(10Z)- and (10E)-19-fluoro-1 α,25-dihydroxyvitamin D3: An improved synthesis via 19-nor-10-oxo-vitamin D

Article abstract of DOI:10.1248/cpb.49.312

An efficient synthetic route to (10Z)- and (10E)-19-fluoro-1α,25-dihydroxyvitamin D₃ was developed. The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5E)-19-nor-10-oxo-vitamin D derivative. The 10-oxo-compo

Full text of DOI:10.1248/cpb.49.312

312
Chem. Pharm. Bull. 49(3) 312—317 (2001)
Vol. 49, No. 3
a
(10Z)- and (10E)-19-Fluoro-1 ,25-dihydroxyvitamin D3:
An Improved Synthesis via 19-Nor-10-oxo-vitamin D
Masato SHIMIZU,* Akiko OHNO, and Sachiko YAMADA*
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2–3–10 Surugadai, Kanda, Chiyoda-
ku, Tokyo 101–0062, Japan. Received November 15, 2000; accepted January 4, 2001
An efficient synthetic route to (10Z)- and (10E)-19-fluoro-1a,25-dihydroxyvitamin D3 was developed. The
key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5E)-19-nor-10-oxo-vitamin D
derivative. The 10-oxo-compound was obtained via a 1,3-dipolar cycloaddition reaction of (5E)-1a,25-dihydroxy-
vitamin D with in situ generated nitrile oxide followed by ring cleavage of the formed isoxazoline moiety with
molybdenum hexacarbonyl. Conversion of the keto group of (5E)-19-nor-10-oxo-vitamin D to the E and Z fluo-
romethylene group was achieved through a two-step sequence involving a reaction of lithiofluoromethyl phenyl
sulfone followed by the reductive desulfonylation of the a-fluoro-b-hydroxy sulfone. The dye-sensitized photoiso-
merization of the (5E)-19-fluorovitamin D afforded the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and
(10E)-19-fluoro-1a,25-dihydroxyvitamin D3.
Key words fluorovitamin D; 19-nor-10-oxo-vitamin D; synthesis; fluorination; photoisomerization
As a physiologically active form of vitamin D3, 1a,25-di- model closely resembles the X-ray structure except for some
hydroxyvitamin D3 [1a,25-(OH)2D3; 1] regulates calcium details. In the crystal structure the A-ring of 1 adopts the b-
and phosphate homeostasis and is also involved in control- conformation, while in our model we assumed the a-form.
ling cellular growth, differentiation and apoptosis.1) The vita-
In our studies to investigate dynamics of the conformation
min D receptor (VDR) is a member of the nuclear receptor of vitamin D in VDR/vitamin D complex, in particular the
superfamily that regulates gene expression in response to A-ring and the triene moieties, by 19F-NMR spectroscopy, we
binding of their specific ligands. Ligand binding stabilizes have reported syntheses of 19-fluoro-1a,25-dihydroxyvita-
the transcriptionally active conformation of the ligand bind- min D3 (2 and 3) and 4,4-difluoro-1a,25-dihydroxyvitamin
ing domain of the receptors,2) enabling the recruitment of D3 as probe compounds (Charts 1 and 2).13—15) In the synthe-
coactivators and results in either gene transactivation or re- sis of 2 and 3, an electrophilic fluorination of a vitamin D–
pression depending on the target gene.
SO2 adduct (II) was used as a key step. The difficulties in
It is critical for better understanding the molecular mecha- this synthesis are 1) electrophilic fluorination of the SO2
nism of gene expression by 1 to clarify the 3-dimensional adduct (II) is not satisfactory and 2) desulfonylation of 19-
structure of 1 bound to VDR. 1a,25-(OH)2D3 1 is a highly fluorovitamin D–SO2 adduct (III) was not effective. To solve
flexible molecule and can adopt a number of conformations these problems, we developed a new method in which a 19-
around the A-ring, seco-B-ring, and side chain. In a series of fluoromethylene group was introduced to 19-nor-10-oxo-vit-
systematic studies on conformation-function relationship of amin D 14. This paper describes the new efficient route to
vitamin D, we have proposed a concept of the active side 19-fluorovitamin D 2 and 3.
chain space region of vitamin D using systematic conforma-
tional analysis and conformationally-restricted analogs as Results and Discussions
tools.3—6) Our research interests have also been directed to
Our improved synthesis of 19-fluorovitamin D 2 and 3 is
the A-ring and the conjugated triene part of 1. The A-ring based on the phenylsulfonylfluoromethylation of 19-nor-10-
conformation of vitamin D is thought to be essential for the oxo-vitamin D derivative 14 followed by the reductive desul-
recognition of the active site of the VDR ligand binding cav- fonylation of 16 as a key step (Chart 4). The synthesis of 14
ity. In solution, vitamin D exists as an approximate equimo- was accomplished starting from (5E)-vitamin D derivative 4
lar mixture of rapidly equilibrating A-ring chair conformers, (Charts 3 and 4). First the 1a-hydroxyl group was introduced
designated as a- and b-forms, according to H-NMR analy- by Hesse’s method16) (SeO2–NMO, 66% based on recovered
1
sis (Chart 1).7) Worldwide controversy concerning which 4) and the hydroxyl group was protected to give 6 (80%).
conformation is responsible for VDR binding has continued Then the side chain part was constructed. After protecting
for a long time. The crystal structures of ligand-binding do- the conjugated triene part of 6 with SO2, the side chain was
mains (LBD) of numerous nuclear receptors including a cleaved by ozonolysis (O3 then NaBH4) to give C(22)-alco-
retinoic acid receptor,2,8) thyroid hormone receptor9) and es- hol 7 (85%). Treatment of 7 with I2 and Ph3P afforded C(22)-
trogen receptor10) have recently been solved. However, the iodide 8 (96%). After extrusion of SO2 from 8 by heating,
crystal structure of the wild type VDR–LBD has not been the formed (5E)-22-iodo-vitamin D derivative was treated
solved. Recently, we proposed a three-dimensional model of with the five carbon synthon 9 to afford 23-phenylsulfone 10
a liganded VDR-LBD constructed by the homology model- (83%) as a mixture of two epimers. This phenylsulfone 10
ing technique in conjunction with mutation studies to sub- was desulfonylated with 10% sodium amalgam (Na–Hg) to
stantiate the model.11) The crystal structure of a deletion mu- yield 11 (65%).
tant (D 165—215) of VDR–LBD complexed with 1a,25-
Finally the 10(19)-methylene was exchanged. Conversion
(OH)2D3 was also reported recently by Moras et al.12) Our of 11 to the 10-oxo compound 14 was accomplished by em-
To whom correspondence should be addressed. e-mail: shimizu@i-mde.tmd.ac.jp
© 2001 Pharmaceutical Society of Japan

March 2001
313
ploying Reischl’s approach with a minor modification.17,18)
Compound 11 was treated with nitrile oxide generated in situ
from PhNCO and nitroethane, affording the 3Ј,5Ј-disubsti-
tuted 2Ј-isoxazoline 12 (94%) as an epimeric mixture at
C(10) in approximately a 1 : 1 ratio. Reischl reported that
the isoxazolines derived from vitamin D3 3-acetate and its
(5E)-isomer were treated with molybdenum hexacarbonyl
[Mo(CO)6] in refluxing anhydrous CH3CN to afford the cor-
responding 10-oxo-vitamin D derivatives in good yield (70—
80%). In our model experiments with the isoxazolines 13a
and 13b, the reaction did not proceed under the same condi-
tions as described by Reischl. In addition, nothing happened
to the isoxazoline ring when a standard procedure of catalytic
hydrogenolysis was applied. Steinmeyer’s modification19) that
includes water in the medium gave a satisfactory result. Re-
action of both isomeric isoxazolines 12a and 12b with
Mo(CO)6 in refluxing wet CH3CN gave the desired 10-oxo
compound 14 (69 and 56%, respectively) together with the
corresponding isomeric b-hydroxyketones 15a and 15b (26
and 39%, respectively). The b-hydroxyketone 15 was readily
and quantitatively converted to 14 on treatment with LDA
(Ϫ78 °C, 1 h).
