Stereoselective synthesis of structurally simplified cephalostatin analogues by multiple heck reactions and their biological evaluation

Article abstract of DOI:10.1002/1521-3765(20020503)8:9<2116::AID-CHEM2116>3.0.CO;2-4

The stereoselective synthesis of structurally simplified heptacyclic cephalostatin analogues 2, 3, 18-21, 31, 32 and 33 by multiple Heck reactions is described. The key step of the synthesis is a selective Heck reaction of hydrindene 7 with 12 and 25, respectively at the vinyl bromide moiety followed by the introduction of a second molecule of 7 and a twofold intramolecular Heck reaction. The obtained bissteroidal heptacyclic compounds 2 and 3, in which the central octahydrophenazine moiety of 1 is replaced by a benzene ring, contain an unusual cis-annulation of the two newly generated rings. The cytotoxicity of some of the derivatives was determined on human lung cancer cell line A 549 in HTFCA tests (Human tumor colony forming ability). They show a rather high activity with an ED₅₀ in the micro molar range.

Full text of DOI:10.1002/1521-3765(20020503)8:9<2116::AID-CHEM2116>3.0.CO;2-4

FULL PAPER
Stereoselective Synthesis of Structurally Simplified Cephalostatin Analogues
by Multiple Heck Reactions and Their Biological Evaluation
[a]
LutzF. Tietze* and Wolf-R¸diger Krahnert
Abstract: The stereoselective synthesis
of structurally simplified heptacyclic
cephalostatin analogues 2, 3, 18 21, 31,
32 and 33 by multiple Heck reactions is
described. The key step of the synthesis
is a selective Heck reaction of hydrin-
dene 7 with 12 and 25, respectively at the
vinyl bromide moiety followed by the
introduction of a second molecule of 7
and a twofold intramolecular Heck re-
action. The obtained bissteroidal hepta-
cyclic compounds 2 and 3, in which the
central octahydrophenazine moiety of 1
is replaced by a benzene ring, contain an
unusual cis-annulation of the two newly
generated rings. The cytotoxicity of
some of the derivatives was determined
on human lung cancer cell line A 549 in
HTFCA tests (Human tumor colony
forming ability). They show a rather
high activity with an ED50 in the micro
molar range.
Keywords: cephalostatin
reaction natural products
palladium ¥ steroids
¥
Heck
¥
¥
Clinical trials with cephalostatin 1 and 7 had to be stalled
because of the lack of material which was mainly obtained
from natural sources.[6] In view of this, synthesis of the
cephalostatins has been the focus of a number of recent
Introduction
In 1988, Petit et al. isolated the unusual dimeric steroid
derivative cephalostatin 1 (1) from the marine worm Ceph-
alodiscus gilchristi.[1] The compound shows a remarkably high
cytostatic activity with a GI50 value of about 2.20 Â 10À9 m in an
in vitro screening against the NCI 60 human cancer cell line.[2]
11]
studies.[7 In 1998, Fuchs et al. have reported the first total
synthesis of 1.[6, 12 15] Considering its biological activity and its
unusual bissteroidal structure as well as the lack of knowledge
of its mode of action, we became interested in the synthesis of
simplified analogues of 1. In contrast to the work of Heath-
cock, Winterfeldt and Fuchs, who built up the backbone of
cephalostatin from commercially available steroids, we herein
describe a new approach to access the bissteroidal backbone
OH
O
OH
HO
O
OH
H
H
20]
using multiple Heck reactions.[16 In a convergent strategy
N
N
H
H
the heptacycles 2 and 3 as simplified analogues of 1, in which
the central octahydrophenazine moiety is replaced by a
benzene ring, were readily accessible by a twofold intra-
molecular Heck reaction of 4 and 5, respectively. Retrosyn-
thetic analysis of 4 and 5 led to tetrafunctionalised benzenes
of type 6 and the hexahydro-1H-indene (7),[21 23] which can be
obtained in a few steps from the Hajos Wiechert ketone 8
(Scheme 1).[24] In addition to the synthesis, we also deter-
mined the cytotoxicity of the new analogues by performing
HTFCA tests (Human tumor colony forming ability).
H
O
H
O
O
1
OH
To date, 19 cephalostatins are known, all of which show a high
cytostatic activity. Together with the recently from the marine
tunikate Ritterella tokioka isolated ritterazins[3 they belong
4]
to the family of steroidal alkaloids, with a backbone composed
of two over a pyrazine ring connected steroids.[5]
Results and Discussion
[a] Prof. Dr. L. F. Tietze, Dr. W.-R. Krahnert
Institut f¸r Organische Chemie
Synthesis of heptacycle 3 and its derivatives: The acid
catalyzed reaction of dibromoterephthalaldehyde 9[26] with
ethylene glycol gave the monoacetal 10 together with the
expected diacetal in a statistical distribution (see Scheme 2).
The diacetal could be separated by column chromatography
Georg-August-Universit‰t Gˆttingen
Tammannstrasse 2, 37077 Gˆttingen (Germany)
Fax : (‡49) 551 399476
E-mail: ltietze@gwdg.de
2116
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Chem. Eur. J. 2002, 8, No. 9

2116 2125
and was subsequently transformed back into 9. Corey Fuchs
tBuO
OtBu
OtBu
16
12
16
30]
reaction[27 of 10 followed by selective debromination with
1
1
14
14
H
H
H
33]
nBu3SnH[31 exclusively furnished the (Z)-2-bromoethenyl-
12
H
H
H
H
H
H
H
H
benzene 12 in 78% overall yield. In the Heck reaction of 12
and hexahydro-1H-indene (7) we expected a selective reac-
tion of the vinyl moiety since we had previously shown that
vinyl bromides are more reactive in Pd0-catalyzed reactions
than bromoarenes.[17] Indeed, the bond formation seems to
have occurred exclusively between the vinyl moiety and C-4 in
7 with complete facial selectivity anti to the angular methyl
group to give 13 with 41% yield; unreacted 7 could be
recovered by chromatography. Neither a transformation at
C-5in 7 nor a formation of the homo coupled product of 12 or
of diastereoisomers of 13 was observed. We assume that the
high regioselectivity of the Heck reaction is due to a fast and
4
8
4
6
6
H
2
3
8
tBuO
OtBu
tBuO
OtBu
H
Br Br
H
Br
H
H
H
H
H
H
Br
4
5
tBuO
À
reversible C C bond formation between 7 and 12 followed by
a fast elimination step when the Pd atom is located at C-5of 7.
