensitized
photoisomerization is well-known for the conversion of
0
1
1
3
1
.54 (s, 3H), 1.19 (s, 3H, J = 5.6 Hz), 1.23 (s, 6H), 1.24–1.37 (m, 2H),
.48–2.08 (m, 13H,), 2.24–2.30 (m, 1H), 2.55(s, br, 1H), 2.65 (s, br,
H), 2.81–2.88 (m, 2H), 3.24–3.27 (m, 1H), 3.46–3.51 (m, 1H),
.82–3.90 (m, 2H), 4.19–4.23 (m, 1H), 4.47–4.49 (m, 1H), 4.96 (s,
H), 5.10 (s,1H), 5.89 (d, 1H, J = 11.2 Hz), 6.55 (d, 1H, J = 11.2 Hz);
13
3
C NMR (100 MHz, CDCl ): d 12.8, 18.9, 22.2, 23.2, 25.8, 28.9, 29.1,
2
7
9.2, 38.7, 39.5, 41.5, 41.9, 44.8, 56.2, 57.1, 65.5, 65.6, 70.7, 70.8,
8.9, 109.5, 116.5, 122.8, 133.5, 144.0, 151.8; MS (ESI) m/z: 441
+
+
[
M+Na] ; HRMS (ESI) m/z calcd. for C26
found: 441.2928; t = 8.52 min.
,25-Dihydroxy-22-oxavitamin D
0 mmol) and 9-acetyl anthracene (2.1 g, 10 mmol) were dissolved
in acetone (3 L). The mixture was stirred and irradiated in a quartz
42 4
H O : 441.2981 [M+Na] ,
R
1a
3
(1): The triol 18 (21 g,
5