McCarthy et al. have reported a convenient two-step syn-
thesis of vinyl fluorides by the Wittig-Horner reaction of ke-
tones and aldehydes with diethyl fluoro(phenylsulfonyl)-
Chart 1
Chart 2
Chart 3
Chart 4

314
Vol. 49, No. 3
methanephosphonate [prepared from fluoromethylphenylsul- 21 and 22 were cleaved by treatment with n-Bu4NF to give
fone (PhSO2CH2F)/diethyl chlorophosphate/2 eq of LDA] the target 19-fluorovitamin D analogs 2 and 3. Overall yield
followed by the reductive removal of the phenylsulfonyl from 11 through 2 and 3 increased about 6 times with the
group of the resulting a-fluoro-a,b-unsaturated sulfones.20,21) present method compared with our previous method via elec-
We applied this approach in the synthesis of 19-fluorovitamin trophilic flurorination of vitamin D–SO2 adducts. In addition,
D derivatives 2 and 3 from the 10-oxo compound 14. Under the present method provided a useful way for synthesizing
the Wittig–Horner conditions described by McCarthy et al., (10E)-isomer 3 in a reasonable yield, although it was difficult
b-hydroxy-a-fluorophenylsulfones 16 were produced in a to obtain 3 by the previous synthetic method.13)
moderate yield in place of the desired a-fluoro-a,b-unsatu-
In conclusion, we have described an efficient pathway for
rated sulfone 17. Treatment of 14 with PhSO2CH2F alone synthesizing the isomeric 19-fluorovitamin D3 analogs 2 and
gave 16 as a mixture of four diastereoisomers in 86% yield, 3 from a 19-nor-10-oxo-vitamin D derivative. Our current re-
which were difficult to completely separate. In the 19F- NMR search efforts are aimed at investigating direct interaction of
spectra of the products, the four diastereomers 16a, b, c and the fluorovitamin D analog 3 with the VDR-ligand binding
d were observed as well-separated four set of doublets at domain by 19F-NMR. These studies are in progress.
Ϫ177.0, Ϫ180.9, Ϫ182.4 and Ϫ184.0 ppm in approximately
Experimental
a 37 : 41 : 7 : 15 ratio. Neither the direct dehydration of 16 to
The NMR spectra were recorded on a Bruker ARX-400 MHz spectrome-
1
ter, operating at 400 MHz for H and 376 MHz for 19F. Chemical shifts are
reported in parts per million (ppm, d) downfield from tetramethylsilane as
an internal standard (d 0 ppm) for 1H-NMR and trifluorotoluene as an exter-
nal standard (d Ϫ63 ppm) for 19F-NMR. Low- and high-resolution mass
spectra (LR-MS and HR-MS) were obtained with electronic ionization (EI)
on a JEOL JMS-AX505HA spectrometer run at 70 eV for EI; m/z values are
given with relative intensities in parentheses. UV spectra were obtained on a
17 nor a mesylation-elimination sequence was successful. A
mixture of the b-hydroxy-a-fluorophenylsulfone 16a and
16d (approx. 9 : 1) was treated with 10% Na–Hg to afford
(10Z)-19-fluorovitamin D derivatives 18a and its (10E)-iso-
mer 18b in about a 1 : 5 ratio in 32% yield along with
epimeric fluoro-alcohols 19a and 19b (stereochemistry not
known) in approximately a 6 : 1 ratio (56%). Under the same Hitachi U-3200 spectrophotometer. Column chromatography was carried out
on silica gel (Wakogel C-200), unless otherwise indicated. All reactions, un-
less specifically mentioned, were conducted under a atmosphere of argon
gas. Yields are not optimized.
Vitamin D2 3-tert-Butyldiphenylsilyl Ether–SO2 Adducts Vitamin D2
conditions, a mixture of 16b, 16c and 16d (approx. 7 : 1 : 2)
afforded 18a and 18b in approximately a 1 : 2 ratio (24%) as
well as epimeric alcohols 19a and 19b in approximately a
5 : 2 ratio as major products. Several attempts were made in
improving the yield of the desired compound 18, but satis-
factory results have not been obtained yet. The major fluoro-
alcohol 19a was produced from the two major diastereomers
16a and 16b, indicating that both compounds have the same
configuration at C(10).
Two geometrical isomers, 18a and 18b, were separated
by HPLC [Inertsil Ph 5 mm, 150 mmϫ4.6 mm i.d.; H2O :
CH3CNϭ1 : 9; 1.5 ml/min; ambient temperature], then pho-
toisomerized into the corresponding (5Z)-isomers 20 in the
presence of anthracene as a sensitizer.22) First (10Z)-isomer
18a was irradiated at a concentration of about 3 mM of sub-
strate in EtOH–benzene and the progress of reaction was
monitored by HPLC. After 1 h of irradiating, the starting ma-
terial disappeared to give an equilibrium mixture of (10Z)-
(20 g, 0.05 mol) was gently refluxed in liquid SO2 (approx. 50 ml) for 2 h.
Excess liquid SO2 was removed under reduced pressure. To this crude SO2
adducts in dry DMF (100 ml) was added imidazole (8.63 g, 0.127 mol) and
tert-butyldiphenylsilyl chloride (17.4 g, 0.06 mol). The mixture was stirred
for 2 h at room temperature, poured into ice water, and extracted with 50%
AcOEt–hexane. The organic extract was washed with brine, dried (MgSO4),
and evaporated in vacuo. The residue was subjected to chromatography on
silica gel (300 g) with 10% AcOEt–hexane to give (6S)- and (6R)-SO2-
adducts (33.8 g, 96%) in a 1 : 1 ratio.
(6S)-SO2-Adduct: 1H-NMR (CDCl3) d: 0.65 (3H, s, 18-H), 0.82, 0.84
(each 3H, d, Jϭ6.4 Hz, 26, 27-H), 0.93 (3H, d, Jϭ6.8 Hz, 28-H), 1.03 (3H,
d, Jϭ6.6 Hz, 21-H), 1.05 (9H, s, Si–tert-Bu), 3.61 (2H, m, 19-H), 4.06 (1H,
m, 3-H), 4.59 (1H, m, 1-H), 4.44, 4.69 (each 1H, d, Jϭ9.4 Hz, 6, 7-H), 5.21
(2H, m, 22, 23-H), 7.3—7.7 (10H, m, arom. H).
