Novel synthesis of 1α,25-dihydroxy-19-norvitamin D from 25-hydroxyvitamin D

Article abstract of DOI:10.1016/j.tet.2009.09.115

19-Norvitamin D analogs 3a and 3b were synthesized from 25-hydroxyvitamin D, obtained via a bioconversion method. The synthetic route features a highly regio- and stereoselective hydroboration reaction to afford 25-hydroxy-3,5-cyclopropyl-vitamin D deriva

Full text of DOI:10.1016/j.tet.2009.09.115

Tetrahedron 65 (2009) 10002–10008
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis of 1
a,25-dihydroxy-19-norvitamin D from 25-hydroxyvitamin D
Asako Toyoda a, Hazuki Nagai a, Tomonari Yamada a, Yusuke Moriguchi b, Junko Abe b,
,
Toshio Tsuchida a, Kazuo Nagasawa b
*
a Mercian Bioresource Laboratories, 1808 Nakaizumi, Iwata-shi, Shizuoka 438-0078, Japan
b Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
19-Norvitamin D analogs 3a and 3b were synthesized from 25-hydroxyvitamin D, obtained via a bio-
conversion method. The synthetic route features a highly regio- and stereoselective hydroboration
reaction to afford 25-hydroxy-3,5-cyclopropyl-vitamin D derivatives 12 having olefin at the C1–
10-position.
Received 21 July 2009
Received in revised form
29 September 2009
Accepted 29 September 2009
Available online 2 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
differentiation-inducing activity with very low calcium mobiliza-
tion.2,3 Currently, the 19-nor analog of 1a, i.e., paricalcitol (3a), is
1
a
,25-Dihydroxyvitamin D2 (1a) and D3 (1b) (Fig. 1), which are
available for the treatment and prevention of secondary hyper-
active forms of vitamins D2 and D3, respectively, show various sig-
nificant biological activities, being involved in the regulation of
calcium and phosphorus homeostasis, bone mineralization, pro-
liferation and differentiation of various types of cells, and immune
regulation.1 Numerous structure–activity relationship studies have
been conducted with the aim of separation and/or enhancement of
these characteristic biological activities. In 1990s,19-nor derivatives
3a and 3b were reported by DeLuca et al. to show highly potent cell
parathyroidism associated with chronic renal failure.2
The 19-nor type vitamin D analog 3b was first synthesized via 2b,
and since then, various attempts have been made to improve the
synthetic method. Some efficient syntheses have been reported
based upon a strategy of coupling A-ring and CD-ring synthons by
the use of Wittig–Horner reaction, Suzuki–Miyaura coupling re-
action, and Julia-type olefination reaction.4,5 These methods allow
the preparation of a variety of 19-norvitamin D analogs, but never-
theless, many reaction steps are required for the preparation of the
A-ring and 25-hydroxylated CD-ring synthons. Although a shorter
direct synthesis of 19-norvitamin D3 3b from 2b was developed,
efficient introduction of the two hydroxyl groups at C1 and 25
remained an issue.3–6
We have recently developed a practical synthesis of 25-
hydroxyvitamin D2 (2a) and D3 (2b) from the corresponding vitamin
D by means of a bioconversion method.7 In this paper, we wish to
report a novel direct synthesis of 1a,25-dihydroxy-19-norvitamin D
(3a) and (3b) from 25-hydroxyvitamin D analogs 2.
2. Results and discussions
At the outset, we chose the 10-keto 6 as a key intermediate
(Scheme 1). A 3,5-cyclovitamin D2 derivative 4a was obtained from
2a by tosylation and solvolysis with methanol, followed by
methoxymethyl ether formation at the C25 hydroxyl group. Regio-
selective dihydroxylation of the C10–19 olefin of 4a with OsO4,
followed by oxidative cleavage of the resulting glycol with sodium
periodinate gave 10-keto-3,5-cyclovitamin D2 6a in 29% yield from
2a (five steps). Vitamin D3 derivative 6b was similarly obtained from
2b in five steps in 38% yield.
Figure 1. Structures of 1
2 and 3.
a,25-dihydroxyvitamin D2 (1a) and D3 (1b), and their analogs
* Corresponding author. Tel./fax: þ81 42 388 7295.
E-mail address: knaga@cc.tuat.ac.jp (K. Nagasawa).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.115

A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
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Scheme 1. Synthesis of 10-keto 6 from 2 by oxidation at C19. (a) p-TsCl (5.1 equiv), Py, rt; (b) MeOH, NaHCO3 (27 equiv), 55 ꢀC; (c) MOMCl (4.7 equiv), DIPEA (9.6 equiv), DMAP
(0.1 equiv), CH2Cl2, rt; (d) OsO4 (1.0 equiv), pyridine; (e) NaIO4 (3.0 equiv), MeOH, 0 ꢀC (6a: 29%, from 2a, 6b: 38% from 2b).
Introduction of a hydroxyl group at C1 and reduction at C10 were
examined with 6a (Scheme 2). Rubottom oxidation conditions were
ketone 8a as a single diastereomer in 66% yield from 6a.8 Reduction of
the carbonyl group of 8a to methylene 10a was examined via mesy-
late 9a, but LiAlH4 wasunreactivewith 9a. Direct transformation of 8a
successfully applied to the ketone 6a to generate
a-hydroxylated
Scheme 2. Oxidation at C1 and investigation of reduction at C10. (a) TBSOTf (2.5 equiv), 2,6-lutidine (4 equiv), DME, 0 ꢀC; (b) m-CPBA (1 equiv), CH2Cl2, 0 ꢀC; (c) TBSOTf (1.2 equiv),
2,6-lutidine (3 equiv), CH2Cl2, 0 ꢀC, 66% (three steps); (d) NaBH4 (4 equiv), EtOH, 0 ꢀC, 58%; (e) MsCl (7 equiv), Et3N (10 equiv), CH2Cl2, 0 ꢀC.

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A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
Finally, the methoxymethyl ether group at C25 was deprotected with
camphor sulfonic acid in THF/MeOH to give 1 ,25-dihydroxy-19-
a
norvitamin D2 (3a) in 31% yield from 13a. The vitamin D3 analog 3b
was synthesized from 6b in six steps in 4% yield.
The present synthetic route was successfully applied to 2a
without protecting the hydroxyl group at C25 (Scheme 4). Every
reaction proceeded similarly to that in the 25-protected case, and
paricalcitol (3a) was obtained efficiently obtained in nine steps
with 3% overall yield.
3. Conclusions
In conclusion we have succeeded in developing a novel direct
synthesis of C1 hydroxylated 19-norvitamin D analogs from the
corresponding 25-hydroxyvitamin D precursors in a highly regio-
and stereoselective manner. The key step is a hydroboration
reaction of alkene 12, which is expected to be a useful synthetic
intermediate for a variety of new vitamin D analogs.
