A simple synthesis of gestodene from 18-methyl-4-estren-3,17-dione

Article abstract of DOI:10.1055/s-2004-829070

A simple synthesis enables us to obtain the progestin, gestodene, in five steps and satisfactory yields from 18-methyl-4-estren-3,17-dione. This was accomplished through the selective protection of the C-3 carbonyl group as a cyclic ketal and the installation of a phenylsulfoxide group at the C-16 position.

Full text of DOI:10.1055/s-2004-829070

1
838
LETTER
A Simple Synthesis of Gestodene from 18-Methyl-4-estren-3,17-dione
a
b
a
a
A
P
S
imple Syn
a
G
e
t
stoden
r
e
f
rom
1
i
8-Meth
z
yl-4-estre
n
i
-3,17-d
a
ione Ferraboschi,* Paride Grisenti, Andrea Onofri, Paolo Prestileo
a
Department of Medical Chemistry, Biochemistry and Biotechnology-Università degli Studi di Milano, Via Saldini 50, 20133 Milan, Italy
Fax +39(02)50316040; E-mail: Patrizia.Ferraboschi@unimi.it
b
Poli Industria Chimica, Via Volturno 45/48, Quinto de’ Stampi, 20089 Rozzano, Italy
Received 22 March 2004
treatment with 2,2-dimethyl-1,3-propandiol, triethyl-
orthoformate and p-toluenesulfonic acid in dichloro-
methane. The 3-ketal,17-ketone 3 was obtained in 90%
Abstract: A simple synthesis enables us to obtain the progestin,
gestodene, in five steps and satisfactory yields from 18-methyl-4-
estren-3,17-dione. This was accomplished through the selective
protection of the C-3 carbonyl group as a cyclic ketal and the instal-
lation of a phenylsulfoxide group at the C-16 position.
7
yield. In principle, the D-ring enone could be obtained by
8
9,10
means of a sulfoxide as well as a selenoxide elimina-
tion: at first, we studied the sulfenylation–dehydrosulfe-
nylation procedure in order to use the less toxic reagents
and in view of a possible scaling up of the method. The
preliminary attempt of sulfenylation with phenyl disulfide
and lithium diisopropylamide in THF and HMPA, fol-
lowed by oxidation (m-chloroperbenzoic acid) of the ob-
tained 16-phenylsulfide 4 to the sulfoxide 5 and
Key words: drugs, steroids, sulfoxides, sulfinylation, progestagen
Gestodene (17a-ethynyl-17b-hydroxy-18-methyl-4,15-
estradien-3-one) (1) is a potent synthetic progestin that is
used, in combination with ethynylestradiol, as an oral con-
1
traceptive (Figure 1).
8
15
thermolysis, gave the D -derivative 6 in promising yield
Starting from the commercially available 18-methyl-4-es-
tren-3,17-dione (2), the crucial step of the synthesis is the
introduction of the double bond in the 15,16-position;
usually this result is achieved by an elimination reaction
carried out on a 15-hydroxy derivative, in turn prepared
(
30%); an improvement, in terms of reactions conditions
and final yields, was achieved through a sulfinylation with
the commercially available methyl benzenesulfinate as
11
suggested by Wicha et al. In fact, in this way it is possi-
ble to introduce a PhSO group directly at the a-position of
2
by means of a microbiological transformation. In another
a ketone in one step. We were able to prepare the phenyl-
two reported syntheses of gestodene starting from a 18-
methyl estradiol derivative, the introduction of the 15,16
double bond is realized by treatment of the proper 17-
12
sulfoxide 5 as a diastereomeric mixture with complete
conversion of the starting 17-ketone 3. We used the same
reactant but replaced the reported sodium hydride as base
and diethyl ether as solvent with potassium t-butylate and
tetrahydrofuran, respectively.13 The obtained phenylsul-
foxide 5 was used directly to accomplish the gestodene 1
synthesis without any further purification.14 Elimination
3
,4
enolsilylether with palladium(II) acetate.
15
in boiling xylene (in presence of triethylamine) afforded
the unsaturated ketone 6,16 which was transformed into
the 17a-ethynyl derivative 7 by treatment with the lithium
acetylide–ethylendiamine complex in tetrahydrofuran.17
Finally, acidic removal of the 3-protecting group afforded
18
gestodene 1 in 50% overall yield from 2, comparable to
the yields reported for the microbiological approach
Figure 1
2
(
47% from 2, see Scheme 1).
