Synthesis of 16α-fluoro ICI 182,780 derivatives: Powerful antiestrogens to image estrogen receptor densities in breast cancer by positron emission tomography

Article abstract of DOI:10.1039/b205571f

We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen 7α-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene -3,17β-diol (ICI 182,780; Faslodex). The latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu(I)-promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the 17-hydroxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key intermediates for the ¹⁸F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me₄NF, followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16α-fluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with ¹⁸F by substituting Me₄NF for ¹⁸F^- in acetonitrile.

Full text of DOI:10.1039/b205571f

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Synthesis of 16ꢀ-fluoro ICI 182,780 derivatives:
powerful antiestrogens to image estrogen receptor densities
in breast cancer by positron emission tomography
1
Yann Seimbille, François Bénard and Johan E. van Lier*
Department of nuclear medicine and radiobiology, Faculty of Medicine,
Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
E-mail: jvanlier@courrier.usherb.ca
Received (in Cambridge, UK) 10th June 2002, Accepted 15th August 2002
First published as an Advance Article on the web 20th September 2002
We prepared a new series of 7α-substituted derivatives of 16α-fluoroestradiol, based on the very potent antiestrogen
7α-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-estra-1,3,5(10)-triene-3,17β-diol (ICI 182,780; Faslodex). The
latter consist of estradiol functionalized with a side chain at the 7α-position, conferring interesting pharmaceutical
properties for endocrine therapy of estrogen receptor (ER) positive breast cancer. The considerable advantages of
ICI 182,780 over other selective ER-modulators (SERMs) already used in hormonal therapy, lead us to develop
three new 16α-fluoro derivatives with potential use in positron emission tomography (PET), for the imaging of
ER densities in breast tumors. Introduction of the long side chain at the 7α-position was accomplished by Cu()-
promoted conjugate addition of a Grignard reagent to 6-dehydro-19-nortestosterone. Subsequent oxidation of the
17-hydoxy group and A-ring aromatization gave a 7α-substituted estrone derivative. Further addition to complete
the side chain gave the ICI 182,780 mimics that were converted to the reactive 16β,17β-cyclic sulfates, i.e. the key
intermediates for the 18F-labeling reaction. Opening of the cyclic sulfates via nucleophilic fluorination with Me4NF,
followed by rapid hydrolysis in acidic ethanol of the protecting ether and sulfate groups, yielded the desired 16α-
fluoro PET derivatives of ICI 182,780. The latter procedure is readily adapted for radiolabeling with 18F by
substituting Me4NF for 18FϪ in acetonitrile.
invasive diagnosis of breast cancer response to hormonal
I
Introduction
therapy.23–25
Knowledge of estrogen receptor (ER) and progestin receptor
(PR) levels in breast tumors is important for prognosis and
therapy of the disease.1 The hormonal dependence of breast
carcinomas is considered to be indicative of the potential
responsiveness of a tumor to hormonal agents.2–5 Currently,
the most widely used drug for hormonal treatment of breast
carcinoma is the partial-antiestrogen tamoxifen.6,7 However,
tamoxifen-based endocrine therapy is effective in only 50 to
60% of ER(ϩ) breast cancer patients, thus underlining the
limitations of partial-antiestrogens in this indication.8 The
combined agonist and antagonist activity of these drugs is
responsible for some of the undesirable side effects. Thus treat-
ment with tamoxifen may increase endometrial proliferation,
induce a slightly increased risk of endometrial carcinoma,
tumor flare and tumor-resistance to the drug. A new generation
of steroidal estrogen-based antagonists devoid of estrogen
agonist activity was developed.9–13 The most promising pure
antiestrogen ICI 182,780 (Faslodex), bearing a pentafluoro-
pentylsulfinyl group at the 7α-position, is undergoing clinical
trials. The compound shows increased efficacy at various levels
including: a more rapid and complete tumor inhibition, an
increased time to relapse, a decreased potential for tumor flare
and induction of endometrial cancer, and an activity against
tamoxifen-resistant ER-positive tumors.14–18
In this paper, we report the preparation of three new
steroidal antiestrogens dedicated to PET-scanning of ER(ϩ)
breast tumors. The new compounds are substituted at the
7α-position, well-known for the ER tolerance of bulky
substituents, with a long side chain identical to that of ICI
182,780, or corresponding to different oxidation states of
the sulfur atom within the chain, such as sulfide and sulfone.
The fluorine-18 labeling was first considered by an exchange
of one of the existing fluorine atoms on the 7α-substituent, but
the specific activities obtained would be low, and would not
obey to the systemic constraint on minimum specific activity,
i.e. 1000 Ci mmolϪ1, required for steroid receptors imaging.
In addition, the time required to complete this reaction is
incompatible with the short half life of 18F (110 min). Instead,
the three derivatives were labeled at the 16α-position with
fluorine to obtain PET mimics of ICI 182,780.
II Results and discussion
Our first attempts to synthesize a fluoro derivative of ICI
182,780 consisted of α-alkylation with alkyl halides of the
protected 6-ketoepiestriol, according to a method described
by Tedesco et al.26,27 This procedure allows for introduction of
a methyl or ethyl group stereoselectively, as well as the long
undecyl carboxyamide chain of ICI 164,384.12 However, all our
attempts to perform alkylation of the enolate, even if the latter
was stabilized by BEt3, failed.28 We concluded that the different
alkyl halides used in our reactions were not sufficiently
functionalized to allow for a high-yield reaction with the
C7-nucleophile.
Efficacy of these therapeutic agents is directly dependent on
their ability to bind with high affinity and selectivity to the ER.