Scheme 3. Synthesis of 3a and 3b. (a) LiHMDS (2.5 equiv), Tf2NPh (2.5 equiv), DME,
ꢁ75 ꢀC; (b) Pd(OAc)2 (0.1 equiv), n-Ph3P (0.2 equiv), n-Bu3N (3.0 equiv), HCO2H
(2.0 equiv), DMF, 60 ꢀC (12a: 49%, two steps, 12b: 32% two steps); (c) 9-BBN (2.5 equiv),
THF, rt, then, 3 mol/L NaOH/30% H2O2(1/1), rt (13a: 39%, 13b: 29%); (d) AcOH, 60 ꢀC; (e)
10% KOH aq, EtOH, 0 ꢀC; (f) CSA (2.5 equiv), THF/MeOH, 0 ꢀC (3a: 31%, three steps, 3b:
37% three steps).
into 10a under a variety of Wolff–Kishner reaction conditions was
also unsuccessful.9
4. Experimental
4.1. General
Thus, conversion of 6a–13a was attempted by applying hydro-
boration reaction to the olefin 12a (Scheme 3). Reaction of ketone 6a
with lithium hexamethyldisilazide and N-phenyltrifluoromethan-
esulfonimide in DME gave vinyl triflate 11a.10 Reduction of 11a to the
corresponding alkene 12a10 was conducted in 49% yield (two steps)
with formic acid and tri-n-butylamine in the presence of catalytic
amounts of palladium diacetate (10 mol %) and triphenylphosphine
(20 mol %). Regio- and stereoselective hydroboration reaction of 12a
was conducted with the bulky reagent 9-BBN at room temperature,
1H and 13C NMR spectra were recorded on BURKER AVANCE 500
instrument. Mass spectra were recorded on Agilent Technologies
Ion Trap LC/MS 6320 spectrometer and JEOL JMS-T100X spec-
trometer with ESI-MS mode using methanol as solvent. Preparative
chromatography was performed using Silica gel 60 N (spherical,
neutral, particle size 63–2 mm, Kanto Chemical Co., Inc., Japan) or
preparative TLC (silica gel 60 F2541.05744, Merck).
affording the 1a-hydroxy-3,5-cyclovitamin D2 derivative 13a exclu-
sively in 39% yield after oxidationwith H2O2 and sodium hydroxide.11
Cycloreversion of 13a with acetic acid followed by hydrolysis of the
resulting acetate with potassium hydroxide in ethanol gave a diol.
4.1.1. 6-Methoxy-25-methoxymethyloxy-3,5-cyclovitamin D2 (4a). To
a solution of 2a (2.90 g, 7.0 mmol) in pyridine (40.0 mL) was added
p-toluenesulfonyl chloride (6.80 g, 35.7 mmol) at 0 ꢀC. After being
Scheme 4. Synthesis of 3a from 2a. (a) p-TsCl (5.0 equiv), Py rt; (b) MeOH, NaHCO3 (27 equiv), 70 ꢀC; (c) OsO4 (0.9 equiv), Py; (d) NaIO4 (3.0 equiv), MeOH, 0 ꢀC, 52% (four steps); (e)
LiHMDS (2.5 equiv), Tf2NPh (2.5 equiv), DME, ꢁ75 ꢀC; (f) Pd(OAc)2 (0.1 equiv), n-Ph3P (0.2 equiv), n-Bu3N (3.0 equiv), HCO2H (2.0 equiv), DMF, 60 ꢀC, 22% (two steps); (g) 9-BBN
(2.5 equiv), THF, rt, then, 3 mol/L NaOH/30% H2O2(1/1), rt; (h) AcOH, 55 ꢀC; (i) 10% KOH aq, EtOH, rt, 25% (three steps).

A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
10005
stirred for 17 h at room temperature, thesolutionwasadjusted to 0 ꢀC
and quenched with water (30 mL). The solution was concentrated,
added water (50 mL) and extracted with ethyl acetate (50 mLꢂthree
times). The organic layer was washed with water, 1 M HCl, saturated
NaHCO3, and brine. The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo, yielding crude 25-
hydroxyvitaminD2 tosylate(3.98 g). Crudetosylate(2.53 g, 4.5 mmol)
and sodium hydrogencarbonate (10.3 g, 122.5 mmol) in methanol
(100 mL) was stirred for 9 h at 55 ꢀC. After cooling, the reaction
mixture was filtered through a pad of Celite. The filtrates were con-
centrated in vacuo, added water (50 mL) and extracted with ethyl
acetate (80 mLꢂtwotimes). The organic layer waswashed withwater
and brine, and dried over anhydrous Na2SO4. The filtrates were con-
centrated in vacuo to give crude 25-hydroxy-3,5-cyclovitamin D2
(1.89 g). To a solution of crude 25-hydroxy-3,5-cyclovitamin D2
(1.62 g, 3.8 mmol) in dichloromethane (30 mL) was added diisopro-
pylethylamine (6.3 mL, 36.4 mmol), methoxymethyl chloride
(1.35 mL, 17.9 mmol), and N,N-dimethylaminopyridine (44.6 mg,
0.36 mmol) at 0 ꢀC. The reaction mixture was stirred for 6 h at room
temperature, and concentrated in vacuo. To the residue was added
water (15 mL) and extracted with ethyl acetate (30 mLꢂthree times).
The organic layer was washed with 1 M HCl, saturated NaHCO3, and
brine. The organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo to give crude 4a (1.69 g) as a brown
(C27), 23.30 (C15), 21.45 (C21), 21.37 (C3), 15.67 (C28), 12.89 (C18),
11.86 (C4); ESI-MS m/z¼527.56 [MþNa]þ, 539.63 [MþCl]ꢁ; HRMS
calcd for C31H52O5Na 527.3712, found 527.3672.
4.1.3. 10,19-Dihydro-6-methoxy-25-methoxymethyloxy-3,5-cyclo-
vitamin D 3 (5b). As described for 5a, 2b (1.07 g, 2.7 mmol) was
converted into crude 5b (1.08 g) as a brown amorphous. 1H NMR
(500 MHz, CD3OD)
d
(ppm) 4.90 (d, 1H, J¼9 Hz, H6), 4.68 (s, 2H,
MOM–CH2), 4.58 (d, 1H, J¼9 Hz, H7), 3.65 (d, 1H, J¼11 Hz, H19a),
3.58 (d, 1H, J¼11 Hz, H19b), 3.33 (s, 3H, MOM–CH3), 3.20 (s, 3H,
OMe), 2.70 (m, 1H, H9a), 2.18 (m, 3H), 1.93 (m, 1H, H16a), 1.70(m,
2H), 1.63 (dd, 1H, J¼7 and 12 Hz, H2b), 1.58–1.20 (m, 15H), 1.20 (s,
6H, H26 and H27), 1.07 (m, 1H, H22b), 0.96 (d, 3H, J¼6 Hz, H21),
0.59 (s, 3H, H18), 0.51 (dd, 1H, J¼5 and 8 Hz, H4a), 0.38 (t, 1H,
J¼5 Hz, H4b); 13C NMR (125 MHz, CD3OD)
d (ppm) 146.88 (C8),
119.17 (C7), 92.01 (MOM–CH2), 85.07 (C10), 78.76 (C6), 77.65 (C25),
68.34 (C19), 58.01 (C17), 56.99 (C14), 55.89 (OMe), 55.45 (MOM–
CH3), 46.64 (C13), 43.38 (C24), 41.59 (C12), 37.67 (C22), 37.46 (C20),
36.48 (C5), 33.76 (C1), 30.20 (C9), 28.70 (C16), 26.81 (C26), 26.73
(C27), 25.27 (C2), 24.46 (C11), 23.34 (C15), 21.62 (C23), 21.33 (C3),
19.38 (C21), 12.61 (C18), 11.85 (C4); ESI-MS m/z¼515.47[MþNa]þ,
527.50[MþCl]ꢁ; HRMS calcd for C30H52O5Na 515.3712, found
515.3705.