(6R)-SO2-Adduct: 1H-NMR (CDCl3) d: 0.43 (3H, s, 18-H), 0.82, 0.84
(each 3H, d, Jϭ6.4 Hz, 26, 27-H), 0.92 (3H, d, Jϭ6.8 Hz, 28-H), 1.02 (3H,
d, Jϭ6.6 Hz, 21-H), 1.07 (9H, s, Si–tert-Bu), 3.63, 3.71 (each 1H, d, Jϭ
15.9 Hz, 19-H), 4.06 (1H, m, 3-H), 4.51, 4.64 (each 1H, d, Jϭ10.0 Hz, 6, 7-
isomer 20a and (10E)-isomer 20b in about a 4 : 1 ratio. After H), 5.21 (2H, m, 22, 23-H), 7.3—7.7 (10H, m, arom. H).
(6S)- and (6R)-Adducts: EI-MS m/z (%): 634 (MϩϪSO2, 73), 577 (46),
509 (4), 378 (18), 317 (43), 253 (19), 199 (100).
4 h, a photostationary state was reached to give an approxi-
mately 2 : 3 mixture of 20a and 20b. Under the same condi-
tions using (10E)-isomer 18b, similar results (after 1 h and
4 h of irradiating) were also obtained. For practical synthesis
at higher substrate concentration, irradiation of isomeric
mixture 18 (10Z : 10Eϭ1 : 5) was stopped after 6 h to yield
20a and 20b in approximately a 1 : 1 ratio (95% yield). We
have reported that triplet sensitized photoisomerization of
(5E)-19-fluoro-1a,25-dihydroxyvitamin D3 (bearing three
hydroxyl groups) afforded a mixture of 2 and 3 in about a
6 : 1 ratio at a photostationary state.13) Interestingly, photoiso-
merization of isomeric mixture 18 yielded (10E)-isomer 20b
as a major product. Detailed studies of the photoisomeriza-
tion of these compounds will be reported elsewhere.
(5E)-Vitamin D2 3-tert-Butyldiphenylsilyl Ether (4) A mixture of vit-
amin D2 3-tert-butyldiphenylsilyl ether–SO2 adducts (33.8 g, 0.048 mol) ob-
tained above, NaHCO3 (90 g, 0.97 mol) and EtOH (700 ml) was refluxed for
1.5 h and cooled to room temperature. The mixture was filtered and the fil-
trate was concentrated to a small volume. The residue was diluted with
water and extracted with AcOEt. The organic extract was washed with brine,
dried (MgSO4), and evaporated to dryness. The residue was chro-
matographed on silica gel (400 g) with 2% AcOEt–hexane to afford 4
(30.0 g, 98%).
1
4: H-NMR (CDCl3) d: 0.54 (3H, s, 18-H), 0.84, 0.86 (each 3H, d, Jϭ
6.5 Hz, 26, 27-H), 0.94 (3H, d, Jϭ6.8 Hz, 28-H), 1.02 (3H, d, Jϭ6.6 Hz, 21-
H), 1.06 (9H, s, Si–tert-Bu), 3.94 (1H, m, 3-H), 4.62 (1H, s, 19-H), 4.91
(1H, d, Jϭ1.8 Hz, 19-H), 5.22 (2H, m, 22, 23-H), 5.71, 6.47 (each 1H, d,
Jϭ11.5 Hz, 6, 7-H), 7.3—7.7 (10H, m, arom. H). EI-MS m/z (%): 634 (Mϩ,
62), 577 (35), 509 (2), 378 (9), 317 (27), 253 (12), 199 (100).
(5E)-1a-Hydroxyvitamin D2 3-tert-Butyldiphenylsilyl Ether (5)
A
Geometrical isomers 20 (10Z : 10Eϭapprox. 1 : 1) were
hydrolyzed with camphor sulfonic acid (CSA) to afford the
isomeric 25-hydroxy-compounds 21a and 21b (48%, approx.
1 : 1) along with the isomeric mixture of 1-silyl ether 22a and
mixture of N-methylmorpholine oxide (NMO, 5.5 g, 4.43 mmol), anhydrous
MgSO4 (3 g) and dry CH2Cl2 (30 ml) was stirred for 30 min at room temper-
ature and this NMO solution was filtered directly into a solution of 4 (6.0 g,
9.45 mmol) in dry CH2Cl2 (45 ml), and the mixture was refluxed for 5 min.
22b (53%, approx. 1 : 1). The silyl protecting groups of both To this solution was added a mixture of selenium oxide (1.05 g, 9.46 mmol)

March 2001
315
which was stirred in MeOH (30 ml) for 45 min at room temperature. The
whole mixture was refluxed for 2 h and cooled to room temperature, and
then poured into ice water. The mixture was extracted with AcOEt and the
organic extract was washed with 5% NaHCO3, then brine, and dried
(MgSO4). The solvent was removed by reduced pressure and the residue was
purified by chromatography on silica gel (200 g). The column was eluted
with 4—10% AcOEt–hexane to yield the unreacted starting material (1.7 g,
28%), 5 (2.90 g, 47%) and its isomer with 1b-hydroxyl group (0.6 g, 10%).
9.6 Hz, 6 or 7-H), 4.58 (1H, m, 1-H), 4.62 (1H, d, Jϭ9.6 Hz, 6 or 7-H),
7.2—7.6 (20H, m, arom. H).
1
(6R)-7: H-NMR (CDCl3) d: 0.39 (3H, s, 18-H), 0.92, 1.01 (each 9H, s,
Si–tert-Bu), 1.05 (3H, d, Jϭ6.6 Hz, 21-H), 2.49 (1H, br d, Jϭ9.6 Hz), 3.29,
3.85 (each 1H, d, Jϭ15.6 Hz, 19-H), 3.40 (1H, dd, Jϭ10.5, 6.6 Hz, 22-H),
3.65 (1H, dd, Jϭ10.5, 2.9 Hz, 22-H), 4.20 (1H, m, 3-H), 4.39 (1H, d, Jϭ
10.2 Hz, 6 or 7-H), 4.58 (1H, m, 1-H), 4.68 (1H, d, Jϭ10.2 Hz, 6 or 7-H),
7.2—7.6 (20H, m, arom. H).
1
(6S)- and (6R)-7: EI-MS m/z (%): 822 (MϩϪSO2, 5), 765 (3), 566 (8),
509 (6), 507 (1), 372 (3), 310 (3), 199 (100). HR-EI-MS m/z: 886.4498
(Calcd for C54H70O5SSi2: 886.4482).
5: H-NMR (CDCl3) d: 0.53 (3H, s, 18-H), 0.84, 0.86 (each 3H, d, Jϭ
6.5 Hz, 26, 27-H), 0.95 (3H, d, Jϭ6.8 Hz, 28-H), 1.03 (3H, d, Jϭ6.6 Hz, 21-
H), 1.05 (9H, s, Si–tert-Bu), 2.47 (1H, dd, Jϭ14.0, 5.9 Hz), 2.85 (1H, m),
4.26 (1H, m, 3-H), 4.59 (1H, m, 1-H), 4.95, 5.07 (each 1H, s, 19-H), 5.22
(2H, m, 22, 23-H), 5.70, 6.53 (each 1H, d, Jϭ11.5 Hz, 6, 7-H), 7.3—7.7
(10H, m, arom. H). EI-MS m/z (%): 650 (Mϩ, 18), 593 (18), 575 (9), 394
(29), 333 (16), 269 (10), 199 (100). HR-EI-MS m/z: 650.4527 (Calcd for
C44H62O2Si: 650.4519).