Considering the pharmacological relevance of gestodene,
we planned to find an alternative method for an easy and
convenient preparation. The known introduction of the
In conclusion, the introduction of the phenylsulfoxide as
a functional group at the 16-position, preceded by the se-
lective protection of 3-carbonylic function as a cyclic ket-
al, gave us a simple synthesis of gestodene 1 starting from
18-methyl-4-estren-3,17-dione (2) with satisfactory
yields.
1
5-16 double bond by a bromination at the 16-position of
a steroidal 17-ketal, by means of treatment with pyridini-
5
um tribromide followed by a dehydrobromination, af-
6
forded negative results.
Thinking that the best solution could be offered by a 16-
functionalization performed in basic conditions, we selec-
tively protected the 3-keto group of 2 as its cyclic ketal by
Acknowledgment
This work was partially supported by the Ministero dell’Università
e della Ricerca Scientifica e Tecnologica (MURST, ex-60%). We
thank Dr Shahrzad Reza-Elahi for technical assistance at the early
stage of the work and Professor Fiamma Ronchetti for helpful dis-
cussions.
SYNLETT 2004, No. 10, pp 1838–1840
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Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829070; Art ID: G08904ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
A Simple Synthesis of Gestodene from 18-Methyl-4-estren-3,17-dione
1839
Scheme 1 Reagents: i. 2,2-Dimethyl-1,3-propandiol, CH(OEt) , TsOH, 10 °C; ii. PhS(O)OCH , t-BuOK, THF, r.t., 2 h; iii. Et N, xylene,
3
3
3
reflux, 2.5 h; iv. Lithium acetylide–H NCH CH NH , THF, 0 °C, 2 h; v. 6 N HCl, acetone, r.t., 45 min; vi. (PhS) , LDA, THF, HMPA, from
2
2
2
2
2
–
78 °C to r.t., 2 h; vii. MCPBA, CH Cl , –78 °C, 30 min.
2 2
References
(10) The selenation–dehydroselenation procedure has already
been reported for the synthesis of a 15-androstene derivative.
See: Reeder, A. Y.; Joannou, G. E. Steroids 1996, 61, 74.
(
(
1) Hoppe, G. Advances in Contraception 1987, 3 (2), 159.
2) (a) Hofmeister, H.; Wiechert, R.; Annen, K.; Laurent, H.;
(11) Groszek, G.; Kabat, M. M.; Kurek, A.; Masnyk, M.; Wicha,
J. Bull. Pol. Acad. Sci., Chem. 1986, 34, 305.
Steinbeck, H. DE 2546062, 1975; Chem. Abstr. 1977, 87,
1
68265. (b) Hofmeister, H.; Annen, K.; Laurent, H.;
Petzoldt, K.; Wiechert, R. Arzneim.-Forsch. 1986, 36 (I),
81.
3) Bohlmann, R.; Laurent, H.; Hofmeister, H.; Wiechert, H. DE
710728, 1987; Chem. Abstr. 1989, 110, 95633.
4) Prendin, R.; Pirovano, S. EP 700926, 1995; Chem. Abstr.
996, 124, 343797.
5) (a) Kelly, R. W.; Sykes, P. J. J. Chem. Soc. C 1968, 416.
b) Liu, D.; Stuhmiller, L. M.; McMorris, T. C. J. Chem.
Soc., Perkin Trans. 1 1988, 2161.
(
12) Due to the new stereocenters at the C-16 and SO group, four
diastereoisomers were obtained, as shown by TLC (toluene–
EtOAc 8:2) analysis.
7
(
(
(
(
13) 3,3-(2¢,2¢-Dimethyl-1¢,3¢-propylenedioxy)-18-methyl-
3
1
6x-phenylsulfoxide-5- and 5(10)-estren-17-one (5).
To a solution of 3 in anhyd THF, t-BuOK (4 equiv) was
1
added. The mixture was kept, under N atmosphere, under
2
vigorous stirring at r.t., and after 10 min, methyl
(
benzenesulfinate (Aldrich, 4 equiv) was added; upon
disappearance of starting material (2 h), the crude product
was recovered by extraction with EtOAc. The combined
1
5
14
(
6) A mixture of D - and D -derivatives was obtained from the
dehydrobromination and it is known that the conversion of
the unconjugated ketone to the conjugated one, occurring in
course of the acidic removal of 17-ketal, leads to an
epimerization at C-14. See: Johnson, W. S.; Johns, W. F. J.
Am. Chem. Soc. 1957, 79, 2005.
organic layers were washed with brine and H O, dried over
2
Na SO and the solvent was removed under reduced
2
4
pressure. TLC (toluene–EtOAc 8:2) analysis showed a few
spots with very similar R values (between 0.16 and 0.35). IR
f
(
1
1% KBr): 3449.9, 2954.9, 2868.9, 1735.9, 1129.6, 1106.5,
093.8, 1048.7 cm . MS: m/z = 497 [M + 1], 496 [M ], 371,
(
7) 18-Methyl-3,3-(2¢,2¢-dimethyl-1¢,3¢-propylenedioxy)-5-
and 5 (10)-estren-17-one (3).
–1
+
370.
3-Carbonylic group of compound 2 (5 g, Keifeng, Shanghai)
1
(
14) The H NMR spectrum of 5 was very complex due to the
was selectively protected by reaction with 2,2-dimethyl-1,3-
propanediol (3 equiv), triethyl-ortho-formate (1.7 equiv) and
p-TsOH (0.5% w/w), in CH Cl , at 10 °C (3 h), and the title
5
presence of four diastereoisomers of a mixture of D and
5 (10)
D
isomers. Except for the signals due to the 5,6-double
2
2
bond (two multiplets at d = 5.38 and 5.44 ppm in a ratio 4:6,
respectively), it was not possible to assign any other signals.
For analytical purposes, the 18-methyl-16x-phenylsulf-
oxide-4-estren-3,17-dione was prepared by removal (6 N
1
compound was obtained in 90% yield. Mp 90–110 °C. H
NMR (500 MHz, CDCl ): d = 0.73 (t, J = 7 Hz, 0.9 H,
3
1
8-CH ), 0.75 (t, J = 7 Hz, 2.1 H, 18-CH ), 0.85 (s, 0.9 H,
3
3
CH -C), 0.89 (s, 2.1 H, CH -C), 1.00 (s, 2.1 H, CH -C), 1.06
1
3
3
3
HCl in acetone) of the 3-cyclic ketal from 5. H NMR (500
(
s, 0.9 H, CH -C), 3.44–3.66 (m, 4 H, CH O), 5.50 (m, 0.7
3
2
MHz, CDCl ): d = 0.63, 0.69, 0.74, 0.75 (4 t, J = 8Hz, in a
3
H, CH=). IR (1% KBr): 3449.5, 2952.2, 2866.7, 1732.2.
Anal. Calcd for C H O : C, 77.38; H, 9.74; O, 12.88.
Found: C, 77.45; H, 9.69; O, 12.95.
ratio 0.14:0.11:0.35:0.40, 18-CH ), 3.20 (dd, J = 8.4 and 10
3
2
4
36
3
Hz, 0.34 H, CHSO), 3.41 and 3.43 (two overlapped dd, 0.53
H, CHSO), 3.48 (dd, J = 8.4 and 10 Hz, 0.13 H, CHSO),
(
(
8) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc.
5
7
.72, 5.73, 5.75 (three m, in a ratio 0.18:0.32:0.50, CH=),
.27–7.42 (m, 5 H, Ar).
1976, 98, 4887.
9) Sharpless, K. B.; Lauer, R. F.; Teranishi, A. Y. J. Am. Chem.
Soc. 1973, 95, 6137.
(
15) We observed a cleaner reaction by employing Et N instead
3
of the N,N-dimethylaniline reported in the original paper
1
1
(
ref. ).
Synlett 2004, No. 10, 1838–1840 © Thieme Stuttgart · New York

1
840
P. Ferraboschi et al.
LETTER
(
16) 3,3-(2¢,2¢-Dimethyl-1¢,3¢-propylenedioxy)-18-methyl-5-
(toluene–EtOAc 8:2) until the starting material disappeared.
To this mixture, 6 N HCl was added to pH 6 and the mixture
was brought to r.t. Extraction with EtOAc and usual work-up
afforded 17a-ethynyl derivative 7 (94%). Differential
and 5(10),15-estradien-17-one (6).
A solution of 5 in xylene (20 mL/g substrate) and Et N (1
3
mL/g substrate) was kept at 140 °C under N atmosphere and
2
the reaction progress was monitored by TLC (toluene–
EtOAc 8:2) until the starting material disappeared (2.5 h).
After cooling to r.t. the crude product was recovered after
addition of toluene, washing of the organic phase with brine
Scanning Calorimetry (DSC, 5 °C/min): two endothermic
1
peaks at 174 °C and 192 °C. H NMR (500 MHz, CDCl ):
3
d = 0.82 (t, J = 8 Hz, 1.35 H, 18-CH ), 0.85 (s, 1.35 H,
3
CH -C), 0.86 (t, J = 8 Hz, 1.65 H, 18-CH ), 0.90 (s, 1.65 H,
3
3
and H O and usual work-up. Purification by silica gel
CH -C), 1.00 (s, 1.65 H, CH -C), 1.06 (s, 1.35 H, CH -C),
2
3
3
3
column chromatography (1:25, elution with hexane–EtOAc
2.60 (s, 0.45 H, H-21), 2.61 (s, 0.55 H, H-21), 3.40–3.70 (m,
9
:1) afforded pure 6, in 65% yield from 3. Mp 115–125 °C.
4 H, CH O), 5.46 (m, 0.55 H, CH=), 5.67 (dd, J = 3.5 and 5.6
Hz, 1 H, CH=), 5.90 (dd, J = 2.0 and 6.0 Hz, 0.55 H, CH=),
5.99 (dd, J = 2.0 and 6.0 Hz, 0.45 H, CH=).
2
1
H NMR (500 MHz, CDCl ): d = 0.74 (t, J = 8 Hz, 1.2 H,
3
18-CH ), 0.77 (t, J = 8 Hz, 1.8 H, 18-CH ), 0.86 (s, 1.8 H,
3
3
CH -C), 0.90 (s, 1.2 H, CH -C), 1.01 (s, 1.2 H, CH -C), 1.08
(18) Gestodene(17a-ethynyl-18-methyl-4,15-estradien-3-one)
3
3
3
(
s, 1.8 H, CH -C), 3.40–3.70 (m, 4 H, CH O), 5.50 (m, 0.4
(1).
3
2
H, CH=), 5.99 (dd, J = 2.8 and 5.6 Hz 1 H, CH=), 7.47 (d,
J = 5.6 Hz, 0.6 H, CH=), 7.54 (d, J = 5.6 Hz, 0.4 H, CH=).
A solution of 7 in acetone was treated with 6 N HCl (1.2
equiv) for 45 min at r.t. Neutralization with a sat. NaHCO3
solution, extraction with EtOAc and usual work-up afforded
crude product that gave pure 1 (90%) by crystallization
(hexane–acetone). DSC (5 °C/min): endothermic peak at
–
1
IR (1% KBr): 3454.0, 2951.3, 2863.7, 1706.0 cm . MS:
+
m/z = 371 [M + 1], 370 [M ], 341.
(
17) 3,3-(2¢,2¢-Dimethyl-1¢,3¢-propylenedioxy)-17a-ethynyl-
2
0
17b-hydroxy-18-methyl-5-and 5(10),15-estradiene (7).
199.75 °C (onset a 198.90 °C). [a]D –187.8 (c 1, CH Cl ).
2 2
To a solution of 6 in anhyd THF (25 mL/g of substrate) the
commercially available (Fluka) lithium acetylide–ethylene-
diamine complex (4 equiv) was added, at 0 °C and under N2
atmosphere. The mixture was kept at 0 °C (2 h) under
stirring. The reaction progress was monitored by TLC
The other chemical-physical data are in agreement with the
reported ones. See: Von Cleve, G.; Frost, E.; Hoyer, G.-A.;
Rosenberg, D.; Seeger, A. Arzneim.-Forsch. 1986, 36 (I),
784.
Synlett 2004, No. 10, 1838–1840 © Thieme Stuttgart · New York