Synthesis of fluorinated analogues of the neurosteroid GABAA receptor antagonist, 17-PA

Article abstract of DOI:10.1016/j.jfluchem.2008.03.004

The steroid 17-PA is a GABA_A receptor antagonist which is finding use as a tool in evaluating agonistic/antagonistic activity at GABA_A receptors. Compounds with improved efficacy over 17-PA would be are advantageous for such studies. Accordingly a series of novel analogues of the neurosteroid 17-PA have been prepared and a convenient two-step route is presented which is amenable to the synthesis of analogues with electron-donating para-aromatic substituents including fluorine. However, for the meta-fluoro analogue then the original four-step route to 17-PA remains more efficient overall. The paper describes these syntheses and discusses the electronic factors which influence this synthetic chemistry.

Full text of DOI:10.1016/j.jfluchem.2008.03.004

Journal of Fluorine Chemistry 129 (2008) 881–887
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of fluorinated analogues of the neurosteroid GABAA receptor antagonist,
17-PA
Gildas Deniau a, Keith T. Sillar b, David O’Hagan a,
*
a School of Chemistry and Centre for Biomolecular Sciences, University of St-Andrews, St-Andrews, Fife, Scotland KY16 9ST, UK
b School of Biology, Bute Building, University of St-Andrews, St-Andrews, Fife KY16 9TS, Scotland KY16 9ST, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
The steroid 17-PA is a GABAA receptor antagonist which is finding use as a tool in evaluating agonistic/
antagonistic activity at GABAA receptors. Compounds with improved efficacy over 17-PA would be are
advantageous for such studies. Accordingly a series of novel analogues of the neurosteroid 17-PA have
been prepared and a convenient two-step route is presented which is amenable to the synthesis of
analogues with electron-donating para-aromatic substituents including fluorine. However, for the meta-
fluoro analogue then the original four-step route to 17-PA remains more efficient overall. The paper
describes these syntheses and discusses the electronic factors which influence this synthetic chemistry.
ß 2008 Elsevier B.V. All rights reserved.
Received 30 January 2008
Received in revised form 9 March 2008
Accepted 11 March 2008
Available online 21 March 2008
Keywords:
Neurosteroids
17-PA
g-Aminobutyric acid receptors
Medicinal chemistry
1. Introduction
In 2004, the first selective steroid antagonist (3
phenylandrost-16-en-3-ol (17-PA) 2 was reported to antagonise
the effects of 5 -reduced neurosteroids at GABAA receptors
whereas 5 -reduced steroids were only weakly affected [6]. This
study suggested the presence of at least two steroid binding sites
(5 and 5 ) on the receptor. To date, 17-PA remains the only
selective steroid antagonist known and therefore, it represents an
attractive pharmaceutical tool to explore the delineation of
different neurosteroids effects and to investigate the pharmaco-
phore of the different steroid binding sites. In this paper we
describe the synthesis of some fluorinated analogues of 17-PA in an
effort to increase the efficacy of 17-PA as a neurosteroid antagonist.
a,5a)-17-
GABAA receptors are chloride ion channels that mediate the fast
synaptic inhibition of the main inhibitory neurotransmitter GABA.
They play a key role in the central nervous system and they are also
the targets for a variety of clinically important therapeutic drugs,
such as benzodiazepines, barbiturates and neuroactive steroids.
The anaesthetic action of endogenous steroids was first observed in
1941 [1] and their ability to enhance neuronal inhibition via the
GABAA receptor was subsequently demonstrated [2,3]. One of the
most potent neurosteroids in this regard is allopregnanolone 1
which has potential therapeutic applications as an anaesthetic [4].
However, the steroid-mediated potentiation of GABAA receptors is
complex and has been clarified only very recently. Indeed, there is
now direct evidence that neurosteroids bind multiple distinct
binding sites on the GABAA receptors and two of them have been
precisely located on the receptor by selective mutation studies [5].
a
b
a
b
2. Results and discussion
Our initial efforts focused on introducing substituents on the
aromatic ring of 17-PA. We decided first to introduce a fluorine
atom in the para- and meta-positions on the phenyl ring. To this
end, the analogues 4–5 were prepared by a modification of the
previous route to 17-PA [6].
4-Fluorophenyllithium was prepared by
a metal-bromine
exchange reaction of 4-fluorobromobenzene with n-BuLi at
ꢀ78 8C in Et2O and was added to a solution of androsterone 3 in
THF to generate (3a,5a,17b)-17-( p-fluorophenyl)androstane-
3,17-diol 4 in a modest yield after purification. The formation of
a strongly UV-active compound after leaving 4 in CHCl3 for a few
days was an indication that the tertiary hydroxyl group was not
stable under acidic conditions and was prone to elimination.
* Corresponding author. Tel.: +44 1334 467176; fax: +44 1334 463808.
E-mail addresses: do1@st-and.ac.uk, do1@st-andrews.ac.uk (D. O’Hagan).
Therefore, compound
4 was subjected to a pTSA-catalysed
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.03.004

882
G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
Scheme 1. Reagents and conditions: (a) 4-Fluorobromobenzene, n-BuLi, Et2O, ꢀ78 to 25 8C, 12 h, 40%; (b) pTSA, DCM, reflux, 4 h, 60%.
dehydration, which generated 5 in a 60% yield. Accordingly the
synthesis of the para-fluoro analogue of 17-PA 5 (Scheme 1) could
be reduced to two straightforward steps and is a more direct
approach than the published route to 17-PA [6].
para-fluorophenyl steroid 4. It seems that the meta- fluorine atom
inductively destabilises a developing carbocation at C [17] and
promotes the rearrangement whereas the para-fluorine in 5
provides mesomeric stabilisation and promotes a straightforward
E1-elimination.