In the other case with the Pd atom at C-4 a slow elimination
can be expected due to an unfavorable orientation of the Pd
atom and the b-hydrogen.
O
OtBu
Br
R
Br
+
O
'R
H
To improve efficiency, we also tried to perform a Heck
reaction of hydrindene 7 and the deprotected 12 containing an
aldehyde moiety, which is accessible from 12 by hydrolysis of
the acetal moiety. However, only decomposed material was
obtained. For the introduction of a second molecule of
hexahydro-1H-indene (7) we therefore hydrolyzed the acetal
moiety in 13 using 80% acetic acid and the obtained aldehyde
was transformed into the (Z)-2-bromovinylbenzene deriva-
tive 14 in 59% yield again using a sequence of a Corey Fuchs
reaction[27 30] and selective debromination.[31 33] Heck reaction
of compound 14 with 7 then yielded the desired diindenyle-
thenylbenzene 5 in 47% yield again in a stereo- and
regioselective way.
The following twofold intramolecular Heck reaction of 5 to
give analogue 3 required a precise control of the reaction time
and temperature. Thus, when 5 was reacted with catalytic
amounts of the palladacycle 15[34] at 130 1408C for 1.5h 3
could be obtained in 80% yield. The conversion proceeded
with high selectivity leading to the exclusive formation of an
unusual cis-annelation of the two newly generated rings.
An even shorter way to 3 would be a double Heck reaction
of hydrindene 7 and the bisvinyl bromide 17, easily accessible
from 9 via 16 (Scheme 3). However, all attempts to run this
transformation resulted in a complete decomposition of 17
already after 30 min in the presence of any palladium catalyst.
6
7
8
Scheme 1. Retrosynthesis of the simplified cephalostatin analogues 2
and 3.
O
Br
Br
Br
Br
a
O
O
O
O
O
35%
Br
Br
9
10
12
O
O
d
O
Br
b, c
Br
98%
80%
Br
Br
Br
11
OtBu
OtBu
O
Br
H
Br
H
f, g, h
59%
O
7, e
H
H
Br
41%
Br
Br
13
14
OtBu
Br
H
7, i
H
H
47%
H
Br
j
80%
5
tBuO
OtBu
1
16
15
R
O
R
13
H
Br
Br
Br
a
b
Br
Br
O
O
P
12
O
Br
Pd
O
Pd
H
H
H
H
75%
80%
Br
Br
Br
H
4
P
O
5
9
16
H
R
R
7
OtBu
9
3
8
tBuO
15: R = oTol
H
7, Pd0
Br
Scheme 2. Synthesis of the heptacycle 3. a) HOCH2CH2OH, pTsOH,
toluene, reflux; b) CBr4, PPh3, CH2Cl2, 08C; c) HOCH2CH2OH, pTsOH,
toluene, reflux, 80% (two steps); d) [Pd(PPh3)4], nBu3SnH, toluene, RT;
e) Pd(OAc)2, PPh3, nBu4NOAc, DMF/CH3CN/H2O 1:1:0.2, 608C;
f) HOAc, 808C, 74%; g) CBr4, PPh3, CH2Cl2, 08C, 90%; h) [Pd(PPh3)4],
nBu3SnH, toluene, RT, 88%; i) Pd(OAc)2, PPh3, nBu4NCl, K2CO3, DMF/
CH3CN/H2O 1:1:0.2, 608C; j) 15, nBu4NOAc, DMF/CH3CN/H2O 1:1:0.2,
130 1408C.
Br
H
Br
Br
H
Br
17
5
tBuO
Scheme 3. Twofold intramolecular Heck reaction of 17 and hydrindene 7
aimed at 5: a) CBr4, PPh3, CH2Cl2, 08C; b) [Pd(PPh3)4], nBu3SnH, toluene,
RT.
Chem. Eur. J. 2002, 8, No. 9
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2117

L. F. Tietze and W.-R. Krahnert
FULL PAPER
The decomposition of 17 was accompanied by the formation
of a black solid, that was insoluble in any solvent.
Br
Br
Br
Br
Br
a
O
O
O
26%
O
O
The bissteroidal arene 3 could be further manipulated in
several ways. Hydrogenation with 10% Pd on charcoal
furnished 18, which was subsequently treated with trimethyl-
iodosilane (TMSI) to yield diol 19 (Scheme 4). On the other
hand, hydrogenation of 3 using the Wilkinson catalyst led to
the tetra-hydrogenated heptacycle 20, which was again
deprotected with TMSI to give diol 21.
O
22
24
23
25
Br
Br
Br
d
b, c
Br
Br
92%
80%
O
Br
O
O
OtBu
OtBu
Br
H
Br
H
OR
Br
Br
f, g, h
57%
7, e
Br
H
H
H
O
50%
a
O
H
H
H
H
26
27
80%
H
tBuO
OtBu
RO
18: R = tBu
19: R = H
H
Br Br
H
H
b 90%
j
3
7, i
47%
2
H
H
H
OR
81%
H
4
c
H
H
H
H
H
tBuO
OtBu
70%
RO
H
H
20: R = tBu
21: R = H
d 77%
28
Scheme 4. Hydrogenation and deprotection of heptacycle 3. a) 10 mol%
10% Pd/C, H2 (3 bar), EtOAc, RT; b) TMSI, CH2Cl2, RT;
c) [(PPh3)3RhCl], H2 (3 bar), EtOAc/MeOH 1:1, RT; d) TMSI, CH2Cl2,
RT.
Scheme 5. Synthesis of heptacycle 2. a) HOCH2CH2OH, pTsOH, toluene,
reflux; b) CBr4, PPh3, CH2Cl2, À208C; c) HOCH2CH2OH, pTsOH,
toluene, reflux, 80% (two steps); d) [Pd(PPh3)4], nBu3SnH, toluene, RT;
e) Pd(OAc)2, PPh3, nBu4NOAc, DMF/CH3CN/H2O 1:1:0.2, 608C; f) PPTS,
acetone/H2O 2:1, reflux, 83%; g) CBr4, PPh3, CH2Cl2, À208C, 75%;
h) [Pd(PPh3)4], nBu3SnH, toluene, RT, 92%; i) Pd(OAc)2, PPh3, nBu4NCl,
K2CO3, DMF/CH3CN/H2O 1:1:0.2, 608C; j) 15, Ag3PO4, DMF/CH3CN/
H2O 1:1:0.2, 1208C.
The high chemoselectivity in the homogenous hydrogena-
tion of 3 is probably due to a conformational effect in 3 where
the angular 8a- and 16a-methyl groups shield the b-face of the
D7,8- and D15,16-double bonds. The a-face of these double bonds
is shielded by the bended molecule structure (see Figure 1b).
