Efficient synthesis of an enantiopure thiasteroid by a double heck reaction

Article abstract of DOI:10.1071/CH04034

The thiaestrane 7 was synthesized by two sequential Heck reactions starting from the thiophene derivatives 8a-8c, which contain a (Z)-halogenovinyl group, and the enantiopure hydrindene 2a. The first intermolecular Pd-catalyzed reaction leads to 11a and 11b in a highly regio- and diastereoselective manner. A subsequent intramolecular Heck reaction catalyzed by the palladacycle 4 then gave the thiasteroid 7 with an unusual cis-junction of the rings B and C.

Full text of DOI:10.1071/CH04034

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CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 635–640
Efficient Synthesis of an Enantiopure Thiasteroid
by a Double Heck Reaction∗
Lutz F. Tietze,A,C Lars P. Lücke,A Felix Major,A and Peter MüllerB
A Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen,
37077 Göttingen, Germany.
B Institut für Anorganische Chemie der Georg-August-Universität Göttingen, 37077 Göttingen, Germany.
C Author to whom correspondence should be addressed (e-mail: ltietze@gwdg.de).
The thiaestrane 7 was synthesized by two sequential Heck reactions starting from the thiophene derivatives 8a–8c,
which contain a (Z)-halogenovinyl group, and the enantiopure hydrindene 2a. The first intermolecular Pd-catalyzed
reaction leads to 11a and 11b in a highly regio- and diastereoselective manner. A subsequent intramolecular Heck
reaction catalyzed by the palladacycle 4 then gave the thiasteroid 7 with an unusual cis-junction of the rings B and C.
Manuscript received: 13 February 2004.
Final version: 14 May 2004.
Natural estrogens and their synthetic analogues are of great
importance due to their pronounced biological activity,[1]
e.g. as oral contraceptives.[2] Recently, it has been shown
that estradiol 6 also acts as a ligand at the β-subunit of the
Maxi-K+ channel which is the key modulator of vascular
smooth muscle tone.[3] Therefore, at present the prepara-
tion of novel estrogens is of great research significance. In
recent years emphasis has been put on the synthesis of nor-
steroids, homosteroids, and heterocyclic steroids.[4] Along
this line several attempts have been made to introduce a thio-
phene moiety as an A-ring of the estrane skeleton, but only
racemic products using non-convergent routes were obtained.
There are several known total syntheses of steroids;[5] how-
ever, most approaches towards this class of compounds start
from naturally occurring precursors.[6] Recently, we have
developed a new highly efficient synthesis of estradiol 6 and
analoguesbasedonadoubleHeckreactionbetween2-bromo-
1-bromovinylbenzene 1 and hydrindene 2a (Scheme 1).[7] In
the first Pd-catalyzed step, the vinyl bromide moiety within
1 reacts in a regio- and stereoselective manner with the olefin
in 2a to give 3. This transformation is followed by a second
Pd-catalyzed reaction using the palladacene 4 to afford 5 con-
taining the complete steroidal skeleton along with an unusual
cis-junction of the rings B and C. Hydrogenation with accom-
panying isomerization of the benzylic stereogenic centre and
deprotection led to the enantiopure estradiol 6 in high yield
and excellent selectivity.
In this paper we describe the use of this approach for
the synthesis of the novel enantiopure thiaestrane 7. The
retrosynthetic analysis of 7 led to the doubly functionalized
(Z)-2-(2-halogenoethenyl)-3-halogenothiophenes 8a–8c and
the hydrindene 2 (Scheme 2).
The dibromothiophene derivative 8a was prepared by a
Corey–Fuchs reaction of 3-bromothiophene-2-carbaldehyde
9a.[11] The initially formed tribromide 10 was then treated
with Bun3SnH as hydride donor and Pd(PPh3)4 to allow a
selective exchange of the (E)-bromo atom for a hydrogen by
a Pd-catalyzed cross-coupling reaction (Scheme 3).[12]
The (Z)-2-(2-iodoethenyl)thiophenes 8b and 8c were
prepared by a Wittig reaction of the aldehydes 9a and 9b
with the phosphonium salt [ICH2PPh3]+·I− in the presence
of KHMDS as a base.The hydrindene 2 was synthesized from
the well-known Hajos–Wiechert ketone[13] in a five step reac-
tion sequence which includes a Pd-catalyzed rearrangement
of an allyl formate[14] to obtain the trans-annulation of the
CD-ring system.[15]
In the Pd-catalyzed reaction between 2 and 8a–8c, it was
expected that attack at the double bond within 2 would occur
from below due to the β-orientation of the angular methyl
group. Alternatively, it was not clear that a selective reaction
of the vinyl halide moiety in 8a–8c would be possible nor
could it be predicted that the C C bond formation would
take place at the more hindered C4 position in 2, as found in
the previous reaction of 1 and 2a.
