Preparation of 3,17- and 3,20-difluoro-derivatives of the androst-5-ene and pregn-5-ene series

Article abstract of DOI:10.1081/SCC-200039449

Unsaturated mono- and difluorosteroids have been prepared in high yield using n-perfluorobutanesulfonyl fluoride 1. The 3,17- and 3,20-difluoro-5,6- dehydrosteroids are reported for the first time. 3-Fluoroderivatives of the androst-5-ene-17-one and 5α-an

Full text of DOI:10.1081/SCC-200039449

This article was downloaded by: [Ams/Girona*barri Lib]
On: 13 October 2014, At: 04:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Preparation of 3,17‐ and
3,20‐Difluoro‐Derivatives
of the Androst‐5‐ene and
Pregn‐5‐ene Series
Richard A. Decréau a & Charles M. Marson a
a Christopher Ingold Laboratories, Department of
Chemistry , University College London , 20 Gordon
Street, London, WC1H OAJ, UK
Published online: 10 Jan 2011.
To cite this article: Richard A. Decréau & Charles M. Marson (2004) Preparation of
3,17‐ and 3,20‐Difluoro‐Derivatives of the Androst‐5‐ene and Pregn‐5‐ene Series,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:23, 4369-4385, DOI: 10.1081/SCC-200039449
To link to this article: http://dx.doi.org/10.1081/SCC-200039449
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.

The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4369–4385, 2004
Preparation of 3,17- and 3,20-Difluoro-
Derivatives of the Androst-5-ene and
Pregn-5-ene Series
*
Richard A. Decreau and Charles M. Marson
´
Christopher Ingold Laboratories, Department of Chemistry,
University College London, London, UK
ABSTRACT
Unsaturated mono- and difluorosteroids have been prepared in high yield
using n-perfluorobutanesulfonyl fluoride 1. The 3,17- and 3,20-difluoro-
5,6-dehydrosteroids are reported for the first time. 3-Fluoroderivatives
of the androst-5-ene-17-one and 5a-androst-17-one series have been pre-
pared, and yields obtained with 1 have been compared with those reported
with other fluorinating agents.
Key Words: 3,17 and 3,20-difluorosteroids; Fluorodehtdroxylation; n-
Perfluorosulfonyl fluoride.
The importance of achieving synthesis of fluorine-containing compounds
with stereocontrol[1–4] is growing in pharmaceuticals[1,2] and bioorganic
*
´
Correspondence: Richard A. Decreau, Christopher Ingold Laboratories, Department
of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ,
UK; E-mail: chembiolmedlab@yahoo.com.
4369
DOI: 10.1081/SCC-200039449
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

´
Decreau and Marson
4370
chemistry,[5,6] where some fluorinated steroids are used as topical anti-
inflammatory agents[4] or as antitumor and antiviral agents.[1a,5]
Fluorinated steroids may be prepared in moderate yield from the reaction
of alcohols with costly reagents like diethylaminosulfur trifluoride
(DAST)[6a–c] or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine (Yarovenko
reagent).[7a–b] Also, two-step procedures involving displacement of tosylates
or triflates with metal fluorides or tetrabutylammonium fluoride,[8] or reaction
of phenyl tetrafluorophosphorane with silyl ethers of the corresponding alco-
hols are reported.[9] Furthermore, a source of unsolvated fluoride ions can be
provided by an anionic exchange resin used as a polymer-supported
reagent.[10]
Fluorodehydroxylation using n-perfluorobutanesulfonyl fluoride
1
(Fig. 1), in the presence of DBU, was previously reported by Bennua-
Skalmowski and Vorbru¨ggen[11a] for the conversion of 5a-cholestan-3b-ol
and its 3a-epimer into the 3a- and 3b-fluoro derivatives, and by our group
for the preparation of a variety of unsaturated 3-fluorosteroids of defined
stereochemistry.[11b] We showed that fluorodehydroxylation proceeded with
retention of configuration for 5,6,16,17-tetradehydro-3b-sterols, but with
inversion for their 3a-analogues, as it did for several 16,17-dehydro-
sterols.[11b] The convenience of handling 1 and its rapidity of reaction was
shown previously[11a,b] and merits further study in the preparation of organo-
fluorine compounds.
Here, we describe the action of 1 on some dihydroxy steroids, pregn-5-ene-
3b,20(R)-diol, androst-5-ene-3b,17b-diol, 5a-androst-3b-ol-17-one, and
androst-5-ene-3b-ol-17-one. A comparison with reported yields using other
fluorinating agents is presented. It is shown that n-perfluorobutanesulfonyl
fluoride 1 can lead to efficient incorporation of fluorine with retention. Fur-
thermore, while several works reported that fluorine had been introduced at
positions 3, 4, 6, 16, 20, and 21[8c,12a–b] of the steroid moiety, this is, to our
knowledge, the first report of steroid fluorinated at position 17.
Certain C19-5,6-dehydrosteroids and C21-5,6-dehydrosteroids are direct
or indirect contributors to pig and human body malodor.[13a–d] To our knowl-
edge, 3,17-difluoro-5-dehydrosteroids and 3,20-difluoro-5-dehydrosteroids
have never been described, and they are of interest in comparison with their
Figure 1. Structure of n-perfluorobutanesulfonyl fluoride 1.