Therefore, once labeled with a gamma or positron emitter,
they could serve as radiopharmaceuticals to visualize in vivo the
ER concentration in breast tumors.19–22 Non-invasive imaging
and quantification of ER, using either single photon emission
tomography (SPECT) or positron emission tomography (PET),
can avoid many disadvantages of in vitro analysis of biopsy
samples. This approach also may yield tracers for the non-
Introduction of the 7α-side chain was thus accomplished by a
less direct but versatile synthetic pathway via Cu()-promoted
DOI: 10.1039/b205571f
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This journal is © The Royal Society of Chemistry 2002
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conjugate-addition of 9-(dimethyl-tert-butylsilyloxy)nonyl-
magnesium bromide to 17β-hydroxyestra-4,6-dien-3-one (1).29,12
This approach is however non-stereoselective, leading to a
mixture of 7α–β- epimers that were separated by flash chrom-
atography (the 7α-isomer 2 is the major and less polar
compound and the 7β-isomer is the minor and more polar
product).12,14 Another disadvantage of this approach is the
requirement of the A-ring aromatization step, which is accom-
plished after protecting the side-chain terminus as an acetate.
Prior to these modifications, the 17β-hydroxy compound 2 was
oxidized with pyridinium chlorochromate in CH2Cl2 at 0 ЊC to
give the corresponding 17-keto derivative 3. Treatment of 3,
under acidic conditions, resulted in hydrolysis of the TBDMS
ether to yield 4. The primary alcohol was acetylated with acetyl
chloride in dichloromethane at 0 ЊC in the presence of N,N-
diisopropylethylamine to give 5 in 93% yield.30 A-ring arom-
atization was then performed by treatment of 5 with CuBr2–
LiBr in refluxing acetonitrile to yield the estrone derivative 6 in
68% yield.31 The presence of the three characteristic aromatic
protons in the 1H NMR spectrum confirmed the assigned
structure of compound 6. The latter was converted to the 3,17-
enol diacetates 7 with isopropenyl acetate in the presence of
acid catalyst. Then, 7 was treated with lead tetraacetate in acetic
acid resulting in the rearrangement of the 17-enol acetate to
give exclusively the 3,16β-diacetate estrone derivative 8. The
stereochemistry of 8 was confirmed by the characteristic signal
reactive intermediates were stereoselectively opened via a
nucleophilic fluorination, under anhydrous conditions, with
Me4NF to yield the 16α-fluoro derivatives 17a–c.40,41,32 The
protecting ether and sulfate groups were hydrolyzed under
acidic conditions in EtOH to give the 7α-substituted 16α-
fluoroestradiols 18a–c. The stereochemistry of products 18a–c
1
was confirmed by their characteristic signals in the H NMR
spectra, i.e. a double doublet at 3.8 ppm (17α-H) and a double
multiplet at 4.9 ppm (16β-H).32 This same procedure was
subsequently adapted for the preparation of the analogous
[16α-18F]-18a–c.
In conclusion, three new 16α-fluoro derivatives of the potent
antiestrogen ICI 182,780 were prepared as potential radio-
pharmaceuticals for PET imaging of ER-densities in breast
cancer patients. Assuming a minor effect of a 16α-fluoro
substituent on receptor binding properties of ICI 182,780, the
16α-18F analog could be a useful radiopharmaceutical to study
SERM action mechanisms during hormonal therapy.42,43
Studies on the receptor binding properties of these new fluoro-
steroids have been planned and micro-PET studies to evaluate
their capacity to visualize ER in a small rodent model are in
progress.
Experimental
Analytical thin layer chromatography (TLC) was performed on
Aldrich aluminium oxide on polyester plates or Macherey–
Nagel silica gel pre-coated plastic sheets, both with fluorescent
indicator (UV 254). Visualization was achieved with short-wave
ultraviolet light and/or color response upon spraying with
H2SO4–EtOH and heating at 120 ЊC. Column chromatography
was performed using silica gel (60–200 mesh) or florisil (60–100
mesh). HPLC was performed with a Waters 600 system, using a
6 µm preparative silica gel column (3.9 mm × 300 mm, Waters,
Nova-Pak HR Silica 6 µm). HPLC eluents were monitored for
UV absorbency at 280 nm.
1
of the 16α-H in the H NMR spectrum, i.e. a triplet at about
5 ppm vs. a deshielded broad doublet for the 16β-H.32 Reduc-
tion of the 17-keto compound 8 with lithium tri-tert-butoxy-
aluminium hydride provided the 17β-OH derivative 9, which
was hydrolyzed under basic conditions to give the 16β, 17β-diol
10. The cis configuration of the 16- and 17-hydroxy groups was
confirmed by the characteristic coupling constant (J) observed
1
between 16α-H and 17α-H in the H NMR spectrum. After
protecting the 3-OH group as a methoxymethyl (MOM) ether,
i.e. compound 11, the primary alcohol was selectively tosylated
with toluene-p-sulfonyl chloride in dichloromethane in the
presence of 4-dimethylaminopyridine (DMAP).33 The use of
DMAP instead of pyridine as a base resulted in a high yield
of 62% of tosylate 12, together with a trace of polytosylates,
and 28% of recovered triol 11. Tosylate 12 was then treated with
potassium thioacetate in ethanol to give 13 quantitatively. A
basic condensation reaction between 13 and 5-iodo-1,1,1,2,2-
pentafluoropentane (readily prepared from 4,4,5,5,5-penta-
fluoropentanol in one step, see Experimental section) afforded
the sulfide 14 in 72% yield.9 The presence of two triplets at
about 2.5 ppm in the 1H NMR spectrum, corresponding to the
two protons of CH2S, confirmed the stucture of 14. As
described in the literature, one of the most widely-used and best
methods for the conversion of thioethers to sulfoxides is the
oxidation with cold sodium metaperiodate. However, this
method could not be applied to obtain 15b from 14, due to the
ability of NaIO4 to cleave the diols.34,14 Our first approach was
therefore to protect the 16β,17β-diol prior to the oxidation step
as a cyclic carbonate, obtained by treatment with an aqueous
solution of NaIO4 in acetonitrile, followed by a base mediated
hydrolysis to provide compound 15b.35,36 However a more
elegant synthetic pathway involves oxidation of 14 with one
equivalent of 3-chloroperoxybenzoic acid in dichloromethane
at Ϫ20 ЊC to yield the sulfoxide 15b. Increasing the reaction
temperature to 0 ЊC in the presence of an excess of the
oxidation agent gave the corresponding sulfone 15c.36–38 The
vicinal diols 15a–c were transformed efficiently to the corre-
sponding cyclic sulfates 16a–c, via treatment with NaH and
sulfonyldiimidazole. Cyclic sulfates are more reactive toward
nucleophiles than epoxides and are usually quite unstable under
mild acidic conditions, thus providing excellent intermediates
for the introduction of a 16α-fluoro substituent.39 Formation of
the 16β,17β-O-cyclic sulfate further confirmed the cis config-
uration of the 16- and 17-hydroxy groups of 15a–c. These
1H NMR spectra were taken in chloroform-d or dimethyl-
sulfoxide-d6, on a Bruker AC-300 spectrometer (at 300.13
MHz) using Me4Si as an internal standard and selected proton
resonances are reported. Chemical shifts are expressed in ppm
(δ) relative to the standard and coupling constants (J) in Hz.