Besides the synthesis of estradiol, we also prepared
the novel d-homoestradiol[8] and a novel 19-nor-steroid[9]
using this method. In addition, several aza-heterocyclic
compounds were also obtained by similar twofold Heck
approaches.[10]
Results and Discussion
The reactions of 2 and 8a–8c were performed using a
mixture of Pd(OAc)2 and PPh3 as the catalyst in either
DMF/CH3CN/H2O (5 : 5 : 1) or CH3CN in the presence of
∗ Dedicated to Professor Lewis N. Mander on the occasion of his 65th birthday.
© CSIRO 2004
10.1071/CH04034
0004-9425/04/070635

636
L. F. Tietze et al.
OBut
OBut
Br
H
Pd(OAc)2, PPh3, Bun4NOAc,
DMF/MeCN/H2O, 80ºC, 7h
Br
Br
ꢀ
H
61%
MeO
MeO
H
1
2a
3
4, Bun4NOAc,
DMF/MeCN/H2O,
115ºC, 4.5h
99%
OH
OBut
(oTol)2
O
O
P
H
H
Pd
Pd
P
O
O
H
H
H
H
(oTol)2
HO
MeO
4
6
5
Scheme 1. Synthesis of estradiol 6 by a twofold Heck reaction.[7]
OR
OR
X
Y
8a
8b
8c
X ꢁ Y ꢁ Br
X ꢁ Br, Y ꢁ I
X ꢁ Y ꢁ I
H
ꢀ
H
H
S
H
S
7
2
X
9a X ꢁ Br
9b X ꢁ I
O
S
Scheme 2. Retrosynthesis of thiasteroid 7.
Bun3SnH,
Br
Br
Br
CBr4, PPh3,
CH2Cl2, room temp., 1h
cat. Pd(PPh3)4,
Br
Br
toluene, room temp., 1.5h
O
Br
85%
91%
S
S
S
9a
10
Scheme 3. Synthesis of dibromothiophene derivative 8a.
8a
tetrabutylammonium acetate or silver phosphate (Scheme 4,
Table 1).
isomerization, caused by a readdition of the H–Pd–X species
and consecutive β-hydride elimination, did not improve
the situation. Furthermore, pure (Z)-product could not be
obtained by chromatography with silver-impregnated silica
gel[16] or by HPLC. Hence, the following step was conducted
using the crude mixture of 11.
In the formation of 11 a migration of the double bond in the
hydrindene moiety was not observed. In addition, as required,
8 reacts exclusively at the vinylhalide and not at the halo-
thiophene moiety. Moreover, the C C bond formation seems
to be very selective, since the only product obtained was that
of an addition at the 4-position within 2a. We assume that the
insertion of the primarily formed Pd–alkenyl species occurs
unselectively at both ends of the double bond in 2a to give the
intermediates A and B (Scheme 5). However, the formation
The best results were obtained for the reaction of 2a and
8a to afford 11a in 83% yield, while the use of 2a and 8b
yielded 11a in 73%, and the use of 2a and 8c provided
11b in 53% yield. We also investigated the transformation
of 8a with the hydrindene 2b, containing a free hydroxyl
group, to provide evidence whether the protecting group is
necessary: unfortunately, here only 22% yield of the corre-
sponding product 12 was obtained. However, in the products
from all reactions a partial isomerization of the exocyclic
double bond was observed (approx. 10% for the first and
second reaction and 30% in the third reaction), even under
strict exclusion of light. The use of silver salts such as
Ag3PO4, known for their ability to suppress double-bond

Synthesis of an Enantiopure Thiasteroid
637
OR
H
OR
X
X
Y
Pd(OAc)2, PPh3
H
ꢀ
S
S
H
R ꢁ But
R ꢁ H
X ꢁ Br, R ꢁ But
X ꢁ I, R ꢁ But
X ꢁ Br, R ꢁ H
8a
8b
8c
2a
2b
11a
11b
12
X ꢁ Y ꢁ Br
X ꢁ Br, Y ꢁ I
X ꢁ Y ꢁ I
Scheme 4. Intermolecular Heck reaction of 8a–8c and 2.
Table 1. Conditions for Heck reaction of 8a–8c and 2
Entry Substrates Catalyst
Solvent
Additive
Product Yield [%] (Z)/(E) Ratio
1
2
3
4
8a/2a
8b/2a
8c/2a
8a/2b
10 mol% Pd(OAc)2,
20 mol% PPh3, 70◦C, 16 h
10 mol% Pd(OAc)2,
80◦C, 20 h
DMF/MeCN/H2O Bun4NOAc
(2.5 equiv.)
11a
11a
11b
12
83
73
53
22
10 : 1
10 : 1
3 : 1
–
MeCN
Ag3PO4
(2.6 equiv.)
Ag3PO4
10 mol% Pd(OAc)2,
MeCN
80◦C, 15 h
(1.3 equiv.)
10 mol% Pd(OAc)2,
20 mol% PPh3, 70◦C, 16 h
DMF/MeCN/H2O Bun4NOAc
(2.5 equiv.)
CH3
OBut
OBut
H
H
Fast
H
H
–HPdX
H
7
R
R
PdXLn
ꢂ-side (unfavoured)
H
H
11
CH3
OBut
eq
ax
H
5
2a
A
H
4
H
H
H
ꢀ
R-PdLn-X (from 8)
OBut
H3C
H
OBut
R
Slow
H
H
–HPdX
eq
6
R
ꢃ-side (favoured)
LnXPd
H
ax
B
Scheme 5. Diastereo- and regioselectivity of the intermolecular Heck reaction of 2a and 8a–8c.
ofA and B should be reversible, and since B would exist in a
boat conformation from which a β-hydride elimination is not
favoured, 11 formed via A is the only product.
OBut
OBut
4, Bun4NOAc,
DMF/MeCN/H2O,
130ºC, 19–24h
H
H
X
For the cyclization of 11a and 11b to provide 7, sev-
eral catalytic Pd systems were screened. The palladacycle 4
developed by Herrmann and Beller[17] was the only catalyst
to allow the transformation. Treating crude 11a with 2 mol%
of 4 and tetrabutylammonium acetate as base in a mixture of
DMF/CH3CN/H2O (5 : 5 : 1) at 130◦C led to the thiaestrane
7 in 50% yield (Scheme 6). Furthermore, crude 11b was also
transformed to 7 in a slightly lower yield, presumably due to
the higher content of (E)-11b which did not cyclize. Sepa-
ration of the thiasteroid 7 from the (E)-configured substrate
was easily performed by standard silica gel chromatography.
The formation of 7 from 2a and 8a can also be performed
in a domino process.[18] Thus, 2a and 8a were heated in the
H
H
H
43–50%
S
S
11a X ꢁ Br
11b X ꢁ I
7
Scheme 6. Intramolecular Heck reaction of 11a/11b.
presence of Pd(OAc)2/PPh3 and palladacycle 4 initially for
16 h at 70◦C and afterwards at 130◦C for 24 h. However, the
yield for this domino process was only 16% which is lower
than the overall yield in the stepwise mode.

638
L. F. Tietze et al.
The relative configuration of 7 with the unusual cis-
(dddd, J 10.0, 6.0, 3.0, 1.5, 1 H, H5ꢀ), 5.44 (dd, J 11.5, 10.5, 1 H, H2ꢀꢀ),
5.73 (dddd, J 10.0, 5.0, 2.5, 2.0, 1 H, H6ꢀ), 6.59 (d, J 11.5, 1 H, H1ꢀꢀ),
6.99 (d, J 5.5, 1 H, H4), 7.22 (d, J 5.5, 1 H, H5). δC (50.3 MHz, CDCl3)
11.5 (7aꢀ-CH3), 24.6 (C3ꢀ), 28.8 [OC(CH3)3], 30.5 (C2ꢀ), 38.79 (C7ꢀ),
39.8 (C4ꢀ), 41.3 (C7aꢀ), 46.8 (C3aꢀ), 72.3 [OC(CH3)3], 80.6 (C1ꢀ), 111.8
(C3), 120.5 (C1ꢀꢀ), 124.7 (C4), 127.8 (C6ꢀ), 128.1 (C5ꢀ), 129.9 (C2ꢀꢀ),
134.1 (C2), 135.1 (C5). m/z (EI, 70 eV) 396.2 (28%, [M+]), 339.1 (18,
[M+ – C4H9]), 321.1 (6, [M+ – C4H9O]), 259.2 (12, [M+ – Br – C4H9]),
241.2 (23, [M+ – Br – C4H9O]), 79.1 (8, [Br+]), 57.1 (100, [C4H+9 ]),
41.1 (22, [C3H+5 ]). Found: 394.0966. Calc. for C20H27BrOS: 394.0966.
connection of the BC-ring system was proven by X-ray
structural analysis.[19]
To conclude, the novel enantiopure 4-thiaestrane 7 was
synthesized stereoselectively in a highly efficient way by
forming the B-ring using two successive Heck reactions. The
connection between ring B and ring C has an unusual cis-
configuration and the two double bonds in the C5 and C10
positions provide the opportunity for further derivatization.
Intermolecular Heck Reaction of 8a and 2b
Experimental
A solution of the hydrindene 2b (6.0 mg, 39 µmol), 8a (16.0 mg,
59.1 µmol), and Bun4NOAc (30.0 mg, 99.0 µmol) in DMF/CH3CN/H2O
(5 : 5 : 1, 1 mL) was thoroughly degassed and warmed to 40◦C. Subse-
quently, Pd(OAc)2 (1.0 mg, 10 mol%) and PPh3 (2.0 mg, 20 mol%) were
added under an atmosphere of argon. The reaction mixture was heated
at 70◦C with stirring for 16 h with exclusion of light.After usual workup
(see above) and column chromatography (pentane) on SiO2, the desired
product 12 (3.0 mg, 8.8 µmol, 22%) was obtained as a mixture of (Z)-12
and (E)-12 (colourless oil).