amorphous.1H NMR (500 MHz, CD3OD)
d
(ppm) 5.35 (dd,1H, J¼8 and
4.1.4. 10-Keto-6-methoxy-25-methoxymethyloxy-3,5-cyclovitamin
D2 (6a). To a solution of crude 5a (1.03 g, 2.0 mmol) in methanol
(10 mL) was added dropwise an aqueous solution (9 mL) of so-
dium periodate (1.32 g, 6.1 mmol) at 0 ꢀC, and the mixture was
stirred for 2 h at 0 ꢀC. The reaction mixture was added saturated
NaHCO3 (10 mL), concentrated, diluted with water (80 mL), and
extracted with ethyl acetate (50 mLꢂthree times). The organic
layer was then washed with water, 1 M HCl, saturated NaHCO3,
and brine. The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel 60 N 18.5 g, n-hexane/ethyl
acetate¼6/1) to give 6a (312.6 mg, combined five-step yield of 29%
from 25-hydroxyvitamin D2 (2a)) as a slightly yellow oil. 1H NMR
15 Hz, H23), 5.27 (dd, 1H, J¼8 and 15 Hz, H22), 5.03 (d, 1H, J¼12 Hz,
H7), 5.01 (brs,1H, H19a), 4.84(br s,1H, H19b), 4.70 (s, 2H, MOM–CH2),
4.17(d,1H, J¼9 Hz, H6), 3.33(s, 3H, MOM–CH3),3.23(s, 3H, OMe), 2.68
(m, 1H, H9a), 2.21 (m, 2H), 2.12–1.99 (m, 4H), 1.77–1.25 (m, 11H), 1.17
(s, 3H, H26), 1.13 (s, 3H, H27), 1.03 (d, 3H, J¼7 Hz, H21), 0.99 (d, 3H,
J¼7 Hz, H28), 0.94 (dd, 1H, J¼5 and 8 Hz, H4a), 0.75 (t, 1H, J¼5 Hz,
H4b), 0.58 (s, 3H, H18); 13C NMR (125 MHz, CD3OD)
d (ppm) 153.41
(C10), 144.84 (C8), 138.46 (C22), 131.24 (C23), 120.33 (C7), 104.36
(C19), 91.93 (MOM–CH2), 79.44 (C6), 79.15 (C25), 57.80 (C17), 57.13
(C14), 56.14 (OMe), 55.46 (MOM–CH3), 48.11 (C24), 46.58 (C13), 41.85
(C20), 41.59(C12), 36.70 (C5), 31.24 (C1), 30.44(C9), 28.97 (C16), 26.38
(C2), 25.73 (C3), 25.21 (C26), 24.72 (C11), 23.60 (C27), 23.19 (C15),
21.47 (C21), 17.31 (C4), 15.68 (C28), 12.73 (C18); ESI-MS m/z¼493.52
[MþNa]þ, 505.72 [MþCl]ꢁ; HRMS calcd for C31H50O5Na 493.3657,
found 493.3623.
(500 MHz, CD3OD)
d
(ppm) 5.35 (dd, 1H, J¼8 and 15 Hz, H23), 5.27
(dd, 1H, J¼8 and 15 Hz, H22), 4.70 (s, 2H, MOM–CH2), 4.65 (d, 1H,
J¼9 Hz, H6), 4.61 (d, 1H, J¼9 Hz, H7), 3.33 (s, 3H, MOM–CH3), 3.18
(s, 3H, OMe), 2.69 (m, 1H, H9a), 2.20 (m, 3H), 2.03 (m, 6H), 1.74 (m,
3H), 1.56–1.23 (m, 7H), 1.17 (s, 3H, H26), 1.13 (s, 3H, H27), 1.03 (d,
3H, J¼7 Hz, H21), 1.03 (m, 1H, H4b), 0.99 (d, 3H, J¼7 Hz, H28),
4.1.2. 10,19-Dihydro-6-methoxy-25-methoxymethyloxy-3,5-cyclo-
vitamin D2 (5a). To a solution of crude 4a (1.05 g, 2.2 mmol) in
pyridine (7 mL) was added dropwise a pyridine (3 mL) solution of
osmium tetraoxide (0.53 g, 2.1 mmol) at 0 ꢀC. The reaction mixture
was stirred for 2 h at room temperature. The solution was adjusted
to 0 ꢀC and 40 mL of 10% NaHSO3 was added, and the mixture was
stirred for 2 h at room temperature. The reaction mixture was
extracted with ethyl acetate (50 mLꢂthree times), and the organic
layer was washed with water, 1 M HCl, saturated NaHCO3, and
brine. The organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo to give crude 5a (1.04 g) as a brown
0.57(s, 3H, H18); 13C NMR (125 MHz, CD3OD)
d (ppm) 216.72 (C10),
146.83 (C8), 138.43 (C22), 131.29 (C23), 118.32 (C7), 91.90 (MOM–
CH2), 79.46 (C25), 74.69 (C6), 57.76 (C17), 57.07 (C14), 56.47 (OMe),
55.47 (MOM–CH3), 48.11 (C24), 46.57 (C13), 41.98 (C5), 41.84
(C20), 41.44 (C12), 33.93 (C1), 30.35 (C9), 28.93 (C16), 25.78 (C3),
25.20 (C26), 24.58 (C11), 23.61 (C27), 23.15 (C15), 22.50 (C2), 21.45
(C21), 17.97 (C4), 15.67 (C28), 12.74 (C18); ESI-MS m/
z¼495.33[MþNa]þ, 507.41[MþCl]ꢁ; HRMS calcd for C30H48O4Na
495.3450, found 495.3489.
amorphous. 1H NMR (500 MHz, CD3OD)
d
(ppm) 5.36 (dd, 1H, J¼8
and 15 Hz, H23), 5.27 (dd, 1H, J¼8 and 15 Hz, H22), 4.89 (d, 1H,
J¼9 Hz, H6), 4.70 (s, 2H, MOM–CH2), 4.58 (d, 1H, J¼9 Hz, H7), 3.65
(d, 1H, J¼11 Hz, H19a), 3.58 (d, 1H, J¼11 Hz, H19b), 3.34 (s, 3H,
MOM–CH3), 3.20 (s, 3H, OMe), 2.71 (m, 1H, H9a), 2.20 (m, 1H, H24),
2.03 (m, 4H), 1.73 (m, 3H), 1.63 (dd, 1H, J¼7 and 12 Hz, H2b), 1.56–
1.30 (m, 9H), 1.17 (s, 3H, H26), 1.13 (s, 3H, H27), 1.03 (d, 3H, J¼7 Hz,
H21), 0.99 (d, 3H, J¼7 Hz, H28), 0.60 (s, 3H, H18), 0.50 (dd, 1H, J¼5
and 8 Hz, H4a), 0.38 (t, 1H, J¼5 Hz, H4b); 13C NMR (125 MHz,
4.1.5. 10-Keto-6-methoxy-25-methoxymethyloxy-3,5-cyclovitamin
D3 (6b). As described for 6a, crude 5b (1.08 g, 2.2 mmol) was
converted into 6b (453.8 mg, 38% from 25-hydroxyvitamin D3 (2b))
as a brown oil. 1H NMR (500 MHz, CD3OD)
d (ppm) 4.68 (s, 2H,
MOM–CH2), 4.65 (d, 1H, J¼9 Hz, H6), 4.62 (d, 1H, J¼9 Hz, H7), 3.33
(s, 3H, MOM–CH3), 3.18 (s, 3H, OMe), 2.63 (m, 1H, H9a), 2.19 (m,
2H), 2.06 (m, 4H), 1.95 (m, 2H), 1.72 (m, 2H), 1.55–1.23 (m, 13H), 1.20
(s, 6H, H26 and H27), 1.03 (m, 2H), 0.96 (d, 3H, J¼6 Hz, H21), 0.57 (s,
CD3OD)
d
(ppm) 146.78 (C8), 138.42 (C22), 131.29 (C23), 119.22 (C7),
3H, H18); 13C NMR (125 MHz, CD3OD)
d (ppm) 216.71 (C10), 146.89
91.94 (MOM–CH2), 85.06 (C10), 79.45 (C25), 78.75 (C6), 68.34 (C19),
57.77 (C17), 57.04 (C14), 55.89 (OMe), 55.47 (MOM–CH3),48.53
(C24), 48.11 (C13), 41.84 (C20), 41.42 (C12), 36.49 (C5), 33.77 (C1),
30.19 (C9), 28.93 (C16), 25.27 (C2), 25.20 (C26), 24.44 (C11), 23.61
(C8), 118.22 (C7), 91.97 (MOM–CH2), 77.62 (C25), 74.70 (C6), 57.96
(C17), 56.99 (C14), 56.45 (OMe), 55.41 (MOM–CH3), 46.64 (C13),
43.34 (C24), 41.95 (C5), 41.57 (C12), 37.64 (C22), 37.42 (C20), 33.90
(C1), 30.32 (C9), 28.68 (C16), 26.77 (C26), 26.69 (C27), 25.73 (C3),

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A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
24.57 (C11), 23.16 (C15), 22.47 (C2), 21.58 (C23), 19.35 (C21), 17.97
(C4), 12.42 (C18); ESI-MS m/z¼483.40[MþNa]þ, 495.51[MþCl]ꢁ;
HRMS calcd for C29H48O4Na 483.3450, found 483.3442.
20.13 (C4), 19.38 (C21), 18.59 (C3), 12.40 (C18); ESI-MS m/
z¼615.37[MþNa]þ; HRMS calcd for C30H47F3O6SiNa 615.2943,
found 615.2990.
4.1.6. 25-Hydroxy-10-keto-6-methoxy-3,5-cyclovitamin D2 (6c). As
described for 6a, 2a (518 mg, 1.3 mmol) was converted into 6c
(279.0 mg, 52% from 25-hydroxyvitamin D2 (2a)) as a brown oil. 1H
4.1.9. 6-Methoxy-25-methoxymethyloxy-1,10-olefin-3,5-cyclo-
vitamin D2 (12a). To a solution of crude 11a (0.32 mmol), triphe-
nylphosphine (16.8 mg, 0.063 mmol), and palladium diacetate
(7.1 mg, 0.031 mmol) in DMF (4 mL) was added dropwise tribu-
tylamine (227 mL, 0.95 mmol) and formic acid (24 mL, 0.63 mmol)
at room temperature, and the resulting mixture was stirred at 60 ꢀC
for 1 h. The reaction mixture was diluted with water (10 mL) and
extracted with ethyl acetate (15 mLꢂthree times). The organic layer
was washed with 1 M HCl, saturated NaHCO3, and brine. The or-
ganic layer was then dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel 60 N 4.0 g, n-hexane/acetone¼50/1) to give
12a (71.6 mg, 49% from 6a) as a slightly yellow oil. 1H NMR
NMR (500 MHz, CD3OD)
d
(ppm) 5.35 (dd, 1H, J¼8 and 15 Hz, H23),
5.27 (dd, 1H, J¼8 and 15 Hz, H22), 4.65 (d, 1H, J¼10 Hz, H6), 4.61 (d,
1H, J¼10 Hz, H7), 3.18 (s, 3H, OMe), 2.67 (m, 1H, H9a), 2.20 (m, 2H),
2.03 (m, 7H), 1.71 (m, 3H), 1.59–1.17 (m, 7H), 1.13 (s, 3H, H26), 1.09
(s, 3H, H27), 1.06 (t, 1H, J¼5 Hz, H4b), 1.04 (d, 3H, J¼7 Hz, H21), 0.99
(d, 3H, J¼7 Hz, H28), 0.57 (s, 3H, H18); 13C NMR (125 MHz, CD3OD)
d
(ppm) 216.73 (C10), 146.85 (C8), 138.33 (C22), 131.55 (C23), 118.31
(C7), 74.69 (C6), 73.36 (C25), 57.77 (C17), 57.08 (C14), 56.47 (OMe),
49.20 (C24), 46.57 (C13), 41.98 (C5), 41.84 (C20), 41.44 (C12), 33.93
(C1), 30.35 (C9), 28.93 (C16), 28.32 (C26), 26.13 (C27), 25.77 (C3),
24.59 (C11), 23.15 (C15), 22.50 (C2), 21.45 (C21), 17.98 (C4), 15.68
(C28), 12.74 (C18); ESI-MS m/z¼451.4 [MþNa]þ, 463.4 [MþCl]ꢁ;
HRMS calcd for C28H44O3Na 451.3188, found 451.3184.
