Selective capture of 1α,25-(OH)2-previtamin D3 utilizing polymer-supported trialkylsilyl triflate in the synthesis of 1α,25-(OH)2-vitamin D3

Article abstract of DOI:10.1016/j.tetlet.2004.05.125

Catch and release method utilizing polymer-support was investigated in the separation of 1α,25-(OH)₂ pre- and provitamin D₃. Polymer-supported alkyldiisopropylsilyl triflate selectively captured the previtamin D₃ from a 26:74 mixture of pre- and provitamin D ₃ produced by photoisomerization of provitamin D₃.

Full text of DOI:10.1016/j.tetlet.2004.05.125

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5727–5729
Selective capture of 1a,25-(OH)2-previtamin D3 utilizing
polymer-supported trialkylsilyl triflate in the synthesis
of 1a,25-(OH)2-vitamin D3
Takayuki Doi, Masahito Yoshida, Ichiro Hijikuro and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro, Tokyo 152-8552, Japan
Received 31 March 2004; revised 13 May 2004; accepted 17 May 2004
Abstract—Catch and release method utilizing polymer-support was investigated in the separation of 1a,25-(OH)2 pre- and pro-
vitamin D3. Polymer-supported alkyldiisopropylsilyl triflate selectively captured the previtamin D3 from a 26:74 mixture of pre- and
provitamin D3 produced by photoisomerization of provitamin D3.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The hormonally active metabolite of vitamin D3, 1a,25-
(OH)2-vitamin D3 (1), has a broad spectrum of biolog-
ical activities such as cell differentiation, regulation of
calcium metabolism and immune system.1 Photo- and
thermal-isomerization of provitamin D3 are conven-
tional methods for the production of vitamin D3 deriv-
atives due to the facile availability of the starting
compounds.2;3 In this synthesis, photo-isomerization of
1a,25-(OH)2-provitamin D3 (2) provides 1a,25-(OH)2-
previtamin D3 (3), which undergoes subsequent thermal-
isomerization leading to 1a,25-(OH)2-vitamin D3 (1).
The problem, however, is the low yield of the desired 1
due to lack of selectivity in the photo-isomerization step
and difficulty of the separation of the isomers produced.
Normally, conversion of 2 would give not only the de-
sired 3 but also tachysterol 4 and lumisterol 5 through
the equilibrium of the products. Therefore, extensive
studies have been reported to resolve this problem.3;4
We focused on the steric hindrance of a hydroxy group
at the Cl position. The 1a-OH groupof provitamin D
2
3
has an axial orientation and is covered by a steroid
skeleton, whereas that of previtamin D3 3 would be less
hindered because the B-ring is expanded by photo-
isomerization. Therefore, it is expected that the less
hindered 1a-OH groupof 3 can be selectively captured
from a mixture of 2 and 3 by polymer-supported trialk-
ylsilyl triflate.6 Subsequently, the previtamin D3 3 could
be released from the polymer-support by treatment with
acid.7 We investigated the selective capture utilizing
three sterically distinct alkyl-substituted silyl triflates on
polymer-supports 6, which are employed for simple
purification (Scheme 1).
Preparation of 10 is shown in Scheme 2. Tosylation of 78
using DMAP, followed by hydrolysis of methyl car-
bonates with KOH afforded diol 8 in 92% yield. Selec-
tive protection of the C-3 hydroxy group with TESCl
and imidazole at )78 ꢁC provided 9. Alkylation of tos-
ylate 9 with 3-methyl-3-(trimethylsilyl)butylmagnesium
bromide at the C-22 position in the presence of copper
catalyst7 furnished the desired 10 in 54% overall yield.9
Our solution for the synthesis of 1a-(OH) derivatives is
the development of a versatile method for the separation
from a mixture of pro- and previtamin D3 derivatives 2
and 3 produced in the early stage of the photo-isomer-
ization. In this paper, we wish to report a catch and
release method5 by selective capture of the previtamin
D3 3 utilizing polymer-supported trialkylsilyl triflate.
Photo-isomerization of 10 was carried out in THF using
high pressure mercury lump with Vycor filter at )8 ꢁC
for 30 min. A mixture of previtamin D3 produced and
the remaining starting provitamin D3 (11:10 ¼ 26:74,
HPLC ratio),10 was treated with polystyrene based silyl
triflate resin 6 (1.3 equiv for previtamin D3) and 2,6-
lutidine at room temperature for 12 h. The resin was
* Corresponding author. Tel.: +81-3-5734-2120; fax: +81-3-5734-2884;
e-mail: ttak@apc.tiitech.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.125