Mass spectra were obtained on a Micromass Model ZAB-1F
high-resolution mass spectrometer (HRMS). The relative
intensity of the salient fragment ions to the base peak (100) is
given in parentheses. Chemicals were obtained from the
following sources and were used as received, unless otherwise
noted: Aldrich, Alfa Aesar, Sigma or Fisher.
Preparation of 9-(dimethyl-tert-butylsilyloxy)nonyl bromide
A solution of dimethyl-tert-butylsilyl chloride (14.1 g, 93 mmol)
in THF (15 mL) was added to a solution of 9-bromononanol
(16.7g, 75 mmol) and imidazole (10.8 g, 0.16 mmol) in 40 mL of
THF and the mixture was kept at laboratory temperature for
2 hours, then diluted with ether (100 mL) and filtered. The
filtrate was evaporated to dryness and the residue purified by
chromatography on silica gel using a 4 : 1 v/v mixture of
petroleum ether and toluene as eluent to yield 9-(dimethyl-tert-
butylsilyloxy)nonyl bromide (24.1 g, 95%) as an oil.1H NMR
(300 MHz, CDCl3) δ 0.04 (s, 6H, CH3–Si), 0.88 (s, 9H, Si–But),
3.40 (t, 2H, J = 6.9 Hz, CH2–Br), 3.59 (t, 2H, J = 6.5 Hz, CH2–
OSi(Me)2But); MS m/z (relative intensity) 337 (Mϩ, 1), 281 (Mϩ
Ϫ C4H9, 7), 279 (Mϩ Ϫ C4H9, 5), 207 (3), 169 (20), 167 (18);
HRMS calcd for C15H33OSiBr Ϫ C4H9, 279.0780, found
279.0784.
17ꢁ-Hydroxy-7-(9-dimethyl-tert-butylsilyloxynonyl)estr-4-en-3-
one (2)
A solution of 9-(dimethyl-tert-butylsilyloxy)nonyl bromide
(24.1 g, 71 mmol) in THF (75 mL) was added over 2 hours to
2276
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a stirred suspension of magnesium turnings (1.8 g, 74 mmol) in
THF (7.5 mL) under normal conditions for preparation of a
Grignard reagent, and the mixture was heated under reflux for
2 hours, diluted with 30 mL of THF and cooled to Ϫ30 ЊC.
Cuprous iodide (7.1 g, 37 mmol) was added, the mixture was
vigorously stirred for 10 min and a solution of 6-dehydro-19-
nortestosterone (5.0 g, 18.4 mmol) in THF (50 mL) was added
dropwise. The mixture was stirred for 40 min, acetic acid (4.5
mL) was added and the mixture was evaporated to dryness.
Water (150 mL) was added to the residue, and the mixture
extracted three times with ethyl acetate. The combined extracts
were washed with water, dried and evaporated to dryness, and
the residue was subjected to chromatography (CH2Cl2–EtOAc
10 : 0 to 19 : 1, silica gel) to give the less polar 7α-isomer (2) (3.6
g, 37%) and the more polar 7β-isomer (2.3 g, 24%).
3-Hydroxy-7ꢀ-(9-acetoxynonyl)estra-1,3,5(10)-trien-17-one (6)
To a solution of 5 (5 mmol) in anhydrous acetonitrile (75 mL)
under argon atmosphere was added CuBr2 (2.1 eq., 2.35 g) and
LiBr (1.1 eq., 0.48 g) which was refluxed for 30 min. Then, the
mixture was cooled and the solvent was evaporated under
reduced pressure. The residue was poured into saturated aque-
ous NaHCO3 and extracted four times with EtOAc. The com-
bined extracts were washed with water, dried and evaporated to
dryness, and the crude product was purified by chromatography
on a silica gel column using a 10 : 0 to 19 : 1 v/v mixture of
CH2Cl2 and EtOAc as eluant, to give pure 6 (1.54 g, 68%).
1
6: H NMR (300 MHz, CDCl3) δ 0.91 (s, 3H, 18-CH3), 2.05
(s, 3H, –OCOCH3), 4.05 (t, 2H, J = 6.8 Hz, –CH2OAc), 6.57 (d,
1H, J = 2.7 Hz, C4-H), 6.64 (dd, 1H, J = 2.7, 8.4 Hz, C2-H),
7.14 (d, 1H, J = 8.5 Hz, C1-H); MS m/z (relative intensity)
454 (Mϩ, 100), 394 (8), 342 (8); HRMS calcd for C29H42O4,
454.3083, found 454.3090.