General
All reactions were performed in oven-dried glassware under an argon
atmosphere. Solvents were degassed using the freeze–pump–thaw
method or by bubbling argon through the solution for 30 min. TLC was
performed on precoated silica gel SIL G/UV254 plates (Macherey, Nagel
& Co.), and silica gel 32–63 (0.032–0.064 mm; Merck) was used for
column chromatography. Melting points were determined on a Mettler
FP61. Optical rotations were determined on a Perkin–Elmer 241. IR
spectra were determined on a Bruker IFS 25. UV-vis spectra were deter-
mined on a Perkin–Elmer Lambda 9. NMR spectra were determined
on Varian VXR 200 (200 MHz, 1H), Bruker AM-300 (300 and 75 MHz
for 1H and 13C, respectively), Varian VXR-500 (500 and 125 MHz for
1H and 13C, respectively), and VXR-600 (600 and 150 MHz for 1H and
13C, respectively) instruments. For 1H and 13C NMR, CDCl3 and C6D6
were used as solvents andTMS as internal standard. Chemical shifts are
reported on the δ scale and signals are quoted as s (singlet), d (doublet),
t (triplet), q (quadruplet), m (multiplet), and br (broad). Mass spectra
were determined on a Varian MAT 311A (70 eV, EI, DCI) instrument.
HRMS were determined on a Varian MAT 731 instrument. Elemental
analyses were determined by the Mikroanalytisches Labor des Instituts
für Organische und Biomolekulare Chemie Göttingen.
(1R,3aS,4S,7aS)-4-(Z)-[2-(3-Bromothiophen-2-yl)vinyl]-7a-methyl-2,
3,3a,4,7,7a-hexahydro-1H-inden-1-ol 12
RF 0.59 (pentane/tert-butyl methyl ether, 1 : 1). δH (300 MHz, CDCl3)
0.83 (s, 3 H, 7aꢀ-CH3), 1.17–1.70 (m, 5 H, 2 × H2ꢀ, H23ꢀ, 1ꢀ-OH), 1.91–
2.15 (m, 3 H, H3aꢀ, H27ꢀ), 3.43 (mc, 1 H, H4ꢀ), 3.78 (t, J 8.6, 1 H,
H1ꢀ), 5.38–5.44 (m, 1 H, H5ꢀ), 5.41 (dd, J 11.5, 10.4, 1 H, H2ꢀꢀ), 5.72
(dddd, J 9.8, 5.2, 2.6, 2.0, 1 H, H6ꢀ), 6.57 (d, J 11.5, 1 H, H1ꢀꢀ), 6.97
(d, J 5.4, 1 H, H4), 7.21 (d, J 5.4, 1 H, H5). δC (50.3 MHz, CDCl3) 10.7
(7aꢀ-CH3), 24.3 (C3ꢀ), 30.1 (C2ꢀ), 38.2 (C7ꢀ), 39.6 (C4ꢀ), 42.0 (C7aꢀ),
46.1 (C3aꢀ), 81.8 (C1ꢀ), 109.2 (C3), 121.6 (C1ꢀꢀ), 123.2 (C4), 127.0
(C6ꢀ), 128.5 (C5ꢀ), 130.5 (C2ꢀ), 135.1 (C5), 137.0 (C2). m/z (EI, 70 eV)
340.1 (24%, [M+]), 323.1 (0.5, [M+ – OH]), 281.0 (0.5, [M+ – C4H9]),
259.1 (3, [M+ – Br]), 241.1 (3, [M+ – Br – H2O]), 189.9 (8, [M+ – Br –
C4H9O]), 41.1 (6, [C3H+5 ]).
Intermolecular Heck Reaction of 8a/8b and 2a
A solution of hydrindene 2a (709 mg, 3.40 mmol), dibromothio-
phene 8a (1.37 g, 5.12 mmol), and Bun4NOAc (2.56 g, 8.51 mmol)
in DMF/CH3CN/H2O (5 : 5 : 1, 20 mL) was thoroughly degassed and
warmed to 40◦C. Subsequently, triphenylphosphane (179 mg, 20 mol%)
and Pd(OAc)2 (76.0 mg, 10 mol%) were added under an atmosphere
of argon. The reaction mixture was heated at 70◦C and stirred for
16 h with the exclusion of light. After cooling the solution to room
temperature, diethyl ether (20 mL) and water (10 mL) were added, the
layers separated, and the aqueous phase was extracted with diethyl
ether (3 × 10 mL).The combined organic layers were washed with brine
(10 mL), dried (MgSO4), and concentrated under vacuum.After column
chromatography (pentane/tert-butyl methyl ether, 100 : 1) on SiO2, the
desiredproduct(1.11 g, 2.81 mmol, 83%)wasobtainedasaninseparable
mixture of (Z)-11a and (E)-11a in a 10 : 1 ratio.
