Novel medium ring sized estradiol derivatives by intramolecular Heck reactions

Article abstract of DOI:10.1055/s-2003-40832

New steroids with a seven-, eight- or nine-membered D-ring have been synthesized from a D-seco-estrone derivative by a Grignard and an intramolecular Heck reaction.

Full text of DOI:10.1055/s-2003-40832

1494
LETTER
Novel Medium Ring Sized Estradiol Derivatives by Intramolecular Heck
Reactions
Novel Medium
u
Ring Sized E
t
stradio
z
l
D
erivatives F. Tietze,*a Konrad M. Sommer,a Gyula Schneider,*b Pál Tapolcsányi,b János Wölfling,b Peter Müller,c Mathias
Noltemeyer,c Heinrich Terlaud
a
Institut für Organische Chemie, Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
b
Department of Organic Chemistry, University of Szeged, Dóm tér 8, 6720 Szeged, Hungary
Fax +36(62)544200; E-mail: schneider@chem.u-szeged.hu
c
Institut für Anorganische Chemie, Universität Göttingen, Tammannstr. 4, 37077 Göttingen, Germany
Fax +49(551)393373; E-mail: m.noltemeyer@gmx.de; E-mail: peterm@shelx.uni-ac.gwdg.de
d
Max-Planck-Institut für Experimentelle Medizin, Hermann-Rein-Straße 3, 37075 Göttingen, Germany
Fax +49(551)3899475; E-mail: hterlau@gwdg.de
Received 7 April 2003
O
Abstract: New steroids with a seven-, eight- or nine-membered
D-ring have been synthesized from a D-seco-estrone derivative by a
Grignard and an intramolecular Heck reaction.
Br
H
H
Br
Key words: carbocycles, steroids, Grignard reactions, Heck reac-
tion, estradiol derivatives
( )n
H
H
2: n = 1
3: n = 0
MeO
1
The Heck reaction is a powerful synthetic tool for the con-
struction of carbo- and heterocyclic compounds.1 Recent-
ly, we have shown, how this transformation can be
successfully used in the synthesis of estradiols, D-homo-
estradiols, aza-heterocycles and 19-nor-steroids.2
a
2 or 3
O
OR
17
( )n
( )n
c
Here, we describe novel estrone derivatives, which are ob-
tained from the D-seco-estrone derivative 13 by a Grignard
and an intramolecular Heck reaction. The new compounds
contain seven-, eight- and nine-membered D-ring systems.
There are only very few examples where seven-,4–8
eight,8,9 and nine-membered8,10 carbocycles were pre-
pared by a Heck reaction.
Br
Br
H
H
R = H: 4 (17S), 5 (17R)
n = 1 (94%)
10: n = 1 (95%)
11: n = 0 (80%)
6 (17S), 7 (17R)
n = 0 (41%)
b
Grignard reaction of 1 with the Mg-compound derived
from 211–14 gave the secondary alcohols 4 and 5 as a 1.9:1
mixture of the two diastereomers in 94% yield, which
were separated by column chromatography (Scheme 1).
R = Ac: 8 (17S) n = 1 (92%)
9 (17R) n = 1 (94%)
Scheme 1 Synthesis of 4–11
Reaction conditions: a) Mg/Et2O; b) Ac2O/pyridine; c) Dess–Martin
reagent/CH2Cl2.
In a similar way, the alcohols 6 and 7 were obtained from
1 in 41% yield and a 1.8:1 ratio with the Grignard reagent
derived from 3.15 Oxidation of 4 and 5 led to the ketone 10
and that of 6 and 7 to the ketone 11 in 95% and 80% yield,
respectively. In addition, we also prepared the acetates 8
and 9 in 92% and 94% yield from 4 and 5 using acetic
anhydride/pyridine. To our surprise, the Heck reaction
of the free alcohol 4 employing the palladacycle trans-
di(m-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipalla-
dium(II)16 as a catalyst led to the nine-membered estrone
derivative 12 with an E-double bond as the main product,
which was formed by an endo attack; in addition, the two
eight-membered ring systems 13 and 15 were obtained