22-Iodo-23,24,25,26,27-pentanor-1a-hydroxyvitamin D3 1,3-Di-tert-
butyldiphenylsilyl Ether–SO2 Adducts (8) To a stirred, cold (Ϫ20 °C) so
-
lution of 7 (5.49 g, 6.19 mmol), Ph3P (2.03 g, 7.75 mmol), imidazole (1.27 g,
18.6 mmol) in dry THF (100 ml) was added I2 (1.73 g, 6.82 mmol) and the
mixture was stirred for 4 h. After 5% NaHCO3 was added, the mixture was
extracted with ether. The organic phase was washed with 2 N Na2S2O3 and
brine, dried (MgSO4), and then evaporated in vacuo. The residue was puri-
fied by chromatography on silica gel (100 g) using 20% AcOEt–hexane to
afford 8 (5.95 g, 96%, 6S : 6Rϭapprox. 3 : 2) as a mixture of two isomers.
1
The isomer of 5 (1b-OH): H-NMR (CDCl3) d: 0.54 (3H, s, 18-H), 0.84,
0.86 (each 3H, d, Jϭ6.4 Hz, 26, 27-H), 0.95 (3H, d, Jϭ6.8 Hz, 28-H), 1.03
(3H, d, Jϭ6.7 Hz, 21-H), 1.06 (9H, s, Si–tert-Bu), 2.61 (1H, dd, Jϭ14.2,
4.2 Hz), 2.90 (1H, m), 4.23 (2H, m, 1, 3-H), 4.92 (1H, s, 19-H), 5.05 (1H, d,
Jϭ1.9 Hz, 19-H), 5.23 (2H, m, 22, 23-H), 5.73, 6.67 (each 1H, d, Jϭ
11.3 Hz, 6, 7-H), 7.3—7.8 (10H, m, arom. H).
1
(6S)-8: H-NMR (CDCl3) d: 0.64 (3H, s, 18-H), 0.93, 1.00 (each 9H, s,
Si–tert-Bu, overlapped with 21-H), 2.49 (1H, br d, Jϭ8.4 Hz), 3.21 (1H, dd,
Jϭ9.6, 5.1 Hz, 22-H), 3.29, 3.85 (each 1H, d, Jϭ15.9 Hz, 19-H, overlapped
with 22-H), 4.20 (1H, m, 3-H), 4.51 (1H, d, Jϭ9.7 Hz, 6 or 7-H), 4.58 (1H,
m, 1-H), 4.61 (1H, d, Jϭ9.7 Hz, 6 or 7-H), 7.3—7.7 (20H, m, arom. H).
(5E)-1a-Hydroxyvitamin D2 1,3-Di-tert-butyldiphenylsilyl Ether (6)
A mixture of 5 (14.0 g, 0.022 mol), imidazole (3.7 g, 0.054 mol), tert-
butyldiphenylsilyl chloride (7 ml, 0.027 mol) and dry DMF (40 ml) was
stirred for 2 h at room temperature and poured into ice water. The mixture
was extracted with 50% AcOEt–hexane and the organic extract was washed
with brine, and dried (MgSO4). After evaporation of the solvent, the residue
was subjected to chromatography on silica gel (200 g). The column was
eluted with 2% AcOEt–hexane to give 6 (15.2 g, 80%) and the unreacted
starting material (1.0 g, 7%).
1
(6R)-8: H-NMR (CDCl3) d: 0.40 (3H, s, 18-H), 0.92, 1.02 (each 9H, s,
Si–tert-Bu, overlapped with 21-H), 2.49 (1H, br d, Jϭ9.6 Hz), 3.16 (1H, dd,
Jϭ9.6, 5.8 Hz, 22-H), 3.29, 3.85 (each 1H, d, Jϭ15.9 Hz, 19-H, overlapped
with 22-H), 4.20 (1H, m, 3-H), 4.38 (1H, d, Jϭ9.8 Hz, 6 or 7-H), 4.58 (1H,
m, 1-H), 4.69 (1H, d, Jϭ9.8 Hz, 6 or 7-H), 7.3—7.7 (20H, m, arom. H).
(6S)- and (6R)-8: EI-MS m/z (%): 932 (MϩϪSO2, 3), 875 (1), 676 (5),
420 (4), 372 (3), 199 (100). HR-EI-MS m/z: 996.3472 (Calcd for
C54H69IO4SSi: 996.3500).
1
6: H-NMR (CDCl3) d: 0.52 (3H, s, 18-H), 0.84, 0.86 (each 3H, d, Jϭ
6.4 Hz, 26, 27-H), 0.95 (3H, d, Jϭ6.9 Hz, 28-H), 0.97, 0.98 (each 9H, s, Si–
tert-Bu), 1.03 (3H, d, Jϭ6.6 Hz, 21-H), 2.27 (1H, dd, Jϭ14.0, 6.6 Hz), 2.84
(1H, m), 4.25 (1H, m, 3-H), 4.64 (1H, m, 1-H), 4.73 (1H, s, 19-H), 4.89 (1H,
d, Jϭ1.5 Hz, 19-H), 5.23 (2H, m, 22, 23-H), 5.64, 6.39 (each 1H, d, Jϭ
11.4 Hz, 6, 7-H), 7.2—7.65 (20H, m, arom. H). EI-MS m/z (%): 888 (Mϩ,
4), 831 (2), 632 (11), 575 (8), 376 (5), 372 (2), 251 (4), 199 (100). HR-EI-
MS m/z: 888.5675 (Calcd for C60H80O2Si2: 888.5697).
(5E)-23-Phenylsulfonyl-1a,25-dihydroxyvitamin D3 1,3-Di-tert-butyl-
diphenylsilyl-25-methoxymethyl Ether (10) A mixture of 8 (12.3 g,
12.3 mmol), NaHCO3 (20.7 g, 0.246 mol) and EtOH (270 ml) was refluxed
for 3 h and cooled to room temperature, and then was filtered. The filtrate
was concentrated to a small volume, and diluted with water. The mixture
was extracted with AcOEt. The AcOEt extract was washed with brine, dried
(MgSO4), and concentrated to dryness. The residue was purified by chro-
matography on silica gel (100 g) using 20% AcOEt–hexane to yield (5E)-22-
iodo-pentanorvitamin D (10.6 g, 92%).
22-Hydroxy-23,24,25,26,27-pentanor-1a-hydroxyvitamin D3 1,3-Di-
tert-butyldiphenylsilyl Ether–SO2 Adducts (7) The silyl ether 6 (15.8 g,
0.018 mol) was refluxed with liquid SO2 (ca. 40 ml) for 2 h. Liquid SO2 was
evaporated in vacuo to give the SO2 adducts (17.0 g, quantitative yield, 6S :
6Rϭ3 : 1). This was used in the next reaction without further purification.
To a stirred, cold (Ϫ78 °C) solution of the formed SO2 adducts (8.1 g,
8.50 mmol) in dry CH2Cl2 (65 ml) and dry pyridine (6.5 ml) was passed a
steam of ozone. After theoretical amounts of ozone gas were passed in a pe-
riod of 50 min, the ozone flow was stopped. The mixture was poured into ice
water, acidified with 2 N HCl, and extracted with AcOEt. The organic layer
was washed with 5% NaHCO3 and brine, dried (MgSO4), and then evapo-
rated in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and to this solu-
tion was added a solution of NaBH4 (643 mg, 0.017 mol) in EtOH (30 ml) at
Ϫ78 °C. The whole mixture was stirred for 30 min at 0 °C, diluted with ice
water, and extracted with AcOEt. The organic extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure. The residue
was chromatographed on silica gel (100 g) using 2% AcOEt–hexane to give
the unreacted starting material (775 mg, 9%) and using 15% AcOEt–hexane
to afford 7 (6.4 g, 85%, 6S : 6Rϭapprox. 3 : 2) as a mixture of two isomers.
