Introduction of fluorine atoms to vitamin D3 side-chain and synthesis of 24,24-difluoro-25-hydroxyvitamin D3

Article abstract of DOI:10.1016/j.jsbmb.2019.105477

During our ongoing studies of vitamin D, we focused on the vitamin D₃ side-chain 24-position, which is the major metabolic site of human CYP24A1. In order to inhibit the metabolism of vitamin D₃, 24,24-difluorovitamin D₃analogues are important candidates. In this paper, we report the practical introduction of the difluoro-unit to the 24-position to synthesize 24,24-difluoro-CD ring (1) and 24,24-difluoro-25-hydroxyvitamin D₃ (2).

Full text of DOI:10.1016/j.jsbmb.2019.105477

Journal of Steroid Biochemistry and Molecular Biology 195 (2019) 105477
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry and Molecular Biology
journal homepage: www.elsevier.com/locate/jsbmb
Introduction of fluorine atoms to vitamin D side-chain and synthesis of 24,
3
2
4-difluoro-25-hydroxyvitamin D ꢀ
3
Fumihiro Kawagoea,b, Sayuri Mototani , Kaori Yasuda , Kazuo Nagasawab,d, Motonari Uesugib,e
Toshiyuki Sakaki , Atsushi Kittaka
a
a
c
,
c
a,b,⁎
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
AMED-CREST, The Japan Agency for Medical Research and Development (AMED), 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004 Japan
Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan
Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan
b
c
d
e
A R T I C L E I N F O
A B S T R A C T
Keywords:
CYP24A1
Synthesis
Vitamin D
During our ongoing studies of vitamin D, we focused on the vitamin D
major metabolic site of human CYP24A1. In order to inhibit the metabolism of vitamin D , 24,24-di-
3
side-chain 24-position, which is the
3
fluorovitamin D
difluoro-unit to the 24-position to synthesize 24,24-difluoro-CD ring (1) and 24,24-difluoro-25-hydroxyvitamin
(2).
3
analogues are important candidates. In this paper, we report the practical introduction of the
3
metabolite
2
4,24-Difluorovitamin D
3
analogues
D
3
2
4,24-Difluoro-CD rings
1. Introduction
have explored a more direct method to synthesize the 24,24-difluoro
unit. This time, we focused on the 24,24-difluoro-CD ring (1), because it
Since the discovery of metabolic pathways of vitamin D
numerous metabolites of VD and their biological roles have been re-
ported [1,2]. Many analogues that are related to VD metabolites have
also been synthesized and their specific biological activities have been
revealed [3–14]. By utilizing this knowledge, fluorinated VD analo-
gues with a longer half-life have been designed and synthesized as well
15–19]. Especially, fluorine atoms were actively introduced to the
side-chain of VD , because it contains important metabolic sites of
CYP24A1, which is the cytochrome P450 component of the 25-hydro-
xyvitamin D [25(OH)D ]-24-hydroxylase enzyme. It is well-known
that C24 hydroxylation and subsequent 5-step oxidation of the 25(OH)
3
(VD
3
),
3
is an important precursor of 24,24-difluorovitamin D analogues if
3
coupled with varieties of A-ring parts. To our knowledge, only one
study has been reported that synthesized the 24,24-difluoro-CD ring (1)
with the Barton-McCombie reduction process to remove a OH group on
a synthetic intermediate [25]. In this paper, we describe a new syn-
3
3
thetic method to produce 1 and 24,24-difluoro-25-hydroxyvitamin D
(2) utilizing the Horner-Emmons reagent 3 (Fig. 1).
3
[
3
2. Results and discussion
3
3
A retrosynthetic plan for 1 and 2 is shown in Scheme 2. Inhoffen-
Lythogoe diol (4) was used as the starting material. Introduction of the
difluoro-unit was performed using N,N-diethylaminosulfur trifluoride
(DAST) against α-ketoester [21,24,26]. The triene unit of 2 was con-
structed by applying the Wittig-Horner method that was reported pre-
viously (Scheme 2) [27].