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4371
3,17- and 3,20-dihydroxy analogues, in terms of odor and as potential inhibi-
tors of steroid biotransformation. This is the first report of fluorine atom intro-
duction at position 17 of the steroid moiety, although literature described other
halogen atoms introduced at this position (Cl, I).[12b]
The reaction of pregn-5-ene-3b,20-diol 2 with n-perfluorobutanesulfonyl
fluoride 1 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in dry toluene gave 3a,20-difluoro-pregn-5-ene 7 (trace) and also 3b,20-
difluoro-pregn-5-ene 8 (40%). Bis-elimination undergoes as the formation
of pregna-3,5,20-triene 3 was formed in 7% yield. Mono-elimination at
C-20 only while hydroxyl displacement is in progress at C-3 gave
3b-fluoro-pregna-5,20-diene 6 (20%), while trace amounts of the 3a-epimer
5 were detected. Elimination at C-3 and hydroxyl displacement at C-20
afford 20-fluoro-pregna-3,5-diene 4 (20%) (Table 1, Figure 2).
Determination of the ratio fluorodehydroxylation (F-compound, F): elim-
ination (alkenic compound, E) (F/E), is an indication of the efficiency of 1 to
undergo fluorodehydroxylation (Tables 2–5). This ratio is difficult to measure
for steroids 2 and 9, because two sites are present. Thus, the treatment of 2
with 1 led to pregn-3,5,17-triene 3 in 7% yield, which means 3.5% yield of
elimination is taking place at C-3, and 3.5% yield of elimination is taking
place at C-20 (Table 3, entry A).
The next reaction product, pregn-3,5-diene-20-fluoro, 4 was obtained in
20% yield, which may be interpreted as a 10% yield of elimination at C-3
and 10% yield of displacement at C-20 (entry B). The same interpretation
can be forwarded for compounds 5–6 (entries C–D) and 7–8 (entries E–F).
Entry H is obtained by adding the values from entry A through entry F.
It corresponds to the overall yield of fluorodehydroxylation (column F, entry
H, 60%) and elimination (column E, entry H, 28%), respectively, on both
sites (C-3 and C-20). The ratio fluorodehydroxylation/elimination (F/E) is
then 60%/28% ¼ 2.2 (entry I).
The reaction of androst-5-ene-3b,17b-diol 9 with 1 gave 3b,17a-
difluoro-androst-5-ene 12 (65%) and 3a,17a-difluoro-androst-5-ene 13
(5%), the product of mono-elimination 3b-fluoro-androsta-5,16-diene 11 in
trace amount, and the product of bis-elimination androst-3,5,16-triene 10
(20%) (Table 1, Figure 2).
The method described above for the determination of the F/E ratio was
applied on the reaction products 10–13 resulting from the treatment of 9 by
1 (Table 4). It led to an overall yield of displacement of 42% and an overall
yield of elimination of 26% (entry F). The F/E ratio calculated gives 42%/
26% ¼ 1.7 (entry G).
The fluoro-dehydroxylation was performed with a set of 17-one steroids
with 1 (Table 2 and Figure 2). Androst-5-ene-17-one-3b-ol 14 afforded
3b-fluoro-androst-5-ene-17-one 17 in 68% yield, while the 3a-fluoro

´
Decreau and Marson
4372
Table 1. Preparation of mono- and di-fluorosteroids bearing F-atoms at positions 3,
17, and 20 using n-perfluorobutanesulfonyl fluoride 1. Squared numbers apply for
sterol precursors.

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4373
Figure 2. Alkenic elimination products.
epimer 16 was detected in trace amount. The elimination product androst-
3,5-diene-17-one 15 (27%) was produced in 27% yield. The resulting F/E
ratio is 2.5.
When the reaction was conducted with 5a-androst-3b-ol-17-one 18, it
afforded 3a-fluoro-5a-androst-17-one 20 (43%) and a small yield of its 3b-
fluoro epimer 21 (8%), while the elimination product 5a-androst-2-ene-17-
one 19 was also formed (45%) (F/E ¼ 1.1). When the reaction was conducted
with 22, the 3a-OH epimer of 18, 3b-fluoro-5a-androst-17-one 21 was
formed in 41% yield, but no 3a-F epimer 20 was found. The elimination
product 5a-androst-2-ene-17-one 19 was formed in 52% yield (F/E ¼ 0.78).
Fluorodehydroxylation yields measured with 1 on 14, 18, 22 were com-
pared with the yields reported in the literature using other fluorodehydroxyla-
tion reagents (Table 5). Under the general procedure, the F/E ratio found for
the fluorodehydroxylation of 5a-androst-17-one-3b-ol 18 with 1 (1.1, entry A)
is more satisfactory than the one reported with tetra-n-butylphosphonium
hydrogen bifluoride (0.2, entry B), tetra-n-butyl-ammonium fluoride (0.44,
entry C), or with a mixture tetra-n-butyl-ammonium fluoride and MSF
(0.14,[14a] entry D); or tetra-ethyl-ammonium fluoride (0.25,[11b] entry E)

´
Decreau and Marson
4374
Table 2. Preparation of 3-Fluoro-17-one-steroids using n-Perfluorobutanesulfonyl
Fluoride 1.
Sterol
Products (Major one shown)
or N-2-chloro-1,2,2-trifluoroethyldiethylamine (35%, entry F).[7a] However
the ratio obtained with 1 is similar to the one reported with the anion exchange
resin (0.71 entry G),[10] or DAST (0.93, entry H);[14a] and 1 is not as
satifactory as 2-chloro-1,1,2-trifluoro-ethylamine,[6c] where 58% F-yield
was reported (entry I).