(6S)-SO2 Adduct of 6: 1H-NMR (CDCl3) d: 0.61 (3H, s, 18-H), 0.82, 0.84
(each 3H, d, Jϭ6.4 Hz, 26, 27-H), 0.93, 1.00 (each 9H, s, Si–tert-Bu, over-
lapped with 21, 28-H), 3.29, 3.84 (each 1H, d, Jϭ16.0 Hz, 19-H), 4.19 (1H,
m, 3-H), 4.51, 4.61 (each 1H, d, Jϭ9.7 Hz, 6 or 7-H), 4.56 (1H, m, 1-H),
5.19 (2H, m, 22, 23-H), 7.2—7.7 (20H, m, arom. H).
To
a stirred, cold (Ϫ20 °C) solution of diisopropylamine (3.2 ml,
23.2 mmol) and n-BuLi (1.6 M solution in THF, 23.2 mmol) in dry THF
(25 ml) was added a solution of 9 (6.32 g, 23.2 mmol) in dry THF (25 ml)
and the mixture was stirred for 20 min. To this solution was added a solution
of (5E)-22-iodo-pentanorvitamin D (10.8 g, 11.6 mmol) in HMPA (8.07 ml,
46.4 mmol) and dry THF (50 ml) and the whole mixture was stirred for 2 h
at Ϫ20 °C. The reaction was quenched with sat. NH4Cl and extracted with
AcOEt. The organic extract was washed with brine, dried (MgSO4), and
evaporated in vacuo. The residue was chromatographed on silica gel (200 g)
using 2—5% AcOEt–hexane to afford the unreacted starting material
(1.74 g, 16%) and 10 (10.4 g, 83%, 23S : 23Rϭapprox. 1 : 1).
10: 1H-NMR (CDCl3) d: 0.40, 0.47 (1 : 1) (3H, s, 18-H), 0.73, 0.93 (1 : 1)
(3H, d, Jϭ6.3 Hz, 21-H), 0.96, 0.97 (9H, s, Si–tert-Bu), 0.98 (9H, s, Si–tert-
Bu), 3.26, 3.30 (1 : 1) (3H, s, OMe), 4.27 (1H, m, 3-H), 4.45—4.70 (4H, m,
1, 22-H, OCH2O), 4.70, 4.75 (1 : 1) (1H, s, 19-H), 4.87, 4.89 (1 : 1) (1H, d,
Jϭ1.6 Hz, 19-H), 5.62, 5.64 (1 : 1) (1H, d, Jϭ11.2 Hz, 6 or 7-H), 6.35, 6.38
(1 : 1) (1H, d, Jϭ11.2 Hz, 6 or 7-H), 7.2—7.9 (20H, m, arom. H). EI-MS m/z
(%): 1076 (Mϩ, 1), 820 (2), 564 (3), 502 (1), 199 (100).
(5E)-1a,25-Dihydroxyvitamin D3 1,3-Di-tert-butyldiphenylsilyl-25-
methoxymethyl Ether (11) To a stirred, cold (0 °C) solution of 10 (10.4 g,
9.65 mmol) in dry THF (25 ml) and dry MeOH (50 ml) was added 10% Na-
Hg (freshly prepared, 22.2 g, 96.7 mmol) and the mixture was filtered
through a filter paper. The filtrate was concentrated to a small volume and
diluted with a mixture of water and AcOEt. The organic layer was separated
and the aqueous phase was extracted with AcOEt. The combined organic ex-
tract was washed with brine, dried (MgSO4), and evaporated to dryness. The
residue was purified by chromatography on silica gel (100 g) using 10%
AcOEt–hexane to give 11 (5.86 g, 65%) and the unreacted starting material
10 (1.3 g, 13%).
(6R)-SO2 Adduct of 6: 1H-NMR (CDCl3) d: 0.37 (3H, s, 18-H), 0.82, 0.84
(each 3H, d, Jϭ6.4 Hz, 26, 27-H), 0.93, 1.00 (each 9H, s, Si–tert-Bu, over-
lapped with 21, 28-H), 3.29, 3.84 (each 1H, d, Jϭ16.0 Hz, 19-H), 4.19 (1H,
m, 3-H), 4.39, 4.67 (1H, d, Jϭ10.2 Hz, 6 or 7-H), 4.56 (1H, m, 1-H), 5.19
(2H, m, 22, 23-H), 7.2—7.7 (20H, m, arom. H).
(6S)- and (6R)-SO2 adducts of 6: EI-MS m/z (%): 888 (MϩϪSO2, 9), 831
(3), 632 (15), 575 (9), 507 (1), 376 (5), 372 (6), 251 (3), 199 (100).
1
(6S)-7: H-NMR (CDCl3) d: 0.63 (3H, s, 18-H), 0.93, 1.00 (each 9H, s,
1
Si–tert-Bu), 1.06 (3H, d, Jϭ6.6 Hz, 21-H), 2.49 (1H, br d, Jϭ9.6 Hz), 3.29,
3.85 (each 1H, d, Jϭ15.6 Hz, 19-H), 3.40 (1H, dd, Jϭ10.5, 6.6 Hz, 22-H),
3.65 (1H, dd, Jϭ10.5, 2.9 Hz, 22-H), 4.20 (1H, m, 3-H), 4.51 (1H, d, Jϭ
11: H-NMR (CDCl3) d: 0.51 (3H, s, 18-H), 0.94 (3H, d, Jϭ6.7 Hz, 21-
H), 0.96, 0.98 (each 9H, s, Si–tert-Bu), 1.23 (6H, s, 26, 27-H), 2.27 (1H, dd,
Jϭ14.1, 6.1 Hz), 2.36 (1H, m), 2.84 (1H, m), 3,38 (3H, s, OMe), 4.27 (1H,

316
Vol. 49, No. 3
m, 3-H), 4.65 (1H, m, 1-H), 4.72 (2H, s, OCH2O), 4.74, 4.89 (each 1H, br s,
19-H), 5.63, 6.39 (each 1H, d, Jϭ11.4 Hz, 6, 7-H), 7.2—7.6 (20H, m, arom.
H). EI-MS m/z (%): 936 (Mϩ, 1), 874 (2), 561 (5), 362 (4), 251 (2), 199
(100). HR-EI-MS m/z: 936.5931 (Calcd for C61H84O4Si2: 936.5908).
Isoxazoline Derivatives (12a and b) Phenyl isocyanate (3.39 ml,
31.1 mmol) was slowly added to a solution of 11 (6.48 g, 6.91 mmol) in dry
toluene (40 ml) and to this solution was added a mixture of nitroethane
(1.56 ml, 20.8 mmol) and several drops of triethylamine in dry toluene
(10 ml). The mixture was stirred for 16 h at room temperature and was fil-
tered. The filtrate was evaporated in vacuo and the residue was subjected to
chromatography on silica gel (200 g) using 5% AcOEt–hexane to yield 12a
and 12b (6.43 g, 94%) in about a 1 : 1 ratio.