Surprisingly, under the conditions described for the reac-
tion of 5 the twofold intramolecular Heck reaction of 4 led to
the desired heptacyclic product 2 in only 32% yield. The main
product of this reaction was heptacycle 28 which was obtained
in 67% yield. Its formation can be explained as a result of a
readdition and elimination of the intermediately formed
H-Pd-Br species at one of the two newly generated double
bonds. However, it is known that in palladium catalyzed
reactions silver salts might suppress the migration of double
bonds.[35, 36] We were therefore pleased to find out that the
twofold intramolecular Heck reaction of 4 using palladacycle
15[34] and Ag3PO4[37, 38] instead of Bu4NOAc as base led to the
exclusive formation of heptacycle 2 in 81% yield without
migration of any double bond.
Synthesis of heptacycle 2 and its derivatives: Reaction of
dialdehyde 22 with ethylene glycol yielded the monoacetal 23
together with the corresponding diacetal, which was separated
by column chromatography and transformed back into 22. A
30]
sequence of a Corey Fuchs reaction[27 followed by palla-
33]
dium-catalyzed debromination with nBu3SnH[31
gave the
desired (Z)-vinyl bromide 25 selectively (see Scheme 5). The
Heck reaction between 25 and hydrindene 7 was carried out
under similar conditions as described for vinyl bromide 12
with the difference that only a twofold excess of hydrindene 7
is necessary to achieve a yield of 50% of Heck product 26.
Again the bond formation takes place between the vinyl
moiety of 25 and C-4 in 7 under formation of only one
diastereoisomer.
However, 2 is also accessible via a shorter, more efficient
synthetic route which failed for the synthesis of 3. Trans-
The acetal moiety in 26 was hydrolyzed using pyridinium p-
toluenesulfonate (PPTS) in acetone/water. Under these con-
ditions the reaction proceeds slower than in case of hydrolysis
of acetal 13 but with a substantially better yield. Corey Fuchs
formation of the dialdehyde 22 in a twofold Corey Fuchs
30]
reaction[27
followed by a twofold palladium catalyzed
debromination reaction[31 33] yields (Z)-di(bromoethenyl)ben-
zene 30 selectively in an overall yield of 44% (Scheme 6). In
contrast to 17, the bis(bromovinyl)arene 30 reacted with
hydrindene 7 in the presence of a catalytic amount of
Pd(OAc)2 and a base system consisting of nBu4NCl and
K2CO3 at 608C to furnish the desired diindenylethenylben-
zene 4 in 13% yield, which was then transformed into 2.
30]
33]
reaction[27
followed by selective debromination[31
gave
the (Z)-2-bromovinylbenzene derivative 27 in 69% yield (two
steps). Heck reaction of 27 and hydrindene 7 proceeded with
the expected high stereo- and regioselectivity and yielded
diindenylethenylbenzene 4 in 47% yield.
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Multiple Heck-Reactions
2116 2125
Br
Br
Br
Br
a
b
Br
Br
O
O
57%
77%
Br
tBuO
Br
22
29
OtBu
H
Br Br
H
Br
Br
7, c
Br
Br
H
H
13%
30
4
Scheme 6. Twofold intramolecular Heck reaction of 30 and hydrindene 7.
a) CBr4, PPh3, CH2Cl2, 08C; b) [Pd(PPh3)4], nBu3SnH, toluene, RT;
c) Pd(OAc)2, PPh3, nBu4NOAc, DMF/CH3CN/H2O 1:1:0.2, 608C.
Hydrogenation of heptacycle 2 using PtO2 ¥ H2O, 50 bar
hydrogen pressure and a protic solvent system furnished the
octahydro analogue 31 and deprotection of 31 by reaction
with TMSI led to the corresponding diol 32 (Scheme 7). A
selective hydrogenation of 2 using the Wilkinson catalyst as in
the case of 3 was not possible. The reaction of 2 with 10% Pd
on charcoal led in absence of a hydrogen atmosphere to the
formation of 33, which contains an equilenin substructure.
Compound 33 was obtained as an inseparable mixture
together with substrate 2, since the reaction was not complete
after six days and was therefore stopped.
Figure 1. X-ray structure of a) 20 and b) 31.
RO
OR
signals for the hydrindene moiety is twice as high and the
signals for the acetal moiety in 13 and 26 are missing. Thus, the
angular methyl groups resonate at d ˆ 0.66 and 0.61, respec-
tively, the hydrogens at the acyclic double bonds in 5 as a
doublet of a doublet at d ˆ 5.47 with J ˆ 11.2 and 11.0 Hz and
as a doublet at d ˆ 6.38 with J ˆ 11.2 Hz and for 4 as a doublet
of a doublet at d ˆ 5.44 with J ˆ 11.2 and 11.0 Hz and at d ˆ
6.34 as doublet with J ˆ 11.2 Hz. The only significant differ-
ence between the 1H NMR spectra of 5 and 4 are the singlet at
d ˆ 7.46 found for the aromatic hydrogens of 5 and the two
singlets at d ˆ 7.13 and 7.78 for those of 4.
H
H
a
98%
H
H
H
H
31: R = tBu
32: R = H
b 100%
tBuO
2
OtBu
c
29%
(72% conversion)
H
H
33
Scheme 7. Hydrogenation and dehydrogenation of heptacycle 2.
a) 10 mol% PtO2 ¥ H2O, H2 (50 bar), MeOH/EtOAc 1:1, RT; b) TMSI,
CH2Cl2, RT; c) 10% Pd/C, MeOH, 508C.
Due to the symmetric structure of 3 and 2 again only one set
of signals is found for the rings A,B,C and E,F,G in these
compounds. As before, for the two aromatic hydrogens in 3
only one singlet is observed at d ˆ 6.86, whereas two singlets
at d ˆ 6.60 and 7.18 are found for the corresponding hydrogens
in 2.
The structures of the newly formed compounds were
determined by NMR spectroscopy. In addition, X-ray anal-
yses were performed from 20 and 31 (Figure 1).[39] As
All other resonances are very similar with the exception of
those for the angular methyl groups at d ˆ 0.61 and 0.85,
respectively. For the hydrogens at the OtBu group multiplets
are found at d ˆ 3.45and 3.47 and at the benzylic double
bonds, doublets of doublets at d ˆ 5.80 and 5.82 with J ˆ 9.6/
9.7 and 5.9/6.1 Hz as well as doublets at d ˆ 6.32 and 6.30 with
J ˆ 9.6/9.7 Hz.