5728
T. Doi et al. / Tetrahedron Letters 45 (2004) 5727–5729
less
OH
HO
hindered
hindered
H
HO
hν
HO
hν
HO
OH
OH
OH
1
1
B
HO
HO
OH
HO
1α,25-(OH)2-
1α,25-(OH)2-
previtaminD3 (3)
1α,25-(OH)2-
tachysterol (4)
1α,25-(OH)2-
lumisterol (5)
v
(2)
3
∆
R
R
Si
selective caputure
and release
OTf
n
PS
OH
H
6a R = i-Pr, n = 3
6b R = Et, n = 1
6c R = Ph, n = 3
∆
3
1α,25-(OH)2-
vitaminD3 (1)
HO
OH
Scheme 1. Photo- and thermal-isomerization of provitamin D3 to vitamin D3.
O
OTs
OH
HO
MeO
O
O
a
b
HO
MeO
O
8
7
OTs
HO
HO
c
OTMS
TESO
TESO
9
10
d
HO
OTMS
10
+
TESO
11
Scheme 2. (a) (i) TsCl, DMAP, CH2Cl2, rt, 4 h; (ii) KOH, MeOH–
THF (1:1), 45 ꢁC. (b) TESCl, imidazole, CH2Cl2, )78 ꢁC. (c)
BrMgCH2CH2C(CH3)2OTMS, CuBrÆMe2S (12 mol %), THF, rt, 1 h.
(d) hm, THF, )8 ꢁC.
filtered and washed with CH2Cl2 and the unreacted
mixture was recovered from the filtrate. Release of the
captured alcohols was carried out by treatment with
HFÆPy at room temperature for 12 h. The cleavage
solution obtained was analyzed by HPLC to determine
the ratio of the captured previtamin D3 and provitamin
D3. The results were depicted in Figure 1. PS-DIPS resin
6a (R ¼ i-Pr, 0.6 mmol/g)11 captured the products total-
ing 17% yield with high selectivity (3:2 ¼ 92:8, Fig. 1a).12
This catch and release method was repeated for the
recovered mixture to afford another 4% of 3 and 2 in a
ratio of 82:18. Alternatively, 3 was obtained in overall
21% (90% purity, 81% yield based on the 26:74 mixture
of 11 and 10), and 10 (76%) was recovered from the
filtrate. The 3 obtained by the catch and release method
was heated at 80 ꢁC to provide 1a,25-(OH)2-vitamin D3
(1) in quantitative yield.12 On the other hand, commer-
cially available PS-DESTM resin 6b (R ¼ Et, 0.96 mmol/
g),13 captured not only previtamin D3 but also provita-
Figure 1. Analytical HPLC of the catch and release product was
performed using InertsilTM ODS-3 3 lm, 4.6 · 75 mm, and linear gra-
dients of 0.1% formic acid in acetonitrile and 0.1% aqueous formic acid
were run at 1.0 mL/min flow rate from 1:9 for 1 min, 1:9 to 1:0 over
4 min, and then 1:0 for 7 min. Figure 1a (above) result using PS-DIPS
resin 6a, 3:2 ¼ 92:8. Figure 1b (below) result using PS-DES resin 6b,
3:2 ¼ 55:45.
min D3 (3:2 ¼ 55:45, Fig. 1b) in 34% yield (90% based on
the used amount of 6b). Presumably, steric effect of the
isopropyl group rather than the ethyl group on a silicon
atom is important in this selection. This application
using PS-DPS resin 6c (R ¼ Ph, 0.65 mmol/g),11 pro-
vided a complex mixture of unknown compounds (data
now shown).

T. Doi et al. / Tetrahedron Letters 45 (2004) 5727–5729
5729
5. Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem.
Eur. J. 2000, 6, 4445–4450.
In summary, we have demonstrated the selective capture
of 1a,25-(OH)2-previtamin D3 (3) utilizing alkyldiiso-
propylsilyl triflate on polymer-support. Since thermal-
isomerization of previtamin D3 affords vitamin D3, this
catch and release method can be an important protocol
in the synthesis of 1a,25-(OH)2-vitamin D3.
6. A bulky trialkylsilyl groupwas used for the selective
protection of ring-opened compounds at the 1a-(OH)
group, mainly vitamin D3. The fully protected vitamin D3
derivative was isolated by silica gel column chromatogra-
phy. See Ref. 3.
7. Doi, T.; Hijikuro, I.; Takahashi, T. J. Am. Chem. Soc.
1999, 121, 6749–6750.
8. (a) Takahashi, T.; Nakagawa, N.; Minoshima, T.; Ya-
mada, H.; Tsuji, J. Tetrahedron Lett. 1990, 31, 4333–4336;
(b) Nakagawa, N. Ph.D. thesis, 1990, University of Tokyo.
Acknowledgements
1
9. Compound 10: H NMR (270 MHz, CDCl3) d 5.62 (br d,
We are grateful to Kuraray Co., Ltd for kindly pro-
viding the steroidal C(22)-alcohol.
J ¼ 3:6 Hz, 1H), 5.39 (m, 1H), 4.05 (m, 1H), 3.77 (br s,
1H), 1.20 (s, 6H), 0.99 (d, J ¼ 7:6 Hz, 3H, f), 0.96 (t,
J ¼ 7:9 Hz, 9H), 0.88 (s, 3H), 0.63 (q, J ¼ 7:9 Hz, 6H),
0.61 (s, 3H), 0.10 (s, 9H). 13C NMR (67.8 MHz, CDCl3) d
141.6, 137.1, 120.9, 115.1, 74.3, 73.9, 60.5, 56.1, 54.9, 45.4,
43.1, 42.8, 40.5, 39.3, 37.6, 36.5, 36.3, 30.0, 28.3, 23.2, 21.0,
20.7, 18.9, 16.5, 12.1, 7.3, 5.3, 2.8.
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