0.92 (3H, d, Jϭ6.2 Hz, 21-H), 1.06 (9H, s, Si–tert-Bu), 1.22 (6H, s, 26, 27-
H), 2.32 (1H, m), 2.95 (1H, m), 3.37 (3H, s, OMe), 3.88 (1H, m, 3-H), 4.05
(1H, s, OH), 4.37 (1H, m, 1-H), 4.71 (2H, s, OCH2O), 5.52 (1H, d, Jϭ
11.8 Hz, 6 or 7-H), 5.97 (1H, d, Jϭ44.5 Hz, 19-H), 6.80 (1H, d, Jϭ11.8 Hz,
6 or 7-H), 7.1—7.9 (20H, m, arom. H). 19F-NMR (CDCl3) d: Ϫ170.0 (d,
Jϭ44.5 Hz).
1
16b: H-NMR (CDCl3) d: 0.40 (3H, s, 18-H), 0.84 (9H, s, Si–tert-Bu),
0.92 (3H, d, Jϭ6.2 Hz, 21-H), 0.96 (9H, s, Si–tert-Bu), 1.22 (6H, s, 26, 27-
H), 2.72 (1H, m), 2.83 (1H, m), 3.37 (3H, s, OMe), 4.06 (1H, m, 3-H), 4.35
(1H, dd, Jϭ11.0, 4.2 Hz, 1-H), 4.71 (2H, s, OCH2O), 5.56 (1H, d, Jϭ
45.2 Hz, 19-H), 5.72, 6.65 (1H, d, Jϭ11.0 Hz, 6 or 7-H), 7.1—7.9 (20H, m,
arom. H). 19F-NMR (CDCl3) d: Ϫ180.9 (d, Jϭ45.2 Hz).
The Less Polar Isoxazoline 12a: 1H-NMR (CDCl3) d: 0.44 (3H, s, 18-H),
0.84, 1.02 (each 9H, s, Si–tert-Bu), 0.93 (3H, d, Jϭ6.3 Hz, 21-H), 1.22 (6H,
s, 26, 27-H), 1.93 (3H, s, Me), 2.48 (1H, d, Jϭ16.5 Hz, 19-H), 2.66 (1H,
br d, Jϭ14.5 Hz), 2.95 (1H, m), 3.37 (3H, s, OMe), 3.40 (1H, d, Jϭ16.5 Hz,
19-H), 3.91 (1H, m, 3-H), 4.53 (1H, dd, Jϭ11.1, 4.7 Hz, 1-H), 4.71 (2H, s,
OCH2O), 5.65, 6.80 (each 1H, d, Jϭ11.3 Hz, 6, 7-H), 7.2—7.8 (20H, m,
arom. H). UV lmax (95% EtOH): 246, 254, 263 nm. EI-MS m/z (%): 993
(Mϩ, 5), 936 (4), 874 (5), 737 (5), 680 (3), 618 (5), 199 (100). HR-EI-MS
m/z: 993.6113 (Calcd for C63H87NO5Si2: 993.6123).
16c: 19F-NMR (CDCl3) d: Ϫ182.4 (d, Jϭ44.3 Hz).
16d: 19F-NMR (CDCl3) d: Ϫ184.0 (d, Jϭ45.6 Hz).
(5E,10Z)- and (5E,10E)-19-Fluoro-1a,25-dihydroxyvitamin D3 1,3-Di-
tert-butyldiphenylsilyl-25-methoxymethyl Ether (18a and b), and (5E)-
10-Hydroxy-10-fluoromethyl-19-nor-1a,25-dihydroxyvitamin D3 1,3-Di-
tert-butyldiphenylsilyl-25-methoxymethyl Ether (19a and b) A mixture
of the less polar fraction 16a and 16d (2.13 g, 1.91 mmol, approx. 9 : 1),
sodiumhydrogenphosphate (2.71 g, 19.1 mmol) in dry THF–MeOH (1 : 2,
15 ml) was stirred for 10 min at 0 °C, and the 10% Na–Hg (4.38 g,
19.1 mmol, freshly prepared) was then added. After being stirred for 3 h at
room temperature, the reaction mixture was filtered, and the filtrate was di-
luted with ice-water, and was extracted with AcOEt. The organic extract was
washed with brine, dried (MgSO4), and evaporated to dryness. The residue
was chromatographed on silica gel (150 g) using 2% AcOEt–hexane to af-
ford a mixture of 18a and 18b (585 mg, 32%, approx. 1 : 5) and using 8%
AcOEt–hexane to yield 19a and 19b (1.04 g, 56%, approx. 6 : 1) as a mix-
ture of two epimers.
The More Polar Isoxazoline 12b: 1H-NMR (CDCl3) d: 0.49 (3H, s, 18-H),
0.90, 0.97 (each 9H, s, Si–tert-Bu), 0.94 (3H, d, Jϭ6.3 Hz, 21-H), 1.23 (6H,
s, 26, 27-H), 1.87 (3H, s, Me), 2.78, 2.92 (each 1H, d, Jϭ17.1 Hz, 19-H),
3.38 (3H, s, OMe), 3.99 (1H, m, 3-H), 4.15 (1H, m, 1-H), 4.72 (2H, s,
OCH2O), 5.64, 6.55 (each 1H, d, Jϭ11.0 Hz, 6, 7-H), 7.2—7.7 (20H, m,
arom. H). UV lmax (95% EtOH): 246, 254, 262 nm. EI-MS m/z (%): 993
(Mϩ, 4), 936 (10), 874 (4), 737 (3), 680 (3), 618 (5), 199 (100). HR-EI-MS
m/z: 993.6123 (Calcd for C63H87NO5Si2: 993.6123).
10-Oxo-19-nor-1a,25-dihydroxyvitamin D3 1,3-Di-tert-butyldiphenylsi-
lyl-25-methoxymethyl Ether (14) and the b-Hydroxyketones (15a and b)
A mixture of 12a (2.73 g, 2.74 mmol), Mo(CO)6 (363 mg, 1.38 mmol,
freshly sublimed), CH3CN (80 ml) and H2O (8 ml) was refluxed for 17 h and
cooled to room temperature. The mixture was filtered through a Celite pad
and washed with 50% AcOEt–hexane. The combined filtrate was evaporated
to dryness. The residue was separated by chromatography on silica gel
(100 g) using 10—20% AcOEt–hexane to give 14 (1.78 g, 69%) and 15a
(661 mg, 26%).
1
18a: H-NMR (CDCl3) d: 0.52 (3H, s, 18-H), 0.85 (9H, s, Si–tert-Bu),
0.95 (3H, d, Jϭ6.1 Hz, 21-H), 1.07 (9H, s, Si–tert-Bu), 1.23 (6H, s, 26, 27-
H), 2.75 (1H, m), 2.97 (1H, m), 3.38 (3H, s, OMe), 4.45 (1H, m, 3-H), 4.72
(2H, s, OCH2O), 4.87 (1H, m, 1-H), 5.60, 6.07 (each 1H, d, Jϭ11.2 Hz, 6 or
7-H), 6.20 (1H, d, Jϭ86.1 Hz, 19-H), 7.2—7.7 (20H, m, arom. H). 19F-NMR
(CDCl3) d: Ϫ132.3 (d, Jϭ86.1 Hz). UV lmax (95% EtOH): 266, 270 (sh)
nm. EI-MS m/z (%): 954 (Mϩ, 3), 897 (2), 892 (4), 835 (5), 698 (3), 636 (4),
579 (4), 199 (100).