The synthesis of Horner-Emmons reagent 3 is shown in Scheme 3
[28,29]. Dimethyl tartrate was used as a starting material. Cleavage of
diol, followed by the nucleophilic addition of diethyl phosphite to al-
dehyde 13 afforded alcohol 14. Protection of 14 with triethylsilyl
chloride in the presence of imidazole successfully yielded 3 [29].
In Scheme 4, the synthesis of the 24,24-difluoro-CD ring (1) is
D
3
side-chain by CYP24A1 leads to calcitroic acid (Scheme 1) [2].
In order to block this (24R)-oxidation metabolic pathway, the in-
troduction of fluorine atoms to the C24 position may be an efficient
strategy. That is why there has been considerable interest in 24,24-di-
fluorovitamin D
been reported. For example the Kobayashi and Takayama groups in-
dependently reported synthetic method to produce 24,24-di-
fluorovitamin D analogues from steroidal skeletons in 1979 [20,21].
After that, the Takayama group reported an improved method to in-
troduce the 24,24-difluoro unit to the vitamin D side-chain starting
in 1992 [22,23] and 1998 [24]. We
3
analogues and some of these related analogues have
a
3
3
from androst-5-ene or vitamin D
2
⁎
Corresponding author at: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
E-mail address: akittaka@pharm.teikyo-u.ac.jp (A. Kittaka).
https://doi.org/10.1016/j.jsbmb.2019.105477
Received 30 July 2019; Received in revised form 29 August 2019; Accepted 18 September 2019
Available online 18 September 2019
0960-0760/ © 2019 Elsevier Ltd. All rights reserved.

F. Kawagoe, et al.
Journal of Steroid Biochemistry and Molecular Biology 195 (2019) 105477
Scheme 1. One of the major metabolic pathways of 25-hydroxyvitamin D
3
by CYP24A1 includes (24R)-oxidation leading to calcitroic acid [2].
F
F
F F
OH
OH
H
H
O
P
EtO
EtO
H
OH
H
COOMe
OTES
HO
2: 24,24-difluoro-25-hydroxyvitamin D3 3: Horner-Emmons reagent
1: 24,24-difluoro-CD ring
3
Fig. 1. Target compounds 24,24-difluoro-CD-ring (1) and 24,24-difluoro-25-hydroxyvitamin D (2) as well as the Horner-Emmons reagent 3 for synthesizing 1.
3
Scheme 2. Retrosynthetic analysis of 24,24-difluoro-CD ring (1) and 24,24-difluoro-25-hydroxyvitamin D (2) via a key compound 10.
Scheme 3. Preparation of Horner-Emmons reagent
28,29].
3
[
shown. The synthetic route started from Inhoffen-Lythgoe diol (4).
Selective iodination of the primary alcohol and nucleophilic displace-
ment of the iodide by KCN allowed conversion to nitrile 6. Silyl pro-
tection of 6, followed by reduction of the nitrile group with DIBAL-H
afforded aldehyde 8 [30]. Horner-Emmons reaction of 3 with aldehyde
reaction was performed by the Wittig-Horner method. The resulting
coupling product was treated with tetrabutylammonium fluoride to
give the desired product 2 in 24% yield (2 steps) (Scheme 6).
3. Conclusion
8
afforded silyl enol ether 9. Hydrolysis of the silyl enol was performed
with tetrabutylammonium fluoride in the presence of acetic acid to
yield α-ketoester 10 [24]. The key part of the 24,24-difluoro unit was
constructed using DAST toward 10, and the difluorination proceeded
smoothly. Treatment of difluoromethylester 11 with an excess amount
of methyl Grignard reagent followed by deprotection of the silyl pro-
tecting group afforded the desired CD-ring 1.
In conclusion, we developed a convenient method to synthesize
4,24-difluoro-CD ring 1, which is an important precursor of 24,24-
difluorovitamin D analogues. Construction of the 24,24-difluoro unit
3
was achieved by treatment of the α-ketoester 10 with N,N-diethyla-
minosulfur trifluoride (DAST). Using 8-keto-CD ring 15, we were able
2
3
to synthesize 24,24-difluoro-25-hydroxyvitamin D (2) as well.