1
2: H NMR (300 MHz, CDCl3) δ 0.03 (s, 6H, CH3–Si), 0.79
(s, 3H, 18-CH3), 0.88 (s, 9H, Si–But), 3.58 (t, 2H, J = 6.6 Hz,
CH2–OSi(Me)2But), 3.66 (t, 1H, J = 8.4 Hz, 17-H), 5.82 (s, 1H,
C4-H); MS m/z (relative intensity) 530 (Mϩ, 1), 515 (2), 473 (Mϩ
Ϫ C4H9, 100), 273 (13); HRMS calcd for C33H58O3Si, 530.4155,
found 530.4139.
3,17-Diacetoxy-7ꢀ-(9-acetoxynonyl)estra-1,3,5(10),16-tetraene
(7)
A mixture of (3.4 mmol) 6, isopropenyl acetate (9 mL) and
catalyst solution (0.4 mL), prepared by mixing isopropenyl
acetate (4 mL) and H2SO4 (0.1 mL), was refluxed for 2 h.
Approximately one third of the solvent was slowly distilled over
a period of 1 h. An additional 5 mL of isopropenyl acetate and
0.25 mL of catalyst were added and the solution was concen-
trated to half the volume by slow distillation for 1 h. The solu-
tion was chilled and EtOAc was added. The EtOAc solution
was washed with ice-chilled sodium bicarbonate (5%) in water
and dried over anhydrous Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified on a column
of florisil (hexane–EtOAc, 10 : 0 to 19 : 1) to yield 7 (1.2 g, 66%)
as a colorless oil.
7ꢀ-(9-Dimethyl-tert-butylsilyloxynonyl)estr-4-ene-3,17-dione (3)
Pyridinium chlorochromate (2 g, 9.3 mmol) was added within
15 min to an ice-cooled solution of 2 (6.8 mmol) in 20 mL of
CH2Cl2. The solution was stirred at 0 ЊC for 30 min, allowed to
warm to room temperature and stirred for another 1.5 h. The
mixture was diluted with ether (20 mL) and filtered through
a short column of florisil, eluted with a 1 : 1 v/v mixture
of hexane–EtOAc. The residue was submitted to flash-
chromatography (hexane–EtOAc 10 : 0 to 9 : 1, silica gel) to
yield 3 (2.91 g, 81%).
1
3: H NMR (300 MHz, CDCl3) δ 0.03 (s, 6H, CH3–Si), 0.88
(s, 9H, Si–But), 0.92 (s, 3H, 18-CH3), 3.58 (t, 2H, J = 6.6 Hz,
CH2–OSi(Me)2But), 5.84 (s, 1H, C4-H); MS m/z (relative inten-
sity) 527 (Mϩ Ϫ H, 1), 513 (Mϩ Ϫ CH3, 2), 471 (Mϩ Ϫ C4H9,
100); HRMS calcd for C33H56O3Si Ϫ H, 527.3920, found
527.3928.
1
7: H NMR (300 MHz, CDCl3) δ 0.91 (s, 3H, 18-CH3), 2.04
(s, 3H, –OCOCH3), 2.18 (s, 3H, 3-OCOCH3), 2.28 (s, 3H,
17-OCOCH3), 4.04 (t, 2H, J = 6.8 Hz, –CH2OAc), 5.51 (m, 1H,
16-H), 6.78 (d, 1H, J = 2.5 Hz, C4-H), 6.84 (dd, 1H, J = 2.5, 8.5
Hz, C2-H), 7.26 (d, 1H, J = 8.5 Hz, C1-H); MS m/z (relative
intensity) 556 (MNH4ϩ, 91), 495 (36), 479 (100), 454 (42), 394
(21); HRMS calcd for C33H46O6 ϩ NH4ϩ, 556.3638, found
556.3650.
7ꢀ-(9-Hydroxynonyl)estr-4-ene-3,17-dione (4)
A mixture of 3 (5.5 mmol), acetic acid (16.5 mL), water
(8.5 mL) and THF (15 mL) was stirred at 50 ЊC overnight. The
solvent was evaporated, the residue was dissolved in EtOAc,
washed with saturated aqueous NaHCO3 (3 × 150 mL), then
dried over anhydrous Na2SO4 and evaporated to dryness to
yield 4.
3,16ꢁ-Diacetoxy-7ꢀ-(9-acetoxynonyl)estra-1,3,5(10)-trien-17-
one (8)
A mixture of 7 (2.2 mmol), lead tetraacetate (1.2eq., 1.2 g) and
AcOH (10 mL) was stirred for 2.5 h. Then 0.15 g of Pb(OAc)4
was added and the mixture was stirred for another 1 h. The
reaction mixture was diluted with CHCl3 (100 mL), washed
(2 × 50 mL aqueous 5% sodium thiosulfate; 4 × 150 mL satur-
ated aqueous NaHCO3), then dried over anhydrous Na2SO4
and distilled to dryness. The crude product was subjected to
chromatography (hexane–EtOAc 10 : 0 to 9 : 1, florisil) to give
8 (1 g, 81%).
4: 1H NMR (300 MHz, CDCl3) δ 0.91 (s, 3H, 18-CH3),
3.61 (t, 2H, J = 6.6 Hz, CH2–OH), 5.84 (s, 1H, C4-H); MS m/z
(relative intensity) 414 (Mϩ, 15), 384 (84), 271 (100); HRMS
calcd for C27H42O3, 414.3134, found 414.3127.