1
18b: H-NMR (CDCl3) d: 0.53 (3H, s, 18-H), 0.91 (9H, s, Si–tert-Bu),
Treatment of the more polar isoxazoline 12b (3.70 g, 3.73 mmol) with
Mo(CO)6 in refluxing wet CH3CN as described above and the same work-up
gave 14 (1.95 g, 56%) and 15b (1.43 g, 39%).
0.94 (3H, d, Jϭ6.2 Hz, 21-H), 1.02 (9H, s, Si–tert-Bu), 1.23 (6H, s, 26, 27-
H), 2.68 (1H, dd, Jϭ14.0, 3.8 Hz), 2.76 (1H, m), 3.38 (3H, s, OMe), 4.32
(2H, m, 1, 3-H), 4.72 (2H, s, OCH2O), 5.71 (1H, d, Jϭ11.4 Hz, 6 or 7-H),
6.01 (1H, d, Jϭ84.9 Hz, 19-H), 6.42 (1H, d, Jϭ11.3 Hz, 6 or 7-H), 7.2—7.7
(20H, m, arom. H). 19F-NMR (CDCl3) d: Ϫ136.9 (d, Jϭ84.9 Hz). UV lmax
(95% EtOH): 270 (sh), 271 nm. EI-MS m/z (%): 954 (Mϩ, 5), 897 (3), 892
(10), 835 (10), 698 (5), 636 (10), 579 (9), 199 (100). HR-EI-MS m/z:
954.5801 (Calcd for C63H87NO5Si2: 954.5814).
14: 1H-NMR (CDCl3) d: 0.51 (3H, s, 18-H), 0.86 (9H, s, Si–tert-Bu), 0.94
(3H, d, Jϭ6.3 Hz, 21-H), 1.11 (9H, s, Si–tert-Bu), 1.22 (6H, s, 26, 27-H),
2.57 (1H, m), 2.97(1H, m), 3.37 (3H, s, OMe), 4.21 (1H, m, 3-H), 4.71 (2H,
s, OCH2O), 4.75 (1H, dd, Jϭ11.2, 6.0 Hz, 1-H), 5.56 (1H, d, Jϭ12.1 Hz, 7-
H), 7.2—7.8 (21H, m, arom. H, overlapped with 6-H). EI-MS m/z (%): 938
(Mϩ, 3), 881 (11), 819 (26), 682 (4), 620 (8), 563 (13), 199 (100). HR-EI-
MS m/z: 938.5715 (Calcd for C60H82O5Si2: 938.5701).
19a and b: 1H-NMR (CDCl3) d: 0.45, 0.47 (6 : 1) (3H, s, 18-H), 0.88 (9H,
s, Si–tert-Bu), 0.93 (3H, d, Jϭ5.7 Hz, 21-H), 1.01 (9H, s, Si–tert-Bu), 1.21,
1.22 (6 : 1) (6H, s, 26, 27-H), 2.43 (1H, s, OH), 2.63 (1H, m), 2.87 (1H, m),
3.37, 3.38 (6 : 1) (3H, s, OMe), 4.03 (1H, m, 3-H), 4.34 (1H, m, 1-H), 4.53,
4.71 (each 1H, dd, Jϭ47.8, 9.2 Hz, 19-H), 4.71, 4.72 (6 : 1) (2H, s, OCH2O),
5.67, 5.71 (1 : 6) (1H, d, Jϭ11.5 Hz, 6 or 7-H), 6.65, 6.68 (1 : 6) 6.42 (1H, d,
Jϭ11.5 Hz, 6 or 7-H), 7.2—7.8 (20H, m, arom. H). 19F-NMR (CDCl3) d:
Ϫ233.9, Ϫ225.9 (6 : 1) (t, Jϭ47.8 Hz).
1
15a: H-NMR (CDCl3) d: 0.43 (3H, s, 18-H), 0.87 (9H, s, Si–tert-Bu),
0.92 (3H, d, Jϭ6.2 Hz, 21-H), 1.03 (9H, s, Si–tert-Bu), 1.22 (6H, s, 26, 27-
H), 2.06 (3H, s, Me), 2.62 (1H, br d, Jϭ14.5 Hz), 2.73, 2.87 (each 1H, d,
Jϭ14.7 Hz, 19-H), 2.83 (1H, m), 3.37 (3H, s, OMe), 3.95 (1H, s, OH), 4.00
(1H, m, 3-H), 4.25 (1H, dd, Jϭ10.3, 4.3 Hz, 1-H), 4.71 (2H, s, OCH2O),
5.64, 6.60 (each 1H, d, Jϭ11.0 Hz, 6, 7-H), 7.2—7.7 (20H, m, arom. H).
1
15b: H-NMR (CDCl3) d: 0.50 (3H, s, 18-H), 0.87 (9H, s, Si–tert-Bu),
(10Z)- and (10E)-19-Fluoro-1a,25-dihydroxyvitamin D3 1,3-Di-tert-
butyldiphenylsilyl-25-methoxymethyl Ether (20a and b) A solution of
18 (140 mg, 0.15 mmol, 10Z : 10Eϭ1 : 5), anthracene (131 mg, 0.74 mmol)
in benzene–EtOH (1 : 9, 250 ml) was purged with Ar, and was irradiated at
0 °C for 6 h using a halogen-lamp (200 W). After evaporation of the solvent,
the residue was purified by chromatography on silica gel (10 g) using ben-
zene to afford a mixture of 20a and 20b (133.1 mg, 95%) in about a 1 : 1
ratio.
0.94 (3H, d, Jϭ6.3 Hz, 21-H), 1.00 (9H, s, Si–tert-Bu), 1.23 (6H, s, 26, 27-
H), 2.04 (3H, s, Me), 2.69 (2H, br s, 19-H), 2.79 (1H, m), 2.89 (1H, m), 2.83
(1H, m), 3.38 (3H, s, OMe), 3.93 (1H, m, 1-H), 4.11 (1H, m, 3-H), 4.72 (2H,
s, OCH2O), 5.64, 6.45 (each 1H, d, Jϭ10.9 Hz, 6, 7-H), 7.2—7.7 (20H, m,
arom. H).
Diastereomers (16a, b, c and d) To a cold (Ϫ78 °C), stirred solution of
LDA (8.15 mmol, prepared from 1.59 M n-BuLi in hexane and diisopropy-
lamine) in dry THF (2 ml) was added a solution of fluoromethyl phenyl sul-
fone (1.14 g, 6.52 mmol) in dry THF (3 ml), and the mixture was further
stirred for 1 h. To this solution was added a cold (Ϫ78 °C) solution of 14
(3.06 g, 3.26 mmol) in dry THF (10 ml). After being stirred for 2 h at the
same temperature, the reaction mixture was quenched with sat. NH4Cl and
extracted with AcOEt. The organic extract was washed with brine, dried
(MgSO4), and evaporated in vacuo. The residue was purified by chromatog-
raphy on silica gel (150 g) with benzene–2% AcOEt–benzene to give the
four diastereoisomers 16: the less polar fraction contains two isomers 16a
and 16d in about a 9 : 1 ratio (1.27 g, 35%), while the more polar fraction in-
cludes three isomers 16b, 16c and 16d in about a ratio 7 : 1 : 2 (1.80 g, 50%).