(500 MHz, CD3OD)
d
(ppm) 5.90 (td, 1H, J¼2 and 5 Hz, H10), 5.39
(brd, 1H, J¼4 Hz, H1), 5.35 (dd, 1H, J¼8 and 15 Hz, H23), 5.27 (dd,
1H, J¼8 and 15 Hz, H22), 4.87 (d, 1H, J¼10 Hz, H7), 4.70 (s, 2H,
MOM–CH2), 3.97 (d, 1H, J¼10 Hz, H6), 3.33 (s, 3H, MOM–CH3), 3.25
(s, 3H, OMe), 2.61 (dd, 1H, J¼5 and 13 Hz, H9a), 2.54 (m, 1H, H2a),
2.27 (brd, 1H, J¼18 Hz, H2b), 2.20 (m, 1H, H24), 2.03 (m, 3H), 1.72
(m, 2H), 1.47 (m, 4H), 1.34 (m, 4H), 1.17 (s, 3H, H26), 1.13(s, 3H, H27),
1.03 (m, 1H, H4a), 1.03 (d, 3H, J¼7 Hz, H21), 0.98 (d, 3H, J¼7 Hz,
H28), 0.55 (s, 3H, H18), 0.16 (t,1H, J¼4 Hz, H4b); 13C NMR (125 MHz,
4.1.7. 6-Methoxy-25-methoxymethyloxy-10-triflate-3,5-cyclovitamin
D2 (11a). To a solution of 6a (150 mg, 0.32 mmol) in dimethoxy-
ethane (3.5 mL) was added dropwise a dimethoxyethane (1.5 mL)
solution of lithium hexamethyldisilazide (1.6 M in THF, 495 mL,
0.79 mmol) at ꢁ75 ꢀC. The mixture was stirred for 1 h at ꢁ75 to
ꢁ70 ꢀC. To this reaction mixture was added N-phenylbis(trifluoro-
methanesulfonimide) (284 mg, 0.79 mmol), and the resulting mix-
ture was stirred at ꢁ75 to 15 ꢀC for 15 h. The reaction mixture was
concentrated, diluted with water (5 mL), and extracted with ethyl
acetate (10 mLꢂthree times). The organic layer was washed with
1 M HCl, saturated NaHCO3, and brine. The organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo to give
crude 11a (290.8 mg) as a brown amorphous. 1H NMR (500 MHz,
CD3OD)
d (ppm) 144.29 (C8), 138.44 (C22), 135.37 (C10), 131.20
(C23), 128.95 (C1), 121.04 (C7), 91.90 (MOM–CH2), 80.18 (C6), 79.43
(C25), 57.77 (C17), 57.05 (C14), 56.09 (OMe), 55.43 (MOM–CH3),
48.08 (C24), 46.61 (C13), 41.83 (C20), 41.61 (C12), 41.28 (C5), 36.91
(C2), 30.50 (C9), 28.95 (C16), 25.16 (C26), 25.13 (C11), 23.56 (C27),
23.04 (C15), 22.48 (C4), 21.42 (C21), 19.98 (C3), 15.63 (C28), 12.48
(C18); ESI-MS m/z¼479.38[MþNa]þ; HRMS calcd for C30H48O3Na
479.3501, found 479.3517.
CD3OD)
d
(ppm) 5.36 (dd, 1H, J¼8 and 15 Hz, H23), 5.32 (d, 1H,
J¼2 Hz, H1), 5.28 (dd, 1H, J¼8 and 15 Hz, H22), 4.70 (s, 2H, MOM–
CH2), 4.65 (d, 1H, J¼10 Hz, H7), 4.37 (d, 1H, J¼10 Hz, H6), 3.44 (s, 3H,
MOM–CH3), 3.23 (s, 3H, OMe), 2.60 (m, 2H), 2.35 (dd, 1H, J¼2 and
17 Hz, H2b), 2.20 (m, 1H, H24), 2.03 (m, 3H), 1.75 (m, 4H), 1.45 (m,
3H), 1.35 (m, 3H),1.17 (s, 3H, H26),1.13 (s, 3H, H27), 1.09 (dd,1H, J¼5
and 8 Hz, H4a), 1.04 (d, 3H, J¼7 Hz, H21), 0.99 (d, 3H, J¼7 Hz, H28),
0.57 (s, 3H, H18), 0.53 (t, 1H, J¼5 Hz, H4b); 13C NMR (125 MHz,
4.1.10. 6-Methoxy-25-methoxymethyloxy-1,10-olefin-3,5-cyclo-
vitamin D3 (12b). As described for 12a, crude 11b (0.68 mmol) was
converted into 12b (98.7 mg, 32% from 6b) as a slightly yellow
amorphous after column chromatography (silica gel 60 N 7.5 g,
n-hexane/ethyl acetate¼60/1–6/1). 1H NMR (500 MHz, CD3OD)
d
(ppm) 5.90 (td, 1H, J¼2 and 5 Hz, H10), 5.39 (brd, 1H, J¼5 Hz, H1),
4.87 (d, 1H, J¼9 Hz, H7), 4.67 (s, 2H, MOM–CH2), 3.97 (d, 1H, J¼9 Hz,
H6), 3.33 (s, 3H, MOM–CH3), 3.25 (s, 3H, OMe), 2.61 (dd,1H, J¼4 and
11 Hz, H9a), 2.54 (m, 1H, H2a), 2.27 (brd, 1H, J¼17 Hz, H2b), 2.01 (m,
2H), 1.92 (m, 1H, H16a), 1.70 (m, 2H), 1.51–1.22 (m, 12H), 1.23 (s, 6H,
H26 and H27), 1.03 (m, 1H, H22b), 1.03 (dd, 1H, J¼4 and 8 Hz, H4a),
0.96 (d, 3H, J¼6 Hz, H21), 0.58 (s, 3H, H18), 0.16 (t, 1H, J¼4 Hz, H4b);
CD3OD) d (ppm) 153.88 (C10),147.23 (C8),138.37 (C22),131.28 (C23),
118.09 (C7), 114.97 (C1), 91.91 (MOM-CH2), 79.43 (C25), 76.51 (C6),
57.73 (C17), 57.03 (C14), 56.44 (OMe), 55.44 (MOM–CH3), 48.08
(C24), 46.52 (C13), 41.80 (C20), 41.36 (C12), 36.90 (C5), 31.02 (C2),
30.31 (C9), 28.88 (C16), 25.16 (C26), 24.73 (C11), 23.58 (C27), 23.08
(C15), 21.41 (C21), 20.08 (C4), 18.55 (C3), 15.63 (C28), 12.65 (C18);
ESI-MS m/z¼627.35 [MþNa]þ; HRMS calcd for C31H47F3O6SiNa
627.2943, found 627.2970.
13C NMR (125 MHz, CD3OD)
d (ppm) 144.38 (C8), 135.38 (C10),
128.95 (C1), 121.00 (C7), 91.97 (MOM–CH2), 80.20 (C6), 77.62 (C25),
58.01 (C17), 57.01 (C14), 56.10 (OMe), 55.42 (MOM–CH3), 46.71
(C13), 43.35 (C24), 41.78 (C12), 41.29 (C5), 37.67 (C2), 37.46 (C20),
36.92 (C22), 30.51 (C9), 28.74 (C16), 26.77 (C26), 26.70 (C27), 25.16
(C11), 23.09 (C15), 22.49 (C4), 21.59 (C23), 19.97 (C3), 19.38 (C21),
12.20 (C18); ESI-MS m/z¼467.45[MþNa]þ; HRMS calcd for
C29H48O5Na 467.3501, found 467.3453.