(Scheme 2).17
The total yield of the reaction was 45% due to the forma-
tion of some side products, which were not characterized.
We then performed the Heck reaction of the acetates 8 and
9, which provided higher yields and showed an interesting
selectivity. Thus, the acetate 8 only led to the eight-mem-
bered derivatives 14 and 16 in 65% total yield, whereas
the diastereomeric acetate 9 gave the eight-membered de-
rivative 17 in 39% and the nine-membered compound 18
in 13% yield. The best results were obtained using the ke-
tone 10, which led to 60% of the octacycle 19 together
with 14% of nonacycle 20 containing a Z-double bond.18
The Heck reaction of 11 using the palladacycle as the cat-
alyst gave the heptacycles 21 and 22 as a 4:1 mixture of
the double bond isomers in 80% yield, which could not be
separated by chromatography.
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1494,1496,ftx,en;G07303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Medium Ring Sized Estradiol Derivatives
1495
OR
16
17
H
H
OR
HO
12 R = H (20%)
Br
a
+
OR
17c
H
H
HO
4 R = H
8 R = Ac
16
H
H
HO
13 R = H (16%) exo
14 R = Ac (48%) exo
15 R = H (9%) Z
16 R = Ac (17%) Z
OAc
17c
OAc
17d
OAc
+
a
16
17
16
Br
H
H
H
H
H
HO
HO
18 (13%)
9
17 (39%)
O
O
OAc
17c
+
17d
a
16
Br
17
H
H
16
H
H
H
HO
HO
19 (60%)
20 (14%)
10
O
O
O
+
a
Br
H
H
H
H
H
HO
HO
11
22
21
21 : 22 = 4:1 (80%)
Scheme 2 Heck reaction of 4, 8 and 9–11
Reaction conditions: a) 2 mol% palladacycle, n-Bu4NOAc, DMF/CH3CN/H2O (5:5:1), 120 °C, 4 h.
The structures of 4 and 20 were determined by X-ray anal- more, reduction of the keto function in 20 led to two dia-
ysis.19 In accordance with the data of these compounds, stereomeric alcohols, none of which is identical with 12.
the structure determination of the other compounds was
performed by NMR spectroscopy employing two-dimen-
Acknowledgment
sional techniques. The configuration of the endocyclic
double bond in 12 was determined by 1H NMR spectros-
Financial support by the Hungarian Scientific Research Found
(OTKA T 042673), by the Hungarian Ministry of Education (FKFP
0110/2000), by the Hungarian-German intergovernmental S & T
program (HUN 00/036) and by the DFG (SFB 416) is gratefully
copy. The large coupling constant of J = 15.5 Hz of the
signals for the hydrogens at C-16 and C-17 confirm the E-
configuration, which is unusual in nonacycles.20 Further-
acknowledged.
Synlett 2003, No. 10, 1494–1496 © Thieme Stuttgart · New York

1496
L. F. Tietze et al.
LETTER
(18) Experimental Procedure for the Synthesis of 19 and 20:
To a degassed solution of 10 (300 mg, 0.64 mmol) and n-
Bu4NOAc (484 mg, 1.60 mmol) in DMF/CH3CN/H2O
(5:5:1) (10 mL) was added under a nitrogen atmosphere
trans-di(m-acetato)-bis[o-(di-o-tolylphosphino)-
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benzyl]dipalladium(II) (12 mg, 2 mol%) and the mixture
was stirred at 120 °C under reflux for 4 h. After cooling, H2O
(40 mL) was added; the resulting mixture was extracted with
Et2O (3 × 25 mL), washed with brine, dried over MgSO4 and
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(m, 10 H), 2.76 (d, 1 H), 2.80 (m, 2 H, 6-H), 3.58 (d, 1 H,
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H), 1.10–2.50 (m, 13 H), 2.88 (m, 2 H, 6-H), 3.12 (d, 1 H,
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Synlett 2003, No. 10, 1494–1496 © Thieme Stuttgart · New York