Intermolecular Heck Reaction of 8c and 2a
A solution of hydrindene 2a (416 mg, 2.00 mmol) and diiodothiophene
8c (362 mg, 1.00 mmol) in CH3CN (20 mL) was thoroughly degassed
and warmed to 40◦C. Subsequently, Pd(OAc)2 (22.4 mg, 10 mol%)
and Ag3PO4 (544 mg, 1.30 mmol) were added under an atmosphere
of argon. The reaction mixture was heated at 80◦C with stirring for 15 h
under exclusion of light. After usual workup (see above) and column
chromatography (pentane) on SiO2, the desired product 11b (43.0 mg,
0.11 mmol, 53%) was obtained as a mixture of (Z)-11b and (E)-11b
(yellow oil) in a 3 : 1 ratio.
Pd(OAc)2 (6.0 mg, 10 mol%) and Ag3PO4 (265 mg, 0.64 mmol)
were added to a degassed solution of 8b (79.0 mg, 0.25 mmol) and
2a (106 mg, 0.58 mmol) in CH3CN (5 mL) at 40◦C under an atmo-
sphere of argon. The reaction mixture was heated at 80◦C for 20 h with
the exclusion of light. After the usual workup (see above) and column
chromatography (pentane/tert-butyl methyl ether, 1 : 100) on SiO2, the
desired product 11a (43.0 mg, 0.11 mmol, 73%) was obtained as an
inseparable mixture of (Z)-11a and (E)-11a in a 10 : 1 ratio.
(1R,3aS,4S,7aS)-3-Iodo-2-(Z)-[2-[1-tert-butoxy-7a-methyl-2,3,
3a,4,7,7a-hexahydro-1H-inden-4-yl]ethenyl]thiophene 11b
RF 0.18(pentane/tert-butylmethylether, 100 : 1). λmax/nm(CH3CN, log
ε)197.0(4.26), 279.0(4.08), 329.0(2.84). νmax/cm−1 (KBr)3082, 3016,
1470, 1077, 859, 699. δH (500 MHz, CDCl3) 1.05 (s, 3 H, 7aꢀ-CH3), 1.07
(s, 9 H, OBut), 1.14–1.80 (m, 6 H, H2ꢀ, H3ꢀ, H7ꢀ), 1.95–2.09 (m, 2 H,
H3aꢀ), 3.26 (t, J 8.3, 1 H, H1ꢀ), 3.65 (dd, J 10.5, 1.5, 1 H, H4ꢀ), 5.41 (dd,
J 11.5, 10.5, 1 H, H2ꢀꢀ), 5.54 (dddd, J 10.0, 6.0, 3.0, 1.5, 1 H, H5ꢀ), 5.69
(dddd, J 10.0, 7.5, 3.0, 2.0, 1 H, H6ꢀ), 6.53 (dd, J 5.3, 0.6, 1 H, H4), 6.71
(d, J 11.5, 1 H, H1ꢀꢀ), 6.77 (d, J 5.3, 1 H, H5). δC (50.3 MHz, CDCl3)
11.5 (7aꢀ-CH3), 24.6 (C2ꢀ), 28.7 [OC(CH3)3], 30.5 (C3ꢀ), 38.7 (C7ꢀ),
39.6 (C4ꢀ), 41.3 (C7aꢀ), 46.7 (C3aꢀ), 72.2 [OC(CH3)3], 80.5 (C1ꢀ), 83.4
(C3), 123.4 (C1ꢀꢀ), 126.1 (C5), 127.7, 128.0 (C5ꢀ, C6ꢀ), 134.7 (C2ꢀꢀ),
136.0 (C4), 137.5 (C2). m/z (EI, 70 eV) 442.1 (58%, [M+]), 385.0 (32,
[M+ – C4H9]), 314.2 (9, [M+ – I]), 258.1 (20, [M+ – I – C4H9]), 241.1
(30, [M+ – I – C4H9O]), 57.0 (100, [C4H9+]), 41.0 (20, [C3H+5 ]). Found:
442.0827. Calc. for C20H27IOS: 442.0827.
(1R,3aS,4S,7aS)-3-Bromo-2-(Z)-[2-[1-tert-butoxy-7a-methyl-2,3,
3a,4,7,7a-hexahydro-1H-inden-4-yl]ethenyl]thiophene 11a
RF 0.32 (pentane/tert-butyl methyl ether, 100 : 1). λmax/nm (CH3CN,
log ε) 282.5 (4.13), 371.0 (2.94). νmax/cm−1 (KBr) 3017, 2971, 1460,
1361, 1018, 700. δH (300 MHz, CDCl3) 0.84 (s, 3 H, 7aꢀ-CH3), 1.16
(s, 9 H, OBut), 1.32–1.66 (m, 3 H, 2 × H2ꢀ, Ha3ꢀ), 1.82–1.96 (m, 2 H,
H3bꢀ, H3aꢀ), 2.06 (dddd, J 17.0, 5.0, 3.5, 1.5, 1 H, H7ꢀa), 2.31–2.44
(m,1 H, H7ꢀb), 3.39–3.47 (mc, 1 H, H4ꢀ), 3.52 (t, J 8.5, 1 H, H1ꢀ), 5.41

Synthesis of an Enantiopure Thiasteroid
639
Synthesis of 7 by Intramolecular Heck Reaction of 11a and 11b
[2] C. Djerassi, Science 1989, 245, 356.
[3] M. A. Valverde, P. Rojas, J. Amigo, D. Cosmelli, P. Orio,
M. I. Bahamonde, G. E. Mann, C. Vergara, et al., Science 1999,
285, 1929. doi:10.1126/SCIENCE.285.5435.1929
[4] (a) A. Magyar, B. Schönecker, J. Wölfling, G. Schneider,
W. Günther, H. Görls, Tetrahedron: Asymmetry 2003, 14, 1925.
doi:10.1016/S0957-4166(03)00362-8
(a) Palladacycle 4 (4.0 mg, 2.0 mol%) was added to a degassed solu-
tion of 11a (90 mg, 0.22 mmol) and Bun4NOAc (172 mg, 0.57 mmol) in
DMF/CH3CN/H2O (5 : 5 : 1, 6 mL) under an atmosphere of argon. The
reaction mixture was heated in a sealed vessel to 130◦C and stirred for
19 h with exclusion of light. After cooling to room temperature, diethyl
ether (20 mL) and water (10 mL) were added, the layers separated,
and the aqueous phase was extracted with diethyl ether (3 × 10 mL).
The combined organic layers were washed with brine (10 mL), dried
(MgSO4), and concentrated under vacuum. After column chromatogra-
phy (pentane) on SiO2, the desired product 7 (36 mg, 0.11 mmol, 50%)
was obtained as white-yellow crystals.
(b) Palladacycle 4 (5.0 mg, 2.0 mol%) was added to a degassed solu-
tion of 11b (112 mg, 0.25 mmol) and Bun4NOAc (153 mg, 0.51 mmol) in
DMF/CH3CN/H2O (5 : 5 : 1, 5.5 mL) under an atmosphere of argon.The
reaction mixture was heated in a sealed vessel to 130◦C and stirred for
24 h with exclusion of light. After usual workup and column chromato-
graphy (pentane) on SiO2, the desired product 7 (34.0 mg, 0.11 mmol,
43%) was obtained as white-yellow crystals.
(b) L. F. Tietze, K. M. Sommer, G. Schneider, P. Tapolcsányi,
J. Wölfling, P. Müller, M. Noltemeyer, H. Terlau, Synlett 2003,
10, 1494. doi:10.1055/S-2003-40832
(c) L. F. Tietze, J. M. Wiegand, C. Vock, J. Organomet. Chem.
2003, 687, 346. doi:10.1016/S0022-328X(03)00720-4
(d) J. H. Rigby, N. C. Warshakoon, A. J. Payen, J. Am. Chem.
Soc. 1999, 121, 8237. doi:10.1021/JA991016W
(e) J. Wölfling, É. Frank, G. Schneider, M. T. Bes, L. F. Tietze,
Synlett 1998, 1205.
(f) R. Grigg, R. Rasul, V. Savic, Tetrahedron Lett. 1997, 38,
1825. doi:10.1016/S0040-4039(97)00161-5
[5] Total syntheses of steroids:
(a) X. Jiang, D. F. Covey, J. Org. Chem. 2002, 67, 4893.
doi:10.1021/JO025535K
(b) W. Yu, Z. Jin, J. Am. Chem. Soc. 2002, 124, 6576. doi:
10.1021/JA012119T
(–)-A-nor-17-tert-Butoxy-4-thia-9β-estra-2,5(10),6,11(12)-
pentaene 7
RF 0.22 (pentane/tert-butyl methyl ether, 100 : 1), mp 112–113◦C,
[α]2D0 −78.4 (c 0.25, CHCl3). λmax/nm (CH3CN, log ε) 234.5 (3.73),
288.0 (3.89), 297.5 (3.92). νmax/cm−1 3095, 2971, 1078, 718. δH 0.95
(s, 3 H, H18), 1.02 (s, 9 H, 17-OBut), 1.07–1.50 (m, 3 H, 2 × H15,
Ha16), 1.54–1.68 (mc, 1 H, Hb16), 1.82 (dt, J 12.9, 6.5, 1 H, H14), 2.54
(ddd, J 8.6, 5.8, 2.5, 1 H, H8), 3.16 (dd, J 8.6, 7.2, 1 H, H17), 3.68 (dd,
J 8.6, 4.4, 1 H, H9), 5.56 (dd, J 10.0, 5.8, 1 H, H7), 5.89 (dd, J 10.0,
4.4, 1 H, H11), 6.13 (dd, J 10.0, 1.8, 1 H, H12), 6.29 (d, J 10.0, 1 H,
H6), 6.75 (d, J 5.2, 1 H, H2), 6.80 (d, J 5.2, 1 H, H3). δC (150 MHz,
C6D6) 15.1 (C18), 23.2 (C15*), 28.8 (OC(CH3)3), 32.0 (C16*), 34.4
(C8), 37.6 (C9), 41.3 (C14), 44.3 (C13), 72.2 (OC(CH3), 76.4 (C17),
119.5 (C6), 122.4 (C2), 125.8 (C11), 126.9 (C3), 127.4 (C7), 132.7 (C-
5), 135.9 (C-12), 136.4 (C-10); resonances marked with an asterisk may
(c) F. Cachoux, M. Ibrahim-Ouali, M. Santelli, Tetrahedron
Lett. 2001, 42, 843. doi:10.1016/S0040-4039(00)02118-3
(d) D. Fortin, F. Gaudette, E. Marsault, P. Deslongchamps, Tetra-
hedron 2001, 57, 4167. doi:10.1016/S0040-4020(01)00290-3
(e) W. S. Johnson, W. R. Bartlett, B. A. Czeskis, A. Gautier,
C. H. Lee, R. Lemoine, E. J. Leopold, G. R. Luedtke,
K. J. Bancroft, J. Org. Chem. 1999, 64, 9587. doi:10.1021/
JO991196S
(f) L. Quellet, P. Langlois, P. Deslongchamps, Synlett 1997, 689.
(g) G. Quinkert, M. del Grosso, A. Döring, W. Döring,
R. I. Schenkel, M. Bauch, G. T. Dambacher, J. W. Bats,
et al., Helv. Chim. Acta 1995, 78, 1345.
(h) P. A. Wender, T. E. Smith, J. Org. Chem. 1995, 60, 2962.
(i) T. Takahashi, K. Shimizu, T. Doi, J. Tsuji, Y. Fukazawa,
J. Am. Chem. Soc. 1988, 110, 2674.
(j) S. H. Lecker, N. H. Nguyen, K. P. C. Vollhardt, J. Am.
Chem. Soc. 1986, 108, 856.
be interchanged. m/z (EI, 70 eV) 314.2 (47%, [M+]), 257.1+(44, [M+
–
C4H9]), 239.1 (100, [M+ – C4H9 – H2O]), 57.0 (66, [C4H9 ]). Found:
C 76.2, H 8.1. Calc. for C20H26OS: C 76.4, H 8.3%.
Domino Heck Reaction of 8a and 2a
(k) K. P. C. Vollhardt, in Strategies and Tactics in Organic Syn-
thesis (Ed. T. Lindberg) 1984, pp. 299–324 (Academic Press:
Orlando, FL).
(l) T. Kametani, H. Nemoto, Tetrahedron 1981, 37, 3. doi:
10.1016/S0040-4020(01)97707-5
A solution of hydrindene 2a (100 mg, 0.48 mmol), dibromothio-
phene 8a (154 mg, 0.58 mmol), and Bun4NOAc (362 mg, 1.20 mmol)
in DMF/CH3CN/H2O (5 : 5 : 1, 5 mL) was thoroughly degassed and
warmed to 40◦C in a sealed vessel. PPh3 (25.0 mg, 20 mol%), Pd(OAc)2
(11.0 mg, 10 mol%), and palladacycle 4 (9.00 mg, 2 mol%) were added
subsequent under an atmosphere of argon. The reaction mixture was
heated in a sealed vessel at 70◦C for 16 h and then at 130◦C for 24 h.
After usual workup (see above) and column chromatography (pentane)
on SiO2, 7 (24 mg, 7.64 µmol, 16%) was obtained as white-yellow
crystals.
[6] (a) J. Wölfling, É. Frank, G. Schneider, L. F. Tietze, Eur. J.
Org. Chem. 2004, 90. doi:10.1002/EJOC.200300500
(b) L.-W. Guo, W. K. Wilson, J. Pang, C. H. L. Shackleton,
Steroids 2003, 68, 31. doi:10.1016/S0039-128X(02)00113-7
(c) J. Wölfling, E. Mernyák, É. Frank, G. Falkay,
Á. Márki, R. Minorics, G. Schneider, Steroids 2003, 68, 277.
doi:10.1016/S0039-128X(02)00181-2
Accessory Materials
(d) S. Stavber, M. Jereb, M. Zupan, Synthesis 2002, 2609.
doi:10.1055/S-2002-35625
(e) É. Frank, J. Wölfling, B. Aukszi, V. König, T. R. Schneider,
G. Schneider, Tetrahedron 2002, 58, 6843. doi:10.1016/S0040-
4020(02)00741-X
Experimental procedures with NMR assignments for com-
pounds 8a–8c and 10 are available from the author or, until
July 2009, the Australian Journal of Chemistry.
(f) V. A. Khripach, V. N. Zhabinskii, D. N. Tsavlovskii,
O. A. Drachenova, G. V. Ivanova, O. V. Konstantinova,
M. I. Zavadskaya, A. S. Lyakhov, et al., Steroids 2001, 66,
569. doi:10.1016/S0039-128X(00)00222-1
(g) P. Maurin, M. Ibrahim-Ouali, M. Santelli, Tetrahedron Lett.
2001, 42, 847. doi:10.1016/S0040-4039(00)02119-5
(h) J. R. Hanson, Nat. Prod. Rep. 1999, 16, 607. doi:10.1039/
A808399A
Acknowledgments
ThisworkwassupportedbytheDeutscheForschungsgemein-
schaft(SFB416)andtheFondsderChemischenIndustrie.We
thank BASF, Bayer, Degussa, and Schering for their generous
gifts of chemicals.
[7] (a) L. F. Tietze, T. Nöbel, M. Spescha, J. Am. Chem. Soc. 1998,
120, 8971. doi:10.1021/JA981539O
References
[1] G. M. Anstead, K. E. Carlson, J. A. Katzenellenbogen, Steroids
1997, 62, 268. doi:10.1016/S0039-128X(96)00242-5
(b) L. F. Tietze, T. Nöbel, M. Spescha, Angew. Chem. Int. Ed.
Engl. 1996, 35, 2259. doi:10.1002/ANIE.199622591

640
L. F. Tietze et al.
[8] L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2000, 1827.
[15] For an excellent review of the synthesis of trans-hydrindanes
and their application in steroid and vitamin D synthesis see:
P. Jankowski, S. Marczak, J. Wicha, Tetrahedron 1998, 54,
12071. doi:10.1016/S0040-4020(98)00570-5
[16] C. M. Williams, L. N. Mander, Tetrahedron 2001, 57, 425.
doi:10.1016/S0040-4020(00)00927-3
doi:10.1002/(SICI)1099-0690(200005)2000:9<1827::AID-EJ
OC1827>3.0.CO;2-V
[9] L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2001, 1619.
doi:10.1002/1099-0690(200105)2001:9<1619::AID-EJOC1619
>3.3.CO;2-K
[10] L. F. Tietze, R. Ferraccioli, Synlett 1998, 145.
[11] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769. doi:
10.1016/S0040-4039(01)94157-7
[17] (a) W.A. Herrmann, C. Broßmer, C. P. Reisinger,T. H. Riermeier,
K. Öfele, M. Beller, Chem. Eur. J. 1997, 3, 1357.
(b) W. A. Herrmann, C. Broßmer, K. Öfele, C. P. Reisinger,
T. Priermeier, M. Beller, H. Fischer, Angew. Chem. Int. Ed.
Engl. 1995, 34, 1844. doi:10.1002/ANIE.199518441
[18] (a) L. F. Tietze, Chem. Rev. 1996, 96, 115. doi:10.1021/
CR950027E
[12] (a) J. Uenishi, R. Kawahama, O. Yonemitsu, A. Wada, M. Ito,
Angew. Chem. Int. Ed. 1998, 37, 320. doi: 10.1002/(SICI)1521-
3773(19980216)37:3<320::AID-ANIE320>3.0.CO;2-4
(b) J. Uenishi, R. Kawahama, O. Yonemitsu, J. Tsuji, J. Org.
Chem. 1996, 61, 5716. doi:10.1021/JO961013R
(c) J. Uenishi, R. Kawahama, Y. Shiga, O. Yonemitsu,
J. Tsuji, Tetrahedron Lett. 1996, 37, 6759. doi:10.1016/S0040-
4039(96)01461-X
[13] (a) Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615.
(b) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl.
1971, 10, 496. doi:10.1002/ANIE.197104961
[14] (a) J. Tsuji, T. Mandai, Synthesis 1996, 1. doi:10.1055/S-
1996-4175
(b) L. F. Tietze, U. Beifuss, Angew. Chem. Int. Ed. Engl. 1993,
32, 131. doi:10.1002/ANIE.199301313
[19] Crystallographic data (excluding structure factors) for the struc-
ture of 7 reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC-230286. Copies of the data can be
obtained free of charge on application to the CCDC (e-mail:
deposit@ccdc.cam.ac.uk).
(b) T. Mandai, T. Matsumoto, J. Tsuji, S. Saito, Tetrahedron
Lett. 1993, 34, 2513. doi:10.1016/S0040-4039(00)60455-0
(c) L. F. Tietze, P. S. V. Subba Rao, Synlett 1993, 291. doi:
10.1055/S-1993-22436