4.1.8. 6-Methoxy-25-methoxymethyloxy-10-triflate-3,5-cyclovitamin
D3 (11b). As described for 11a, 6b (315.9 mg, 0.68 mmol) was
converted into crude 11b (733.9 mg) as a brown amorphous. 1H
NMR (500 MHz, CD3OD)
d
(ppm) 5.33 (d, 1H, J¼2 Hz, H1), 4.68 (s,
2H, MOM–CH2), 4.66 (d, 1H, J¼9 Hz, H7), 4.37 (d, 1H, J¼9 Hz, H6),
3.33 (s, 3H, MOM–CH3), 3.24 (s, 3H, OMe), 2.59 (m, 2H), 2.34 (dd,
1H, J¼2 and 17 Hz, H2b), 2.02 (m, 2H), 1.93 (m, 1H, H16a), 1.74 (m,
3H), 1.51–1.25 (m, 12H), 1.20 (s, 6H, H26 and H27), 1.09 (dd, 1H, J¼4
and 8 Hz, H4a),1.07 (m,1H, H22b), 0.96 (d, 3H, J¼6 Hz, H21), 0.56 (s,
3H, H18), 0.52 (t, 1H, J¼4 Hz, H4b); 13C NMR (125 MHz, CD3OD)
4.1.11. 25-Hydroxy-6-methoxy-1,10-olefin-3,5-cyclovitamin D2 (12c). As
described for 11a and 12a, 6c (100 mg, 0.23 mmol) was converted into
12c (20.8 mg, 22% from 6c) as a slightly yellow amorphous after puri-
fication by preparative TLC (n-hexane/acetone¼3/1). 1H NMR
(500 MHz, CD3OD)
d
(ppm) 5.90 (td, 1H, J¼2 and 5 Hz, H10), 5.39 (brd,
d
(ppm) 153.92 (C10), 147.33 (C8), 118.10 (C7), 115.01 (C1), 92.01
1H, J¼5 Hz, H1), 5.35 (dd,1H, J¼8 and 15 Hz, H23), 5.27 (dd,1H, J¼8 and
15 Hz, H22), 4.87 (d, 1H, J¼10 Hz, H7), 3.97 (d, 1H, J¼10 Hz, H6), 3.25 (s,
3H, OMe), 2.61 (dd, 1H, J¼4 and 11 Hz, H9a), 2.54 (m, 1H, H2a), 2.27
(brd, 1H, J¼17 Hz, H2b), 2.04 (m, 4H), 1.72 (m, 4H), 1.48 (m, 3H), 1.34 (m,
3H), 1.13 (s, 3H, H26), 1.09 (s, 3H, H27), 1.03 (m, 1H, H4a), 1.03 (d, 3H,
(MOM–CH2), 77.64 (C25), 76.57 (C6), 58.00 (C17), 57.02 (C14), 56.47
(OMe), 55.44 (MOM–CH3), 46.66 (C13), 43.38 (C24), 41.56 (C12),
37.67 (C22), 37.47 (C20), 36.94 (C5), 31.06 (C2), 30.35 (C9), 28.70
(C16), 26.80 (C26), 26.73 (C27), 24.79 (C11), 23.16 (C15), 21.62 (C23),

A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
10007
J¼7 Hz, H21), 0.99 (d, 3H, J¼7 Hz, H28), 0.55 (s, 3H, H18), 0.16 (t, 1H,
J¼7 Hz, H21), 0.99 (d, 3H, J¼7 Hz, H28), 0.62 (s, 3H, H18), 0.55 (dd,
1H, J¼4 and 8 Hz, H4a), 0.37 (t, 1H, J¼4 Hz, H4b); 13C NMR
J¼4 Hz, H4b); 13C NMR (125 MHz, CD3OD)
d (ppm) 144.35 (C8), 138.39
(C22), 135.41 (C10), 131.50 (C23), 128.99 (C1), 121.07 (C7), 80.22 (C6),
73.36 (C25), 57.82 (C17), 57.10 (C14), 56.13 (OMe), 49.22 (C24), 46.65
(C13), 41.86 (C20), 41.66 (C12), 41.32 (C5), 36.95 (C2), 30.54 (C9), 28.99
(C16), 28.33 (C26), 26.12 (C27), 25.17 (C11), 23.08 (C15), 22.52 (C4), 21.47
(C21), 20.01 (C3), 15.69 (C28), 12.52 (C18); ESI-MS m/
z¼435.38[MþNa]þ, 447.43[MþCl]ꢁ; HRMS calcd for C28H44O2Na
435.3239, found 435.3223.
(125 MHz, CD3OD) d (ppm) 144.87 (C8), 138.38 (C22), 131.51 (C23),
120.41 (C7), 81.19 (C6), 73.35 (C25), 71.27 (C1), 57.82 (C17), 57.19
(C14), 56.20 (OMe), 49.00 (C24), 46.59 (C13), 41.86 (C20), 41.62
(C12), 37.91 (C10), 37.31 (C2), 31.56 (C5), 30.54 (C9), 29.00 (C16),
28.33 (C26), 26.12 (C27), 25.01 (C11), 23.15 (C15), 21.48 (C21), 19.49
(C3), 15.69 (C28), 14.80 (C4), 12.83 (C18); ESI-MS m/
z¼453.37[MþNa]þ, 465.61[MþCl]ꢁ; HRMS calcd for C28H46O3Na
453.3344, found 453.3300.
4.1.12. 1
a
-Hydroxy-25-methoxymethyloxy-3,5-cyclovitamin
D2
(13a). To a solution of 12a (44.9 mg, 0.098 mmol) in THF (1 mL)
4.1.15. 1a,25-Dihydroxy-19-norvitamin D2, Paricalcitol (3a). A solu-
was added dropwise 9-borabicyclo[3.3.1]nonane 0.5 M in THF
tion of 13a (17.1 mg, 0.036 mmol) in acetic acid (0.4 mL) was stirred
for 20 min at 60 ꢀC. This solution was diluted with ice and saturated
NaHCO3 (10 mL), and extracted with ethyl acetate (5 mLꢂthree
times). The organic layer was washed with water and brine. The
organic layer was dried over anhydrous Na2SO4, filtered and con-
centrated in vacuo. To the residue (17.3 mg) was added a 10% KOH–
ethanol solution (0.5 mL) at 0 ꢀC, and stirred for 1 h. The reaction
mixture was concentrated, diluted with water (5 mL), and extrac-
ted with ethyl acetate (5 mLꢂthree times). The organic layer was
then washed with brine, dried over anhydrous Na2SO4, filtered, and
(490
room temperature. To the resulting mixture was added water
(300 L), 30% H2O2 (300 L) and 3 M NaOH (300
L) at 0 ꢀC, and the
m
L, 0.25 mmol) at 0 ꢀC, and the mixture was stirred for 2 h at
m
m
m
mixture was stirred for 30 min at room temperature. The reaction
mixture was diluted with water (5 mL) and extracted with ethyl
acetate (5 mLꢂthree times). The organic layer was washed with
1 M HCl, saturated NaHCO3, and brine. The organic layer was dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by preparative TLC (n-hexane/acetone¼3/1) to
give 13a (18.0 mg, 39%) as a colorless oil. 1H NMR (500 MHz,
concentrated in vacuo, to give crude 1
ymethyloxy-19-norvitamin D2 (15.2 mg) as a colorless amorphous.