The synthesis of the meta-fluoro analogue of 17-PA was
attempted following the sequence described above for the
preparation of 5. Intermediate 6 was prepared by reaction of 3-
fluorophenyllithium with androsterone. However, the tertiary
hydroxyl group in 6 proved more resistant to elimination under
acidic conditions than that experienced for the para-fluorophenyl
steroid 4. More forcing conditions (i.e. two equivalents of pTSA and
heating under reflux of DCM for 5 h) were necessary to achieve
complete dehydration of 6 but in this case, a mixture of two
isomeric products was obtained, 7 (major) and 8 (minor) as
illustrated in Scheme 2.
In the event the meta-fluoro analogue
8 of 17-PA was
successfully obtained by following the published route to 17-PA
[6]. Treatment of 6 with acetic anhydride generated acetate 9 and
subsequent dehydration of the tertiary alcohol and then hydrolysis
of the acetate, furnished 8 in 15% overall yield (Scheme 2).
The synthesis of the meta-difluorophenyl analogue was also
addressed, again starting with a metal exchange reaction of 3,5-
difluorobromobenzene 11 with n-BuLi (Et2O, ꢀ78 8C) and then
addition to androsterone 3. In our hands, this reaction gave a
complex mixture from which compounds 12 and 13 could be
identified by NMR and mass spectrometry, but they were not
purified. The increased acidity of the hydrogen atom ortho to the
This rearrangement to 7 has precedent in related steroids [7–
12]. The reactivity of meta-6 is noticeably different to that of the
Scheme 2. Preparation of 8 and formation of 7 by Wagner–Meerwein rearrangement under acidic conditions. Reagents and conditions: (a) 3-fluorobromobenzene, n-BuLi,
Et2O, ꢀ78 8C to 25 8C, 15 h, 31%; (b): pTSA (2 eq), DCM, 40 8C, 5 h, 52%; (c) Ac2O, pyridine, DMAP, 25 8C, 15 min, 80%; (d) MsCl, Et3N, CH2Cl2, 0 8C, 45 min, 67%; (e) NaOH, H2O,
MeOH, 65 8C, 1 h, 90%.

G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
883
Scheme 3. The combined electron withdrawing effect of the two fluorine atoms render the ortho hydrogen susceptible to exchange, leading to a mixture of 12 and 13.
fluorine atoms clearly results in a competing lithium-hydrogen
exchange, leading to a mixture of 1,3-difluorophenyl-5-lithium 14
and 1,3-difluorophenyl-2-lithium 15 giving rise to product
mixture of 12 and 13 after reaction with androsterone (Scheme
3). Generally, fluorinated phenyllithiums are stable only at low
temperature and in the case of ortho-fluorophenyllithiums, LiF
elimination occurs above ꢀ50 8C to generate benzynes [13–16].
Thus this proved to be an inefficient reaction.
The striking difference in the elimination behaviour between 4
and 6 prompted us to investigate the effects of electron-donating
groups on the aromatic ring, with the idea that they will favour
dehydration of the tertiary alcohol. To this end, para-methylphenyl
17 and para-methoxyphenyl 19 derivatives were prepared by the
two-step sequence show in Scheme 4.
(19) in 90% yield, and there was no evidence of any rearranged
product in this case.
In summary we have developed
procedure for the preparation of the p-fluoro-, p-methyl-17 and
p-methoxyl 19 analogues of 17-PA, development on the
a convenient two-step
a
published [6] four-step route to 17-PA in those cases. However,
in circumstances where significant rearrangement occurs during
tertiary alcohol dehydration, then product ratios can be biased
against the desired product and separation of the isomers is
difficult. Therefore, the four-step procedure e.g. to generate the
meta-fluoro analogue 8, is advantageous.
It is tempting to correlate the extent of rearranged product to
the Hammett parameter of the substituent (Table 1).
Table
1 indicates that the more electron-donating the
As anticipated E1 elimination was promoted by both of these
donors and dehydration of 16 with a catalytic amount of pTSA in
DCM resulted in an efficient conversion to (3a,5a)-(17-p-
toluene)androst-16-en-3-ol 17, which was recovered in good
yield (71%) with recovery of the rearranged product (5%) as a minor
component. In the case of the para-methoxyl analogue it is
noteworthy that the tertiary alcohol 18 could not be held in
solution at all and dehydrated rapidly, consistent with the
increased donor ability of the p-methoxyl group. Dehydration of
substituent, then E1 elimination is promoted and methyl
migration is suppressed. Although the Hammett parameter of
fluorine in the para-position of an aromatic ring is positive, it
appears from Table 1 that it acts to stabilise the carbocation at C
[17] of 4 similar to that of para-hydrogen in 20. In fact, it is
recognised by both theoretical and experimental observations
that para-fluorine has an ability to stabilise a benzylic positive
charge due, to its albeit limited
p-donor ability which overcomes
the –I effect [18–20]. Conversely at the meta-position in 6, only a –I
18 furnished (3
a
,5
a
)-17-( p-methoxyphenyl)androst-16-en-3-ol
effect is observed.
Scheme 4. Reagents and conditions: (a) 4-bromotoluene (R = CH3) or 4-bromoanisole (R = OCH3), n-BuLi, Et2O, RT, 12 h; (b) pTSA, DCM, RT.

884
G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
Table 1
Influence of the aromatic substituent on dehydration under acidic conditions
Structure
% Of rearranged product
s
ꢃ75
+0.34
30
0
15
ꢃ5
0
+0.06 (or +0.15) [17]
ꢀ0.17
ꢀ0.29
Finally to add some structural diversity in this series of 17-PA
analogues, hydrogenation of the double bond was explored. In this
event, the para-methyl 17 and para-methoxyl 19 analogues of 17-
PA were hydrogenated using palladium on carbon as a catalyst.
This furnished the saturated compounds 21 and 22 in good yields
and as single stereoisomers (Scheme 5). The stereo-chemistry at C
[17] was confirmed by 1H NMR-NOESY experiments on 21, which
clearly indicated that the protons of the C [18] methyl group are
close to the aromatic ring protons and are not syn to the methine
hydrogen –H [17].