7ꢀ-(9-Acetoxynonyl)estr-4-ene-3,17-dione (5)
Compound 4 (5.4 mmol) was dissolved in CH2Cl2 (10 mL),
and cooled to 0 ЊC in an ice bath. To the chilled solution
was added N,N-diisopropylethylamine (2 eq., 1.8 mL) and
the mixture was stirred at 0 ЊC for 10 min before addition of
acetyl chloride (1.2 eq., 0.47 mL). The mixture was stirred
at 0 ЊC for 30 min. Then the solvent was removed under reduced
pressure, the residue poured into water and extracted with
EtOAc. Evaporation of the dried (Na2SO4) extract yielded a
yellow oil which was submitted to flash-chromatography
(CH2Cl2–EtOAc 10 : 0 to 19 : 1, silica gel) to give 5 (2.28 g,
93%).
1
8: H NMR (300 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 2.04
(s, 3H, –OCOCH3), 2.13 (s, 3H, 3-OCOCH3), 2.28 (s, 3H,
16-OCOCH3), 4.04 (t, 2H, J = 6.7 Hz, –CH2OAc), 5.07 (t, 1H,
J = 8.4 Hz, 16α-H), 6.80 (d, 1H, J = 2.4 Hz, C4-H), 6.86 (dd,
1H, J = 2.4, 8.4 Hz, C2-H), 7.27 (d, 1H, J = 7.5 Hz, C1-H); MS
m/z (relative intensity) 554 (Mϩ, 2), 512 (12), 476 (23), 452 (100),
434 (25); HRMS calcd for C33H46O7, 554.3243, found 554.3248.
3,16ꢁ-Diacetoxy-7ꢀ-(9-acetoxynonyl)estra-1,3,5(10)-trien-17ꢁ-ol
(9)
5: 1H NMR (300 MHz, CDCl3) δ 0.92 (s, 3H, 18-CH3),
2.03 (s, 3H, –OCOCH3), 4.03 (t, 2H, J = 6.8 Hz, –CH2OAc),
5.84 (s, 1H, C4-H); MS m/z (relative intensity) 456 (Mϩ, 15),
413 (Mϩ Ϫ CH3CO, 5), 369 (2), 271 (100); HRMS calcd for
C29H44O4, 456.3239, found 456.3250.
A solution of 8 (1.8 mmol), lithium tri-tert-butoxyaluminium
hydride (1.5 g, 5.9 mmol), and THF (35 mL) was stirred for 1 h
and then poured with stirring into a mixture of ice (100 g), H2O
(100 mL), and AcOH (15 mL). The mixture was extracted with
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CHCl3, washed (3 × 200 mL saturated aqueous NaHCO3),
dried (Na2SO4), and distilled to dryness to afford 9.
9: H NMR (300 MHz, CDCl3) δ 0.85 (s, 3H, 18-CH3), 2.05
(s, 3H, –OCOCH3), 2.10 (s, 3H, 3-OCOCH3), 2.28 (s, 3H,
16-OCOCH3), 3.67 (m, 1H, 17-H), 4.04 (t, 2H, J = 6.7 Hz,
–CH2OAc), 5.12 (m, 1H, 16α-H), 6.50–7.00 (m, 3H, aromatic-
H); MS m/z (relative intensity) 556 (Mϩ, 4), 514 (75), 472 (17),
454 (94), 437 (88); HRMS calcd for C33H48O7, 556.3400, found
556.3412.
7ꢀ-[9-(Acetylthio)nonyl]-3-O-methoxymethylestra-1,3,5(10)-
triene-3,16ꢁ,17ꢁ-triol (13)
1
A mixture of 12 (0.84 mmol), potassium thioacetate (2 eq., 193
mg) and ethanol (6 mL) was stirred at 50 ЊC for 2.5 h. The
resulting solution was evaporated and the residue was taken up
in ethyl acetate. Work-up and chromatography was performed
on a silica gel column (hexane–EtOAc, 5 : 0 to 4 : 1, v/v) gave 13
(0.41 g, 91%).
13: 1H NMR (300 MHz, CDCl3) δ 0.84 (s, 3H, 18-CH3), 2.32
(s, 3H, CH3–C(O)–), 2.85 (t, 2H, J = 7.4 Hz, –CH2S–), 3.48 (m,
1H, 17-H), 3.48 (s, 3H, 3-OCH2–OCH3), 4.24 (m, 1H, 16α-H),
5.15 (s, 2H, 3-OCH2–), 6.75 (d, 1H, J = 2.6 Hz, C4-H), 6.83 (dd,
1H, J = 2.7, 8.6 Hz, C2-H), 7.19 (d, 1H, J = 8.6 Hz, C1-H); MS
m/z (relative intensity) 532 (Mϩ, 10), 487 (49), 458 (100), 424
(58); HRMS calcd for C31H48O5S, 532.3222, found 532.3210.
7ꢀ-(9-Hydroxynonyl)estra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (10)
The crude compound 9 thus obtained was dissolved in MeOH
(15 mL), treated with 15 mL of an aqueous solution of potas-
sium carbonate (100 mg mLϪ1), and stirred at room temper-
ature for 2 h under N2. The solution was acidified with 10%
hydrochloric acid and extracted with ethyl acetate. The extract
was washed with water, dried (Na2SO4) and evaporated under
reduced pressure to yield a yellow oil which was submitted to
chromatography (toluene–acetone 4 : 0 to 3 : 1, silica gel) to give
10 (0.64 g) as a pale yellow solid.
7ꢀ-{9-[(4,4,5,5,5-Pentafluoropentyl)thio]nonyl}-3-O-methoxy-
methylestra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (14)
Preparation of 5-iodo-1,1,1,2,2-pentafluoropentane. Iodine
(1 eq., 292 mg) was added while stirring to an ice-cooled
solution of triphenylphosphine (1 eq., 302 mg) and imidazole
(1 eq., 78 mg) in CH2Cl2 (2 mL). After 5 min 4,4,5,5,5-
pentafluoropentanol (205 mg, 1.15 mmol) was added dropwise.
The ice bath was removed after 2.5 h and the formed crystals
were removed by filtration.
1
10: H NMR (300 MHz, d6-DMSO) δ 0.71 (s, 3H, 18-CH3),
3.24 (d, 1H, J = 7.3 Hz, 17-H), 3.33 (m, 2H, –CH2OH), 3.96 (m,
1H, 16α-H), 6.40 (d, 1H, J = 2.3 Hz, C4-H), 6.48 (dd, 1H, J =
2.4, 8.4 Hz, C2-H), 7.03 (d, 1H, J = 8.5 Hz, C1-H); MS m/z
(relative intensity) 430 (Mϩ, 90), 414 (35), 355 (10), 300 (25),
157 (100); HRMS calcd for C27H42O4, 430.3083, found
430.3093.
Condensation. The above crude solution of the iodopenta-
fluoro derivative (1.15 mmol) was added, under an argon
atmosphere, to a solution of thioacetate (13) (0.77 mmol) in
methanol (4 mL), followed by 10 M aqueous sodium hydroxide
(0.16 mL). After heating to 50 ЊC for 1 h, the mixture was
acidified with 2 M hydrochloric acid and the product was
extracted with ethyl acetate. Usual work-up and chrom-
atography (hexane–EtOAc 5 : 0 to 4 : 1, SiO2) afforded 14 (0.36
mg, 72%).
7ꢀ-(9-Hydroxynonyl)-3-O-methoxymethylestra-1,3,5(10)-triene-
3,16ꢁ,17ꢁ-triol (11)
10 (1.5 mmol), THF (anhydrous, 5 mL) and a magnetic stirrer
were placed in a bulb. After adding NaH (60% suspension in
mineral oil, 1.6 mmol, 64 mg), the suspension was stirred and a
solution of methoxymethyl chloride (0.18 mL, 2.4 mmol) in
THF (0.3 mL) was added dropwise. After the suspension had
been stirred for 1 h, EtOH (abs., 5 mL) was added. The solvent
was removed in vacuo, and the residue extracted with EtOAc.
The extract was washed with water, dried (Na2SO4), and evap-
orated to dryness. Chromatography (CH2Cl2–acetone 4 : 0 to
3 : 1, SiO2) afforded 11 (0.64 g, 91%).
14: 1H NMR (300 MHz, CDCl3) δ 0.84 (s, 3H, 18-CH3), 2.50
(t, 2H, J = 7.4 Hz, –CH2S–), 2.58 (t, 2H, J = 7.0 Hz, –CH2S–),
3.48 (m, 1H, 17-H), 3.48 (s, 3H, 3-OCH2–OCH3), 4.24 (m, 1H,
16α-H), 5.15 (s, 2H, 3-OCH2–), 6.75 (d, 1H, J = 2.6 Hz, C4-H),
6.83 (dd, 1H, J = 2.6, 8.6 Hz, C2-H), 7.19 (d, 1H, J = 8.6 Hz,
C1-H); MS m/z (relative intensity) 650 (Mϩ, 47), 605 (100),
569 (23), 424 (82); HRMS calcd for C34H51O4SF5, 650.3428,
found 650.3419.
1
11: H NMR (300 MHz, CDCl3) δ 0.84 (s, 3H, 18-CH3),
3.48 (m, 1H, 17-H), 3.48 (s, 3H, 3-OCH2–OCH3), 3.63 (t, 2H,
J = 6.6 Hz, –CH2OH), 4.23 (m, 1H, 16α-H), 5.15 (s, 2H,
3-OCH2–), 6.75 (d, 1H, J = 2.6 Hz, C4-H), 6.83 (dd, 1H, J = 2.7,
8.6 Hz, C2-H), 7.20 (d, 1H, J = 8.5 Hz, C1-H); MS m/z (relative
intensity) 474 (Mϩ, 5), 442 (100), 412 (45), 285 (8); HRMS calcd
for C29H46O5, 474.3345, found 474.3356.
7ꢀ-{9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl}-3-O-
methoxymethylestra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (15b)
m-Chloroperbenzoic acid (containing 77% peracid) (1 eq.,
41 mg) was added to a cooled solution (Ϫ20 ЊC) of sulfide
14 (120 mg, 0.18 mmol) in CH2Cl2 (3 mL). After 20 min, the
mixture was diluted with methylene chloride and washed with
aqueous 5% sodium thiosulfate (75 mL) and saturated aqueous
NaHCO3 (75 mL). The crude product was purified by chrom-
atography (benzene–acetone–MeOH 10 : 0 : 0 to 48 : 1 : 1, silica
gel) to yield pure 15b (114 mg, 93%).
7ꢀ-[9-(4-Methylbenzylsulfonyloxy)nonyl]-3-O-methoxymethyl-
estra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (12)
To a pre-cooled solution (0 ЊC) of 11 (1.35 mmol) and DMAP
(1.1 eq., 182 mg) in dry CH2Cl2 (10 mL) was added tosyl chlor-
ide (1.4 eq., 360 mg). The solution was stirred at 0 ЊC for 1 h,
and then it was allowed to warm to room temperature and was
stirred for another 14 h. It was then filtered through a column
of silica gel, eluted with a 4 : 0 to 3 : 1 v/v mixture of hexane and
EtOAc to give 12 (0.53 g, 62%) and unreacted starting material
(0.18 g, 28%).
15b: 1H NMR (300 MHz, CDCl3) δ 0.83 (s, 3H, 18-CH3), 2.74
(m, 4H, 2CH2SO), 3.48 (m, 1H, 17-H), 3.48 (s, 3H, 3-OCH2–
OCH3), 4.23 (m, 1H, 16α-H), 5.14 (s, 2H, 3-OCH2–), 6.75 (d,
1H, J = 2.6 Hz, C4-H), 6.83 (dd, 1H, J = 2.7, 8.6 Hz, C2-H),
7.19 (d, 1H, J = 8.6 Hz, C1-H); MS m/z (relative intensity) 667
(MHϩ, 10), 635 (24), 621 (44), 604 (18), 585 (19), 456 (100);
HRMS calcd for C34H51O5SF5 ϩ H, 667.3455, found 667.3469.