1
20a: H-NMR (CDCl3) d: 0.40 (3H, s, 18-H), 0.86, 1.04 (each 9H, s, Si–
tert-Bu, overlapped with 21-H), 1.21 (6H, s, 26, 27-H), 2.56 (1H, m), 2.77
(1H, m), 3.36 (3H, s, OMe), 4.42 (1H, m, 3-H), 4.70 (2H, s, OCH2O), 4.90
(1H, m, 1-H), 5.91, 6.22 (each 1H, d, Jϭ11.2 Hz, 6 or 7-H), 6.22 (1H, d, Jϭ
86.3 Hz, 19-H), 7.2—7.7 (20H, m, arom. H). 19F-NMR (CDCl3) d: Ϫ129.7
(d, Jϭ86.3 Hz).
20b: 1H-NMR (CDCl3) d: 0.47 (3H, s, 18-H), 0.92, 0.99 (each 9H, s, Si–
tert-Bu, overlapped with 21-H), 1.22 (6H, s, 26, 27-H), 2.44 (1H, m), 2.77
(1H, m), 3.37 (3H, s, OMe), 4.33 (2H, m, 1, 3-H), 4.71 (2H, s, OCH2O),
5.58 (1H, dd, Jϭ11.0, 5.0 Hz, 7-H), 5.98 (1H, d, Jϭ85.0 Hz, 19-H), 6.25
(1H, d, Jϭ11.0 Hz, 6-H), 7.2—7.7 (20H, m, arom. H). 19F-NMR (CDCl3) d:
Ϫ129.6 (broad signal).
1
16a: H-NMR (CDCl3) d: 0.38 (3H, s, 18-H), 0.78 (9H, s, Si–tert-Bu),

March 2001
317
20a and b: EI-MS m/z (%): 954 (Mϩ, 3), 892 (5), 835 (5), 698 (3), 636 EI-MS m/z (%): 672 (Mϩ, 13), 654 (8), 597 (9), 579 (5), 408 (20), 378 (5),
(4), 199 (100).
351 (19), 333(2), 199 (100).
(10Z)- and (10E)-19-Fluoro-1a,25-dihydroxyvitamin D3 1,3-Di-tert-
1H-NMR, 19F-NMR, MS, and UV spectra of 2 and 3 were in agreement
butyldiphenylsilyl Ether (21a and b) and (10Z)- and (10E)-19-Fluoro- with those of the known specimens prepared earlier in our laboratory.15)
1a,25-dihydroxyvitamin D3 1-tert-Butyldiphenylsilyl Ether (22a and b)
A mixture of 20 (127.9 mg, 0.13 mmol, 10Z : 10Eϭ1 : 1), d,l-comphor-10- References and Notes
sulfonic acid (77.8 mg, 0.34 mmol) in dry THF–dry MeOH (1 : 3, 2 ml) was
stirred for 3 h at room temperature and quenched with 5% NaHCO3. The
mixture was extracted with AcOEt and the AcOEt extract was washed with
brine, dried (MgSO4) and evaporated in vacuo. The residue was separated by
chromatography on silica gel (10 g) using CH2Cl2 to afford 21a and 21b
(58.9 mg, 48%, approx. 1 : 1) and 22a and b (48 mg, 52%, approx. 1 : 1).
A mixture of 21 (58.8 mg, 0.065 mmol, 10Z : 10Eϭ1 : 1), n-Bu4NF (1 M
solution in THF, 0.16 mmol) and dry THF (0.5 ml) was heated at 50 °C for
8 h and quenched with 5% NaHCO3. The mixture was extracted with AcOEt
and the organic extract was washed with brine, dried (MgSO4) and evapo-
rated to dryness. The residue was purified by chromatographed on silica gel
(20 g) using 50% AcOEt–hexane to give the unreacted 21a (14.8 mg) and 2
(4.1 mg, 15%), and then using 10% MeOH–AcOEt to give 3 (11.7 mg,
41%).
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A mixture of 22 (30.6 mg, 0.046 mmol, 10Z : 10Eϭ1 : 1), n-Bu4NF (1 M
solution in THF, 0.12 mmol) and dry THF (0.5 ml) was heated at 50 °C for
23 h and quenched with 5% NaHCO3. The mixture was extracted with
AcOEt and the organic extract was washed with brine, dried (MgSO4) and
evaporated to dryness. The residue was purified by chromatographed on sil-
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1
21a: H-NMR (CDCl3) d: 0.40 (3H, s, 18-H), 0.86, 1.03 (each 9H, s, Si–
tert-Bu), 1.21 (6H, s, 26, 27-H), 2.55 (1H, m), 2.77 (1H, m), 4.42 (1H, m, 3-
H), 4.90 (1H, m, 1-H), 5.91 (1H, d, Jϭ11.4 Hz, 7-H), 6.21 (1H, d, Jϭ
11.4 Hz, 6-H), 6.22 (1H, d, Jϭ86.3 Hz, 19-H), 7.2—7.7 (20H, m, arom. H).
19F-NMR (CDCl3) d: Ϫ129.5 (d, Jϭ86.3 Hz).
21b: 1H-NMR (CDCl3) d: 0.46 (3H, s, 18-H), 0.92, 0.99 (each 9H, s, Si– 14) Shimizu M., Iwasaki Y., Yamada S., Tetrahedron Lett., 40, 1697—
tert-Bu), 1.22 (6H, s, 26, 27-H), 2.44 (1H, m), 2.77 (1H, m), 4.32 (2H, m, 1,
1700 (1999).
3-H), 5.58 (1H, dd, Jϭ11.0, 5.0 Hz, 7-H), 5.98 (1H, d, Jϭ84.0 Hz, 19-H), 15) Shimizu M., Iwasaki Y., Ohno A., Yamada S., Chem. Pharm. Bull., 48,
6.52 (1H, d, Jϭ11.0 Hz, 6-H), 7.2—7.7 (20H, m, arom. H). 19F-NMR
(CDCl3) d: Ϫ129.6 (broad signal).
1484—1493 (2000).
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21a and b: EI-MS m/z (%): 910 (Mϩ, 5), 892 (4), 835 (3), 579 (3), 390
(10), 199 (100).
1
22a: H-NMR (CDCl3) d: 0.46 (3H, s, 18-H), 0.92 (3H, d, Jϭ5.4 Hz, 21-
H), 1.21 (6H, s, 26, 27-H), 4.30 (1H, m, 3-H), 5.04 (1H, m, 1-H), 6.02 (1H,
d, Jϭ11.0 Hz, 7-H), 6.33 (1H, d, Jϭ86.3 Hz, 19-H), 6.46 (1H, d, Jϭ11.0 Hz, 19) Steinmeyer A., Neef G., Tetrahedron Lett., 34, 4879—4882 (1992).
6-H), 7.2—7.7 (10H, m, arom. H). 19F-NMR (CDCl3) d: Ϫ129.5 (d, Jϭ
86.3 Hz). EI-MS m/z (%): 672 (Mϩ, 4), 654 (6), 597 (6), 579 (4), 577 (7),
408 (20), 378 (13), 351 (12), 333(3), 199 (100).
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22b: 1H-NMR (CDCl3) d: 0.49 (3H, s, 18-H), 0.94 (3H, d, Jϭ5.9 Hz, 21-
H), 1.22 (6H, s, 26, 27-H), 4.30 (2H, m, 1, 3-H), 5.66 (1H, dd, Jϭ11.0,
4.7 Hz, 7-H), 6.11 (1H, d, Jϭ84.3 Hz, 19-H), 6.49 (1H, d, Jϭ11.0 Hz, 6-H),
7.3—7.7 (10H, m, arom. H). 19F-NMR (CDCl3) d: Ϫ128.8 (broad signal).