A set of seven analogues of 17-PA, bearing different substituents
on the aromatic ring has been prepared. These compounds are
currently under investigation as neurosteroid antagonists on
GABAA receptors, although preliminary assays have been con-
founded by solubility problems, similar to that experienced for 17-
PA. However, the solubility problems of 17-PA in the original
assays [6] have recently been partially addressed by dissolution of
rected. Optical rotations were determined using
a A-1000
polarimeter (Optical Polarimeter Ltd.) [ values are measured
a
]
D
at 589 nm and given in 10ꢀ1deg cm2 gꢀ1. Elemental analyses were
carried out on a CE instrument EA 1110 CHNS analyser. IR spectra
were recorded on a PerkinElmer Spectrum GX FT-IR system as KBr
disc or as thin film on NaCl plates.
3.2. (3a,5a,17b)-17-( p-Fluorophenyl)androstane-3,17-diol (4)
n-BuLi (3.8 cm3, 2.5 M in hexane, 9.5 mmol) was added at
ꢀ78 8C under N2 to a solution of 4-fluoro-bromobenzene (1.1 cm3,
10.0 mmol) in dry diethyl ether (10 cm3). The mixture was stirred
for 3 h at ꢀ78 8C and then 3 h at ꢀ40 8C. The solution was then
added dropwise via cannula at ꢀ40 8C to a solution of androsterone
(300 mg, 1.0 mmol) in dry THF (15 cm3). The reaction mixture was
stirred for 8 h at ꢀ40 8C and the temperature was allowed to warm
to RT over 12 h. A saturated solution of NH4Cl (10 cm3) was added
and the organic phase was extracted into EtOAc (3 ꢁ 50 cm3). The
combined organic extracts were dried and evaporated and the
product was purified over silica gel (hexane/EtOAc 6:1) to give
compound 4 as a colourless solid (158 mg, 40%).
the steroid with
b-cyclodextrins [21].
3. Experimental
Mp: 173–176 8C (from CHCl3); ½a D20
þ 18:0 (c 1.5, CHCl3); nmax
ꢂ
3.1. General experimental procedures
(KBr plate)/cmꢀ1 3464 (br), 2932, 2855, 1603, 1508, 1226, 1162,
1075, 1016, 1005, 832; dH (300 MHz, CDCl3) 7.23 (2 H, dd, J = 5.6 Hz,
All moisture sensitive reactions were carried out under a
positive pressure of nitrogen. Solvents were dried prior to use and
column chromatography was performed using silica gel 60 (40–
J = 8.8 Hz, Ar-H), 6.91 (2 H, dd, J = 8.8 Hz, J = 8.8 Hz, Ar-H), 3.94–3.99
(1 H, m, C3H), 2.24 (1 H, ddd, J = 5.2 Hz, J = 9.7 Hz, J = 14.7 Hz, C16HA),
1.93–2.05 (1 H, m, C16HB), 0.72–1.77 (20 H, m), 0.95 (3 H, s, C18H3),
0.67 (3 H, s, C19H3); 0.20–0.39 (2 H, m);
dC (75 MHz, CDCl3) 162.1 (d,
J = 245.2 Hz, Ar-F), 142.1 (d, J = 3.1 Hz, Ar), 129.3 (2 ꢁ C, d, J = 7.8 Hz,
Ar), 114.3 (2 ꢁ C, d, J = 20.9 Hz, Ar), 86.1 (C17), 66.8 (CH), 54.1 (CH),
49.5 (CH), 47.0 (C13), 39.4 (CH), 39.1 (CH2), 36.6 (CH), 36.4 (C10), 36.1
(CH2), 33.9 (CH2), 32.4 (CH2), 32.0 (CH2), 29.3 (CH2), 28.8 (CH2), 24.6
63
mm) from Apollo Scientific Ltd. High-resolution mass spectro-
metry was performed on a Waters LCT or GCT time-of-flight mass
spectrometer. NMR spectra were recorded on either Bruker AV-300
(1H at 300.06 MHz, 13C at 75.45 MHz, 19F at 282.34 MHz), or Bruker
AV-500 (1H at 499.90 MHz, 19F at 470.33 MHz). Chemical shifts
d
are reported in parts per million (ppm) and quoted relative to
internal standard Me4Si for 1H and 13C and to external standard
CFCl3 for 19F. Melting points were measured using a GallenKamp
Griffin MPA350.BM2.5 melting point apparatus and are uncor-
(CH2), 20.7(CH2), 15.2 (CH3), 11.5 (CH3);
d
F (282 MHz, CDCl3) ꢀ117.0
(1 F, tt, J = 5.4 Hz, J = 8.6 Hz); m/z (+ES), found (M + Na+): 409.2517,
C25H35O2NaF requires 409.2519 (ꢀ0.4 ppm).
Scheme 5. Reagents and conditions: (a) Pd/C, H2 (1 atm), EtOAc, 91–93%.

G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
885
3.3. (3
a
,5
a
)-17-( p-Fluorophenyl)androst-16-en-3-ol (5)
The product was extracted into DCM (2 ꢁ 20 cm3), the combined
organic extracts were dried and the solvent was evaporated under
reduced pressure. The product was purified over silica gel (hexane/
EtOAc 10:1) to give title compound 7 as a colourless oil (25 mg,
52%).
p-Toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) was
added at RT to a solution of (3 ,5 ,17 )-17-( p-fluorophenyl)an-
drostane-3,17
-diol 4 (120 mg, 0.31 mmol) in dry DCM (20 cm3).
a
a
b
b
The reaction solution was heated under reflux for 4 h and stirred at
RT for 2 h. The reaction solution was washed with a 10% solution of
NaHCO3 (10 cm3) and the organic phase was extracted into diethyl
ether (2 ꢁ 40 cm3). The combined organic extracts were dried and
the solvent was removed under reduced pressure. The residue was
purified over silica gel (hexane/EtOAc 8:1) to give title compound 5
as a colourless solid (65 mg, 57%).