1
12: H NMR (300 MHz, CDCl3) δ 0.84 (s, 3H, 18-CH3),
2.44 (s, 3H, –O3Sꢀ-CH3), 3.48 (m, 1H, 17-H), 3.48 (s, 3H,
3-OCH2–OCH3), 4.01 (t, 2H, J = 6.5 Hz, –CH2OTs), 4.24
(m, 1H, 16α-H), 5.14 (s, 2H, 3-OCH2–), 6.75 (d, 1H, J = 2.7 Hz,
C4-H), 6.83 (dd, 1H, J = 2.6, 8.6 Hz, C2-H), 7.19 (d, 1H,
J = 8.6 Hz, C1-H), 7.34 (d, 2H, J = 8.1 Hz, –O3S–C6H4–), 7.78
(d, 2H, J = 8.3 Hz, –O3S–C6H4–); MS m/z (relative intensity)
628 (Mϩ, 10), 596 (62), 536 (14), 492 (52), 460 (48), 442 (27),
424 (100); HRMS calcd for C36H52O7S, 628.3433, found
628.3419.
7ꢀ-{9-[(4,4,5,5,5-Pentafluoropentyl)sulfonyl]nonyl}-3-O-
methoxymethylestra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (15c)
m-Chloroperbenzoic acid (containing 77% peracid) (2,4 eq.,
99 mg) was added to an ice-cooled solution of sulfide 14
(120 mg, 0.18 mmol) in CH2Cl2. After 1 h, the mixture was
diluted with methylene chloride and washed with aqueous 5%
2278
J. Chem. Soc., Perkin Trans. 1, 2002, 2275–2281

View Article Online
Scheme 1 a) MgBr(CH2)9OTBDMS, CuI, THF; b) PCC, CH2Cl2, 0 ЊC; c) AcOH, H2O–THF, 50 ЊC; d) N,N-diisopropylethylamine, CH2Cl2 then
AcCl; e) CuBr2, LiBr, CH3CN, reflux; f ) CH3CO2C(CH3)᎐᎐CH2, H2SO4 cat; g) Pb(OAc)4, AcOH; h) Li(t-BuO)3AlH, THF; i) K2CO3, MeOH–H2O; j)
NaH, THF then MOMCl; k) DMAP, CH2Cl2 then TsCl; l) KSAc, EtOH, 50 ЊC; m) C2F5(CH2)3I, NaOH, MeOH, 50 ЊC; n) m-CPBA, CH2Cl2; o)
NaH, THF then sulfonyldiimidazole; p) Me4NF, CH3CN, reflux; q) EtOH–H2SO4.
sodium thiosulfate (150 mL) and saturated aqueous NaHCO3
(150 mL). The crude product was purified by chromatography
(benzene–acetone–MeOH 10 : 0 : 0 to 48 : 1 : 1, silica gel) to
yield pure 15c (120 mg, 95%).
sulfonyl]nonyl}-3-O-methoxymethyl-16ꢁ,17ꢁ-O-sulfurylestra-
1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol (16c)
In a bulb fitted with a magnetic stirrer, 15a (or 15b or 15c)
(0.17 mmol) was dissolved in anhydrous THF (3 mL) and NaH
(60% suspension in mineral oil, 2.5 eq., 17 mg) was added while
stirring. After 10 min a solution of sulfonyldiimidazole (1.05
eq., 36 mg) in anhydrous THF (1 mL) was added dropwise and
stirring was continued. After 1 h the solution was filtered and
evaporated. The residue was extracted with EtOAc, washed
with water, brine and dried (Na2SO4). Upon evaporation of the
solvent, 16a (117 mg, 97%), 16b (122 mg, 93%) or 16c (116 mg,
95%) were respectively obtained as oils.
1
15c: H NMR (300 MHz, CDCl3) δ 0.84 (s, 3H, 18-CH3),
3.00 (m, 4H, 2CH2SO2), 3.48 (m, 1H, 17-H), 3.48 (s, 3H, 3-
OCH2–OCH3), 4.23 (m, 1H, 16α-H), 5.14 (s, 2H, 3-OCH2–),
6.75 (d, 1H, J = 2.6 Hz, C4-H), 6.83 (dd, 1H, J = 2.7, 8.6 Hz,
C2-H), 7.19 (d, 1H, J = 8.6 Hz, C1-H); MS m/z (relative inten-
sity) 682 (Mϩ, 100), 650 (60), 619(30), 601 (28), 507 (28);
HRMS calcd for C34H51O6SF5, 682.3326, found 682.3318.
7ꢀ-{9-[(4,4,5,5,5-Pentafluoropentyl)thio]nonyl}-3-O-methoxy-
methyl-16ꢁ,17ꢁ-O-sulfurylestra-1,3,5(10)-triene-3,16ꢁ,17ꢁ-triol
(16a) or 7ꢀ-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-3-O-
methoxymethyl-16ꢁ,17ꢁ-O-sulfurylestra-1,3,5(10)-triene-
3,16ꢁ,17ꢁ-triol (16b) or 7ꢀ-{9-[(4,4,5,5,5-pentafluoropentyl)-
16a: 1H NMR (300 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 2.50
(t, 2H, J = 7.3 Hz, –CH2S–), 2.58 (t, 2H, J = 7.0 Hz, –CH2S–),
3.48 (s, 3H, 3-OCH2–OCH3), 4.60 (d, 1H, J = 7.5 Hz, 17α-H),
5.15 (s, 2H, 3-OCH2–), 5.17 (m, 1H, 16α-H), 6.76 (d, 1H, J = 2.6
Hz, C4-H), 6.85 (dd, 1H, J = 2.6, 8.6 Hz, C2-H), 7.17 (d, 1H,
J. Chem. Soc., Perkin Trans. 1, 2002, 2275–2281
2279

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J = 8.6 Hz, C1-H); MS m/z (relative intensity) 712 (Mϩ, 17),
680 (40), 667 (100), 587 (12), 569 (8); HRMS calcd for
C34H49O6S2F5, 712.2890, found 712.2883.
(t, 2H, J = 7.4 Hz, –CH2S–), 2.58 (t, 2H, J = 7.0 Hz, –CH2S–),
3.87 (dd, 1H, J = 4.6, 28.5 Hz, 17α-H), 4.95 (dm, 1H, J = 54 Hz,
16β-H), 6.54 (d, 1H, J = 2.7 Hz, C4-H), 6.63 (dd, 1H, J = 2.7,
8.4 Hz, C2-H), 7.14 (d, 1H, J = 8.4 Hz, C1-H); MS m/z (relative
intensity) 608 (Mϩ, 42), 570 (27), 530 (10), 475 (9); HRMS calcd
for C32H46O2SF6, 608.3123, found 608.3117.
16b: 1H NMR (300 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 2.72
(m, 4H, 2CH2SO), 3.48 (s, 3H, 3-OCH2–OCH3), 4.60 (d, 1H,
J = 7.5 Hz, 17α-H), 5.15 (s, 2H, 3-OCH2–), 5.18 (m, 1H, 16α-H),
6.76 (d, 1H, J = 2.6 Hz, C4-H), 6.84 (dd, 1H, J = 2.7, 8.6 Hz,
C2-H), 7.17 (d, 1H, J = 8.6 Hz, C1-H); MS m/z (relative inten-
sity) 728 (Mϩ, 2), 712 (4), 683 (100), 667 (31), 603 (29); HRMS
calcd for C34H49O7S2F5, 728.2840, found 728.2827.
18b: 1H NMR (300 MHz, CDCl3) δ 0.80 (s, 3H, 18-CH3), 2.73
(m, 4H, 2CH2SO), 3.86 (dd, 1H, J = 4.7, 28.5 Hz, 17α-H), 4.93
(dm, 1H, J = 54 Hz, 16β-H), 6.56 (d, 1H, J = 2.6 Hz, C4-H),
6.63 (dd, 1H, J = 2.8, 8.4 Hz, C2-H), 7.12 (d, 1H, J = 8.5 Hz,
C1-H); MS m/z (relative intensity) 624 (Mϩ, 88), 448 (46),
414 (100); HRMS calcd for C32H46O3SF6, 624.3072, found
624.3082.
16c: 1H NMR (300 MHz, CDCl3) δ 1.00 (s, 3H, 18-CH3), 3.00
(m, 4H, 2CH2SO2), 3.48 (s, 3H, 3-OCH2–OCH3), 4.60 (m, 1H,
J = 7.5 Hz, 17α-H), 5.15 (s, 2H, 3-OCH2–), 5.18 (m, 1H, 16α-H),
6.76 (d, 1H, J = 2.6 Hz, C4-H), 6.84 (dd, 1H, J = 2.7, 8.5 Hz,
C2-H), 7.17 (d, 1H, J = 8.6 Hz, C1-H); MS m/z (relative inten-
sity) 744 (Mϩ, 68), 699 (37), 664 (40), 646 (21), 620 (37); HRMS
calcd for C34H49O8S2F5, 744.2789, found 744.2798.
18c: 1H NMR (300 MHz, CDCl3) δ 0.79 (s, 3H, 18-CH3), 3.00
(m, 4H, 2CH2SO2), 3.86 (dd, 1H, J = 4.7, 28.5 Hz, 17α-H), 4.94
(dm, 1H, J = 54 Hz, 16β-H), 6.55 (d, 1H, J = 2.7 Hz, C4-H),
6.63 (dd, 1H, J = 2.7, 8.5 Hz, C2-H), 7.14 (d, 1H, J = 8.5 Hz,
C1-H); MS m/z (relative intensity) 640 (Mϩ, 100), 570 (15), 289
(19); HRMS calcd for C32H46O4SF6, 640.3021, found 640.3014.
Tetramethylammonium 16ꢀ-fluoro-7ꢀ-{9-[(4,4,5,5,5-penta-
fluoropentyl)thio]nonyl}-3-O-methoxymethyl-3-hydroxyestra-
1,3,5(10)-trien-17ꢁ-yl sulfate (17a) or tetramethylammonium
16ꢀ-fluoro-7ꢀ-{9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl}-3-
O-methoxymethyl-3-hydroxyestra-1,3,5(10)-trien-17ꢁ-yl sulfate
(17b) or tetramethylammonium 16ꢀ-fluoro-7ꢀ-{9-[(4,4,5,5,5-
pentafluoropentyl)sulfonyl]nonyl}-3-O-methoxymethyl-3-
hydroxyestra-1,3,5(10)-trien-17ꢁ-yl sulfate (17c)
Acknowledgements
Supported by the Canadian Institutes of Health Research
(CIHR) grant MOP-44065 and the Canadian Breast Cancer
Research Initiative (CBCRI) grant 012301.
References
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nonyl}estra-1,3,5(10)-triene-3,17ꢁ-diol (18c)
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Nova-Pak HR Silica 6-µm, 15% EtOAc in hexane; 1 mL minϪ1
)
provides analytical samples of 18a (tR = 14 min), or 18c (tR = 17
min) by using 25% EtOAc in hexane or 18b (tR = 16 min) when
performed with 50% EtOAc in hexane.
18a: 1H NMR (300 MHz, CDCl3) δ 0.79 (s, 3H, 18-CH3), 2.49
2280
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