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4375
Table 3. Use of 1 as fluorodehydroxylation reagent on 2. Yields of fluorodehydroxy-
lation and elimination at C-3 and C-20 on 2 using 1, and overall F/E ratio.
Fluorodehydroxylation
(F)
Elimination (E)
Isolated
yields (%)
Entry
Steroid
C-3
C-20
C-3
C-20
A
B
C
D
E
F
3
7
20
—
—
—
10
—
—
—
20
30
3.5
10
3.5
—
4
5
0.5
20
0.25
—
—
0.25
10
—
6
7
10
Trace
40
—
—
20
30.25
—
—
8
Total
—
14
G
H
I
13.5
Total C-3 þ C-20
F/E ratio
60.25
27.50
2.2
The experiment carried out with the a-epimer 5a-androst-17-one 5a-ol
22, afforded a 0.91 F/E ratio (entry J) that is bigger than the ratios reported
in the literature, with other reagents like anion exchange resin (26:57, entry
K),[10] N-2-chloro-1,1,2-trifluoroethyl-amine (16%, entry M),[7a] or DAST
(0.16, entry L).[14b]
On androst-5-ene-17-one-3b-ol 14, the fluorodehydroxylation yield with
1 (68%, entry N) is not as high as the one reported with N-2-chloro-1,1,2-tri-
fluoroethyldiethyl-amine (78%, entry O)[7a] or DAST (91%, entry P).[14b]
After a major modification had been introduced to the general procedure
by lowering the temperature to 2408C and decreasing the injection rate
Table 4. Determination of the overall yields of displacement and
elimination obtained on 9 by treatment with 1.
F
E
Entry
Steroid
Isolated yield
C-3
C-17
C-3
C-17
A
B
C
D
E
F
10
11
12
13
20
—
6
—
—
10
—
—
—
10
10
10
—
—
16
4.9
33.8
5
17
17
2.5
25.5
2.5
19.5
Total
Total C-3 þ C-20
F/E ratio
45
26
G
1.7

´
Decreau and Marson
4376
b
b
a
a

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4377
of 1 into the solution of steroid to 1 mL/h, the ratio found for 5a-androst-17-
one 3b-ol 18 became 2.3 (entry Q); for 5a-androst-17-one 3a-ol 22 became
1.6 (entry R); and for androst-5-ene-17-one-3b-ol, 14 became 3.8 (entry S).
For the 5a-androstane series, the modifications led to better F/E ratios than
those previously reported for other reagents. However, the yields obtained
on the androst-5-ene series (14) (76%), are not as good as those reported by
Bird with DAST (91%).[14b,11b] In conclusion, 1 works more efficiently with
a-androstane compounds than androst-5-ene compounds for the fluorodehy-
droxylation at C-3.
1H NMR spectra of 17-F compounds (12–13) exhibited a characteristic
doublet at d 4.5 ppm assigned to H-17 (Figs. 3 and 4). No distinction
between the 20(S) and the 20(R) compounds has been made possible. Also,
with 20-F steroids (4, 7–8) a characteristic doublet at d 4.10 ppm was assigned
to H-20. 1H–NMR spectra of 3-fluorosteroids display a characteristic doublet
of complex multiplets around d 4.3 ppm for 3b-epimers (6, 8, 11–12), and a
doublet of multiplets at around d 4.8–5.0 ppm for the 3a-epimers (5, 7,
13)(Figs 3, 4).[8b] Difluorosteroids were obtained as an oil or as prisms with
Figure 3. 1H NMR spectrum of 3b, 17a-androst-5-ene 12.

´
Decreau and Marson
4378
Figure 4. 1H NMR spectrum of 3a, 17a-androst-5-ene 13.
lower melting points than monofluorosteroids. Similarly for 3-fluorosteroids,
the 3a-epimers have substantially lower melting points than the 3b-epimers,
which is consistent with our previous report on other steroids.[11b]
We confirm our previous observations that for 5,6-dehydro-3b-sterols,
fluorodehydroxylation proceeds with retention of configuration (presumably
by neighboring group participation).[6c,9,11b] However, inversion was observed
with 3-sterols saturated at the 5,6 position.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker AMX 300
spectrometer (operating at 300 and 75 MHz, respectively), using CDCl3 as
solvent. Chemical shifts are expressed in d (ppm) downfield of tetramethylsi-
lane. Mass spectra (EI) were recorded on a Micromass LC QUATTRO mass
spectrometer. Melting points were measured on a Bu¨chi 535 apparatus. Thin-
layer chromatography was performed on precoated silica gel; components
were detected by UV fluorescence and using iodine vapor. Androsterone,