1
examples, the H NMR data of 2 5 as well as of 13 and 26
are discussed.
For the angular methyl group in 13 a singlet at d ˆ 0.65and
for 4-H a multiplet at d ˆ 2.82 is found. NOESY experiments
confirmed that 4-H is cis-orientated to the methyl group.
Further signals are observed at d ˆ 3.46 as triplet with J ˆ
8.8 Hz for 1-H, at d ˆ 5.48 as doublet of doublet with J ˆ 11.5
and 11.0 Hz for 1'-H and at d ˆ 6.36 as doublet with J ˆ
11.5Hz for 2 '-H. The coupling constants indicate that the
double bond has a Z-configuration. The two aromatic hydro-
The proof for the cis-annulation of rings BC and EF
demonstrated for 2 is given by a coupling constant of J ˆ
6.9 Hz for the hydrogens 13a-H and 14b-H at d ˆ 3.70,
whereas the trans orientation of rings AB and FG is indicated
by a coupling constant of J ˆ 11.8 Hz of the signal for 3b-H
and 8a-H at d ˆ 2.63.
1
gens resonate at d ˆ 7.43 and 7.76. The H NMR spectrum of
26 is nearly identical; here the aromatic hydrogens resonate at
d ˆ 7.51 and 7.77. Also the 1H NMR spectra of 5 and 4 are very
similar with the only difference that the integration of the
The cis orientation of the rings BC and EF in 18 is
confirmed by NOESY experiments.
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2119

L. F. Tietze and W.-R. Krahnert
FULL PAPER
toluene (430 mL) was heated under reflux for 1.5h. After cooling the
mixture was washed with water (100 mL) and brine (100 mL), dried over
NaSO4 and the solvent was removed in vacuo. Purification of the residue by
column chromatography (n-pentane/CH2Cl2 2:1) furnished 10 (12.3 g,
36.6 mmol, 35%) as a white solid together with the corresponding diacetal
(10.1 g, 26.6 mmol, 25%) and 2,5-dibromobenzene-1,4-dicarbaldehyde
(8.96 g, 30.7 mmol, 29%). Analytical data for 10: Rf ˆ 0.34 (n-pentane/
CH2Cl2 2:1); m.p. 1128C; UV/Vis (CH3CN): lmax (lg e) ˆ 224.0 (4.422),
Biological evaluation of analogues 19, 21, and 32: The
cytotoxicities of the new structurally simplified cephalostatin
analogues were determined by performing a HTFA tests
(Human tumor colony forming ability). For this purpose, 102
to 105 human lung cancer cells of the line A549 were placed in
six-well multiplates and cultivated in a culture medium that
contained 90% DMEM (Dulbeco×s modified Eagle×s medi-
um) and 10% FCS (fetal calf serum). After 24 h of cultivation,
the medium was removed, and the cells were incubated with
different concentrations of the synthesized analogues dis-
solved in DMSO/culture medium for 24 h. The remaining cells
were cultivated for a further 8 9 days at 378C in air with a
CO2 content of 7.5% and dyed with Lˆfflers methylene blue;
finally the relative colony-forming rate was determined.[40]
Since we only had a restricted amount of 19 and 21 for the
determination of the cytotoxicity, we were just able determine
effective dosage ranges (ED50) for these two compounds,
which are 1 100mm for 19 and 13 130mm for 21. The
effective dosage value for 32 is ED50 ˆ 59mm.[41] Though the
observed cytotoxicities of the analogues 19, 21 and 32 are not
in the range of those found for the natural cephalostatins, they
are still remarkably high since the compounds do not contain
any obviously toxic functionalities as the well known and
clinically used alkylating anticancer agent cyclophosphamide,
which has an ED50 value of 251mm against the same cell line.
252.0 (3.996), 313.0 nm (3.297); IR (KBr): nÄ ˆ 2902, 1695, 1085, 1055 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 4.06 4.22 (m, 4H), 6.03 (s, 1H), 7.86 (s,
1H), 8.07 (s, 1H), 10.26 (s, 1H); 13C NMR (75MHz, CDCl 3): d ˆ 65.66,
101.4, 122.4, 125.4, 133.0, 134.0, 134.6, 143.7, 190.1; MS (70 eV, EI): m/z (%):
‡
‡
‡
335.8 (58) [M] , 306.8 (11) [M À CHO] , 290.8 (24) [M À C2H5O] , 262.8
‡
‡
‡
(20) [M À C3H5O2] , 254.9 (37) [M À Br] , 73.0 (100) [C3H5O2] ; elemental
analysis calcd (%) for C10H8Br2O3 (336.0): C 35.75, H 2.40; found C 35.75,
H 2.37.
1,4-Dibromo-2-(2,2-dibromovinyl)-5-[1,3]dioxolan-2-ylbenzene (11):
A
solution of PPh3 (15.9 g, 60.7 mmol) in CH2Cl2 (50 mL) was added slowly
to a solution of CBr4 (10.1 g, 15.2 mmol) in CH2Cl2 (50 mL) at 08C. After
stirring the reaction mixture for 1 h benzaldehyde 10 (5.10 g, 15.2 mmol) in
CH2Cl2 (80 mL) was added within 10 min. Stirring was continued for 1 h at
08C followed by 1 h at room temperature. The reaction mixture was
concentrated in vacuo until a precipitation of triphenylphospine oxide was
seen and then purified by column chromatography (n-pentane/CH2Cl2 3:1)
to yield a mixture of 11 and the corresponding deprotected benzaldehyde.
This mixture was dissolved in toluene (100 mL), ethylene glycol (3.40 mL,
3.77 g, 60.7 mmol) and pTsOH ¥ H2O (14.5mg, 76.2 mmol) were added and
the reaction mixture was heated under reflux for 5h with a Dean Stark
tube. After cooling down it was washed with water (50 mL) and brine
(50 mL), dried over Na2SO4. The solvent was removed in vacuo to yield 11
(5.94 g, 12.1 mmol, 80%) as white solid. Rf ˆ 0.25( n-pentane/CH2Cl2 3:1);
m.p. 1138C; UV/Vis (CH3CN): lmax (lg e) ˆ 212.0 (4.353), 263.0 nm (3.982);
IR (KBr): nÄ ˆ 2889, 1597, 1360 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ
4.03 4.20 (m, 4H), 6.02 (s, 1H), 7.43 (s, 1H), 7.79 (s, 2H); 13C NMR
Conclusion
(75MHz, CDCl 3): d ˆ 65.59, 94.59, 101.7, 121.3, 122.0, 131.8, 134.2, 135.0,
‡
138.1, 138.3; MS (70 eV, EI): m/z (%): 491.6 (52) [M] , 446.5(14) [ M À
With the synthesis of 2 and 3 as well as of their derivatives, we
have developed a short entrance to structurally simplified
cephalostatin analogues starting from simple molecules. Some
of the analogues synthesized show a remarkably high
cytotoxicity against the human cancer cell line A549, which
encourages us to undertake further investigations in this area.
