886 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 3
Brief Articles
0.147 mmol, 1.8 equiv). After usual workup, the crude mixture
was purified by column chromatography on silica gel (pentane/
CH2Cl2, 2/3) to yield 3,17ꢀ-bisbenzyloxy-11ꢀ-[9-(4,4,5,5,5-pen-
tafluoropentylsulfanyl)non-3-enyl]estra-1,3,5(10)-triene (61 mg,
97%) as a glass. Hydrogen peroxide (35% solution, 31 µL, 0.32
mmol, 2 equiv) was slowly poured at 0 °C into a solution of the
preceding thioether (120 mg, 0.16 mmol) in hexafluoroisopropanol
(0.6 mL). After 5 min of stirring, sodium sulfite (25 mg, 0.2 mmol)
was added and the mixture was stirred for 30 min. Usual workup
afforded, without further purification, the desired sulfoxide 8 in
quantitative yield (121 mg).
3-Hydroxy-11ꢀ-[9-(4,4,5,5,5-pentafluoropentane-1-sulfinyl)non-
3-enyl]-17ꢀ-benzyloxyestra-1,3,5(10)-triene 9. Palladium(II) hy-
droxide (100% mass) was added to a solution of sulfoxide 8 (65
mg, 0.083 mmol) in ethyl acetate (2 mL). After 24 h of being stirred
under hydrogen, the crude mixture was filtered through a pad of
Celite and purified by preparative TLC (CH2Cl2/MeOH, 95/5) to
afford the monodebenzylated product 9 as a glass. Yield 68%.
3,17ꢀ-Dihydroxy-11ꢀ-[9-(4,4,5,5,5-pentafluoropentane-1-sulfi-
nyl)nonyl]estra-1,3,5(10)-triene 3. Steroid 9 (35 mg, 0.045 mmol)
was dissolved in CH2Cl2 (1.25 mL), and the solution was cooled
to -78 °C. A solution of BCl3 in CH2Cl2 (0.5 M, 0.6 mL, 0.3 mmol,
6.6 equiv) was then slowly added. After 10 min, the reaction was
quenched with methanol (1 mL). The final compound was obtained
after usual workup by purification on preparative TLC (CH2Cl2/
MeOH:90/10) as a white solid. Yield 56%.
equivalence of the 7R and 11ꢀ substitutions in terms of
interactions with ERR.6,7 The side chain of these two isomers
probably protrudes from the LBD in a similar way, resulting in
interactions with a same region of the receptor surface. Partial
fluorination of this side chain, which limits its flexibility, would
logically decrease such an interaction. Could this property be
related to the absence of effect of 4 on ERR turnover? Analysis
of various 11ꢀ perfluorinated estrogens and antiestrogens may
be informative in this respect. Whatever the answer would be,
our data suggest that an interaction with a given part of the
receptor surface is not required to abrogate the recruitment of
coactivators harboring an LxxLL motif. Repulsion of such
coregulators from the receptor area seems to be a more likely
explanation: the functionalized terminal part of the side chain
may shield the receptor against interacting motifs of coactivators
rather than obstruct their binding sites. In fact, this concept is
in agreement with previous reports suggesting the existence of
a “passive” antagonism in addition to an “active” antagonism
based on a direct blockade of the recruitment site.24 Studies
devoted to the effect of flexible and nonflexible side chains at
11ꢀ are warranted to test this hypothesis.
Experimental Section
General. Usual workup refers to a quench with saturated NH4Cl
solution, extraction with CH2Cl2, washing of the organic layers with
water, drying over MgSO4, and concentration under reduced
pressure. Additional data may be found in the Supporting Informa-
tion.
Synthesis of the 11ꢀ Analogue of Fulvestrant. 3-(3,17ꢀ-
Bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-yl)propan-1-al 6. To a
solution of oxalyl chloride (296 mg, 2.33 mmol, 1.1 equiv) in
dichloromethane (5 mL) was added dimethyl sulfoxide (363 mg,
4.66 mmol, 2.2 equiv) at -60 °C, followed after 5 min by a solution
of 3-(3,17ꢀ-bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-yl)propan-1-ol10b
(1.08 g, 2.12 mmol) in dichloromethane (5 mL). After 15 min,
triethylamine (1.07 g, 10.6 mmol, 5 equiv) was added dropwise.
After the mixture was warmed to room temperature and the usual
workup, column chromatography on silica gel (CH2Cl2) afforded
aldehyde 6 (938 mg, 1.85 mmol, 87%) as a white foam.
[9-(3,17ꢀ-Bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-yl)non-6-eny-
loxy]-tert-butyldimethylsilane 7. A solution of n-butyllithium (2.5
M in hexanes, 570 µL, 1.43 mmol, 1.9 equiv) was slowly added to
a suspension of the phosphonium salt 10 (817 mg, 1.5 mmol, 2
equiv) in THF (3 mL) at -78 °C. After the mixture was stirred for
15 min, a solution of aldehyde 6 (380 mg, 0.75 mmol) in THF (3
mL) was added. After 30 min of being stirred, the mixture was
warmed to room temperature for an additional 2 h. After usual
workup, the silylated product 7 (499 mg, 94% yield) was obtained
by flash chromatography on silica gel (pentane/CH2Cl2, 3/2) as a
glass.