To a solution of the crude (3.9 mg, 8.5 mol) in a mixed solution
a-hydroxy-25-methox-
CD3OD)
d
(ppm) 5.36 (dd, 1H, J¼8 and 15 Hz, H23), 5.28 (dd, 1H, J¼8
and 15 Hz, H22), 4.94 (d, 1H, J¼9 Hz, H7), 4.70 (s, 2H, MOM–CH2),
3.92 (m, 1H, H1), 3.89 (d, 1H, J¼9 Hz, H6), 3.34 (s, 3H, MOM–CH3),
3.21 (s, 3H, OMe), 2.64 (m, 1H, H9a), 2.20 (m, 1H, H24), 2.03 (m, 4H),
1.78–1.28 (m, 12H), 1.17 (m, 1H, H3), 1.17 (s, 3H, H26), 1.13 (s, 3H,
H27), 1.04 (d, 3H, J¼7 Hz, H21), 0.99 (d, 3H, J¼7 Hz, H28), 0.62 (s,
3H, H18), 0.55 (dd, 1H, J¼4 and 8 Hz, H4a), 0.33 (t, 1H, J¼4 Hz, H4b);
m
(1:3) (0.5 mL) of THF and methanol was added camphor sulfonic
acid (5.8 mg, 0.025 mmol) at 0 ꢀC and the mixture was stirred for
3 h at room temperature. The reaction mixture was quenched with
saturated NaHCO3 (5 mL) and extracted with ethyl acetate
(5 mLꢂthree times). The organic layer was then washed with brine.
The organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by preparative TLC
(chloroform/methanol¼10/1) to give paricalcitol (3a) (1.2 mg, 31%
13C NMR (125 MHz, CD3OD)
d (ppm) 144.86 (C8), 138.47 (C22),
131.24 (C23), 120.41 (C7), 91.94 (MOM–CH2), 81.19 (C6), 79.45
(C25), 71.26 (C1), 57.76 (C17), 57.18 (C14), 56.20 (OMe), 55.46
(MOM–CH3), 48.11 (C24), 46.58 (C13), 41.87 (C20), 41.61 (C12),
37.90 (C10), 37.31 (C2), 31.56 (C5), 30.53 (C9), 29.01 (C16), 25.20
(C26), 25.01 (C11), 23.60 (C27), 23.15 (C15), 21.48 (C21), 19.49 (C3),
15.67 (C28), 14.80 (C4), 12.83 (C18); ESI-MS m/z¼497.34[MþNa]þ,
509.35[MþCl]ꢁ.
from 13a) as a white powder. 1H NMR (500 MHz, CD3OD)
d (ppm)
6.21 (d, 1H, J¼11 Hz, H6), 5.88 (d, 1H, J¼11 Hz, H7), 5.35 (dd, 1H, J¼8
and 15 Hz, H23), 5.27 (dd,1H, J¼8 and 15 Hz, H22), 4.04 (m, 1H, H1),
3.98 (m, 1H, H3), 2.84 (brd, 1H, J¼11 Hz, H9a), 2.59 (brd, 1H,
J¼13 Hz, H4a), 2.41 (brd, 1H, J¼13 Hz, H10a), 2.21 (dd, 1H, J¼8 and
13 Hz, H4b), 2.16 (dd, 1H, J¼7 and 13 Hz, H10b), 2.04 (m, 4H), 1.84
(m, 1H, H2a), 1.76 (m, 2H), 1.67 (m, 2H), 1.55 (m, 3H), 1.35 (m, 3H),
1.13 (s, 3H, H26), 1.09 (s, 3H, H27), 1.04 (d, 3H, J¼7 Hz, H21), 0.99 (d,
3H, J¼7 Hz, H28), 0.58 (s, 3H, H18); 13C NMR (125 MHz, CD3OD)
4.1.13. 1a-Hydroxy-25-methoxymethyloxy-3,5-cyclovitamin D3
(13b). As described for 13a, 12b (33 mg, 0.074 mmol) was con-
verted into 13b (10.0 mg, 29%) as a colorless oil after purification by
preparative TLC (n-hexane/ethyl acetate¼3/1). 1H NMR (500 MHz,
d
(ppm) 142.07 (C8), 138.46 (C22), 133.98 (C5), 131.45 (C23), 123.47
CD3OD)
d
(ppm) 4.95 (d, 1H, J¼9 Hz, H7), 4.69 (s, 2H, MOM–CH2),
(C6), 117.22 (C7), 73.37 (C25), 68.04 (C1), 67.76 (C3), 57.84 (C17),
57.63 (C14), 49.10 (C24), 46.75 (C13), 45.46 (C10), 42.74 (C2), 41.90
(C20), 41.82 (C12), 37.69 (C4), 29.87 (C9), 29.02 (C16), 28.33 (C26),
26.12 (C27), 24.55 (C11), 23.30 (C15), 21.49(C21), 15.70 (C28),
12.75(C18); ESI-MS m/z¼439.32[MþNa]þ, 452.53[MþCl]ꢁ; HRMS
calcd for C27H44O3Na 439.3188, found 439.3199.
3.93 (m, 1H, H1), 3.89 (d, 1H, J¼9 Hz, H6), 3.33 (s, 3H, MOM–CH3),
3.21 (s, 3H, OMe), 2.63 (m, 1H, H9a), 2.04 (m, 4H), 1.93 (m, 1H,
H16a), 1.75 (dd, 1H, J¼8 and 13 Hz, H10b), 1.71–1.24 (m, 14H), 1.20
(s, 6H, H26 and H27), 1.13 (m, 1H, H3), 1.05 (m, 1H, H22b), 0.97 (d,
3H, J¼7 Hz, H21), 0.62 (s, 3H, H18), 0.55 (dd, 1H, J¼5 and 9 Hz, H4a),
0.38 (t, 1H, J¼5 Hz, H4b); 13C NMR (125 MHz, CD3OD)
d (ppm)
144.92 (C8), 120.33 (C7), 91.97 (MOM–CH2), 81.20 (C6), 77.62 (C25),
71.24 (C1), 58.01 (C17), 57.10 (C14), 56.17 (OMe), 55.41 (MOM–CH3),
46.67 (C13), 43.35 (C24), 41.75 (C12), 37.85 (C10), 37.67 (C2), 37.46
(C20), 37.27 (C22), 31.53 (C5), 30.52 (C9), 28.76 (C16), 26.77 (C26),
26.70 (C27), 25.00 (C11), 23.16 (C15), 21.60 (C23), 19.46 (C3), 19.39
(C21), 14.79 (C4), 12.52 (C18); ESI-MS m/z¼485.43[MþNa]þ,
497.30[MþCl]ꢁ; HRMS calcd for C29H50O4Na 485.3606, found
485.3572.
4.1.16. 1a,25-Dihydroxy-19-norvitamin D2, paricalcitol (3a) from
13c. As described for 3a, crude 13c (0.016 mmol) was converted
into paricalcitol 3a (1.7 mg, 25% from 12c) as a white powder after
purification by preparative TLC (chloroform/methanol¼10/1).
4.1.17. 1a,25-Dihydroxy-19-norvitamin D3 (3b). As described for 3a,
13b (9.5 mg, 0.020 mmol) was converted into 1
a,25-dihydroxy-19-
norvitamin D3 (3b) (3.0 mg, 37% from 13b) as a white powder after
purification by preparative TLC (chloroform/methanol¼10/1). 1H
4.1.14. 1
13a, 12c (19.8 mg, 0.048 mmol) was converted into crude 13c
(86.1 mg) as a colorless oil. 1H NMR (500 MHz, CD3OD)
(ppm) 5.35
a,25-Dihydroxy-3,5-cyclovitamin D2 (13c). As described for
NMR (500 MHz, CD3OD)
d
(ppm) 6.21 (d, 1H, J¼11 Hz, H6), 5.88 (d,
1H, J¼11 Hz, H7), 4.03 (m, 1H, H1), 3.98 (m, 1H, H3), 2.83 (m, 1H,
H9a), 2.59 (dd, 1H, J¼4 and 13 Hz, H4a), 2.41 (dd, 1H, J¼4 and 13 Hz,
H10a), 2.20 (dd, 1H, J¼7 and 13 Hz, H4b), 2.16 (dd, 1H, J¼6 and
13 Hz, H10b), 2.02 (m, 2H), 1.93 (m, 1H, H16a), 1.83 (m, 1H, H2a),
1.77 (m, 1H, H2b), 1.72–1.23 (m, 14H), 1.17 (s, 6H, H26 and H27), 1.07
(m, 1H, H22b), 0.96 (d, 3H, J¼6 Hz, H21), 0.57 (s, 3H, H18); 13C NMR
d
(dd,1H, J¼8 and 15 Hz, H23), 5.27 (dd,1H, J¼8 and 15 Hz, H22), 4.94
(d,1H, J¼9 Hz, H7), 3.92 (m,1H, H1), 3.89 (d,1H, J¼9 Hz, H6), 3.21 (s,
3H, OMe), 2.64 (m, 1H, H9a), 2.11–1.99 (m, 6H), 1.83–1.26 (m, 10H),
1.13 (m, 1H, H3), 1.13 (s, 3H, H26), 1.09 (s, 3H, H27), 1.04 (d, 3H,

10008
A. Toyoda et al. / Tetrahedron 65 (2009) 10002–10008
8299; (e) Zhou, S.; Anne´, S.; Vandewalle, M. Tetrahedron Lett. 1996, 37, 7637;
(125 MHz, CD3OD)
d (ppm) 142.15 (C8), 133.93 (C5), 123.49 (C6),
(f) Yong, W.; Vandewalle, M. Synlett 1996, 911.
117.19 (C7), 71.53 (C25), 68.04 (C1), 67.75 (C3), 58.06 (C17), 57.57
(C14), 48.54 (C13), 45.45 (C10 or C24), 43.35 (C10 or C24), 42.74
(C2), 41.98 (C12), 37.81 (C4 or C22), 37.70 (C4 or C22), 37.52 (C20),
29.88 (C9), 29.31 (C26), 29.18 (C27), 28.81 (C16), 24.57 (C11), 23.34
(C15), 21.96 (C23), 19.43 (C21), 19.46 (C18); ESI-MS m/z
(%)¼427.38[MþNa]þ, 439.39[MþCl]ꢁ; HRMS calcd for C26H44O5Na
427.3188, found 427.3148.
5. Recent direct synthesis of the other vitamin D derivatives, see: (a) Inaba, Y.;
Yoshimoto, N.; Sakamaki, Y.; Nakabayashi, M.; Ikura, T.; Tamamura, H.; Ito, N.;
Shimizu, M.; Yamamoto, K. J. Med. Chem. 2009, 52, 1438; (b) Okabe, M. Org.
Synth. 1999, 76, 275; Indirect synthesis of 19-norvitamin D derivatives, see: (c)
Shimizu, M.; Miyamoto, Y.; Takaku, H.; Matsuo, M.; Nakabayashi, M.; Masuno,
H.; Udagawa, N.; DeLuca, H. F.; Ikura, T.; Ito, N. Bioorg. Med. Chem. 2008, 16,
6949; (d) Glebocka, A.; Sokolowska, K.; Sicinski, R. R.; Plum, L. A.; DeLuca, H. F. J.
Med. Chem. 2009, 52, 3496; (e) Yoshida, A.; Ono, K.; Suhara, Y.; Saito, N.; Ta-
kayama, H.; Kittaka, A. Synlett 2003, 1175; (f) Ono, K.; Yoshida, A.; Saito, N.;
Fujishima, T.; Honzawa, S.; Suhara, Y.; Kishimoto, S.; Sugiura, T.; Waku, K.;
Takayama, H.; Kittaka, A. J. Org. Chem. 2003, 68, 7407.
Acknowledgements
6. (a) Paaren, H. E.; DeLuca, H. F.; Schnoes, H. K. J. Org. Chem. 1983, 48, 3819; (b)
Paaren, H. E.; Schnoes, H. K.; DeLuca, H. F. J. Org. Chem. 1980, 45, 3253.
7. Takeda, K.; Asou, T.; Matsuda, A. J. Ferment. Bioeng. 1994, 78, 380.
8. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319
Stereochemistry at C1 could not be determined at this stage.
9. Representative reaction conditions; (a) NH2NH2–H2O, KOH, ethylene glycol,
150 ꢀC; (b) NH2NH2–H2O, tert-BuOK, DMSO- tert-BuOH, 70 ꢀC; (c) Ts NH2NH2,
EtOH, 70 ꢀC.
We thank Professor Masato Shimizu of Tokyo Medical and
Dental University for supplying 1H NMR spectra of authentic
1a,25-dihydroxy-19-norvitamin D3 (3b).
References and notes
10. (a) Cacchi, S.; Morera, E.; Ortar, G. Org. Synth. 1990, 68, 138; (b) McMurry, J. E.;
Scott, W. J. Tetrahedron Lett. 1983, 24, 979; (c) Scott, W. J.; Crisp, G. T.; Stille, J. K.
J. Am. Chem. Soc. 1984, 106, 4630; (d) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1984, 25, 4821; (e) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033;
(f) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D. Tetrahedron Lett.
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1. (a) Bouillon, R.; Okamura, W. H.; Norman, A. W. Endocr. Rev. 1995, 16, 200; (b)
Jones, G.; Strugnell, S. A.; DeLuca, H. F. Physiol. Rev. 1998, 78, 1193.
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(b) Robinson, D. M.; Scott, L. J. Drugs 2005, 65, 559.
3. Direct synthesis for 3b, see: Parlman, K. L.; Sicinski, R. R.; Schnoes, H. K.;
DeLuca, H. F. Tetrahedron Lett. 1990, 31, 1823.
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E.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett. 1991, 32, 7663; (b) Ono, Y.;
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Huang, P.; Sabbe, K.; Pottie, M.; Vandewalle, M. Tetrahedron Lett. 1995, 36,
11. Brown, H. C.; Liotta, R.; Brener, L. J. Am. Chem. Soc. 1977, 99, 3427 Hydroboration
reaction took place from the convex face, and 13a was generated as a single
diastereomer. The stereochemistry of 13a- c at C1 was confirmedn by con-
verting into the paricalcitol (3a)12a and its analog 3b.12b
.
12. (a) Ng, C.S.; Wei, C.P. US patent US2009/0149678A1. (b) Spectral data for 3b was
supplied by Dr. Masato Shimizu.