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4379
epiandrosterone, dehydroepiandrosterone, and pregnenolone were used as
purchased. Pregn-5-ene-3b,-20-R-diol 7,[15] androst-5-ene-3b,17b-diol
11[16a–c] were prepared using procedures from the literature. Known fluoro-
1
steroids were characterized by H NMR and 13C NMR and also HRMS and
were compared against authentic standards.
General Procedure
To a stirred solution of the sterol and DBU (3 equiv.) in toluene (35 mL
per mmol of steroid) cooled to 0–58C in an ice-water bath, n-perfluorobutane-
sulfonyl fluoride 1 (Aldrich, typically 1.5 equiv. for hydroxysteroids, 3.0
equiv. for dihydroxy steroids) was introduced drop-wise over 5 min. The
mixture was then stirred for 1 h, maintaining the temperature between
0–58C using an ice-water bath. After 1 h (the ice having melted), the solvent
was evaporated, and the yellowish-orange oil was extracted with hexane
(5 ꢀ 100 mL). After evaporation of the solvent, the residue was subjected
to chromatography on silica (70 g silica per 500 mg of oil) using hexane
as eluent. Typically, dehydrosteroids eluted during the first 200–300 mL
of eluent, followed by any monofluorosteroid in the range 400–500 mL, and
lastly any difluorosteroid in the 500–600 mL portion.
Reaction of Pregn-5-ene-3b,-20-R-Diol (2) with (1)
Pregn-5-ene-3b,-20-R-diol (2) (0.362 g, 1.13 mmol) was treated with 1
(0.665 ml, 3.70 mmol) according to the general procedure. Chromatography
1
afforded first pregna-3,5,17-triene (3)[15b](0.005 g, 7%), as an oil; H NMR
(CDCl3) 5.65–5.45 (3H, m, 3,4,6-H), 4.87 (1H, d, 20-H), 2.50–0.85 (20H,
m), 1.12 (3H, s, 18-CH3), 1.11 (3H, s, 19-CH3); m/z (EI): 282 (Mþ, 100),
267 (M-CH3, 27), 253 (8), 225 (6), 213 (13), 199 (13), 199 (13), 185 (5),
173 (10), 161 (57), 145 (43), 131 (16), 121 (30), 105 (28), 91 (30), 81 (27),
67 (16), 55 (17), 41 (18); HRMS, Mþ found 282.2348, C21H30 requires
282.2338; Rf 0.35. Subsequent elution gave 20-fluoro-pregna-3,5-diene (4)
1
as an oil (0.082 g, 20%); H NMR (CDCl3) 5.53–5.11 (3H, m), 3.84 (1H,
2
dm, JHF, 49.64 Hz, 20-H), 2.36–0.72 (27H, m); m/z (EI): 302 (Mþ, 100),
287 (M-CH3, 48), 267 (10), 231 (7), 211 (4), 195 (10), 181 (13), 173 (5),
161 (9), 145 (18); HRMS, Mþ found 302.2410, C21H31F requires 302.2414.
Further elution gave trace amount of 3a-fluoro-pregna-5,17-diene (5) as
1
an oil (0.002 g, 0.5%) H NMR (CDCl3) 5.32 (1H, d, J ¼ 6.0 Hz, 5-H), 4.79
2
(1H, s), 4.64 (1H, s), 4.80 (1H, dm, JHF 48.0 Hz, 3b-H), 3.38 (2H, m),
2.00–0.75 (18H, m), 1.69 (3H, s, 21-H), 0.96 (3H, s, 18-CH3), 0.51 (3H, s,
19-CH3), m/z (EI): 302 (Mþ, 50), 287 (M-CH3, 100), 267 (22), 233 (19),