dH (500 MHz, CDCl3) 7.23 (1 H, ddd, J = 6.4 Hz, J = 8.0 Hz,
J = 8.0 Hz, Ar-H), 7.03 (1 H, ddd, J = 2.0 Hz, J = 2.0 Hz, J = 7.9 Hz, Ar-
H), 6.95 (1 H, ddd, J = 2.0 Hz, J = 2.0 Hz, J = 11.1 Hz, Ar-H), 6.84 (1 H,
ddd, J = 2.5 Hz, J = 8.3 Hz, J = 8.4 Hz, Ar-H), 4.06–4.08 (1 H, m, C3H),
2.32–2.40 (1 H, m, C15HA), 2.12–2.21 (2 H, m, C15HB + C8H), 1.80–
2.02 (5 H, m), 1.04–1.77 (14 H, m), 1.40 (3 H, C18H3), 0.78 (3 H,
C19H3); dC (75 MHz, CDCl3) 163.0 (d, J = 244.2 Hz, Ar), 152.0 (d,
J = 6.2 Hz, Ar), 139.9 (C14), 139.6 (C13), 129.3 (d, J = 8.2 Hz, Ar), 121.6
(d, J = 2.3 Hz, Ar), 113.0 (d, J = 21.4 Hz, Ar), 112.1 (d, J = 21.2 Hz, Ar),
66.6 (C3), 53.1 (C17), 51.8 (C9), 42.2 (C16), 39.1 (C5), 36.9 (C8), 36.1
(C10), 35.7 (C4), 31.9 (C1), 31.5 (C7), 30.5 (C15), 29.0 (C6 + C2), 24.2
Mp: 182–187 8C (from CHCl3); ½a D18
þ 18:0 (c 1.5, CHCl3); nmax
ꢂ
(KBr plate)/cmꢀ1 3332 (br), 2929, 2858, 1601, 1505, 1442, 1230,
1218, 1034, 1005, 810; dH (300 MHz, CDCl3) 7.28–7.33 (2 H, m, Ar-
H), 6.94–7.00 (2 H, m, Ar-H), 5.83 (1 H, dd, J = 1.8 Hz, J = 3.2 Hz,
C16H), 4.03–4.07 (1 H, m, C3H), 2.19 (1 H, ddd, J = 3.3 Hz, J = 6.2 Hz,
J = 15.4 Hz, C15HA), 1.92–2.04 (2 H, m), 0.73–1.77 (18 H, m), 0.99 (3
H, s, C18H3), 0.83 (3 H, s, C19H3); dC (75 MHz, CDCl3) 162.3 (d,
J = 245.4 Hz, Ar), 154.3 (C17), 133.9 (d, J = 3.2 Hz, Ar), 128.6 (2 ꢁ C,
d, J = 7.7 Hz, Ar), 127.5 (C16), 115.3 (2 ꢁ C, d, J = 21.1 Hz, Ar), 67.0
(CH), 58.0 (CH), 55.0 (CH), 47.8 (C13), 39.7 (CH), 36.7 (C10), 36.3
(CH2), 35.9 (CH2), 34.5 (CH), 32.4 (CH2), 32.2 (CH2), 31.9 (CH2), 29.4
(C18), 22.9 (C12), 22.2 (C11), 10.7 (C19);
d
F (282 MHz, CDCl3) ꢀ114.3
(1 F, ddd, J = 6.3 Hz, J = 8.5 Hz, J = 11.2 Hz); m/z (+CI), found MH+:
369.2594, C25H34OF requires 369.2594 (+0.2 ppm).
3.6. (3a,5a,17b)-17-(m-Fluorophenyl)androstane-3,17-diol, 3-
acetate (9)
(CH2), 28.9 (CH2), 21.2 (CH2), 17.1 (CH3), 11.6 (CH3);
d
F (282 MHz,
Ac2O (0.2 cm3) and 4-DMAP (8 mg) were added to a solution of
,5 ,17 )-17-(m-fluorophenyl)androstane-3,17-diol 6 (62 mg,
CDCl3) ꢀ116.7 (1 F, tt, J = 5.5 Hz, J = 8.7 Hz); m/z (+CI), found MH+:
(3a
a
b
369.2585, C25H34OF requires 369.2594 (ꢀ2.3 ppm).
0.16 mmol) in pyridine (0.5 cm3). The mixture was stirred at RT for
15 min and poured into 10% NaHCO3 (8 cm3). After further stirring
for 20 min, the product was extracted into EtOAc (3 ꢁ 20 cm3). The
combined organic extracts were dried over MgSO4 and evaporated
under reduced pressure. The product was purified over silica gel
(hexane/EtOAc 10:1) to give compound 9 as a colourless solid
(55 mg, 80%).
3.4. (3a,5a,17b)-17-(m-Fluorophenyl)androstane-3,17-diol (6)
n-BuLi (2.0 cm3, 2.5 M in hexane, 5.0 mmol) was added at
solution of 3-fluoro-bromobenzene
ꢀ78 8C under N2 to
a
(0.55 cm3, 5.0 mmol) in dry diethyl ether (5 cm3). The mixture
was stirred for 30 min at ꢀ78 8C and added dropwise via cannula
over 10 min to a solution of androsterone (300 mg, 1.0 mmol) in
dry THF (20 cm3). The reaction mixture was stirred 3 h at ꢀ78 8C
and the temperature was allowed to warm to RT over 15 h. A
saturated solution of NH4Cl (10 cm3) was added and the organic
phase was extracted into EtOAc (3 ꢁ 50 cm3). The combined
organic extracts were washed with brine and dried. After
evaporation of the solvent, the product was purified over silica
gel (hexane/EtOAc 6:1) to give compound 6 as a colourless solid
(125 mg, 31%).
