Stereoselective synthesis of tacalcitol via (R)-MeCBS catalyzed borane reduction

Article abstract of DOI:10.1016/j.tetasy.2017.02.007

A novel and efficient approach for the synthesis of 1α, 24(R)-dihydroxyvitamin D₃ (tacalcitol) starting from readily available enone 1 has been achieved with high stereoselectivity. The key step involved in the synthesis of tacalcitol was the stereoselective reduction of enone 1 using borane as the reducing agent, and the effects of the critical reaction parameters such as temperature, various borane complexes have been examined. Finally, tacalcitol was obtained in five steps from enone 1 with an overall yield of 32% and a ratio of 24-R/S = 95/5.

Full text of DOI:10.1016/j.tetasy.2017.02.007

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of tacalcitol via (R)-MeCBS catalyzed borane
reduction
⇑
Hengrui Zhang, Wei Guo, Zhijie Fang
Department of Chemical Engineering, Nanjing University of Science & Technology, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient approach for the synthesis of 1a, 24(R)-dihydroxyvitamin D3 (tacalcitol) starting
Received 31 October 2016
Revised 21 January 2017
Accepted 8 February 2017
Available online xxxx
from readily available enone 1 has been achieved with high stereoselectivity. The key step involved in
the synthesis of tacalcitol was the stereoselective reduction of enone 1 using borane as the reducing
agent, and the effects of the critical reaction parameters such as temperature, various borane complexes
have been examined. Finally, tacalcitol was obtained in five steps from enone 1 with an overall yield of
32% and a ratio of 24-R/S = 95/5.
Ó 2017 Published by Elsevier Ltd.
OH
1. Introduction
The physiologically active form of vitamin D3, 1a,25-dihydroxy-
vitamin D3 (calcitriol) has exhibited various pharmacological
activities.1 As a consequence of its classical role in calcium
homeostasis and bone mineralization,2 calcitriol also regulates
the proliferation and differentiation of various types of cancer
cells3 and has been used as a potent drug for the treat of prolifer-
ative diseases such as psoriasis and leukemia.4 Inspired by this, the
syntheses of vitamin D3 analogues have been received considerable
attention and more than 3000 vitamin D3 analogues with different
structural modifications have been synthesized.5 Among these
HO
OH
Figure 1. Structure of tacalcitol.
analogues, tacalcitol (1a,24(R)-dihydroxyvitamin D3, Fig. 1), which
differs structurally from calcitriol by hydroxylation at the 24
position instead of the 25 position displays higher antiproliferative
activity and has been already used clinically for the treatment of
psoriasis.6
as a reducing agent.10 However, the stereoselective reduction of
the prochiral ketone intermediate of tacalcitol is still a difficult
problem that remains to be resolved.
To date, many efficient synthesis routes of tacalcitol have been
reported. The very first attempt to synthesize tacalcitol using
fucosterol as the starting material was reported in 1975, which
was obtained through chromatographic separation of a diastere-
omeric mixture.7 Fall et al. reported an efficient stereoselective
synthesis of tacalcitol through a convergent dienyne approach.8
Okamoto et al. achieved the total synthesis of tacalcitol via the pal-
ladium-catalyzed alkylative enyne cyclization reaction.9 Matsuo
and Ishibashi’s group later also accomplished its enantioselective
synthesis through asymmetric reduction of 24-oxocholesteryl ester
to 24(R)-hydroxycholesteryl ester by using borane-diethylaniline
Since our group has successfully synthesized several vitamin D
analogues,11 as a continuation, we herein report an efficient stere-
oselective synthesis of tacalcitol by (R)-MeCBS catalyzed asymmet-
ric reduction12 of enone 1 with borane as the reducing agent.
2. Results and discussion
2.1. Synthesis of (R)-alcohol by stereoselective reduction
The synthesis began from known enone 1, which was derived
from commercially available vitamin D2 by using our previously
reported procedures.10,11 In order to achieve a concise, flexible
approach for the synthesis of (R)-alcohol 4, two different synthetic
routes were investigated.
⇑
Corresponding author.
E-mail address: zjfang@njust.edu.cn (Z. Fang).
http://dx.doi.org/10.1016/j.tetasy.2017.02.007
0957-4166/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Zhang, H.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.007

2
H. Zhang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
OH
O
(a)
(b)
SBTO
OTBS
SBTO
OTBS
SBTO
OTBS
4
1
2
86%
24-R/S=71:29
Scheme 1. Synthetic route to the key intermediate 4. (a) Na2S2O4, NaHCO3, (C10H21)3NMeCl, PhCH3, H2O, 80 °C; (b) (S)-MeCBS, borane-THF, THF.
Table 1
The reducing agents effect on the enantioselectivity for reduction of ketone 2
Entry
Alcohol
Catalyst
Reducing agent
Temperature (°C)
Yield (%)
24-R/S
1
2
3
4
5
4
4
4
4
4
—
NaBH4
BH3-THF
BH3-Me2S
BH3-Et2NPh
Catecholborane
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
98
86
83
94
87
53/47
71/29
54/46
58/42
66/34
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
First, enone 1 was reduced with Na2S2O4 and NaHCO3 under
phase transfer conditions to give prochiral ketone 2 in a yield of
72% (Scheme 1).10,11 Then the prochiral ketone 2 was reduced to
give the (R)-alcohol 4 by the (S)-MeCBS catalyzed asymmetric
reduction using borane as the reducing agent. Prior to the prepara-
tion of (R)-alcohol 4, the effect of the critical reaction parameters
such as temperature, and various borane complexes have been
examined. In an initial study, the influence of various reducing
agents, including sodium borohydride, borane-THF, borane-Me2S,
and borane-Et2NPh was examined on the stereoselectivity of
reduction of prochiral ketone 2. The results are summarized in
Table 1. It was found that reduction with BH3-THF afforded the
reaction conditions for the borane reduction catalyzed by
(S)-MeCBS in hand (entry 4), the reaction was finally carried out
and the corresponding optically active alcohol 4 was obtained in
an excellent yield and a moderate stereoselectivity.
The second synthetic strategy was also attempted as depicted in
Scheme 2. Treatment of enone 1 in THF with (R)-MeCBS at ꢀ20 °C
provided compound 3 with an excellent yield of 95% and highly
stereoselectivity (24-R/S = 5:95), because the sizes of the aliphatic
vinyl groups on the side chain were more differentiated. Finally
the conversion of 3 into the corresponding (R)-alcohol 4 was read-
ily achieved in 70% yield under phase transfer conditions.
(R)-alcohol with
a
moderate stereoselectivity (24-R/S = 71/29,
2.2. Synthesis of tacalcitol by photo-isomerisation and
deprotection
entry 1), while the reaction with borane-Me2S borane-Et2NPh
and catecholborane provided less stereoselectivity. Since borane
complexes not only react with carbonyl, but also react with the
conjugated double bonds of the ketone 2, the results suggest that
the reducing agent borane-THF gives the (R)-alcohol in a better
reaction yield due to minimized side reactions.
To further optimize the reaction conditions of enone 1 reduc-
tion, we next examined the effect of temperature on the stereose-
lectivity and reaction yield. The results are summarized in Table 2.
When the temperature was decreased from 20 °C to 0 °C and
ꢀ20 °C, the product yield of the target compound greatly increased
from 0 to 38% and 86%, respectively. However, lowering the reac-
tion temperature did not improve the stereoselectivity and the
reaction a required longer reaction time. With the optimized
In order to synthesize the target compound, (R)-alcohol 4
was firstly subjected to photoisomerisation to give
5 using
9-acetylanthracene (9-AA) as sensitizer with the yield of 71%
(Scheme 3). Under similar reaction conditions to those described
earlier,10 5 was then subjected to remove the TBS protecting group
using tetrabutylammonium fluoride in THF. When, we tried to
remove the TBS protecting group prior to the photo-isomerisation
step, we found that the reactant and product were hard to
separate. At this point, the former scheme was used to obtain
the compound 6. Finally, tacalcitol was obtained by preparative
HPLC using
a chiralcel AYH column, ACN 100%, 30 mL/min,
retention time = 7.29 min.
Table 2
The temperature effect on the enantioselectivity for reduction of ketone 2
Entry
Alcohol
Catalyst
Time (min)
Temperature (°C)
Yield (%)
24-R/S
1
2
3
4
5
6
4
4
4
4
4
4
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
(S)-MeCBS
30
5
30
30
90
180
20
20
0
ꢀ20
ꢀ40
ꢀ40
—
—
38
86
83
87
—
—
70/30
71/39
69.5/30.5
70.5/29.5
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H. Zhang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
OH
OH
O
(a)
(b)
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
4
1
3
95%
24-R/S=5:95
Scheme 2. Synthetic route to the key intermediate 4. (a) (R)-MeCBS, borane-THF, THF; (b) Na2S2O4, NaHCO3, (C10H21)3NMeCl, PhCH3, H2O, 80 °C.
OH
OH
OH
OH
(c)
(b)
(a)
HO
OH
HO
OH
TBSO
OTBS
TBSO
OTBS
4
tacalcitol
6
5
Scheme 3. Synthetic route of tacalcitol. (a) 9-AA, hv, toluene, 20 °C; (b) n-Bu4NF, THF, 60 °C; (c) Pre-HPLC.
The solvent was removed under reduced pressure. The crude pro-
duct was purified by silica gel column chromatography (SiO2, PE:
Et2O = 100:3, v/v) to yield 2 as a colorless liquid (2.12 g, 73.4%).
3. Conclusion
In conclusion, tacalcitol was obtained by using enone 1 as start-
ing material in 32% overall yield in 5 steps, via a novel and concise
synthetic route. (R)-MeCBS catalyzed asymmetric reduction of
enone 1 was the key step. Our synthetic route is a viable route to
synthesize tacalcitol.
mp: 76–78 °C; ½a 2D0
ꢂ
= +38.1 (c 0.02, CDCl3), 1H NMR (500 MHz,
CDCl3): d 6.46 (d, 1H, J = 11.5 Hz), 5.82 (d, 1H, J = 11.5 Hz), 4.98
(s, 1H), 4.94 (s, 1H), 4.54 (m, 1H), 4.22 (m, 1H),1.09 (d, 6H,
J = 6.9 Hz), 0.92 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H), 0.86 (s, 9H), 0.54
(s, 3H); 13C NMR (125 MHz, CDCl3): d 215.5, 153.8, 143.4, 135.6,
121.8, 116.6, 106.7, 70.3, 67.3, 56.5, 46.0, 44.0, 41.0, 40.7, 37.4,
36.6, 35.8, 29.9, 29.1, 27.7, 26.0, 25.9, 23.6, 22.4, 18.7, 18.5, 18.4,
18.2, 12.1; HRMS [M+H]+: calcd for C39H70O3Si2 642.4863, Found
643.4927.
4. Experimental
4.1. General
All operations were carried out under an atmosphere of ultra-
high purity argon in oven-dried glassware. Most of the organic
compounds utilized in this study were commercial products of
the highest purity. The reactions were monitored by thin-layer
chromatography (TLC). 1H nuclear magnetic resonance (NMR) spec-
tra were recorded at 500 MHz with Bruker AvanceIII 500 MHz NMR
spectrometer in CDCl3. 13C nuclear magnetic resonance (NMR) were
recorded at 125 MHz with Bruker AvanceIII 125 MHz NMR spec-
trometer in CDCl3. All chromatographic experiments were carried
out using a liquid chromatographic system consisting of LC-20AT
separation module and ultraviolet detector SPD-20A (all Shimadzu,
Japan).
4.3. Synthesis of compound 4
To a solution of (S)-MeCBS (1 M in toluene, 0.2 mL) was added
to a solution of borane-THF (2 mol/L) in THF (0.2 mL) under argon
atmosphere. The reaction mixture was stirred for 2 h at rt and
cooled to ꢀ20 °C. To this mixture was added slowly a toluene solu-
tion of 2 (128 mg, 0.2 mmol) and stirred for 0.5 h at this tempera-
ture. The reaction was showed complete by TLC, then a solution of
ammonium chloride in water was added to this mixture, and stir-
red for additional 30 min. After this, another solution of ammo-
nium chloride in water (30 mL) was poured into this mixture.
The aqueous layer was extracted with ethyl acetate (3 ꢁ 20 mL),
which was in turn washed with saturated brine (2 ꢁ 20 mL)
and water (2 ꢁ 20 mL) and dried over sodium sulfate. The
solvent was evaporated under reduced pressure and purified by
chromatography (SiO2, PE: EA = 10:1, v/v) to give 4 as a colorless
4.2. Synthesis of compound 2
Enone 1 (2.88 g, 4.4 mmol) was added to the stirred mixture of
sodium bicarbonate (7.84 g. 45 mmol), sodium hyposulfite (7.56 g,
90 mmol) and methyltridecylammonium chloride (0.7 g) in
toluene (100 mL) and water (100 mL) at 80 °C. Upon completion
of reaction, extracted with EA (2 ꢁ 50 mL), washed with water
(2 ꢁ 60 mL), brine (2 ꢁ 60 mL) and dried over anhydrous Na2SO4.
liquid (110 mg, 86%). ½a D20
= ꢀ38.6 (c 0.02, CDCl3), the ratio of
ꢂ
24-R/S = 71/29, which was determined by HPLC analysis using a
Chiralcel OD column, hexane/iPrOH = 95:5, 0.1 mL/min [retention
times = 56.4 and 59.9 min for (R) and (S), respectively]. 1H NMR
Please cite this article in press as: Zhang, H.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.007

4
H. Zhang et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(500 MHz, CDCl3)
d
6.46 (d, 1H, J = 11.4 Hz), 5.83 (d, 1H,
preparative HPLC (Chiralcel AYH column, ACN100%, 30 mL/min,
retention time = 7.29 min) to give the target compound tacalcitol.
J = 11.5 Hz), 4.99 (s, 1H), 4.94 (s, 1H), 4.54 (m, 1H), 4.22 (m, 1H),
3.32 (m, 1H), 0.93 (m, 9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.55 (d, 3H,
J = 2.1 Hz). 13C NMR (125 MHz, CDCl3) d 152.7, 142.3, 134.4,
120.8, 115.5, 105.6, 76.4, 76.1, 69.2, 66.3, 55.5, 44.9, 42.9, 39.6,
35.5, 35.7, 32.6, 32.2, 31.2, 31.1, 29.8, 29.6, 27.5, 26.7, 26.6, 24.8,
21.9, 21.2, 17.9, 17.2, 17.1, 16.3, 15.7, 11.1, 5.8.
mp: 99–102 °C,
½
a 2D0
ꢂ
= +49.8 (c 0.02, CDCl3) {lit.9
½
a 2D0
ꢂ
= +54
6.37 (d, 1H,
(c 0.05, EtOH)}, 1H NMR (500 MHz, CDCl3)
d
J = 11.2 Hz), 6.02 (d, 1H, J = 11.1 Hz), 5.32 (s, 1H), 4.99 (s, 1H),
4.42 (m, 1H), 4.22 (m, 1H), 3.32 (m, 1H), 0.92 (m, 9H), 0.55
(s, 3H); 13C NMR (125 MHz, CDCl3) d 147.7, 143.1, 133.0, 124.9,
117.1, 111.8, 77.4, 70.7, 66.8, 56.3, 45.9, 45.2, 42.8, 40.5, 36.0,
33.6, 33.2, 32.0, 30.6, 29.1, 27.6, 23.6, 22.3, 18.9, 17.2, 16.7, 12.0.
MS [M+H]+: calcd for C27H44O3 416.32, Found 417.20.
4.4. Synthesis of compound 3
Similar to the synthesis of 4 from 2, we obtained the target
compound 3 (0.176 g, 0.27 mmol) from 1 (0.191 g, 0.3 mmol) in
95% yield and highly stereoselectivity (24-R/S = 5/95) as a white
Acknowledgement
solid. mp: 83–86 °C, ½a D20
ꢂ
= ꢀ49.2 (c 0.02, CDCl3). The ratio was
This work was supported by the prospective joint project of
Production, Education & Research in Jiangsu Province, China (Grant
No. BY2013004-02).
determined by HPLC analysis using
a
Chiralcel OD column,
hexane/iPrOH = 95:5, 0.1 mL/min [retention times = 58.4 and
62.2 min for (R) and (S), respectively], 1H NMR (500 MHz, CDCl3)
d 6.46 (d, 1H, J = 11.4 Hz), 5.83 (d, 1H, J = 11.5 Hz), 5.51 (dd, 1H,
J = 15.5, 8.4 Hz), 5.40 (dd, 1H, J = 15.4, 6.9 Hz), 4.99 (s, 1H), 4.94
(s, 1H), 4.54 (m, 1H), 4.22 (m, 1H), 3.78 (t, 1H, J = 6.4 Hz),
1.07 (d, 3H, J = 6.6 Hz), 0.94 (d, 3H, J = 6.7 Hz), 0.92 (s, 9H), 0.90
(d, 3H, J = 7.0 Hz), 0.89 (s, 9H), 0.58 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 153.6, 143.0, 139.5, 135.4, 128.7, 121.6, 116.4, 106.6,
78.5, 70.2, 67.2, 56.4, 55.9, 45.8, 43.9, 40.4, 40.3, 36.5, 33.9, 28.9,
28.0, 25.8, 25.7, 23.4, 22.2, 20.6, 18.3, 18.2, 18.1, 18.0, 12.2.
A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.02.
007.
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4.6. Synthesis of tacalcitol
To the stirred solution of alcohol 5 (645 mg, 1 mmol) in THF
(30 mL) was added 1 M tetrabutylammonium fluoride solution in
THF (5 mL, 5 mmol) under Ar. The reaction mixture was then stir-
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TLC, water (100 mL) was added to the reaction and extracted with
ethyl acetate (3 ꢁ 50 mL). The combined organic extract was
washed with saturated brine (2 ꢁ 20 mL) and water (2 ꢁ 20 mL)
and dried over sodium sulfate. The solvent was evaporated
under reduced pressure and purified by chromatography
(SiO2, PE: EA = 1:1, v/v) to give 6 as a white solid (279 mg, 67%).
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