´
Decreau and Marson
4380
205 (16), 181 (21), 163 (40), 145 (30); Rf 0.30 (hexane 100%). Further elution
gave 3b-fluoro-pregna-5,17-diene (6) as prisms (0.082 g, 20%), mp 59–
1
638C (CHCl3-Et2O); H NMR (CDCl3) 5.32 (1H, m, 5-H), 5.06 (1H, m, 20-
2
H), 4.31 (1H, dm, JHF 48.8 Hz, 3a-H), 2.39–0.54 (19H, m), 1.47 (3H, d,
21-H), 0.97 (3H, s, 18-CH3), 0.82 (3H, s, 19-CH3); 13C NMR (CDCl3)
150.5 (C-5), 123.3 (C-6), 115.0 (C-20), 113.9 (C-17), 93.2 (d,
1JCF ¼ 165 Hz, C-3), 56.8 (C-14), 50.8, 44.4, 39.6 (d, J ¼ 14.0 Hz), 37.3,
36.9, 36.7, 32.1, 31.8, 31.7, 29.2 (d, J ¼ 15.0 Hz, C-2), 24.8, 21.6, 19.7,
19.6, 17.0, 13.5; m/z (EI): 302 (Mþ, 100), 287 (M-CH3, 80), 267 (22), 233
(19), 205 (16), 181 (21), 163 (40), 145 (30); HRMS, Mþ found 302.2412,
C21H31F requires 302.2414; Rf 0.27 (hexane 100%). Further elution afforded
a trace amount of 3a,20-difluoro-pregn-5-ene (7) (less than 1 mg) that
1
allowed us to get a coarse H NMR (data not shown) among which signals
2
were found dH 5.00 (1H, dm, JHF 48.8 Hz, 3b-H) and Rf 0.14 (hexane
100%). The last fraction eluted with a CHCl3-Et2O (1 : 1 vol.) mixture was
3b,20-difluoro-pregn-5-ene (8) as a mixture of prisms in an oil (0.130 g,
1
40%); H NMR (CDCl3) 5.57 (1H, m, 5-H), 4.58 (1H, dm, JHF 45.3 Hz,
2
2
3a-H), 4.10 (1H, dm, JHF 49.5, 20-H), 2.36–0.93 (23H, m), 1.47 (3H, d,
21-H), 1.20 (3H, s, 18-CH3), 0.93 (3H, s, 19-CH3); HRMS, Mþ found
320.4234, C21H32F2 requires 322.4828; Rf 0.15 (hexane 100%), Rf 0.65
(hexane/Et2O 3 : 2 vol.).
Reaction of Androst-5-ene-3b,17b-Diol (9) with (1)
Androst-5-ene-3b,17b-diol (9) (0.580 g, 2.0 mmol) was reacted with (1)
(5.969 mmol, 1.802 mL) according to the general procedure. Chromatography
afforded first androsta-3,5,16-triene (10)[7,11b] (0.203 g, 40%) as an oil. Sub-
sequent elution gave 3b-fluoro-androst-5,16-diene (11)[11b](0.065 g, 11.9%),
mp 83–848C (hexane); Subsequent elution gave 3b,17a-difluoro-androst-5-
ene (12) as crystals (0.208 g, 34%) mp 85–908C (hexane-toluene 7 : 3 vol); 1H
2
NMR (CDCl3) 5.38 (1H, d, J ¼ 7.0 Hz, 5-H), 4.49 (1H, dd, JHF ¼ 53.9 Hz,
2
17b-H), 4.36 (1H, dm, JHF ¼ 50.9 Hz, 3a-H), 2.42–0.65 (19H, m), 1.02
(3H, s, 19-CH3), 0.65 (3H, s, 18-CH3); 13C NMR (CDCl3) 139.7 (C-5, d,
3JCF ¼ 12.3 Hz), 123.1 (C-6), 101.4 (C-17, d, 1JCF ¼ 179.9 Hz), 93.0 (C-3, d,
2
1JCF ¼ 174.1 Hz), 50.2 (C-14), 49.6 (C-9), 45.4 (C-13, d, JCF ¼ 17.5 Hz),
2
3
39.7 (C-4, d, JCF ¼ 19.3 Hz), 37.0 (C-10), 36.7 (C-12, d, JCF ¼ 10.6 Hz),
3
31.2 (C-1, d, JCF ¼ 5.6 Hz), 32.3 (C-8), 32.4 (C-7), 30.6 (C-16, d,
2JCF ¼ 22.7 Hz), 29.1 (C-2, d, JCF ¼ 17.6 Hz), 20.8 (C-11), 24.8 (C-15),
2
19.7 (C-19), 15.5 (C-18, d, JCF ¼ 7.61 Hz); HRMS, Mþ found 294.2162,
3
C19H28F2 requires 294.2159. Subsequent elution gave 3a,17a-difluoro-
1
androst-5-ene (13) (0.029 g, 5%) as an oil; H NMR (CDCl3) 5.42 (1H,
2
d, J ¼ 7.0 Hz, 5-H), 4.86 (1H, dm, JHF ¼ 49.2 Hz, 3b-H), 4.54 (1H, dd,

