Pd(0)-mediated cross coupling of 2-iodoestradiol with organozinc bromides: A general route to the synthesis of 2-alkynyl, 2-alkenyl and 2-alkylestradiol analogs

Article abstract of DOI:10.1055/s-1999-2773

Treatment of 3,17-O-bis(tert-butyldimethylsilyl)-2-iodoestradiol with in situ-generated organozinc bromides in the presence of a catalytic amount of Pd(PPh₃)₄ as a Pd(0) source led to efficient displacement reactions.

Full text of DOI:10.1055/s-1999-2773

LETTER
1097
Pd(0)-Mediated Cross Coupling of 2-Iodoestradiol with Organozinc
Bromides: A General Route to the Synthesis of 2-Alkynyl, 2-Alkenyl and 2-
Alkylestradiol Analogs
Arasambattu K. Mohanakrishnan, Mark Cushman*
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West
Lafayette, Indiana 47907, U.S.A.
Fax +1 (765) 494-6790; E-mail: cushman@pharmacy.purdue.edu
Received 14 May 1999
for its preclinical development as an anticancer agent, it
Abstract: Treatment of 3,17-O-bis(tert-butyldimethylsilyl)-2-io-
was decided to develop a more practical route for its syn-
doestradiol with in situ-generated organozinc bromides in the pres-
thesis which could possibly be extended to the preparation
of related compounds as well.
ence of a catalytic amount of Pd(PPh ) as a Pd(0) source led to
efficient displacement reactions.
3
4
Keywords: estradiol, antitumor compounds, palladium, cross cou-
pling, organozinc bromides
In order to define the structural parameters associated Scheme 2
1
2,3
with the antitublin activity and cytotoxicity of 2-meth-
oxyestradiol, an array of 2-substituted estradiol analogs
were synthesized and evaluated for biological activity.4
Several of them were very potent inhibitors of tubulin po-
lymerization acting at the colchicine binding site. In view
of the cytotoxic activities of these compounds in human
cancer cell cultures, a systematic study was undertaken to
synthesize 2-alkynyl, 2-alkenyl, and 2-alkylestradiols.
Regioselective lithiation of 3,17-O-bis(methoxymeth-
,5
6
yl)estradiol(1) followed by quenching with I or perfluo-
2
7
rohexyl iodide gave the 2-iodoestradiol derivative 2 in
7
8% yield (Scheme 1). Deprotection of the two hydroxyl
groups followed by reprotection with TBDMSCl gave
8
compound 3.
Scheme 3
Initially, the coupling reaction of compound 3 was at-
tempted unsuccessfully under Kumada conditions using
commercially available 1-propynylmagnesium bromide.
The use of Pd(PPh ) in place of the Ni(II) complex also
3
4
failed. Finally, the 2-propynylestradiol analog 4 was pre-
pared in 82% yield in the presence of tetrakis(triphe-
nylphosphine)palladium and in situ-generated 1-
propynylzinc bromide. Under these conditions the cou-
pling reaction was very facile and the starting material
was totally consumed.
Scheme 1
1
0
The Sonogashira procedure involving the reaction of ter-
minal alkynes with aryl halides in the presence of amines
and a catalytic amount of Pd(II) complex and CuI
(
Scheme 2) has been widely used for the synthesis of aryl- Encouraged by the remarkable effect of the employment
9
-11
alkynes.
However, the reaction of compound 3 with of the organozinc bromide, the coupling reaction was ex-
propyne under the Sonogashira coupling conditions pro- tended further to the synthesis of several alkynyl, alkenyl
5
vided only a 12% yield of the required product. Since rel- and alkyl estradiol analogs. As documented in Table 1, the
atively large amounts of 2-propynylestradiol were needed presently employed Negishi coupling procedure12 pro-
Synlett 1999, No. 07, 1097–1099 ISSN 0936-5214 © Thieme Stuttgart · New York