Thus, application of the developed method to heterocyclic
arenes and further substituted hydrindenes should allow the
preparation of more complex symmetrical and unsymmetrical
cephalostatin analogues.
‡
‡
‡
C2H5O] , 410.6 (83) [M À Br] , 337.7 (12) [M À BrÀ C3H5O2] , 330.8 (17)
‡
[M À 2 Â Br] ; elemental analysis calcd (%) for C11H8Br4O2 (491.8): C
26.86, H 1.64; found C 27.17, H 1.75.
1,4-Dibromo-2-[(Z)-2-bromovinyl]-5-[1,3]dioxolan-2-ylbenzene
(12):
[Pd(PPh3)4] (4.00 mol%, 938 mg, 0.81 mmol) was added to a solution of
11 (10.0 g, 20.3 mmol) in degassed toluene (120 mL) and the solution was
stirred until homogeneous. Then nBu3SnH (5.92 mL, 6.50 g, 22.3 mmol)
was added dropwise at room temperature and the solution was stirred for
1.5h. n-Pentane (120 mL) was added to the reaction mixture, it was washed
with water (100 mL) and brine (100 mL), dried over Na2SO4 and the
solvents were removed in vacuo. Purification by column chromatography
(n-pentane/CH2Cl2 3:1) furnished 12 (8.21 g, 19.9 mmol, 98%) as white
solid. Rf ˆ 0.18 (n-pentane/CH2Cl2 3:1); m.p. 768C; UV/Vis (CH3CN): lmax
(lg e) ˆ 214.5nm (4.311); IR (KBr): nÄ ˆ 2887, 1609, 1354 cmÀ1
;
1H NMR
Experimental Section
(300 MHz, CDCl3): d ˆ 4.03 4.21 (m, 4H), 6.04 (s, 1H), 6.65(d, J ˆ 7.9 Hz,
1H), 7.13 (d, J ˆ 7.9 Hz, 1H), 7.80 (s, 1H), 7.96 (s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 65.55, 101.8, 111.0, 121.0, 122.6, 130.9, 131.7, 134.3, 137.3, 137.9;
General: All reactions were performed in oven-dried glassware under an
argon atmosphere. Solvents were degassed by the freeze pump thaw
methology. TLC chromatography was performed on precoated aluminium
silica gel SIL G/UV254 plates (Macherey, Nagel Co.), and silica gel 32 63
(0.032 0.064 mm) (Macherey, Nagel Co.) was used for column chroma-
tography. Melting points: Mettler FP61. Optical rotations: Perkin Elmer
241. IR: Bruker IFS25. UV/Vis: Perkin Elmer Lambda9. NMR: Varian
VXR-200 (200 MHz, 1H), Bruker AM-300 (300 MHz, 75MHz, for 1H and
13C, respectively), Varian VXR-500 (500 MHz, 125 MHz, for 1H and 13C,
respectively), Varian Unity Inova-600 (600 MHz, 150 MHz, for 1H and 13C,
respectively). For 1H and 13C NMR, CDCl3 as solvent, TMS as internal
standard. Chemical shifts are reported on the d scale. Signals are quoted
as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet) and
br (broad). MS: Varian MAT 731. Elemental analysis: Mikroanalyti-
sches Labor des Institutes f¸r Organische Chemie der Universit‰t
Gˆttingen.
‡
‡
MS (70 eV, EI): m/z (%): 411.7 (24) [M] , 366.7 (8) [M À C2H5O] , 332.8
‡
‡
(51) [M À Br] , 288.8 (9) [M À BrÀ C2H4O] , 260.8 (12) [M À BrÀ
‡
C3H4O2] ; elemental analysis calcd (%) for C11H9Br3O2 (412.9): C 32.00,
H 2.20; found C 31.96, H 2.18.
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,5-dibromo-4-([1,3]dioxolan-
2-yl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene (13):
A
solution of 12 (79 mg, 191 mmol), hydrindene 7 (10 mg, 48 mmol) and
nBu4NOAc (116 mg, 384 mmol) in degassed DMF/CH3CN/H2O (1:1:0.2,
1 mL) was heated to 608C. At 508C PPh3 (20 mol%, 10.0 mg, 38.4 mmol)
and Pd(OAc)2 (10 mol%, 4.30 mg, 19.1 mmol) were added and the mixture
was heated at 608C for 21 h. After cooling down it was diluted with Et2O
(10 mL), washed with water (2 Â 5mL) and the combined aqueous layers
were washed with Et2O (2 Â 5mL). The combined organic layers were
washed with brine, dried over Na2SO4, the solvent was removed in vacuo
and the residue purified by column chromatography (n-pentane/CH2Cl2
1:1) to yield 13 (10.6 mg, 19.6 mmol, 41%) as colorless oil. Rf ˆ 0.30 (n-
pentane/CH2Cl2 1:1); [a]D20 ˆ À8.78 (c ˆ 1 in CHCl3); UV/Vis (CH3CN):
lmax (lg e) ˆ 207.0 (4.342), 224.0 (4.333), 345.0 nm (2.561); IR (KBr):
2,5-Dibromo-4-[1,3]dioxolan-2-ylbenzaldehyde (10): A suspension of 2,5-
dibromobenzene-1,4-dicarbaldehyde (30.9 g, 106 mmol), ethylene glycol
(5.92 mL, 6.57 g, 106 mmol) and pTsOH ¥ H2O (101 mg, 0.53 mmol) in
2120
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0809-2120 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 9

Multiple Heck-Reactions
2116 2125
nÄ ˆ 2968, 2883, 1589, 1387 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 0.65(s,
1H), 3.47 (t, J ˆ 8.2 Hz, 1H), 5.41 (d, J ˆ 10.0 Hz, 1H), 5.50 (dd, J ˆ 11.2,
11.0 Hz, 1H), 5.69 (ddt, J ˆ 10.0, 5.0, 2.5 Hz, 1H), 6.37 (d, J ˆ 11.2 Hz, 1H),
6.60 (d, J ˆ 8.0 Hz, 1H), 7.12 (d, J ˆ 8.0 Hz, 1H), 7.48 (s, 1H), 8.02 (s, 1H);
13C NMR (125.7 MHz, CDCl3): d ˆ 11.41, 24.82, 28.73, 30.48, 38.73, 38.80,
41.21, 46.24, 72.25, 80.53, 110.2, 122.0, 122.2, 127.77, 127.79, 128.2, 130.8,
3H), 1.11 (s, 9H), 1.10 1.20 (m, 1H), 1.27 1.44 (m, 2H), 1.58 1.67 (m,
1H), 1.77 1.88 (m, 2H), 1.99 (ddt, J ˆ 17.5, 5.2, 1.8 Hz, 1H), 2.80 2.89 (m,
1H), 3.47 (t, J ˆ 8.8 Hz, 1H), 4.02 4.19 (m, 4H), 5.39 (d, J ˆ 10.0 Hz, 1H),
5.48 (dd, J ˆ 11.5, 11.0 Hz, 1H), 5.68 (ddt, J ˆ 10.0, 5.0, 2.2 Hz, 1H), 6.00 (s,
1H), 6.36 (d, J ˆ 11.5Hz, 1H), 7.43 (s, 1H), 7.76 (s, 1H); 13C NMR
(75MHz, CDCl 3): d ˆ 11.44, 24.77, 28.71, 30.43, 38.72, 38.80, 41.19, 46.23,
65.52, 65.64, 72.22, 80.53, 101.9, 120.92, 122.95, 127.7, 127.8, 128.2, 131.6,
‡
133.6, 133.9, 134.8, 137.7, 139.1; MS (70 eV, EI): m/z (%): 573.7 (4) [M] ,
‡
‡
517.7 (9) [M À C4H8] , 497.7 (11) [M À C4H10O] , 418.9 (11) [M À
‡
‡
‡
C4H10O À Br] , 339.9 (2) [M À C4H10O À 2 Â Br] , 57.1 (52) [C4H9] ;
HRMS: calcd for C24H29Br3O: 571.9748; found 571.9748; elemental analysis
calcd (%) for C24H29Br3O (573.2): C 50.29, H 5.10; found C 50.54, H 5.03.
‡
134.3, 136.5, 137.7, 140.2; MS (70 eV, EI): m/z (%): 540.0 (7) [M] , 483.9
‡
‡
(100) [M À C4H8] , 465.9 (12) [M À C3H6O2] , 385.0 (10) [M À BrÀ
‡
‡
C3H6O2] , 57.0 (69) [C4H9] ; HRMS: calcd for C25H32Br2O3: 538.0718;
found 538.0718; elemental analysis calcd (%) for C25H32Br2O3 (540.3): C
55.57, H 5.97; found C 55.31, H 5.88.
(À)-1,4-Dibromo-2,5-bis{(Z)-2-[(1S,3aS,4S,7aS)-1-tert-butoxy-7a-methyl-
2,3,3a,4,7,7a-hexahydro-1H-inden-4-yl]vinyl}benzene (5): A solution of 14
(40.0 mg, 69.8 mmol), hydrindene 7 (29.0 mg, 140 mmol), K2CO3 (24.0 mg,
174 mmol) and nBu4NCl (19.0 mg, 69.8 mmol) in degassed DMF/CH3CN/
H2O (1:1:0.2, 1 mL) was heated to 508C when PPh3 (20 mol%, 3.70 mg,
14 mmol) and Pd(OAc)2 (10 mol%, 1.60 mg, 6.98 mmol) were added with
stirring; afterwards the mixture was stirred at 608C for 5h. After cooling
the reaction mixture was diluted with Et2O (10 mL), washed with water
(2 Â 5mL) and the combined aqueous layers were washed with Et 2O (2 Â
5mL). Then the combined organic layers were washed with brine, dried
over Na2SO4, the solvent was removed in vacuo and the residue was
purified by column chromatography (n-pentane/CH2Cl2 3:1) to yield 5
(23.0 mg, 32.8 mmol, 47%) as colorless oil. Rf ˆ 0.33 (n-pentane/CH2Cl2
3:1); [a]2D0 ˆ À21.28 (c ˆ 0.25in CHCl 3); UV/Vis (CH3CN): lmax (lg e) ˆ
(À)-2,5-Dibromo-4-{(Z)-2-[(1S,3aS,4S,7aS)-1-tert-butoxy-7a-methyl-
2,3,3a,4,7,7a-hexahydro-1H-inden-4-yl]vinyl}benzaldehyde (13a): A solu-
tion of acetal 13 (500 mg, 92.5 mmol) in 80% acetic acid (20 mL) was heated
at 808C for 2 h. After cooling down it was diluted with Et2O (10 mL)
followed by addition of a saturated solution of NaHCO3 until the end of the
gas formation. The organic layer was washed with water (10 mL) and brine
(10 mL), dried over Na2SO4 and the solvent was removed in vacuo.
Purification of the residue by column chromatography furnished 13a
(34.0 mg, 68.5 mmol, 74%) as colorless oil. Rf ˆ 0.46 (n-pentane/Et2O 20:1);
[a]2D0 ˆ À32.88 (c ˆ 1 in CHCl3); UV/Vis (CH3CN): lmax (lg e) ˆ 221.5
(4.206), 283.0 nm (3.911); IR (KBr): nÄ ˆ 3009, 2971, 2874, 1692 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.67 (s, 3H), 1.13 (s, 9H), 1.00 2.12 (m,
7H), 2.77 2.97 (m, 1H), 3.49 (t, J ˆ 8.0 Hz, 1H), 5.42 (d, J ˆ 10.0 Hz, 1H),
5.61 (dd, J ˆ 11.5, 11.0 Hz, 1H), 5.74 (ddt, J ˆ 10.0, 5.0, 2.5 Hz, 1H), 6.43 (d,
J ˆ 11.5, 1H), 7.56 (s, 1H), 8.10 (s, 1H), 10.26 (s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 11.36, 24.80, 28.70, 30.41, 38.67, 39.02, 41.19, 46.13, 72.28, 80.41,
123.7, 124.8, 127.4, 127.6, 128.3, 132.8, 133.5, 135.1, 139.1, 145.0, 190.1; MS
226.0 (4.299), 260.0 nm (4.030); IR (KBr): nÄ ˆ 2972, 1730, 1643, 1465cm À1
;
1H NMR (300 MHz, CDCl3): d ˆ 0.66 (s, 6H), 1.12 (s, 18H), 1.07 1.72 (m,
8H), 1.75 1.91 (m, 4H), 2.00 (dd, J ˆ 17.0, 5.0 Hz, 2H), 2.83 2.97 (m, 2H),
3.46 (t, J ˆ 8.5Hz, 2H), 5.40 (d, J ˆ 10.0 Hz, 2H), 5.47 (dd, J ˆ 11.2, 11.0 Hz,
2H), 5.67 (ddt, J ˆ 10.0, 5.0, 2.5 Hz, 2H), 6.38 (d, J ˆ 11.2 Hz, 2H), 7.46 (s,
2H); 13C NMR (75MHz, CDCl 3): d ˆ 11.34, 24.88, 28.74, 30.52, 38.73,
38.75, 41.28, 46.24, 72.24, 80.58, 122.1, 127.6, 127.9, 128.5, 133.8, 137.4, 137.8;
‡
‡
(70 eV, EI): m/z (%): 496 (2) [M] , 440 (56) [M À C4H8] , 343 (8) [M À
‡
‡
C4H9O À Br] , 57 (100) [C4H9] ; HRMS: calcd for C23H28Br2O2: 494.0456;
found 494.0456; elemental analysis calcd (%) for C23H28Br2O2 (496.3): C
55.66, H 5.69; found C 55.90, H 5.68.
‡
‡
MS (70 eV, EI): m/z (%): 700.0 (10) [M] , 643.9 (7) [M À C4H8] , 625.9 (8)
‡
‡
[M À C4H10O] , 587.8 (12) [M À 2 Â C4H8] , 569.9 (14) [M À C4H8 À
‡
‡
C4H10O] , 57.1 (100) [C4H9] ; HRMS: calcd for C38H52Br2O2: 698.2334;
found 698.2334.
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,5-dibromo-4-(2,2-dibromo-
vinyl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene (13b): A
solution of PPh3 (235mg, 895 mmol) in CH2Cl2 (0.4 mL) was added slowly
to a solution of CBr4 (148 mg, 447 mmol) in CH2Cl2 (0.4 mL) at 08C. After
stirring of the reaction mixture for 30 min, benzaldehyde 13a (111 mg,
224 mmol) in CH2Cl2 (0.4 mL) was added within 10 min. Stirring was
continued for 1 h at 08C followed by 1 h at room temperature. The reaction
mixture was concentrated in vacuo until a precipitation of triphenylpho-
spine oxide was seen and then purified by column chromatography (n-
pentane/CH2Cl2 6:1) to yield 13b (131 mg, 201 mmol, 90%) as colorless oil.
Rf ˆ 0.49 (n-pentane/CH2Cl2 6:1); [a]2D0 ˆ À22.38 (c ˆ 0.7 in CHCl3); UV/
Vis (CH3CN): lmax (lg e) ˆ 229.5(4.241), 272.0 nm (4.062); IR (KBr): nÄ ˆ
2972, 1642, 1598 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 0.69 (s, 3H), 1.09
1.73 (m, 4H), 1.14 (s, 9H), 1.78 1.94 (m, 2H), 1.97 2.09 (m, 1H), 2.83
2.96 (m, 1H), 3.50 (t, J ˆ 8.2 Hz, 1H), 5.42 (d, J ˆ 10.0 Hz, 1H), 5.53 (dd,
J ˆ 11.2, 11.0 Hz, 1H), 5.72 (ddt, J ˆ 10.0, 5.0, 2.5 Hz, 1H), 6.38 (d, J ˆ
11.2 Hz, 1H), 7.46 (s, 1H), 7.49 (s, 1H), 7.85(s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 11.42, 24.84, 28.75, 30.48, 38.74, 38.85, 41.24, 46.23, 72.29, 80.52,
93.86, 121.3, 122.5, 127.7, 127.9, 128.1, 133.6, 133.9, 135.1, 135.6, 139.5, 137.9;
(À)-(1S,3aS,3bS,6bR,8aS,9S,11aS,11bS,14bR,16aS)-1,9-Di-tert-butoxy-
8a,16a-dimethyl-2,3,3a,3b,6b,8a,10,11,11a,11b,14b,16a-dodecahydro-di-1H-
indeno[4,5-a:4,5-h]anthracene (3): A solution of 5 (100 mg, 143 mmol),
nBu4NOAc (215mg, 714 mmol) and trans-di(m-acetato)-bis[ortho-(di-or-
tho-tolylphosphino)benzyl]dipalladium(ii) (15; 5.00 mol%, 6.54 mg,
7.14 mmol) in degassed DMF/CH3CN/H2O (1:1:0.2, 5mL) was heated for
1.5h at 130 140 8C in a preheated oil bath. After cooling down, water
(15mL) was added and the reaction mixture was extracted with Et 2O (2 Â
20 mL). The combined organic layers were washed with brine (10 mL) and
dried over Na2SO4. Removal of the solvent and chromatographic
purification (n-pentane/CH2Cl2 5:1) yielded 3 (62.0 mg, 115 mmol, 80%)
as colorless oil. Rf ˆ 0.32 (n-pentane/CH2Cl2 5:1); [a]2D0 ˆ À39.08 (c ˆ 0.2 in
CHCl3); 1H NMR (500 MHz, CDCl3): d ˆ 0.86 (s, 6H), 1.11 (s, 18H), 1.35
1.57 (m, 6H), 1.69 1.89 (m, 4H), 2.62 2.69 (m, 2H), 3.45 (dd, J ˆ 8.7,
6.6 Hz, 2H), 3.67 (dd, J ˆ 5.6, 4.4 Hz, 2H), 5.80 (dd, J ˆ 9.6, 5.9 Hz, 2H),
6.04 (d, J ˆ 10.0 Hz, 2H), 6.12 (dd, J ˆ 10.0, 4.4 Hz, 2H), 6.32 (d, J ˆ 9.6 Hz,
2H), 6.86 (s, 2H); 13C NMR (75MHz, CDCl 3): d ˆ 14.94, 22.84, 28.72,
31.89, 33.92, 37.47, 41.84, 44.69, 72.33, 76.22, 125.0, 125.3, 128.8, 129.2, 131.8,
‡
‡
MS (70 eV, EI): m/z (%): 651.7 (2) [M] , 595.7 (10) [M À C4H8] , 496.8 (10)
‡
134.6, 135.9; MS (70 eV, EI): m/z (%): 538.5 (38) [M] , 481.4 (25) [M À
‡
‡
[M À C4H9O À HBr] , 57.1 (100) [C4H9] ; HRMS: calcd for C24H28Br4O:
647.8874; found 647.8874; elemental analysis calcd (%) for C24H28Br4O
(652.1): C 44.20, H 4.33; found C 44.48, H 4.57.
‡
‡
‡
C4H9] , 425.4 (10) [M À C4H8 À C4H9] , 407.3 (18) [M À C4H9 À C4H10O] ,
‡
57.1 (100) [C4H9] ; HRMS: calcd for C38H50O2 538.3811; found 538.3810.
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,5]-dibromo-4-((Z)-2-bromo-
1,4-Dibromo-2,5-di(2,2-dibromovinyl)benzene (16): A solution of PPh3
(16.6 g, 63.2 mol) in CH2Cl2 (60 mL) was added slowly to a solution of
CBr4 (10.5g, 31.6 mmol) in CH 2Cl2 (87 mL) at 08C. After stirring of the
reaction mixture for 30 min, terephthalaldehyde 9 (2.57 g, 7.89 mmol) in
CH2Cl2 (118 mL) was added within 10 min. Stirring was continued for 1 h at
08C followed by 1 h at room temperature. The reaction mixture was
concentrated in vacuo until triphenylphospine oxide precipitated, and
subsequently purified by column chromatography (n-pentane) to yield 16
(3.57 g, 5.91 mmol, 75%) as white solid. Rf ˆ 0.51 (n-pentane); m.p. 1768C;
UV/Vis (CH3CN): lmax (lg e) ˆ 223.0 (4.106), 276.0 nm (3.864); IR (KBr):
nÄ ˆ 3014, 1604, 863, 632 cmÀ1; 1H NMR (200 MHz, CDCl3): d ˆ 7.44 (s, 2H),
7.85(s, 2H); 13C NMR (75MHz, CDCl 3): d ˆ 94.39, 121.3, 133.4, 134.7,
vinyl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene
(14):
[Pd(PPh3)4] (4.00 mol%, 30.0 mg, 25.8 mmol) was added to a solution of
13b (420 mg, 644 mmol) in degassed toluene (3.8 mL) and the solution was
stirred until homogeneous. Then nBu3SnH (179 mL, 197 mg, 676 mmol) was
added dropwise at room temperature and the solution was stirred for 1.5h.
n-Pentane (5mL) was added to the reaction mixture, it was washed with
water (5mL) and brine (5mL), dried over Na 2SO4 and the solvents were
removed in vacuo. Purification by column chromatography (n-pentane/
Et2O, 100:1) furnished 14 (323 mg, 564 mmol, 88%) as colorless oil. Rf ˆ
0.20 (n-pentane/Et2O, 100:1), [a]2D0 ˆ À39.38 (c ˆ 0.8 in CHCl3); UV/Vis
(CH3CN): lmax (lg e) ˆ 226.5(4.401), 266.5nm (4.214); IR (KBr): nÄ ˆ 2971,
1
‡
‡
1461, 1197 cmÀ1; H NMR (300 MHz, CDCl3): d ˆ 0.67 (s, 3H), 1.08 1.71
137.3; MS (70 eV, EI): m/z (%): 603.7 (100) [M] , 522.8 (9) [M À Br] , 443.8
‡
‡
‡
(m, 4H), 1.15(s, 9H), 1.76 1.92 (m, 2H), 1.95 2.06 (m, 1H), 2.83 2.96 (m,
(27) [M À 2 Â Br] , 364.9 (6) [M À 3 Â Br] , 283.9 (32) [M À 4 Â Br] , 124.1
0947-6539/02/0809-2121 $ 20.00+.50/0
2121
Chem. Eur. J. 2002, 8, No. 9
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002

L. F. Tietze and W.-R. Krahnert
FULL PAPER
‡
(20) [M À 6 Â Br] ; elemental analysis calcd (%) for C10H4Br6 (603.6): C
2H), 6.10 (dd, J ˆ 9.8, 4.2 Hz, 2H), 6.16 (d, J ˆ 9.8 Hz, 2H), 7.14 (s, 2H);
13C NMR (125MHz, CDCl 3): d ˆ 15.44, 23.24, 25.83, 26.14, 28.78, 31.90,
32.21, 39.55, 42.56, 45.09, 72.16, 77.04, 128.6, 129.3, 135.0, 136.4, 135.4; MS
19.90, H 0.67; found C 20.19, H 0.69.
1,4-Dibromo-2,5-di[(Z)-2-bromovinyl]benzene
(17):
[Pd(PPh3)4]
‡
‡
(70 eV, EI): m/z (%): 542.5 (76) [M] , 485.4 (100) [M À C4H9] , 429.3 (24)
(8.00 mol%, 140 mg, 121 mmol) was added to a solution of 16 (912 mg,
1.51 mmol) in degassed toluene (100 mL) and the solution was stirred until
homogeneous. Then nBu3SnH (0.88 mL, 968 mg, 3.32 mmol) was added
dropwise at room temperature and the solution was stirred for 3.5h. n-
Pentane (100 mL) was added and the mixture was washed with water
(50 mL), brine (50 mL), dried over Na2SO4 and the solvents were removed
in vacuo. Purification by column chromatography (n-pentane) furnished 17
as white solid (536 mg, 1.20 mmol, 80%). Rf ˆ 0.40 (n-pentane); m.p.
1218C; UV/Vis (CH3CN): lmax (lg e) ˆ 225.0 (4.277), 270.0 nm (4.116); IR
(KBr): nÄ ˆ 3080, 1772, 1619 cmÀ1; 1H NMR (200 MHz, CDCl3): d ˆ 6.66 (d,
J ˆ 8.1 Hz, 2H), 7.14 (d, J ˆ 8.1 Hz, 2H), 8.04 (s, 2H); 13C NMR (50 MHz,
CDCl3): d ˆ 110.8, 122.0, 130.8, 133.8, 136.1; MS (70 eV, EI): m/z (%): 445.9
‡
‡
‡
[M À C4H8 À C4H9] , 411.3 (26) [M À C4H9 À C4H10O] , 57.0 (24) [C4H9] ;
HRMS: calcd for C38H54O2: 542.4124; found 542.4123.
(1S,3aS,3bS,6bR,8aS,9S,11aS,11bS,14bR,16aS)-1,9-Dihydroxy-8a,16a-di-
methyl-2,3,3a,3b,4,5,6b,8a,10,11,11a,11b,12,13,14b,16a-hexadecahydro-di-
1H-indeno[4,5-a:4,5-h]anthracene (21): Reaction of 20 (6.7 mg, 12 mmol)
with TMSI (3.4 mL, 4.9 mg, 25 mmol) as described for 19 gave 21 (4.1 mg,
9.5 mmol, 77%) as colorless oil. