Total synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)

Article abstract of DOI:10.1016/j.tet.2020.131081

A convergent method for the synthesis of ED-71 has been developed. Starting from the reported epoxide 5 which could be easily prepared from D-mannitol, ED-71 was synthesized in 11 linear steps with 17% overall yield.

Full text of DOI:10.1016/j.tet.2020.131081

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Total synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D (ED-71)
3
Wutong Deng, Qingyin Pu, Yimou Gong, Li Zhou, Jian Sun, Chao Wang
PII:
S0040-4020(20)30202-7
https://doi.org/10.1016/j.tet.2020.131081
TET 131081
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 January 2020
Revised Date: 5 February 2020
Accepted Date: 24 February 2020
Please cite this article as: Deng W, Pu Q, Gong Y, Zhou L, Sun J, Wang C, Total synthesis of 1α,25-
dihydroxy-2β-(3-hydroxypropoxy)vitamin D (ED-71), Tetrahedron (2020), doi: https://doi.org/10.1016/
3
j.tet.2020.131081.
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Total synthesis of 1ꢀ,25-dihydroxy-2ꢁ
-(3-hydroxypropoxy)vitamin D3 (ED-71)
Wutong Denga,b, Qingyin Pua, Yimou Gonga, Li Zhoua, Jian Suna, and Chao Wanga
aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu
610041, China. bUniversity of Chinese Academy of Sciences, Beijing 100049, China

1
Tetrahedron
journal homepage: www.elsevier.com
Total synthesis of 1ꢀ,25-dihydroxy-2ꢁ-(3-hydroxypropoxy)vitamin D3 (ED-71)
Wutong Denga,b, Qingyin Pua, Yimou Gonga, Li Zhoua, Jian Suna, and Chao Wanga
aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
bUniversity of Chinese Academy of Sciences, Beijing 100049, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convergent method for the synthesis of ED-71 has been developed. Starting from the reported
epoxide 5 which could be easily prepared for D-mannitol, ED-71 was synthesized in 11 linear
steps with 17% overall yield.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
ED-71
Convergent synthesis
Vitamin D3
Osteoporosis
Eldecalcitol
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
1. Introduction
2. Results and discussion
Osteoporosis[1] is a condition in which bone becomes porous
and fragile, leading to loss of bone mineral density that can result
in bone fracture, a common disease of elder patients, associated
with pain and a decrease in physical and social function. 1
ꢀ,25-Dihydroxy-2ꢁ-(3-hydroxypropoxy)vitamin D3 (ED-71),[2]
an analog of vitamin D3, can significantly increase bone mineral
density, prevent bone fracture, and has been used as a once-a-day
oral drug for the treatment of osteoporosis in Japan.[3]
Starting from the reported epoxide 5 (Figure 2), which is
readily available from D-mannitol in five steps,[12] the
intermediate 6 was easily prepared with 93% yield by Michael
addition. Using tert-butyl acrylate as the Michael acceptor is the
key point for the reaction to get high yield. Intermediate 6 was
converted to 7 with 87% yield. During our experiment, we found
the order of adding the materials and the concentration of the
reaction were very important for this conversion to get high yield.
Boron trifluoride diethyl etherate should be added to the lithium
solution of acetylide before epoxide 6, otherwise, only a small
amount of product could be determined. Reduction of 7 with
lithium tetrahydro aluminum led to alcohol 8 with 88% yield.
The two hydroxyls of 8 were protected as TBS ether with
tert-butyldimethylsilyl chloride to get 9. The p-methoxybenzyl
Extensive efforts have been made by Kubodera and
co-workers for the development of practical synthesis method for
production ED-71 (Figure 1). Initially, they reported the first
synthesis route of ED-71 from lithocholic acid in 27 linear steps
and with a 0.03% overall yield.[4] And then, starting from
cholesterol, they also developed a biomimetic method for the
preparation of ED-71 in 16 linear steps and with a 0.5% overall
yield.[5]
(PMB)
group
of
9
was
cleaved
with
2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) oxidation to get
propargyl alcohol 10 with 72% yield (2 steps). 10 was reduced
with sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) at
Next, they reported two convergent approaches for the
synthesis of ED-71 by Horner-Wadsworth-Emmons reaction and
the Trost coupling, respectively.[6] As shown in figure 1, starting
from the known C2-symmetrical epoxide 3, Kubodera and
co-workers prepared the A-ring phosphine oxide 1 in 11 linear
steps with 2.5% overall yield. ED-71 could be obtained by the
coupling of the A-ring phosphine oxide (1) and C/D-ring ketone
(2) by Horner-Wadsworth-Emmons reaction.[7]
o
o
0 C, and then quenched with iodine at -55 C to get the vinyl
iodide 11 with 76% yield. Transformation of 11 to the exocyclic
diene 12 was achieved by palladium catalyzed Heck cyclization.
Chlorination the propargyl alcohol of 12 with triphosgen (BTC)
to get 13 with 99% yield. The chloride of 13 was substituted with
lithium diphenylphosphide, and then oxidized with hydrogen
peroxide in one port to get 14 with 96% yield.
In 1993, using the epoxide 4 as the key building block,
Takahashi and workers developed a new route to synthesize the
A-ring phosphine oxide of 1ꢀ,2ꢁ,25-trihydroxyvitamin D3.[8]
Starting from the same epoxide 4, Liu and co-workers reported a
new strategy to synthesize the A-ring phosphine oxide of
ED-71.[9] The designed A-ring phosphine oxide was obtained in
18 linear steps with 16% overall yield and the final product
ED-71 was synthesized with 6% overall yield which was
undoubtedly a big improvement for the construction of this
molecule.
Figure 2. Preparation of A-ring phosphine oxide.
At the beginning of our study, we had planned to protect all
the hydroxyls with methoxymethyl (MOM) to get intermediate
18 (Figure 3). Thus, we first protected the hydroxyl of 7 with
chloromethyl methyl ether (MOMCl), and then deprotected the
PMB group of 15 with DDQ to lead compound 16. But
unfortunately, we found 16 could not be reduced with Red-Al.
All the experiments to prepare 17 from 16 were failed. We
thought the oxygen atom of the ester group could coordinate with
Red-Al and form an inactive complex. Therefore, we had tried to
reduce the ester group of 15 with lithium tetrahydro aluminum to
get compound 19, and then protected the new formed hydroxyl
with MOMCl to get 20. The PMB group of 20 could be easily
cleaved with DDQ to obtain compound 21 with 94% yield. But
we found 21 still could not be reduced with Red-Al, that indicate
Figure 1. Structures and retrosynthetic analysis of ED-71.
Currently, the biomimetic linear route was used in industry for
large scale synthesis of ED-71.[5b, 10] But a lot of work have been
done about the convergent synthesis because it not only has a
higher yield, comparing with linear approach, but also provides a
versatile planform for the discovering of new active vitamin D3
analogs.[6d, 11] In order to discover new active analogs of ED-71,
we are interested in the construction of ED-71 by convergent
approaches. Herein, we wish to report a new route to synthesize
A-ring phosphine oxide and the total synthesis of ED-71.

3
both the MOM and the ester oxygen could coordinate with
Red-Al.
methyl(trifluoromethyl)dioxirane (TFDO) which was formed in
situ by the oxidation of trifluoroacetate with oxone to get
compound 28.[11e] The new formed hydroxyl in 28 was protected
with triethylsilyl trifluoromethanesulfonate (TESOTf) in
dichloromethane to get compound 29 with 80% yield.
Horner-Wadsworth-Emmons reaction was used to coupling 29
with 14 to get protected ED-71 which was deprotected with
camphorsulfonic acid (CSA) in methanol to obtain ED-71 with
80% yield. Its spectral data were in full agreement with that
reported by Kudodera and Liu, respectively.
3. Conclusion
In conclusion, a convergent method for the synthesis of ED-71
has been developed. Starting from the reported epoxide 5, ED-71
could be synthesized in 11 linear steps with 17% overall yield.
4. Experimental Section
General. All experiments were performed under a dry N2
atmosphere, unless noted otherwise. All the reagents were used
1
as it purchased unless noted otherwise. H, 13C NMR spectra, 2D
HMBC and 2D HSQC were recorded on Bruker-400 NMR
1
spectrometers. H spectra were recorded relative to CDCl3 (7.26
Figure 3. Route for the preparation of MOM protected A-ring.
ppm) or TMS (0.00 ppm) as internal standard, and 13C NMR
spectra were recorded relative to CDCl3 (77.0 ppm). High
resolution mass spectra were performed on BioTOF Q instrument
by electrospray ionization (ESI). Column chromatography was
performed on silica gel (300-400 mesh). THF was distilled from
sodium, and DCM was distilled from CaH2 before use.
Next, we had planned to prepare all TBS protected A-ring
phosphine oxide (Figure 4). Compound 23 was first prepared by
the same process for the preparation of 5, and then reacted with
tert-butyl acrylate. Just as Liu and his co-worker reported, the
migration of TBS has also been observed and a mixture of 24 and
25 were obtained which was very difficult to be separated with
column chromatograph. Thus, A-ring phosphine oxide 14 was
used for the total synthesis of ED-71.
tert-Butyl
3-(((1S,2R)-2-(methoxymethoxy)-1-((R)-oxiran-2-yl)but-3-en-1-y
l)oxy)propanoate (6). To a stirred solution of compound 5 (930
mg, 5.3 mmol) in tert-butyl acrylate (12 mL), NaHꢂ104 mg, 60%
in oilꢃ was added slowly and stirred at 15 for 4 h, and then
quenched with H2O, extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuo. The residue was
purified by silica gel column chromatography (hexane/EtOAc =
5:1) to give compound 6 (1.5 g, 93%) as a yellowish oil. 1H NMR
(400 MHz, CDCl3) δ 5.84 (ddd, J = 17.9, 10.3, 7.7 Hz, 1H), 5.34
(d, J = 17.4 Hz, 2H), 4.71 (d, J = 6.7 Hz, 1H), 4.60 (d, J = 6.7
Hz, 1H), 4.21 (dd, J = 7.4, 3.9 Hz, 1H), 3.88 – 3.81 (m, 1H), 3.77
– 3.71 (m, 1H), 3.38 (s, 3H), 3.26 (t, J = 4.6 Hz, 1H), 3.14– 3.11
(m, 1H), 2.80 (d, J = 3.2 Hz, 2H), 2.52 – 2.42 (m, 2H), 1.43 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 170.6, 134.2, 119.0, 93.9,
81.2, 80.5, 77.2, 67.4, 55.5, 50.7, 45.5, 36.4, 28.0. HRMS (ESI)
m/z calcd for C15H26O6 [M+Na]+ 325.1627, found 325.1618.
Figure 4. Migration of TBS under the Michael reaction conditions.
tert-Butyl
3-(((3R,4R,5R)-5-hydroxy-9-((4-methoxybenzyl)
oxy)-3-(methoxymethoxy)non-1-en-7-yn-4-yl)oxy)propanoate
(7). To a solution of 1-methoxy-4-((prop-2-yn-1-yloxy)methyl)
benzene (1.9 g, 10.8 mmol) in THF (30 mL) was added n-BuLi
(3.0 mL, 2.5 M solution in hexane) at -78 under nitrogen, and
the mixture was stirred for 2 h. BF3·OEt2 (3.0 mL, 23.8 mmol)
was added and stirred for another 30 min, and then a solution of
compound 6 (1.1 g, 3.6 mmol) in THF (10 mL) was added at the
same temperature. The mixture was stirred for another 4 h, and
then quenched with saturated NaHCO3 solution, extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated
under vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 3:1) to give compound 7 (1.52
g, 87%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.27 (d,
J = 8.4 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.85 (ddd, J = 17.5,
10.4, 7.3 Hz, 1H), 5.33 (t, J = 14.0 Hz, 2H), 4.67 (d, J = 6.6 Hz,
1H), 4.60 (d, J = 6.6 Hz, 1H), 4.51 (s, 2H), 4.30 (dd, J = 7.1, 4.7
Figure 5. Preparation of ketone 29 and the completion of ED-71.
The C/D ring of ED-71 was prepared with the known
procedure from Vitamin D3 (Figure 5). The double bonds of
Vitamin D3 were cleaved with ozone in anhydrous methanol, and
then reduced with sodium borohydride to get compound 26 with
66% yield.[11a] The hydroxyl of 26 was oxidized with
Dess-Martin reagent to get ketone 27 with 99% yield.
Oxidational
functionalization
of
27
with

4
Hz, 1H), 4.14 (t, J = 2.0 Hz, 2H), 3.94 – 3.83 (m, 3H), 3.79 (s,
3H), 3.45 (dd, J = 6.3, 4.6 Hz, 1H), 3.38 (s, 4H), 2.60 – 2.43 (m,
4H), 1.44 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 171.1, 159.3,
134.3, 129.6, 129.5, 118.8, 113.6, 94.3, 83.5, 80.7, 78.0, 77.5,
70.8, 69.4, 68.2, 57.3, 55.8, 55.2, 36.3, 28.0, 23.2. HRMS (ESI)
m/z calcd for C26H38O8 [M+Na]+ 501.2464, found 501.2462.
5.30 (d, J = 10.3 Hz, 1H), 4.67 (d, J = 6.6 Hz, 1H), 4.62 (d, J =
6.7 Hz, 1H), 4.22 (s, 3H), 4.00 – 3.96 (m, 1H), 3.86 – 3.65 (m,
4H), 3.45 – 3.30 (m, 4H), 2.55 – 2.51 (m, 2H), 1.93 (bs, 1H),
1.79 – 1.73 (m, 2H), 0.92 (s, 9H), 0.90 (s, 9H), 0.12 (s, 3H), 0.10
(s, 3H), 0.02 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 135.8,
118.8, 94.4, 85.6, 84.2, 80.1, 77.6, 71.7, 70.2, 60.3, 55.6, 51.3,
33.6, 25.9, 25.8, 23.2, 18.3, 18.0, -4.4, -4.6, -5.3. HRMS (ESI)
m/z calcd for C26H52O6Si2 [M+Na]+ 539.3200, found 539.3194.
(3R,4R,5R)-4-(3-hydroxypropoxy)-9-((4-methoxybenzyl)oxy)
-3-(methox-ymethoxy)non-1-en-7-yn-5-ol (8). To
a stirred
solution of compound 7 (1.5 g, 3.1 mmol) in THF (20 mL),
LiAlH4ꢂ238 mg, 6.3 mmolꢃ was added slowly and stirred at
room temperature for 2 h, and then quenched by the addition of
H2O (250 µL), aqueous NaOH (250 µL,15%) and H2O (750 µL).
The whole mixture was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under vacuo. The
residue was purified by silica gel column chromatography
(hexane/EtOAc = 1:2) to give compound 8 (1.12 g, 88%) as a
yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.5 Hz,
2H), 6.87 (d, J = 8.6 Hz, 2H), 5.87 (ddd, J = 17.4, 10.4, 7.2 Hz,
1H), 5.38 (d, J = 17.4 Hz, 1H), 5.34 (d, J = 10.8 Hz, 1H), 4.68 (d,
J = 6.5 Hz, 1H), 4.61 (d, J = 6.5 Hz, 1H), 4.51 (s, 2H), 4.36 (dd, J
= 7.0, 3.7 Hz, 1H), 4.14 (t, J = 1.8 Hz, 2H), 3.92 (dd, J = 11.5,
5.5 Hz, 1H), 3.85 – 3.67 (m, 7H), 3.43 (dd, J = 7.1, 3.8 Hz, 1H),
3.39 (s, 3H), 3.18 (bs, 1H), 2.62 (dd, J = 4.9, 1.9 Hz, 2H), 2.46
(bs, 1H), 1.86 – 1.74 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
159.3, 134.5, 129.6, 129.4, 118.9, 113.8, 94.6, 83.2, 83.0, 78.5,
77.2, 71.2, 71.0, 69.1, 60.8, 57.3, 55.9, 55.3, 32.4, 23.4. HRMS
(ESI) m/z calcd for C22H32O7 [M+Na]+ 431.2046, found
431.2040.