1
098
A. K. Mohanakrishnan, M. Cushman*
LETTER
2
ceeds very well with sp (entries 1-4), sp (entries 5 and 6), Acknowledgement
3
and sp (entries 7 and 8) carbon-based organozinc re-
This research was made possible by the National Institutes of He-
alth (NIH) through support of this work with Contract NO1-CM-
1
3-17
agents.
Excellent yields were obtained in most of the
cases and the formation of side products was minimal.
6
7260.
In summary, we have developed a mild, efficient and gen-
eral synthetic route to several 2-substituted estradiol ana-
logs using in situ-generated organozinc bromides in the
presence of Pd(0). Further studies of the scope and utility
of this method are presently under investigation.
References and Notes
(
1) D’Amato, R. J.; Lin, C.; Flynn, E.; Folkman, J.; Hamel, E.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3964.
(2) Seegers, J. C.; Aveling, M.-L.; Aswegen, C. H.; Cross, M.;
Koch, F.; Joubert, W. S. J. Steroid Biochem. 1989, 32, 797.
Synlett 1999, No. 07, 1097–1099 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A General Route to the Synthesis of 2-Alkynyl, 2-Alkenyl and 2-Alkylestradiol Analogs
1099
(
(
(
3) Lottering, M.-L. Haag, M.; Seegers, J. C. Cancer Res. 1992,
2, 5926.
4) Cushman, M.; He, H.-M.; Katzenellenbogen, J. A.; Lin, C.
M.; Hamel, E. J. Med. Chem. 1995, 38, 2041.
5) Cushman, M.; He, H.-M.; Katzenellenbogen, J. A.; Varma, R.
K.; Hamel, E.; Lin, C. M.; Ram, S.; Sachdeva, Y. P. J. Med.
Chem. 1997, 40, 2323.
6) Lovely, C. J.; Gilbert, N. E.; Liberto, M. M.; Sharp, D. W.;
Lin, Y. C.; Brueggemeier, R. W. J. Med. Chem. 1996, 39,
(19) The corresponding Grignard reagent was not commercially
available. It was prepared from propargyloxy trimethylsilane
and ethylmagnesium bromide in THF.
(20) The crude product was contaminated with 3,17-O-bis(tert-
butyldimethylsilyl)estradiol. However, when the coupling
reaction was carried out with the iodo compound 2 instead of
3, the corresponding 2-vinyl-3,17-bis(methoxymethyl)-
estradiol was isolated in 89% yield as a pure compound.
(21) Satisfactory spectral and analytical data were obtained for all
of the products. A typical experimental procedure is as follows
5
(
1917.
(
(
(
7) Shimizu, T.; Koizumi, T.-a.; Yamaguchi, I.; Osakada, K.;
Yamamoto, T. Synthesis 1998, 259.
8) He, H.-M.; Fanwick, P. E.; Wood, K.; Cushman, M. J.
Org.Chem 1995, 60, 5905.
9) Sonogashira, K.; Tohda, Y.; Hagihara, N. A. Tetrahedron
Lett. 1975, 4467.
(Table 1, entry 2): Anhydrous ZnBr (0.289 g, 1.28 mmol) was
2
dissolved in dry THF (40 mL) under argon. A solution of
ethynylmagnesium bromide in THF (2.6 mL, 0.5 M) was
added, and the reaction mixture was stirred under argon
(solution turns turbid). After 10 min, Pd(PPh ) (0.074 g,
3
4
0.064 mmol) and iodo compound 3 (0.4 g, 0.64 mmol) were
added, and the stirring was continued for 6 h at rt. The reaction
mixture was poured into ice water (100 mL), extracted with
ethyl acetate (3 X 20 mL), washed with brine (50 mL) and
dried (Na SO ). The removal of organic solvent followed by
(
(
10) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
11) Krause, M.; Ligneau, X.; Stark, H.; Garbarg, M.; Schwartz,
J.-C.; Schunack, W. J. Med. Chem. 1998, 41, 4171.
(
(
(
(
12) Negishi, E.-i, Kotora, M.; Xu, C. J. Org. Chem. 1997, 62,
2
4
8
957.
13) Knochel, P.; Peria, J. J. A.; Jones, P. Tetrahedron 1998, 54,
275.
14) Palmgren, A.; Thorarensen, A.; Bäckvall, J.-E. J. Org.Chem.
988, 63, 3764.
15) Betzemeier, B.; Knochel, P. Angew. Chem. Int. Ed. Engl.
997, 36, 2623.
column chromatographic purification (silica gel, 230-420
mesh, 5% ethyl acetate in hexane) gave pure product (0.32 g,
95%) as a pale yellow solid: mp 126-128 °C; IR (KBr) 3307,
8
-1 1
2925, 2855, 2101, 1488, 1398 cm ; H NMR (500 MHz,
1
CDCl ) δ 7.30 (s, 1 H), 6.49 (s, 1 H), 3.61 (t, J = 6 Hz, 1 H),
3
3.10 (s, 1 H), 2.77-2.75 (m, 13 H), 0.96 (s, 9 H), 0.87 (s, 9 H),
0.71 (s, 3 H), 0.22 (s, 6 H), 0.05 (s, 6 H). Anal. Calcd for
C H O Si : C, 73.22; H, 9.98. Found: C, 73.14; H, 10.26.
1
(16) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441.
(17) Kristensen, J.; Begtrup, M.; Vedsø,P. Synthesis 1998, 1604.
(18) The organozinc bromides were prepared from the
3
2
52
2
2
corresponding Grignard reagent and anhydrous ZnBr in dry
Article Identifier:
2
THF.
1437-2096,E;1999,0,07,1097,1099,ftx,en;S02399ST.pdf
Synlett 1999, No. 07, 1097–1099 ISSN 0936-5214 © Thieme Stuttgart · New York