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4381
2JHF ¼ 53.9 Hz, 17b-H), 2.39–0.70 (19H, m), 1.05 (3H, s, 19-CH3), 0.70 (3H,
3
s, 18-CH3); 13C NMR (CDCl3) 139.7 (C-5, d, JCF ¼ 12.3 Hz), 123.1 (C-6),
1
1
101.4 (C-17, d, JCF ¼ 179.9 Hz), 90.0 (C-3, d, JCF ¼ 164.1 Hz), 50.2 (C-
2
14), 49.6 (C-9), 45.4 (C-13, d, JCF ¼ 17.5 Hz), 39.9 (C-4, d,
2JCF ¼ 19.3 Hz), 37.0 (C-10), 36.7, 31.0 (C-1, d, 3JCF ¼ 5.6 Hz), 32.1 (C-8),
2
2
32.4 (C-7), 30.6 (C-16, d, JCF ¼ 22.7 Hz), 27.1 (C-2, d, JCF ¼ 17.6 Hz),
3
20.8 (C-11), 24.8 (C-15), 19.7 (C-19), 15.5 (C-18, d, JCF ¼ 7.61 Hz);
HRMS, Mþ found 294.2162, C19H28F2 requires 294.2159.
Reaction of Androst-5-ene-17-one-3b-ol (14) with (1)
Androst-5-ene-17-one-3b-ol 14 (0.951 g, 3.27 mmol) was reacted with 1
(4.92 g, mmol, 0.884 mL) according to the general procedure. Chromato-
graphy afforded first androsta-3,5-diene-17-one (15) as prisms (0.235 g,
27%) mp 84–888C, lit. mp 85–898C;[18] Rf (hexane 100%) 0.35. Subsequent
elution gave 3a-fluoro-androst-5-ene-17-one (16) as prisms (trace) mp 113–
1148C (hexane); 1H NMR (CDCl3) 5.35 (1H, m, 5-H), 4.30 (1H, dxm, 3b-H,
2JHF 48.69 Hz), 0.96 (3H, s, 18-H), 0.86 (3H, s, 19-H), 2.40–0.86 (18H); 13
C
1
NMR (CDCl3) 139.1, 122.6, 90.0 (C-3, –, JCF ¼ 166 Hz), 52.1, 50.5, 47.9,
39.8, 39.6, 37.0, 36.7, 36.1, 31.8, 31.1, 29.2, 28.9, 22.2, 20.8, 19.7, 13.9;
m/z (EI) ¼ 290 (Mþ, 100), 275 (Mþ- 32), 270 (50), 255 (27), 247 (10), 233
(33), 213 (15), 203 (49), 177 (71), 163 (25), 145 (26), 131 (10), 121 (30),
107 (40), 105 (38), 91 (41), 79 (35), 67 (22), 55 (28), 41 (35); HRMS, Mþ
found 290.2035, C19H27FO requires 290.2046; Rf (hexane 100%) 0.28. Sub-
sequent elution gave 3b-fluoro-androst-5-ene-17-one (17)[6c,18b] as prisms
(0.651 g, 68%), mp 135–1408C (hexane), lit.[10a] mp 152–1548C (hexanes),
1
2
1558C[18c]; H NMR (CDCl3) 5.35 (1H, m, 5-H), 4.30 (1H, dm, 3a-H, JHF
53.03 Hz), 0.98 (3H, s, 18-H), 0.82 (3H, s, 19-H), 2.45–0.82 (18H); 13C
1
NMR (CDCl3) 139.1, 122.4, 92.9 (C-3, d, JCF ¼ 19 Hz), 52.3, 50.6, 47.9,
2
39.9, 39.6, 37.0, 36.8, 36.2, 31.9, 31.2, 29.22 (C-3, d, JCF), 22.3, 20.8,
19.7, 13.9; m/z (EI) ¼ 290 (Mþ, 100), 275 (M-CH3), 270 (51.7), 255 (39),
247 (8), 233 (32.8), 213 (13), 203 (47), 177 (69), 163 (21), 145 (27), 131
(20), 121 (25), 107 (44), 105 (42), 91 (43), 79 (37), 67 (24), 55 (27), 41
(33); HRMS, Mþ found 290.2035, C19H27FO requires 290.2046; Rf
(hexane) 0.22.
Reaction of 5a-Androst-17-one-3b-ol (18) with (1)
5a-Androst-17-one-3b-ol 18 (0.951 g, 3.27 mmol) was reacted with 1
(4.91 mmol, 0.884 mL) according to the general procedure. Chromatography
affords 5a-androst-2-ene-17-one (19) (0.401 g, 45%) mp 92–968C, lit. mp 104–
1058C.[7a,10] Subsequent elution afforded 3a-fluoro-5a-androst-17-one (20)

´
Decreau and Marson
4382
as prisms (0.076 g, 43%) mp 112–1138C, lit. mp 114–1158C,[8b] 119–
1208C[7a]. MS (EI) m/z ¼ 292 (Mþ, 100), 277 (15), 259 (16), 248 (44), 235
(21), 221 (42), 213 (3), 193 (4), 179 (4), 167 (17), 147 (15), 135 (9), 121
(21), 108 (68), 97 (38), 93 (45), 79 (50), 67 (68), 59 (10), 55 (49), 41 (68).
2
1H NMR (CDCl3)[18b,10] 4.80 (1H, dm, 3a-H, JHF 48.73), 0.86 (3H,
s, 18-H), 0.81 (3H, s, 19-H), 2.62–0.81 (remaining protons of the steroidal
1
backbone); 13C NMR (CDCl3) 90.7 (C-3, d, JCF 165.93 Hz), 54.6, 51.8,
48.1, 39.8, 36.3, 35.4, 34.4, 34.1, 32.8, 31.9, 31.1, 28.4, 27.6, 27.3 (d,
2JCF ¼ 21 Hz), 22.1, 20.4, 14.2, 11.5; HRMS, Mþ found 292.2191,
C19H29FO requires 292.2205; Rf(hexane) 0.37. Subsequent elution afforded
3b-fluoro-5a-androst-17-one (21)[10] as prisms (0.411 g, 8%), mp 131–
1338C (hexane), lit. mp 129–1318C,[7a] 125–1278C.[10] MS (EI) m/z ¼ 292
(Mþ, 100), 274 (Mþ - 8), 259 (13), 248 (42), 233 (16), 221 (22), 213 (2),
193 (3), 179 (4), 167 (11), 147 (11), 135 (6), 108 (37), 93 (22), 79 (24), 73
1
(3), 67 (30), 55 (23), 49 (2), 41 (29). H NMR (CDCl3) 4.40 (1H, dm, 3a-
H, 2JHF 52.08 Hz), 1.15 (3H, s, 18-H), 1.14 (3H, s, 19-H), 2.38–0.74 (remain-
ing protons of the steroidal backbone); 13C NMR (CDCl3) 90.75 (C-3, d, 1JCF
165.93 Hz), 54.6, 51.8, 48.1, 39.8, 36.2, 35.4, 34.4, 34.1, 32.7, 31.9, 31.1, 28.4,
27.5, 27.2, 22.1, 20.4, 14.2, 11.5. HRMS, Mþ found 292.2191, C19H29FO
requires 292.2205; Rf(hexane) 0.32.
Reaction of 5a-Androst-17-one-3a-ol (22) with (1)
5a-Androst-17-one-3b-ol 22 (0.252 g, 0.86 mmol) was reacted with
1 (g, 1.60 mmol, 0.289 mL) according to the general procedure. Chromato-
graphy afforded first the alkene 19 (0.122 g, 52%) and, subsequently, trace
amounts of 3a-fluoro-androst-5-ene-17-one 20 and 3b-fluoro-5a-androst-
17-one 23 as prisms (0.102 g, 41%).
ACKNOWLEDGMENT
We acknowledge generous support from Quest International. We are
grateful to Mike Cocksedge of the ULIRS for obtaining mass spectra.
REFERENCES
1. (a) Aoloshonok, V. Practical synthesis of enantiopure fluoroamino acids
of biological interest by asymmetric aldol reactions. In Biomedical Fron-
tiers of Fluorine Chemistry; Ojima, I., McCarthy, J.R., Welch, J.T., Eds.;
American Chemical Society Symposium Series: Washington, DC, 1996;