(5R,6S,7R)-5-((tert-butyldimethylsilyl)oxy)-6-(3-((tert-butyl
dimeth-ylsilyl)oxy)propoxy)-3-iodo-7-(methoxymethoxy)nona-2,
8-dien-1-ol (11). To a solution of compound 10 (130 mg, 0.25
mmol) in THF (3.5 mL) under nitrogen, Red-Al (0.5 mL, 3.6 M
solution in toluene) was added dropwise at 0 . The mixture was
stirred at 0
for 17 h and then cooled to -55 , quenched by
ethyl acetate (0.2 mL). Then a solution of iodine (190 g, 0.75
mmol) in THF (1.5 mL) was added dropwise, and the suspension
was stirred for another 2 h. The reaction was quenched by the
addition of the saturated Na2S2O3 and NaHCO3 solution, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under vacuo. The residue was purified by silica gel
column chromatography (hexane/EtOAc
= 8:1) to give
compound 11 (123 mg, 76%) as a greenish oil. 1H NMR (400
MHz, CDCl3) δ 5.90 (t, J = 5.7 Hz, 1H), 5.75 (ddd, J = 17.9,
10.3, 7.9 Hz, 1H), 5.40 (d, J = 17.0 Hz, 1H), 5.36 (d, J = 13.9 Hz,
1H), 4.69 (d, J = 6.6 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.21 –
4.10 (m, 2H), 4.04 – 3.94 (m, 2H), 3.83 – 3.89 (m, 1H), 3.77 –
3.65 (m, 3H), 3.39 – 3.42 (m, 4H), 2.81 – 2.69 (m, 2H), 1.86 –
1.73 (m, 2H), 1.65 (bs, 1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.09 (s,
3H), 0.07 (s, 6H), 0.05 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
136.9, 134.6, 119.7, 106.8, 94.0, 86.4, 77.7, 71.3, 70.1, 67.4,
60.4, 55.5, 48.3, 33.7, 29.7, 25.9, 25.8, 18.3, 17.9, -4.1, -4.2, -5.2,
-5.3. HRMS (ESI) m/z calcd for C26H53IO6Si2 [M+Na]+
667.2323, found 667.2331.
(5R,6S)-6-((R)-1-((tert-butyldimethylsilyl)oxy)-5-((4-methoxy
benzyl)oxy)pent-3-yn-1-yl)-12,12,13,13-tetramethyl-5-vinyl-2,4,
7,11-tetraoxa-12-silatetradecane (9). A mixture of 8 (200 mg, 0.5
mmol), imidazole (536 mg, 7.9 mmol) and TBSCl (588 mg, 3.9
mmol) in DCM (5 mL) was stirred at 40 for 16 h. The reaction
was quenched with saturated NaHCO3 solution, and the whole
mixture was extracted with DCM. The organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under vacuo. The residue was purified by silica gel
(Z)-2-((3R,4S,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(3-((tert-
butyldimethylsilyl)oxy)propoxy)-3-(methoxymethoxy)-2-methyl
enecyclohexy-lidene)ethan-1-ol (12). A solution of compound 11
(300 mg, 0.46 mmol), PdCl2(PPh3)2 (35 mg, 0.05 mmol) and
DIEA (0.5 mL, 3.0 mmol) in MeCN (10 mL) was refluxed for 3
h. The mixture was evaporated and diluted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuo. The residue was
purified by silica gel column chromatography (hexane/EtOAc =
column chromatography (hexane/EtOAc
= 10:1) to give
compound 9 (364 mg) as a yellowish oil which contained a small
amount of TBSCl. The oil was used without further purification
1
in the next reaction. H NMR (400 MHz, CDCl3) δ 7.27 (d, J =
8.3 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.86 (ddd, J = 17.9, 10.3,
7.9 Hz, 1H), 5.32 (d, J = 17.9 Hz, 1H), 5.29 (d, J = 10.4 Hz, 1H),
4.69 (d, J = 6.6 Hz, 1H), 4.61 (d, J = 6.6 Hz, 1H), 4.51 (s, 2H),
4.16 – 4.12 (m, 3H), 3.99 (dd, J = 9.4, 5.2 Hz, 1H), 3.85 – 3.80
(m, 4H), 3.75 – 3.65 (m, 3H), 3.37 (s, 4H), 2.56 (d, J = 4.5 Hz,
2H), 1.82 – 1.76 (m, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.15 (s, 3H),
0.11 (s, 3H) 0.06 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 159.3,
135.9, 129.7, 129.6, 118.4, 113.8, 94.5, 85.4, 84.8, 78.0, 77.6,
71.7, 70.9, 70.1, 60.2, 57.4, 55.6, 55.2, 33.6, 29.7, 25.9, 25.8,
23.4, 18.3, 18.1, -4.4, -4.6, -5.3. HRMS (ESI) m/z calcd for
C34H60O7Si2 [M+Na]+ 659.3775, found 659.3775.
1
5:1) to give compound 12 (220 mg, 91%) as a yellow oil. H
NMR (400 MHz, CDCl3) δ 5.57 (t, J = 6.8 Hz, 1H), 5.30 (d, J =
0.8 Hz, 1H), 4.96 (d, J = 1.7 Hz, 1H), 4.64 (q, J = 6.6 Hz, 2H),
4.29 – 4.10 (m, 4H), 3.79 – 3.61 (m, 4H), 3.43 – 3.33 (m, 4H),
2.55 – 2.45 (m, 1H), 2.21 (dd, J = 13.0, 3.7 Hz, 1H), 1.83 – 1.71
(m, 2H), 1.65 (bs, 1H), 0.88 (s, 18H), 0.10 (s, 3H), 0.09 (s, 3H),
0.06 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 141.5, 137.8, 127.4,
116.6, 94.6, 82.4, 78.0, 69.4, 68.1, 60.2, 59.4, 55.5, 40.5, 33.5,
29.6, 25.9, 25.9, 18.3, 18.1, 14.05, -4.7, -5.3. HRMS (ESI) m/z
calcd for C26H52O6Si2 [M+Na]+ 539.3200, found 539.3198.
(5R,6S,7R)-5-((tert-butyldimethylsilyl)oxy)-6-(3-((tert-butyl
dimethylsilyl)oxy)propoxy)-7-(methoxymethoxy)non-8-en-2-yn-
1-ol (10). A mixture of compound 9 (0.5 mmol), H2O (0.4 mL)
and DDQ (162 mg, 0.7 mmol) in DCM (4 mL) was stirred at
room temperature for 2 h. The reaction was diluted with DCM
and filtered through celite. The organic layer was washed with
brine, dried over anhydrous Na2SO4, filtered, and evaporated
under vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc = 1:1) to give compound 10
(187 mg, 72% for two steps) as a yellowish oil. 1H NMR (400
MHz, CDCl3) δ 5.87 – 5.76 (m, 1H), 5.33 (d, J = 17.2 Hz, 1H),
tert-Butyl(3-(((1S,2R,6R,Z)-6-((tert-butyldimethylsilyl)oxy)-4-(
2-chloroethylidene)-2-(methoxymethoxy)-3-methylene
cyclohexyl)oxy)propoxy)dimethylsilane (13). A solution of
compound 12 (50 mg, 0.1 mmol) and triphosgene (60 mg,
0.2 mmol) in hexane (1mL), and a solution of pyridine (46
uL, 0.6 mmol) in hexane (1 mL) were mixed at 0 , and
then warmed to room temperature, stirred for 2 h. The
reaction was quenched with saturated NaHCO3 solution,
and then extracted with hexane. The organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated under vacuo. The residue was purified by

5
silica gel column chromatography (hexane/EtOAc = 15:1)
= 9.0, 2.8) Hz, 1H), 2.86 – 2.73 (m, 1H), 2.53 (dd, J =
1
to give compound 13 (51 mg, 99%) as a yellowish oil. H
14.5, 3.9 Hz, 1H), 2.41 (d, J = 13.9 Hz, 1H), 2.00 – 1.77
(m, 5H), 1.67 (dd, J = 24.9, 10.3 Hz, 3H), 1.55 – 1.25 (m,
11H), 1.21 (s, 6H), 1.04 (dd, J = 19.2, 9.2 Hz, 1H), 0.93 (d,
J = 6.4 Hz, 3H), 0.54 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 144.31, 142.74, 132.29, 124.67, 117.21, 111.74, 85.29,
71.36, 71.07, 68.15, 66.45, 60.85, 56.49, 56.30, 45.81,
44.34, 40.42, 36.33, 36.05, 31.75, 29.64, 29.26, 29.12,
29.06, 27.60, 23.64, 22.29, 20.76, 18.77, 11.88. These
spectral data are completely identical to that reported by
Kubodera and Liu, respectively.
NMR (400 MHz, CDCl3) δ 5.55 (t, J = 8.0 Hz, 1H), 5.35
(s, 1H), 5.16 (s, 1H), 4.64 (q, J = 6.6 Hz, 2H), 4.26 – 4.05
(m, 4H), 3.82 – 3.57 (m, 4H), 3.36 (s, 4H), 2.48 (dd, J =
12.8, 8.5 Hz, 1H), 2.21 (dd, J = 13.1, 3.5 Hz, 1H), 1.83 –
1.68 (m, 2H), 0.90 (s, 9H), 0.89 (s, 9H), 0.09 (s, 3H), 0.08
(s, 3H), 0.04 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 141.5,
140.8, 123.4, 95.0, 82.7, 77.9, 69.2, 68.1, 60.2, 55.6, 41.4,
40.6, 33.5, 25.9, 25.8, 18.3, 18.1, -4.6, -4.8, -5.3. HRMS
(ESI) m/z calcd for C26H51ClO5Si2 [M+Na]+ 557.2861,
found 557.2860.
5. Acknowledgments
((Z)-2-((3R,4S,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(3-((tert
-butyldimethylsilyl)oxy)propoxy)-3-(methoxymethoxy)-2-methyl
enecyclohexy-lidene)ethyl)diphenylphosphine oxide (14). To a
solution of diphenylphosphine (245 µL, 1.4 mmol) in THF (3
mL), n-BuLi (0.8 mL, 2.5 M solution in hexane) was added at
We are grateful to Miss Dongmei Fang and Miss Yuqin Wang
for the spectroscopic measurements.
6. References and notes
-78
under nitrogen. And then stirred for 25 min before a
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solution of compound 13 (130 mg, 0.24 mmol) in THF (1 mL)
was added. After stirring for another 3 h, the mixture was
warmed to 0 . Then water (1 mL) and H2O2 (1.5 mL, 30% in
H2O) were added successively. The mixture was stirred at 0
for another 1 h, and then quenched with saturated Na2SO3
solution. The whole mixture was extracted with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under vacuo. The residue was
purified by silica gel column chromatography (hexane/EtOAc =
[2] a) T. Okano, N. Tsugawa, S. Masuda, A. Takeuchi, T. Kobayashi,
Y. Takita and Y. Nishii, Biochem. Biophys. Res. Commun. 1989,
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Masaki, A. Shira-Ishi, K. Sato, N. Kubodera, K. Ikeda and E.
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Uchiyama and K. Endo, J. Cell. Biochem. 2003, 88, 286-289; d)
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2007, 103, 584-586; e) A. J. Brown and C. S. Ritter, Calcif.
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T. Shintani, S. N. Z. Rosli, F. Takatsu, Y. F. Choon, Y.
Hayashido, S. Toratani, E. Usui and T. Okamoto, J. Steroid
Biochem. Mol. Biol. 2016, 164, 79-84; l) Y. Hirota, K. Nakagawa,
K. Isomoto, T. Sakaki, N. Kubodera, M. Kamao, N. Osakabe, Y.
Suhara and T. Okano, Plos One 2018, 13.
1
2:1) to give compound 14 (164 mg, 96%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 7.68 – 7.75 (m, 4H), 7.55 – 7.41 (m,
6H), 5.38 (q, J = 7.4 Hz, 1H), 5.28 (s, 1H), 5.01 (s, 1H), 4.67 –
4.61 (m, 2H), 4.20 (d, J = 6.5 Hz, 1H), 4.11 – 4.01 (m, 1H), 3.76
– 3.56 (m, 4H), 3.43 – 3.26 (m, 5H), 3.25 – 3.16 (m, 1H), 2.47 –
2.36 (m, 1H), 2.17 (d, J = 13.0 Hz, 1H), 1.94 (bs, 1H), 1.82 –
1.68 (m, 2H), 0.89 (s, 9H), 0.82 (s, 9H), 0.05 (s, 6H), 0.04 (s,
3H), 0.01 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 140.1, 139.9,
132.0, 131.8, 131.7, 131.1, 131.0, 130. 9, 128.6, 128.5, 115.7,
94.9, 83.1, 77.72, 69.3, 68.2, 60.2, 55.6, 41.3, 33.5, 31.7, 31.0,
29.7, 25.9, 25.8, 18.3, 18.1, -4.7, -4.8, -5.3. HRMS (ESI) m/z
calcd for C38H61O6Si2P [M+Na]+ 723.3642, found 723.3649.
[3] Y. Ono, J. Steroid Biochem. Mol. Biol. 2014, 139, 88-97.
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Kubodera, Chem. Pharm. Bull. 1993, 41, 1111-1113.
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and S. Hatakeyama, Anticancer Res. 2012, 32, 303-309.
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9836-9845; b) B. M. Trost, J. Dumas and M. Villa, J. Am. Chem.
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Hatakeyama, A. Kawase, Y. Uchiyama, J. Maeyama, Y. Iwabuchi
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S. Hatakeyama, Anticancer Res. 2009, 29, 3571-3578; f) N.
Kubodera and S. Hatakeyama, Heterocycles 2009, 79, 145-162; g)
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(1R,2R,3R,Z)-5-(2-((1R,7aR,E)-1-((R)-6-hydroxy-6-methyl
heptan-2-yl)-7a-methyloctahydro-4H-inden-4-ylidene)ethyli
dene)-2-(3-hydroxypropoxy)-4-methylenecyclohexane-1,3-diol
(ED-71). To a cooled solution of compound 14 (90 mg, 0.128
mmol) in THF (1.5 mL) at -78
under nitrogen was added
n-BuLi (130 uL, 2.5 M solution in hexane) dropwise, and then
stirred for 40 min. A solution of compound 29 (36 mg, 0.09
mmol) in THF (0.5 mL) was added, and then stirred for another 4
h. The reaction was quenched with H2O, and then extracted with
ethyl acetate. The organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexane/EtOAc = 70:1) to give the protected ED-71 (50 mg,
63%) as a colorless oil. To a stirred solution of the protected
ED-71 (80 mg, 0.09 mmol) in methanol (4 mL), CSA (220
mg, 0.95 mmol) was added. The mixture was stirred at
room temperature for 43 h. The reaction was quenched
with saturated NaHCO3 solution and extracted with ethyl
acetate. The organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (DCM/MeOH = 20:1) to give compound
ED-71 (36 mg, 80%) as a white foam. 1H NMR (400 MHz,
CDCl3) δ 6.35 (d, J = 11.3 Hz, 1H), 6.04 (d, J = 11.3 Hz,
1H), 5.49 (t, J = 2.0 Hz, 1H), 5.07 (t, J = 2.0 Hz, 1H), 4.28
(dd, J = 22.4, 6.0 Hz, 2H), 3.97 – 3.67 (m, 5H), 3.25 (dd, J
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51, 1264-1269; b) N. Saito, Y. Suhara, M. Kurihara, T. Fujishima,
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2004, 69, 7463-7471; c) S. Hatakeyama, S. Nagashima, N. Imai,
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8050-8056; d) N. Saito, Y. Suhara, D. Abe, T. Kusudo, M. Ohta,
K. Yasuda, T. Sakaki, S. Honzawa, T. Fujishima and A. Kittaka,
Biorg. Med. Chem. 2009, 17, 4296-4301; e) V. Sikervar, J. C.

6
Fleet and P. L. Fuchs, J. Org. Chem. 2012, 77, 5132-5138; f) R.
Samala, S. Sharma, M. K. Basu, K. Mukkanti and F. Porstmann,
Tetrahedron Lett. 2016, 57, 1309-1312.
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2012, 59, 389-393.

Highlights
A convergent method for the synthesis of ED-71 has been developed. Starting from the reported epoxide 5 which could
be easily prepared for D-mannitol, ED-71 was synthesized in 11 linear steps with 17% overall yield.