Synthesis of the Fluorinated 11ꢀ Analogue of Fulvestrant
4. Acetic Acid 3,3,4,4,5,5,6,6-Octafluoro-1,6-diiodohexyl Ester
11. To a solution of 1,4-diiodoperfluorobutane (4.85 g, 10.7 mmol)
in 1,2-dichloroethane (15 mL) was added freshly distilled vinyl
acetate (0.4 mL, 4.28 mmol, 0.4 equiv) and 1 M triethylborane
(0.2 mL, 0.2 mmol, 1.8 mol%). This addition was repeated two
times after a 30 min delay. The solvent was removed under vacuum
after 1 h, and the crude mixture was purified by silica gel
chromatography (CH2Cl2/pentane, 40/60). Monoadduct 11 (2.82 g,
58%) was isolated as a colorless oil (highly unstable when exposed
to light).
Acetic Acid 9-[3,17ꢀ-Bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-
yl]-3,3,4,4,5,5,6,6-octafluorononyl Ester 14. To a solution of 11ꢀ-
allylestrane 5 (680 mg, 1.38 mmol) in 1,2-dichloroethane (2.15 mL)
were simultaneously added adduct 11 (4 × 185 mg ) 745 mg,
1.38 mmol, 1 equiv) and triethylborane (1 M solution in hexane,
∼4 × 0.10 mL ) 0.38 mL, 28% mol) every 30 min and in four
equal portions. The mixture was stirred 5 min at room temperature,
and triphenyltin hydride (∼2 × 0.6 g ) 1.21 g, 3.45 mmol, 2.5
equiv) and triethylborane (0.28 mL, 2 × 10% mol) were introduced
in two equal portions. Reaction was allowed to proceed overnight.
After usual workup, column chromatography on silica gel (pure
pentane to CH2Cl2/pentane, 30/70) afforded addition product 14
(354 mg, 33%) as a glass. Acetic acid 7-[1,11ꢀ-ethano-3,17ꢀ-
bisbenzyloxyestra-1,3,5(10)-trien-1′-yl]-3,3,4,4,5,5,6,6-octafluo-
rononyl ester 13 was also isolated (15%).
3,17ꢀ-Bisbenzyloxy-11ꢀ-[4,4,5,5,6,6,7,7-octafluoro-9-(4,4,5,5,5-
pentafluoropentane-1-sulfinyl)nonyl]estra-1,3,5(10)-triene 16.
The preparation of this compound closely follows that of its
nonfluorinated analogue 8 (vide supra). LiAlH4 (10 mg, 0.262
mmol, 1.5 equiv) was added to a solution of acetate 14 (135 mg,
0.173 mmol) in THF (4.5 mL). After completion of the reaction,
water (10 µL), a 15% NaOH solution (10 µL), and finally water
(30 µL) were added. The precipitate was removed by filtration and
the filtrate was evaporated under reduced pressure to obtain
9-(3,17ꢀ-bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-yl)-3,3,4,4,5,5,6,6-
octafluorononan-1-ol (132 mg, 98%) as a glass. To a solution of
the preceding alcohol (43 mg, 0.058 mmol) in CH2Cl2 (1 mL) were
added triethylamine (17 mg, 0.168 mmol, 2.9 equiv) and meth-
anesulfonyl chloride (16 mg, 0.140 mmol, 2.4 equiv). After usual
workup, the crude mixture was purified by column chromatography
(CH2Cl2) to afford methanesulfonic acid 9-[3,17ꢀ-bisbenzylox-
yestra-1,3,5(10)-trien-11ꢀ-yl]-3,3,4,4,5,5,6,6-octafluorononyl ester
(45 mg, 95%) as a glass. To a solution of the preceding mesylate
(85 mg, 0.10 mmol) and 4,4,5,5,5-pentafluoropentylthiol (100 mg,
3,17ꢀ-Bisbenzyloxy-11ꢀ-[9-(4,4,5,5,5-pentafluoropentane-1-
sulfinyl)non-3-enyl]estra-1,3,5(10)-triene 8. To a solution of
steroid 7 (480 mg, 0.68 mmol) in dry THF (3 mL) was added solid
tetrabutylammonium fluoride (530 mg, 2.04 mmol, 3 equiv) at 0
°C. The reaction was stopped after completion (TLC) by pouring
it into water (2 mL) and CH2Cl2 (10 mL). After usual workup,
column chromatography (CH2Cl2/MeOH, 99.5/0.5) afforded the free
alcohol 9-(3,17ꢀ-bisbenzyloxyestra-1,3,5(10)-trien-11ꢀ-yl)non-6-
en-1-ol (344 mg, 86%) as a glass. Triethylamine (86 mg, 0.86 mmol,
1.5 equiv) and mesyl chloride (78 mg, 0.68 mmol, 1.2 equiv) were
added at 0 °C to a solution of the preceding alcohol (340 mg, 0.57
mmol) in CH2Cl2 (4 mL). After usual workup, the crude mixture
was purified by column chromatography (CH2Cl2) to afford
methanesulfonic acid 9-(3,17ꢀ-bisbenzyloxyestra-1,3,5(10)-trien-
11ꢀ-yl)non-6-enyl ester (346 mg, 91%) as a white solid. To a
solution of the preceding mesylate (55 mg, 0.082 mmol) in distilled
THF (0.5 mL) was first added 4,4,5,5,5 pentafluoropentylthiol (32
mg, 0.164 mmol, 2 equiv) and then sodium hydride (80%, 4.5 mg,