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4383
Vol. 639, 26–41; (b) McCarthy, J.R.; Sunkasa, P.S.; Matthews, D.P.;
Bitoniti, A.J.; Jarvi, E.T.; Sabol, J.S.; Resvick, R.J.; Huber, E.W.; van
der Donk, W.A.; Yu, G.; Stubbe, J. Design of fluoro-olefin cytidine
nucleoside as a bioprecursor of a mechanism-based inhibitor of ribo-
nucleotide reductase. ibid.246–264.
2. (a) Welch, J.T. Advances in the preparation of biologically active organo-
fluorine compounds. Tetrahedron 1987, 43, 3123; (b) Bravo, P.;
Resnati, G. Preparation and properties of chiral fluoroorganic compounds.
Terahedron: Asymmetry 1990, 1, 661.
3. Wilkinson, J.A. Recent advances in the selective formation of the C-F
bond. Chem. Rev. 1992 (92), 505.
4. Mann, J.E. Metabolites derived from mevalonate: isoprenoids. In Second-
ary Metabolish; Oxford University Press: Oxford, 2nd Ed., 1987; 95–
171.
5. Welch, J.T.; Eswarakrishnan, S. Fluorine in Bio-organic Chemistry;
Wiley: New York, 1991.
6. (a) Hudlicky, M. Fluorination with diehtylaminosulfur trifluoride and
related aminofluorosulfanes. Org. React. 1988, 35, 513; (b) Rozen, S.;
Faust, Y.; ben-Yakov, H. New method for fluorination of sterols. Tetra-
hedron Lett. 1979, 20, 1823; (c) Knox, L.H.; Velarde, E.; Berger, S.;
Cuadriello, D.; Cross, A.D. Steroids. 240. Reaction of steroidal alcohol
with 2-chloro-1,1,2-trifluorothylamine. J. Org. Chem. 1964, 29, 2187.
7. (a) Ayer, D.E. A new method for the preparation of fluorosteroids. Tetra-
hedron Lett. 1962, 23, 1065; (b) Borgna, J.-L.; Mousseron-Canet, M.
Flourinated steroids – synthesis of 3a-fluoro-17-b-acetoxy-estr-5(10)-
ene. Bull. Soc. Chim. Fr. 1970, 2218.
8. (a) Henbest, H.B.; Jackson, W.R. Use of aprotic solvents for nucleophilic
substitution reactions at C(3) and C(17) in steroids. J. Chem. Soc. 1962,
954; (b) Schneider, H.-J.; Buchheit, U.; Becker, N.; Schmidt, G.;
1
Siehl, U. H-NMR analyses, shielding mechanism, coupling constants,
and conformations in steroids bearing halogen, hydroxy, oxo groups,
and double-bonds. J. Am. Chem. Soc. 1985, 107, 7027;
(c) Pomper, M.G.; Van Brocklin, H.; Thieme, A.M.; Thomas, D.R.;
et al. 11-b-methoxy-substituted, 11-b-ethyl-substituted and 17-a-
ethynyl-substituted 16-a-fluoroestradiols-based imaging agents with
enhanced uptake efficiency and selectivity. J. Med. Chem. 1990, 33,
3143–3155.
9. Boutin, N.E.; Robert, D.U.; Cambon, A.R. New method of preparation of
D5-3b-fluorosteroids. Bull. Soc. Chim. Fr. 1974, 12, 2861.
10. Colonna, S.; Re, A.; Gelbard, G.; Cesarotti, E. Anionic activation in
polymer supported reactions 2. Stereochemical studies on the introduction

´
Decreau and Marson
4384
of fluorine at chiral centers and in biologically significant molecules.
J. Chem. Soc. Perkin Trans. I 1979, 2248.
11. (a) Bennua-Skalmowski, B.; Vorbru¨ggen, H. A facile conversion of
primary or secondary alcohols with n-perfluorobutanesulfonyl fluoride/
1,8-diazabicyclo[5.4.0]undec-7-ene into their corresponding fluorides.
Tetrahedron Lett. 1995, 36, 2611; (b) Marson, C.M.; Decreau, R.A.;
Smith, K.E. Preparation of 3-a-fluoro- and 3-b-fluoroderivatives of 5-
a-androst-16-enes and androsta-5,16-dienes. Synth. Commun. 2002, 32,
2125.
12. (a) Ali, H.; Rousseau, J.; Gantchev, T.G.; vanLier, J.E. 2-Fluorinated and
4-fluorinated 16-a-[I-125]iodoestarndiol derivatives synthesis and effect
on estrogen-receptor binding and receptor binding mediated target
tissue uptake. J. Med. Chem. 1993, 36, 4255; (b) Cowell, B.D.;
Davis, A.K.; Mathieson, D.W.; Nicklin, P.D. Bromo-derivatives, chloro-
derivatives, and amino derivatives of 5a-androstan and 5a-estrane.
J. Chem. Soc. Perkin 1, 1974, 1, 505.
13. (a) Brooksband, B.W.L.; Brown, R.; Gustafsson, J.-A. Detection of 5-a-
androst-16-en-3-a-ol in human male auxillary sweat. Experientia 1974,
30, 864; (b) Gasparini, F.J.; Hochberg, R.B.; Lieberman, S. Biosynthesis
of steroid sulfates by the boar testes. Biochemistry 1976, 15, 3969;
(c) Gower, D.B.; Holland, K.T.; Mallet, A.I.; Rennie, P.J.;
Watkins, W.J. Comparison of 16-androstene steroid concentartions in
sterile apocrine sweat and axillary secretions: interconversions of 16-
androstenes by the axillary microflora and a mechanism for axillary
odour production in man?. J. Steroid Biochem. Molec. Biol. 1994, 48,
409; (d) Decreau, R.A.; Marson, C.M.; Smith, K.E.; Behan, J. Production
of malodorous steroids from androsta-5,16-dienes and androsta-4,16-
dienes by corynebacteria and other human axillary bacteria. J. Steroid
Biochem. Mol. Biol. 2003, 87, 327–336.
14. (a) Seto, H.; Qian, Z.H.; Yoshioka, H.; Uchibor, Y.; Umeno, M. Facile
preparation of tetrabutylphosphonium fluoride and its HF adducts –
new fluoride anion sources for selective nucleophilic fluorination.
Chem. Lett. 1991, 7, 1185–1188; (b) Bird, T.G.; Fredericks, P.M.;
Jones, E.R.H.; Meakins, G.D. Convenient general preparation pf oxy-
genated monofluoro-5a-androstanes using diethylaminosulfur trifluoride.
J. Chem. Soc. Chem. Commun. 1979, 65.
15. (a) Gamoh, K.; Hirayama, M.; Ikekawa, N. Stereocontrolled synthesis of
withanolide-D and related compounds. J. Chem. Soc. Perkin Trans. I
1984, 449; (b) Hoellinger, H.; Nguyen-Hoang, N.; Pichet, L. Synthesis
of [4-C-14]-3-a-diaminopregn-5-ene or [4-C-14] 3-epi-irehdiamine-A
1975 (1–2), 237.

Preparation of 3,17- and 3,20-Difluoro-Derivatives
4385
16. (a) Cardwell, H.M.E.; Cornforth, J.W.; Duff, S.R.; Holtermann, H.;
Robinson, R. Experiments on the synthesis of substances related to the
sterols 51. Completion of the syntheses of androgenic hormones and of
the cholesterol group of sterols. J. Chem. Soc. 1953, 361–384;
(b) Giacopello, S.; Deluca, M.E.; Seldes, A.M. Synthesis and NMR
studies of some steroidal isoxazoles. Zeitschrift Nat. Forschung B 1992,
47, 891; (c) Wilson, M.R.; Gallimore, W.A.; Reese, P.B. Steroid trans-
formations with Fusarium oxysporum var. cubense and Colletotrichum
musae. Steroid 1999, 64, 834.
17. Cacchi, S.; Morera, E.; Ortar, G. Palladium-catalyzed reduction of enol
triflates to alkenes. Tetrahedron Lett. 1984, 25, 4821.
18. (a) Ward, M.G.; Orr, J.C.; Engell, L.L. A convenient synthesis of
3-b-hydroxyandrost-4-en-17-1. J. Org. Chem. 1965, 30, 1421;
(b) Jones, E.R.H.; Meakins, G.D.; Miners, J.O.; Wilkins, A.L. Micro-
biological hydroxylation. 21. Hydroxylations of 3-halogeno-17-oxo-
androstanes, 3-halogeno-7-oxo-androstanes, and 17-halogeno-3-oxo-
androstanes by fungi Calonectria-Decora, Rhizopus-Nigricans, and
Aspergillus-Ochraceus. J. Chem Soc. Perkin Trans I 1975, 2308.
Received in the USA July 30, 2004