Mp: 195–197 8C (from CHCl3); dH (300 MHz, CDCl3) 6.92–7.31
(4 H, Ar-H), 4.93–4.98 (1 H, m, C3H), 2.34 (1 H, ddd, J = 5.3 Hz,
J = 9.7 Hz, J = 14.5 Hz, C16HA), 2.09 (1 H, ddd, J = 4.2 Hz, J = 12.4 Hz,
J = 14.4 Hz, C16HB), 1.99 (3 H, s, CH3CO2), 0.57–1.94 (19 H, m), 1.04
(3 H, s, C18H3), 0.77 (3 H, s, C19H3), 0.31–0.51 (2 H, m);
dC (75 MHz,
CDCl3) 171.1 (CO2), 162.6 (d, J = 244.3 Hz, Ar-F), 149.5 (d, J = 6.3 Hz,
Ar), 128.9 (d, J = 8.1 Hz, Ar), 123.4 (d, J = 2.4 Hz, Ar), 115.0 (d,
J = 22.1 Hz, Ar), 113.9 (d, J = 21.0 Hz, Ar), 86.3 (C17), 70.5 (CH), 54.0
(CH), 49.5 (CH2), 47.3 (C13), 40.3 (CH), 39.1 (CH2), 36.6 (CH), 36.2
(C10), 34.0 (CH2), 33.2 (CH2), 33.1 (CH2), 31.9 (CH2), 28.6 (CH2), 26.4
(CH2), 24.7 (CH2), 21.9 (CH3CO2), 20.7 (CH2), 15.3 (CH3), 11.7 (CH3);
dF (282 MHz, CDCl3) ꢀ114.6 (1 F, ddd, J = 6.1 Hz, J = 8.4 Hz,
J = 11.1 Hz).
Mp: 182–188 8C (from hexane/EtOAc); ½a D20
þ 25:3 (c 0.4,
ꢂ
CHCl3); nmax (KBr plate)/cmꢀ1 3422 (br), 2926, 2854, 1613,
1586, 1437, 1262, 1096, 1016, 804; dH (300 MHz, CDCl3) 6.92–
7.45 (4 H, m, Ar-H), 3.95–4.01 (1 H, m, C3H), 2.33 (1 H, ddd,
J = 5.3 Hz, J = 9.7 Hz, J = 14.4 Hz, C16HA), 2.08 (1 H, ddd, J = 4.4 Hz,
J = 12.5 Hz, J = 14.4 Hz, C16HB), 0.53–1.87 (20 H, m), 1.03 (3 H, s,
3.7. (3a,5a)-17-(m-Fluorophenyl)androst-16-en-3-ol acetate (10)
C18H3), 0.76 (3 H, s, C19H3), 0.29–0.49 (2 H, m);
d
C (75 MHz, CDCl3)
Et3N (0.2 cm3) and MsCl (60
L, 0.77 mmol) were added at 0 8C
solution of (3 ,5 ,17b)-17-(m-fluorophenyl)androstane-
m
162.6 (d, J = 244.2 Hz, Ar-F), 149.5 (d, J = 6.4 Hz, Ar), 128.9 (d,
J = 8.1 Hz, Ar), 123.4 (d, J = 2.4 Hz, Ar), 115.0 (d, J = 22.1 Hz, Ar),
113.9 (d, J = 21.1 Hz, Ar), 86.3 (C17), 66.8 (CH), 54.1 (CH), 49.5 (CH),
47.2 (C13), 39.4 (CH), 39.1 (CH2), 36.6 (CH), 36.4 (C10), 36.2 (CH2),
34.0 (CH2), 32.4 (CH2), 32.0 (CH2), 29.3 (CH2), 28.8 (CH2), 24.7 (CH2),
to
a
a
a
3,17-diol, 3-acetate 9 (50 mg, 0.12 mmol) in dry DCM (5 cm3).
The solution was stirred for 45 min at 0 8C and DCM was removed
under reduced pressure. The crude product was purified over silica
gel (hexane/EtOac 15:1) to give compound 10 as a colourless solid
(32 mg, 67%).
20.7 (CH2), 15.3 (CH3), 11.6 (CH3);
d
F (282 MHz, CDCl3) ꢀ114.6 (1 F,
ddd, J = 6.1 Hz, J = 8.4 Hz, J = 11.0 Hz); m/z (+ES), found (M + Na+):
409.2512, C25H35O2NaF requires 409.2519 (ꢀ1.8 ppm).
Mp: 148–150 8C (from CHCl3); dH (300 MHz, CDCl3) 7.20–7.28
(1 H, m, Ar-H), 7.12–7.16 (1 H, m, Ar-H), 7.03–7.09 (1 H, m, Ar-H),
6.87–6.94 (1 H, m, Ar-H), 5.94 (1 H, dd, J = 1.8 Hz, J = 3.2 Hz, C16H),
5.00–5.04 (1 H, m, C3H), 2.21 (1 H, ddd, J = 3.3 Hz, J = 6.3 Hz,
J = 15.7 Hz, C15HA), 1.94–2.08 (2 H, m), 2.06 (3 H, s, CH3CO2), 0.78–
3.5. 17a-(m-Fluorophenyl)-17b-methyl-5a-androsten-13-3a-ol (7)
p-Toluenesulfonic acid monohydrate (40 mg, 0.26 mmol) was
added at RT to a solution of (3 ,5 ,17 )-17-(m-fluorophenyl)an-
1.78 (17 H, m), 1.01 (3 H, s, C18H3), 0.85 (3 H, s, C19H3);
dC (75 MHz,
a
a
b
CDCl3) 171.2 (CH3CO2), 163.1 (d, J = 244.4 Hz, Ar-F), 154.2 (d,
J = 1.9 Hz, C17), 140.0 (d, J = 7.7 Hz, Ar), 129.8 (d, J = 8.4 Hz, Ar),
128.9 (C16), 122.7 (d, J = 2.6 Hz, Ar), 113.8 (d, J = 21.5 Hz, Ar), 113.8
(d, J = 21.1 Hz, Ar), 70.5 (CH), 58.0 (CH), 54.9 (CH2), 47.8 (C13), 40.6
drostane-3,17-diol 6 (50 mg, 0.13 mmol) in dry DCM (10 cm3). The
mixture was heated under reflux for 5 h, cooled down to RT, 1 M
NaHCO3 (5 cm3) was added and the solution was stirred for 15 min.

886
G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
(CH), 36.4 (C10), 35.8 (CH2), 34.4 (CH), 33.3 (CH2), 33.1 (CH2), 32.2
(CH2), 31.9 (CH2), 28.7 (CH2), 26.5 (CH2), 22.0 (CH3CO2), 21.2 (CH2),
17.2 (CH3), 11.7 (CH3); dF (282 MHz, CDCl3) ꢀ114.3 (1 F, ddd,
J = 6.1 Hz, J = 8.6 Hz, J = 10.6 Hz); m/z (+ES), found (M + Na+):
433.2516, C27H35O2FNa requires 433.2519 (ꢀ0.7 ppm).
combined organic extracts were dried and the solvent was
removed under reduced pressure. The residue was purified over
silica gel (hexane/EtOAc 7:1) to give title compound 17 as a
colourless solid (95 mg, 71%).
Mp: 182–185 8C (from CHCl3); ½a D18
þ 25:1 (c 1.5, CHCl3);
ꢂ
(Found: C, 85.41; H, 10.38%, C26H36O requires C, 85.66; H, 9.95%);
3.8. (3
a
,5a
)-17-(m-Fluorophenyl)androst-16-en-3-ol (8)
nmax (KBr plate)/cmꢀ1 3333 (br), 3048, 2924, 2846, 1508, 1443,
1368, 1357, 1001, 794; dH (300 MHz, CDCl3) 7.26 (2 H, d, J = 8.0 Hz),
5 N NaOH (0.15 cm3) was added at RT to a solution of (3
a
,5a
)-
7.10 (2 H, d, J = 8.0 Hz), 5.84 (1 H, dd, J = 1.8 Hz, J = 3.2 Hz, C16H),
4.03–4.07 (1 H, m, C3H), 2.33 (3 H, s, PhCH3), 2.18 (1 H, ddd,
J = 3.3 Hz, J = 6.3 Hz, J = 15.4 Hz, C15HA), 1.92–2.07 (2 H, m), 0.77–
17-(m-fluorophenyl)androst-16-en-3-ol acetate 10 (21 mg,
0.05 mmol) in MeOH (2.5 cm3). The mixture was heated under
reflux for 1 h and cooled to RT. Water (2 cm3) was added and the
product was extracted into DCM (3 ꢁ 10 cm3). The combined
organic extracts were dried and the solvent removed under
reduced pressure. The product was purified over silica gel (hexane/
EtOAc 9:1) to give title compound 8 as a colourless solid (17 mg,
90%).
Mp: 179–184 8C (from CHCl3); dH (300 MHz, CDCl3) 7.20–7.27
(1 H, m, Ar-H), 7.12–7.15 (1 H, m, Ar-H), 7.03–7.08 (1 H, m, Ar-H),
6.87–6.94 (1 H, m, Ar-H), 5.93 (1 H, J = 1.8 Hz, J = 3.1 Hz, C16H),
4.04–4.07 (1 H, m, C3H), 2.21 (1 H, ddd, J = 3.3 Hz, J = 6.2 Hz,
J = 15.6 Hz, C15HA), 1.94–2.01 (2 H, m), 0.75–1.78 (18 H, m), 1.01 (3
H, s, C18H3), 0.84 (3 H, s, C19H3); dC (75 MHz, CDCl3) 163.1 (d,
J = 244.5 Hz, Ar-F), 154.3 (d, J = 2.0 Hz, C17), 140.0 (d, J = 7.8 Hz, Ar),
129.8 (d, J = 8.5 Hz, Ar), 128.9 (C16), 122.7 (d, J = 2.6 Hz, Ar), 113.8
(d, J = 21.5 Hz, Ar), 113.7 (d, J = 21.1 Hz, Ar), 67.0 (CH), 58.0 (CH),
55.0 (CH), 47.8 (C13), 39.7 (CH), 36.7 (C10), 36.3 (CH2), 35.8 (CH2),
34.4 (CH), 32.4 (CH2), 32.2 (CH2), 31.9 (CH2), 29.4 (CH2), 28.9 (CH2),
1.77 (18 H, m), 1.00 (3 H, s, C18H3), 0.83 (3 H, s, C19H3);
dC (75 MHz,
CDCl3) 154.7 (C17), 136.3 (Ar), 134.5 (Ar), 128.9 (2 ꢁ C, Ar), 126.6
(2 ꢁ C, Ar), 126.4 (C16), 66.6 (C3), 57.7 (C14), 54.7 (C9), 47.4 (C13),
39.4 (C5), 36.3 (C10), 35.9 (C4), 35.6 (C12), 34.1 (C8), 32.1 (C1), 31.9
(C7), 31.5 (C15), 29.1 (C2), 28.6 (C6), 21.1 (PhCH3), 20.8 (C11), 16.8
(C18), 11.2 (C19); m/z (+CI), found MH+: 365.2856, C26H37O requires
365.2844 (3.0 ppm).
3.11. (3a,5a,17b)-17-( p-Methoxyphenyl)androstane-3,17-diol (18)
n-BuLi (2 cm3, 2.5 M in hexane, 5.0 mmol) was added at RT
under N2 to a solution of 4-bromoanisole (0.63 cm3, 5.0 mmol) in
dry diethyl ether (5 cm3). The mixture was stirred for 2 h at RT and
added dropwise via cannula to a solution of androsterone (300 mg,
1.0 mmol) in dry THF (10 cm3). The reaction mixture was stirred at
RT for 15 h. A 10% solution of NH4Cl (10 cm3) was added and the
organic phase was extracted into Et2O (3 ꢁ 40 cm3). The combined
organic extracts were dried and after evaporation of the solvent
under reduced pressure, the product was purified over silica gel
(hexane/EtOAc 5:1) to give compound 18 as a white foam (122 mg,
30%). Note: 18 was not stable in solution and rapidly dehydrated to
19.
21.2 (CH2), 17.2 (CH3), 11.6 (CH3);
d
F (282 MHz, CDCl3) ꢀ114.3 (1 F,
ddd, J = 6.2 Hz, J = 8.7 Hz, J = 10.7 Hz); m/z (+CI), found MH+:
369.2599, C25H34OF requires 369.2594 (+1.3 ppm).
3.9. (3a,5a,17b)-(17-p-Toluene)androstane-3,17-diol (16)
dH (300 MHz, CDCl3) 7.27 (2 H, J = 9.0 Hz, Ar-H), 6.86 (2 H, d,
J = 9.0 Hz, Ar-H), 3.97–4.01 (1 H, m, C3H), 3.82 (3 H, s, OCH3), 2.33 (1
H, ddd, J = 5.2 Hz, J = 9.8 Hz, J = 14.6 Hz, C16HA), 2.02–2.13 (1 H, m,
C16HB), 0.81–1.83 (20 H, m), 1.03 (3 H, s, C18H3), 0.76 (3 H, s, C19H3);
n-BuLi (2 cm3, 2.5 M in hexane, 5.0 mmol) was added at RT
under N2 to a solution of p-bromotoluene (860 mg, 5.0 mmol) in
dry diethyl ether (5 cm3). The mixture was stirred for 2 h at RT and
added dropwise via cannula to a solution of androsterone (262 mg,
0.9 mmol) in dry THF (10 cm3). The reaction mixture was stirred
for 15 h at RT and then a 10% solution of NH4Cl (10 cm3) was added.
The reaction mixture was extracted into EtOAc (3 ꢁ 40 cm3) and
the combined extracts were washed with brine and dried. After
evaporation of the solvent under reduced pressure, the product
was purified over silica gel (hexane/EtOAc 7:1) to give compound
16 as a colourless solid (148 mg, 43%).
0.34–0.52 (2 H, m); dC (75 MHz, CDCl3) 158.7 (Ar), 138.5 (Ar), 128.8
(2 ꢁ C, Ar), 112.9 (2 ꢁ C, Ar), 86.1 (C17), 66.9 (CH), 55.6 (OCH3), 54.1
(CH), 49.5 (CH2), 47.1 (C13), 39.5 (CH), 39.1 (CH2), 36.6 (CH), 36.5
(C10), 36.2 (CH2), 34.0 (CH2), 32.4 (CH2), 32.1 (CH2), 29.4 (CH2), 28.9
(CH2), 24.7 (CH2), 20.7 (CH2), 15.3 (CH3), 11.6 (CH3); m/z (+ES),
found (M + Na+): 421.2730, C26H38O3Na requires 421.2719
(+2.7 ppm).
Mp: 173–174 8C (from CHCl3);
d
H (500 MHz, CDCl3) 7.22 (2 H, d,
3.12. (3a,5a)-17-( p-Methoxyphenyl)androst-16-en-3-ol (19)
J = 8.0 Hz, Ar-H), 7.11 (2 H, d, J = 8.0 Hz, Ar-H), 3.94–3.96 (1 H, m,
C3H), 2.29–2.35 (1 H, ddd, J = 5.2 Hz, J = 9.8 Hz, J = 14.4 Hz, C16HA),
2.33 (3 H, s, PhCH3), 2.03–2.09 (1 H, m, C16HB), 0.82–1.92 (20 H, m),
1.02 (3 H, s, C18H3), 0.74 (3 H, s, C19H3), 0.34–0.44 (2 H, m); dC
(75 MHz, CDCl3) 143.6 (Ar), 136.6 (Ar), 128.3 (2 ꢁ C, Ar), 127.6
(2 ꢁ C, Ar), 86.2 (C17), 66.8 (C3), 54.0 (C9), 49.5 (C14), 47.0 (C13), 39.4
(C5), 39.0 (C16), 36.6 (C8), 36.4 (C10), 36.2 (C4), 34.0 (C12), 32.4 (C1),
32.1 (C7), 29.3 (C2), 28.9 (C6), 24.8 (C15), 21.4 (C24), 20.7 (C11), 15.3
(C18), 11.6 (C19); m/z (+ES), found (M + Na+): 405.2766, C26H38O2Na
requires 405.2770 (ꢀ0.8 ppm).
p-Toluenesulfonic acid monohydrate (2 mg) was added at RT to
solution of (3 ,5 ,17 )-17-( p-methoxyphenyl)androstane-
a
a
a
b
3,17-diol 18 (55 mg, 0.14 mmol) in dry DCM (5 cm3). The reaction
mixture turned pink very rapidly. After 8 h the colour had
disappeared and DCM was removed under reduced pressure.
The residue was purified over silica gel (petroleum ether/diethyl
ether 3:1) to give title compound 19 as a colourless solid (47 mg,
90%).
Mp: 171–176 8C (from CHCl3); ½a D20
þ 27:4 (c 1.5, CHCl3);
ꢂ
(Found: C, 81.50; H, 9.85%, C26H36O2 requires C, 82.06; H, 9.53%);
3.10. (3
a,5
a)-(17-p-Toluene)androst-16-en-3-ol (17)
nmax (KBr plate)/cmꢀ1 3322 (br), 2924, 2846, 1600, 1508, 1443,
1362, 1253, 1242, 1175, 1108, 1035; dH (300 MHz, CDCl3) 7.30 (2 H,
p-Toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) was
added at RT to a solution of (3 ,5 ,17 )-(17-p-toluene)andros-
tane-3,17
-diol 16 (140 mg, 0.37 mmol) in dry DCM (20 cm3) and
the reaction mixture was stirred at RT for 2 days. A 10% solution of
NaHCO3 (5 cm3) was then added, the organic phase was separated
and the aqueous phase extracted into DCM (2 ꢁ 20 cm3). The
d, J = 8.8 Hz, Ar-H), 6.83 (2 H, d, J = 8.8 Hz, Ar-H), 5.79 (1 H, dd,
J = 1.7 Hz, J = 3.1 Hz, C16H), 4.02–4.06 (1 H, m, C3H), 3.80 (3 H, s,
OCH3), 2.18 (1 H, ddd, J = 3.2 Hz, J = 6.2 Hz, J = 15.3 Hz, C15HA),
1.91–2.06 (2 H, m), 0.77–1.76 (18 H, m), 0.99 (3 H, s, C18H3), 0.83 (3
a
a
b
b
H, s, C19H3); C (75 MHz, CDCl3) 158.9 (Ar), 154.7 (C17), 130.5 (Ar),
d
128.2 (2 ꢁ C, Ar), 126.0 (C16), 113.9 (2 ꢁ C, Ar), 67.0 (CH), 58.0 (CH),

G. Deniau et al. / Journal of Fluorine Chemistry 129 (2008) 881–887
887
55.7 (OCH3), 55.1 (CH), 47.8 (C13), 39.8 (CH), 36.7 (C10), 36.3 (CH2),
36.0 (CH2), 34.5 (CH), 32.5 (CH2), 32.3 (CH2), 31.8 (CH2), 29.4 (CH2),
29.0 (CH2), 21.2 (CH2), 17.1 (CH3), 11.6 (CH3); m/z (+CI), found MH+:
381.2796, C26H37O2 requires 381.2794 (+0.6 ppm).
10.01%); nmax (KBr plate)/cmꢀ1 3522 (br), 3457 (br), 2930, 2914,
1609, 1512, 1463, 1249, 1238, 1028; H (300 MHz, CDCl3) 7.12 (2 H,
d
d, J = 8.6 Hz, Ar-H), 6.82 (2 H, d, J = 8.6 Hz, Ar-H), 4.02–4.06 (1 H, m,
C3H), 3.79 (3 H, s, OCH3), 2.61 (1 H, t, J = 9.8 Hz, C17H), 1.87–2.08 (2
H, m), 0.80–1.81 (21 H, m), 0.77 (3 H, s, C19H3), 0.44 (3 H, s, C18H3);
dC (75 MHz, CDCl3) 158.2 (Ar), 133.7 (Ar), 129.9 (2 ꢁ C, Ar), 113.4
(2 ꢁ C, Ar), 67.0 (C3), 56.6 (C14 + C17), 55.6 (OCH3), 55.0 (C9), 44.5
(C13), 39.7 (C5), 38.2 (C12), 36.6 (C10), 36.4 (C8), 36.3 (C4), 32.6 (C1),
32.5 (C7), 29.4 (C2), 29.0 (C6), 26.8 (C16), 24.8 (C15), 20.9 (C11), 13.2
(C18), 11.7 (C19); m/z (+CI), found MH+: 383.2952, C26H39O2
requires 383.2950 (+0.5 ppm).
3.13. (3a,5a)-(17b-p-Toluene)androstan-3-ol (21)
Pd/C 5% (5 mg) was added to a solution of (3
a,5a)-(17-p-
toluene)androst-16-en-3-ol 17 (12 mg, 0.03 mmol) in EtOAc
(5 cm3). The mixture was stirred at RT under a positive atmosphere
of H2. After 12 h, the reaction mixture was filtered over Celite and
the solvent was removed under reduced pressure. The product was
purified over silica gel (hexane/EtOAc 6:1) to give title compound
21 as a colourless solid (11 mg, 91%).
Acknowledgements
Mp: 230–234 8C (from hexane/EtOAc); ½a D20
þ 7:4 (c 0.65,
ꢂ
We thank the University of St. Andrews for an Interdisciplinary
Studentship (GD).
CHCl3); (Found: C, 84.97; H, 10.82%, C26H38O requires C, 85.19;
H, 10.45%); nmax (KBr plate)/cmꢀ1 3289 (br), 2931, 2869, 2842,
1514, 1446, 1262, 1098, 1035, 1002, 807; dH (300 MHz, CDCl3)
7.00–7.05 (4 H, dd, Ar-H), 4.03–4.06 (1 H, m, C3H), 2.63 (1 H, t,
J = 9.9 Hz, C17H), 2.32 (3 H, s, PhCH3), 2.01–2.09 (1 H, m, C16HA),
1.88–1.96 (1 H, m, C16HB), 0.74–1.80 (21 H, m), 0.77 (3 H, s, C19H3),
References
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(1986) 1004–1007.
0.45 (3 H, s, C18H3);
dC (75 MHz, CDCl3) 138.6 (Ar), 135.7 (Ar), 129.0
(2 ꢁ C, Ar), 128.8 (2 ꢁ C, Ar), 67.0 (CH), 57.1 (C17), 56.7 (CH), 55.0
(CH), 44.6 (C13), 39.7 (CH), 38.2 (CH2), 36.6 (C10), 36.4 (CH), 36.3
(CH2), 32.6 (CH2), 32.5 (CH2), 29.4 (CH2), 29.0 (CH2), 26.6 (CH2), 24.8
(CH2), 21.4 (PhCH3), 20.9 (CH2), 13.2 (CH3), 11.7 (CH3); m/z (+CI),
found MH+: 367.2992, C26H39O requires 367.3001 (ꢀ2.4 ppm).
[4] D. Bitran, R.J. Hilvers, C.K. Kellogg, Brain Res. 561 (1991) 157–161.
[5] A.M. Hosie, M.E. Wilkins, H.M.A. da Silva, T.G. Smart, Nature 444 (2006) 486–489.
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3.14. (3
a
,5a
)-(17b
-p-Methoxyphenyl)androstan-3-ol (22)
Pd/C 5% (5 mg) was added to a solution of (3
a
,5a)-(17-p-
methoxyphenyl)androst-16-en-3-ol 19 (50 mg, 0.13 mmol) in
EtOAc (10 cm3). The mixture was stirred at RT under a positive
atmosphere of H2. After 12 h, the reaction mixture was filtered over
Celite and the solvent was removed under reduced pressure. The
product was purified over silica gel (petroleum ether/diethyl ether
2:1) to give title compound 22 as a colourless solid (47 mg, 93%).
[20] Z.B. Maksic, B. Kovacevic, D. Kovacek, J. Phys. Chem. A 101 (1997) 7446–7453.
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Morrow, Eur. J. Pharmacol. 572 (2007) 94–101.
Mp: 224–231 8C (from CHCl3); ½a D20
þ 8:0 (c 0.8, CHCl3);
ꢂ
(Found: C, 81.76; H, 10.29%, C26H38O2 requires C, 81.63; H,