3
Next, the 24,24-difluorovitamin D precursor 15 was synthesized
from 24,24-difluoro-CD-ring (1) (Scheme 5). The C8-OH group was
oxidized by tetrapropylammonium perruthenate (TPAP) in the presence
of 4-methylmorpholine N-oxide (NMO) followed by triethylsilylation of
the C25-OH group furnished 8-ketone 15 [25,31].
4
. Experimental section
1H and 13C NMR spectra were recorded on JEOL AL-400 NMR
1
(
400 MHz) and ECP-600 NMR (600 MHz) spectrometers. H NMRꢀ
We synthesized 24,24-difluoro-25-hydroxyvitamin D
3
(2) using the
spectra were referenced with (CH
standard. C NMR spectra were referenced with deuterated solvent (δ
3
)
4
Si (δ 0.00 ppm) as an internal
CD-ring and the A-ring precursor phosphine oxide 18. The coupling
13
2

F. Kawagoe, et al.
Journal of Steroid Biochemistry and Molecular Biology 195 (2019) 105477
Scheme 4. Synthesis of 24,24-difluoro-CD ring (1).
4.2. Methyl 5-{4-[(tert-butyldimethylsilyl)oxy]-7a-methyloctahydro-1H-
inden-1-yl}-2-oxohexanoate (10)
To the solution of Horner-Emmons reagent 3 (7.34 g, 21.6 mmol) in
THF (20 mL) was added LDA (lithium diisopropylamide) (10.9 mL, 2 M
THF/heptane/ethylbenzene solution, 21.8 mmol) at -40 °C, the mixture
was stirred at the same temperature for 20 min, and a solution of 8 [30]
(6.65 g, 19.6 mmol) in THF (15 mL) was added. The reaction mixture
was stirred at 0 °C for 5 min. After the reaction had been quenched with
Scheme 5. Synthesis of 8-keto-24,24-difluoro-CD ring 15.
H
2
O and saturated aqueous NH
with EtOAc three times, dried over Na
The crude residue of 9 was used for the next reaction without further
purification. To the crude residue of 9 in CH Cl (40 mL) were added
4
Cl at 0 °C, the mixture was extracted
2
4
SO , filtered, and concentrated.
2
2
AcOH (6 mL) and tetrabutylammonium fluoride (27.4 mL, 1 M THF
solution, 27.4 mmol) at 0 °C, and the mixture was stirred at room
temperature for 30 min. After the reaction had been quenched with H
at room temperature, the mixture was extracted with CH Cl three
times, dried over Na SO , filtered, and concentrated. The residue was
2
O
2
2
Scheme 6. Coupling reaction and deprotection steps for 2.
2
4
purified by flash column chromatography on silica gel (hexane :
EtOAc = 7 : 1) to obtain 10 (7.77 g, 97%) as a colorless oil [24].
3 3
77.0 ppm for CDCl and 49.3 ppm for CD OD). IR spectra were recorded
on a JASCO FT-IR-800 Fourier transform infrared spectrophotometer.
High resolution mass spectra were obtained on a SHIMADZU LCMS-IT-
TOF mass spectrometer with a positive electrospray ionization (ESI)
method. Optical rotations were measured on a JASCO DIP-370 digital
polarimeter. Column chromatography was performed on silica gel 60 N
4.3. 1-(5,5-Difluoro-6-hydroxy-6-methylheptan-2-yl)-7a-methyloctahydro-
1H-inden-4-ol (1)
2 2
To the solution of 10 (8.08 g, 19.7 mmol) in CH Cl (30 mL) was
slowly added N,N-diethylaminosulfur trifluoride (DAST) (6.5 mL, 7.3 g,
49.2 mmol) at 0 °C, and the mixture was stirred at room temperature for
(
0
Kanto Chemical Co., Inc., 40–50 μm) or silica gel 60 (Merck, 0.040-
.063 mm). Preparative thin-layer chromatography was performed on
silica gel 60 F254 (Merck, 0.5 mm). All experiments were performed
under anhydrous conditions in an atmosphere of argon, unless other-
wise stated.
17 h. The mixture was cooled to −78 °C and MeOH and H
slowly added. The mixture was extracted with CH Cl three times, dried
over Na SO , filtered, and concentrated. The residue was roughly
2
O were
2
2
2
4
purified by flash column chromatography on silica gel (hexane :
EtOAc = 20 : 1) to obtain a crude residue of 11. To the solution of the
crude residue of 11 in THF (30 mL) was added MeMgCl (16.7 mL, 3.0 M
THF solution, 50.0 mmol) at 0 °C, and the mixture was stirred for
4.1. Methyl 2-(diethoxyphosphoryl)-2-[(triethylsilyl)oxy]acetate (3)
This reagent was prepared according to the literature [29].
3
15 min. After the reaction had been quenched with H
in H O), the mixture was extracted with EtOAc three times, dried over
Na SO , filtered, and concentrated. The crude residue of 12 was used
for the next reaction without further purification. To the crude residue
of 12 in MeOH (30 mL) was added p-toluenesulfonic acid monohydrate
(6.12 g, 32.2 mmol), and the mixture was stirred at room temperature
2
O and HCl (1.0 M
: IR (neat) 1754, 1268, 1133, 1025, 969, 810, 750 cm 1; 1H NMR
−
2
(
1
=
=
600 MHz, CDCl
.33 (q, J =6.6 Hz, 6 H), 3.79 (s, 3 H), 4.12–4.26 (m, 4 H), 4.16 (d, J
3
) δ 0.64 (q, J =7.8 Hz, 6 H), 0.96 (t, J =7.8 Hz, 9 H),
2
4
1
3
17.4 Hz, 1 H); C NMR (150 MHz, CDCl
3
) δ 4.4, 6.5, 16.4 (d, J
5.7 Hz), 52.5, 63.6 (d, J =7.2 Hz), 70.5 (t, J =24.8 Hz), 169.1; HRMS
ESI ) calcd for C13
+
+
(
H
30
O
6
SiP [M+H] 341.1544, found 341.1556.
for 19 h under air. After the reaction had been quenched with H
2
O and
saturated aqueous NaHCO at room temperature, the mixture was
3
3

F. Kawagoe, et al.
Journal of Steroid Biochemistry and Molecular Biology 195 (2019) 105477
extracted with EtOAc three times, dried over Na
concentrated. The residue was purified by flash column chromato-
graphy on silica gel (hexane : EtOAc = 3 : 1) to obtain 1 (4.0 g, 64%, in
2
SO
4
, filtered, and
M. Odagi, K. Nagasawa, Stereoselective synthesis of four calcitriol lactone dia-
stereomers at C23 and C25, J. Org. Chem. 84 (2019) 7630–7641.
[
5] Y. Akagi, A. Nagata, M. Odagi, K. Nagasawa, Synthetic studies of (23S,25R)-1α,25-
3
dihydroxyvitamin D 26,23-lactone (calcitriol lactone) and its derivatives, J.
3
steps) as a white powder [25].
Steroid Biochem. Mol. Biol. 177 (2018) 240–246.
2
7
[
[
6] N. Saito, A. Kittaka, Highly potent vitamin D receptor antagonists: design, synthesis,
and biological evaluation, ChemBioChem 7 (2006) 1478–1490.
7] F. Kawagoe, T. Sugiyama, K. Yasuda, M. Uesugi, T. Sakaki, A. Kittaka, Concise
synthesis of 23-hydroxylated vitamin D3 metabolites, J. Steroid Biochem. Mol. Biol.
186 (2019) 161–168.
1
: [α]D +32.3 (c 0.98, CHCl
3
); IR (neat) 3414, 1471, 1380, 1180,
021, 735 cm ; H NMR (400 MHz, CDCl ) δ 0.92 (d, J =6.4 Hz, 3 H),
.94 (s, 3 H), 1.06–2.07 (m, 25 H), 4.08 (brs, 1 H); C NMR (100 MHz,
) δ 13.5, 17.4, 18.3, 22.5, 23.6, 26.6, 27.0, 27.3 (t, J =24.8 Hz),
3.5, 34.9, 40.3, 41.9, 52.6, 56.3, 69.4, 73.3 (t, J =26.7 Hz), 125.5 (t, J
−
1 1
1
0
CDCl
3
1
3
3
[
8] N.E. Lee, G. Satyanarayana Reddy, A.J. Brown, P.G. Williard, Synthesis, stereo-
3
chemistry, and biological activity of 1α,23,25-trihydroxy-24-oxovitamin D
3
, a
−
−
=
246.0 Hz); HRMS (ESI
)
calcd for
C
19
H
33
O
4
[M + HCOO]
major natural metabolite of 1α,25-dihydroxyvitamin D
3
, Biochemistry 36 (1997)
449.3058, found 449.3064.
9429–9437.
[
9] R. Sigüeiro, P. González-Berdullas, J. Loureiro, A. Mouriño, M.A. Maestro,
Stereoselective synthesis of 25S,26-dihydroxyvitamin D
Biol. 177 (2018) 247–249.
3
, J. Steroid Biochem. Mol.
4
.4. 24,24-Difluoro-25-hydroxyvitamin D (2)
3
[
10] W. Stepanenko, J. Wicha, Enantioselective synthesis of 24,25-dihydroxy vitamin D
northern portion from (S)-3-hydroxy-2,2-dimethylcyclohexane-1-one. Remote
asymmetric introduction in an acid-catalysed conjugated addition, Tetrahedron
Lett. 39 (1998) 885–888.
3
nBuLi (45.1 μL, 1.6 M hexane solution, 0.073 mmol) was added to
the solution of A-ring phosphine oxide 18 (29.9 mg, 0.066 mmol) in
THF (0.5 mL) at −78 °C. After stirring for 30 min, the solution of ketone
3
[11] H.-Y. Lam, H.K. Schnoes, H.F. DeLuca, T.C. Chen, 24,25-Dihydroxyvitamin D .
Synthesis and biological activity, Biochemistry 12 (1973) 4851–4855.
1
5 (17.1 mg, 0.040 mmol) in THF (0.5 mL) was added to the reaction
mixture, and the mixture was stirred at −78 °C for 1 h. After the re-
action had been quenched with H O at room temperature, the mixture
was extracted with EtOAc three times, washed with brine, dried over
Na SO , filtered, and concentrated. The residue was purified by flash
[
12] D. Nicoletti, C. Gregorio, A. Mouriño, M. Maestro, A short practical approach to
4R,25-dihydroxyvitamin D , J. Steroid Biochem. Mol. Biol. 212 (2010) 43–45.
[13] C. Fernández, Z. Gándara, G. Gómez, B. Covelo, Y. Fall, D- and L-Serine, useful
synthons for the synthesis of 24-hydroxyvitamin D metabolites. A formal synthesis
of 1α,24R,25-(OH) -D , 24R,25-(OH) -D and 24S,25-(OH) -D , Tetrahedron Lett.
8 (2007) 2939–2942.
2
3
2
3
3
3
2
3
2
3
2
4
4
column chromatography on silica gel (hexane : EtOAc = 20 : 1) to
obtain the crude coupling product (12.4 mg), and it was used for the
next reaction without further purification. Tetrabutylammonium
fluoride (300 μL, 1 M THF solution, 0.30 mmol) was added to the so-
lution of the crude coupling product (12.4 mg) in THF (1 mL), and the
mixture was stirred at room temperature for 5 h. After the reaction had
[14] I. Cornella, R.M. Suárez, A. Mouriño, J. Pérez Sestelo, L.A. Sarandeses,
Stereoselective convergent synthesis of 24-substituted metabolites and analogues of
vitamin D, J. Steroid Biochem. Mol. Biol. 89-90 (2004) 19–23.
[
15] F. Kawagoe, T. Sugiyama, M. Uesugi, A. Kittaka, Recent developments for in-
troducing a hexafluoroisopropanol unit into the vitamin D side chain, J. Steroid
Biochem. Mol. Biol. 177 (2018) 250–254.
[
16] F. Kawagoe, K. Yasuda, S. Mototani, T. Sugiyama, M. Uesugi, T. Sakaki, A. Kittaka,
Synthesis and CYP24A1-dependent metabolism of 23-fluorinated vitamin D
3
ana-
been quenched with H
tracted with EtOAc three times, dried over Na
2
O at room temperature, the mixture was ex-
SO , filtered, and con-
logues, ACS Omega 4 (2019) 11332–11337.
[17] T. Taguchi, S. Mitsuhashi, A. Yamanouchi, Y. Kobayashi, H. Sai, N. Ikekawa,
Synthesis of 23,23-difluoro-25-hydroxyvitamin D , Tetrahedron Lett. 25 (43)
1984) 4933–4936.
2
4
3
centrated. The residue was purified by flash column chromatography on
silica gel (hexane : EtOAc = 2 : 1 – EtOAc only) to obtain 2 (4.1 mg,
(
[
18] M. Ikeda, H. Matsumura, N. Sawada, K. Hashimoto, T. Tanaka, T. Noguchi,
M. Hayashi, Synthesis and biological evaluations of C-23-modified
2
4%, in 2 steps) as a white powder.
2
7
26,26,26,27,27,27-F -vitamin D analogues, Bioorg. Med. Chem. 8 (2000)
2
: [α]D +97.8 (c 0.32, EtOH); IR (neat) 3395, 1468, 1380, 1176,
6
3
049 cm ; 1H NMR (600 MHz, CD
−
1
1809–1817.
1
=
3
OD) δ 0.61 (s, 3 H), 1.01 (d, J
[
19] S.-J. Shiuey, J.J. Partridge, M.R. Uskoković, Triply convergent synthesis of 1α,25-
dihydroxy-24(R)-fluorocholecalciferol, J. Org. Chem. 53 (5) (1988) 1040–1046.
20] Y. Kobayashi, T. Taguchi, T. Terada, J. Oshida, M. Morisaki, N. Ikekawa, Synthesis
6.6 Hz, 3 H), 1.29–1.41 (m, 11 H), 1.48–1.63 (m, 5 H), 1.71–1.90 (m,
[
4
3
1
H), 1.94–2.25 (m, 7 H), 2.44 (dt, J = 4.8, 13.8 Hz, 1 H), 2.58 (dd, J =
.9, 12.9 Hz, 1 H), 2.90–2.92 (m, 1 H), 3.80 (ddd, J = 3.3, 9.0, 12.6 Hz,
H), 4.79 (brs, 1 H), 5.08 (brs, 1 H), 6.08 (d, J =11.4 Hz, 1 H), 6.26 (d,
of 24,24-difluoro- and 24ξ-fluoro-25-hydroxyvitamin D
1979) 2023–2026.
[21] S. Yamada, M. Ohmori, H. Takayama, Synthesis of 24,24-difluoro-25-hydro-
xyvitamin D , Tetrahedron Lett. 20 (21) (1979) 1859–1862.
22] K. Konno, K. Ojima, T. Hayashi, H. Takayama, An alternative and efficient synthesis
3
, Tetrahedron Lett. 20 (22)
(
1
3
J =11.4 Hz, 1 H); C NMR (150 MHz, CD
3
OD) δ 12.7, 19.5, 23.5, 24.2,
3
[
2
4
1
4.2, 24.8, 28.4, 28.7 (t, J =24.5 Hz), 28.9, 30.2, 33,9, 36.9, 37.4, 42.2,
of 24,24-difluoro-1α,25-dihydroxyvitamin D
3
, Chem. Pharm. Bull. 40 (5) (1992)
7.2, 47.3, 57.8, 57.9, 70.9, 74.0 (t, J =27.3 Hz), 112.9, 119.3, 122.9,
1120–1124.
−
27.1 (t, J =246.3 Hz), 137.7, 142.7, 147.3; HRMS (ESI ) calcd for
[23] K. Ando, F. Kondo, F. Koike, H. Takayama, An improved synthesis of 24,24-di-
fluoro-1α,25-dihydroxyvitamin D from vitamin D , Chem. Pharm. Bull. 40 (6)
1992) 1662–1664.
−
3
2
28 43 4 2
C H O F [M + HCOO] 481.3135, found 481.3137.
(
[
24] H. Iwasaki, R. Hosotani, Y. Miyamoto, Y. Nakano, K. Yamamoto, S. Yamada,
T. Shinki, T. Suda, K. Yamaguchi, K. Konno, H. Takayama, Stereoselective synthesis
and structural establishment of (25S)-24,24-difluoro-1α,25,26-trihydroxyvitamin
Acknowledgements
D
3
3
, a major metabolite of 24,24-difluoro-1α,25-dihydroxyvitamin D , Tetrahedron
This work was supported in part by Grant-in-Aid from the Japan
Society for the Promotion of Science (18K06556 to A. K.). The authors
are grateful to AMED-CREST, The Japan Agency for Medical Research
and Development (AMED)(JP18gm0710007h0105), for partial support
for the preparation of this manuscript.
5
4 (49) (1998) 14705–14724.
[25] A. Flores, I. Massarelli, J.B. Thoden, L.A. Plum, H.F. DeLuca, A methylene group on
markedly increases bone
C-2 of 24,24-difluoro-19-nor-1α,25-dihydroxyvitamin D
3
calcium mobilization in vivo, J. Med. Chem. 58 (24) (2015) 9731–9741.
26] A.H. Fauq, Diethylaminosulfurtrifluoride, e-EROS Encyclopedia of Reagents for
Organic Synthesis, (2006), pp. 1–14.
[
[
[
27] H.T. Toh, W.H. Okamura, Studies on a convergent route to side-chain analogues of
3
vitamin D: 25-hydroxy-23-oxavitamin D , J. Org. Chem. 48 (1983) 1414–1417.
References
28] E. Nakamura, New acyl anion equivalent. A short route to the enol lactam inter-
mediate in cytochalasin synthesis, Tetrahedron Lett. 22 (1981) 663–666.
[
1] G. Jones, S.A. Strugnell, H.F. DeLuca, Current understanding of the molecular ac-
tions of vitamin D, Physiol. Rev. 78 (4) (1998) 1193–1231.
[29] C. Kuroda, T. Ueshino, S. Honda, H. Suzuki, Homo-cope-type five-carbon ring-ex-
pansion reaction via silyl enol ether, Synlett 17 (2006) 2830–2832.
[30] Y. Kato, Y. Hashimoto, K. Nagasawa, Novel heteroatom-containing vitamin D
3
[2] T. Sakaki, N. Sawada, K. Komai, S. Shiozawa, S. Yamada, K. Yamamoto, Y. Ohyama,
analogs: efficient synthesis of 1α,25-dihydroxyvitamin D
3
-26,23-lactam, Molecules
3
K. Inouye, Dual metabolic pathway of 25-hydroxyvitamin D catalyzed by human
CYP24, Eur. J. Biochem. 267 (2000) 6158–6165.
8 (2003) 488–499.
[3] T. Eguchi, S. Takatsuto, M. Ishiguro, N. Ikekawa, Y. Tanaka, H.F. DeLuca, Synthesis
[31] K. Ono, A. Yoshida, N. Saito, T. Fujishima, S. Honzawa, Y. Suhara, S. Kishimoto,
and determination of configuration of natural 25-hydroxyvitamin D
3
26,23-lactone,
T. Sugiura, K. Waku, H. Takayama, A. Kittaka, Efficient synthesis of 2-modified
Proc. Natl. Acad. Sci. U. S. A. 78 (11) (1981) 6579–6583.
1α,25-dihydroxy-19-norvitamin D
3
with Julia olefination: high potency in induc-
tion of differentiation on HL-60 cells, J. Org. Chem. 68 (2003) 7407–7415.
[4] A. Nagata, Y. Akagi, S. Sedghi Masoud, M. Yamanaka, A. Kittaka, M. Uesugi,
4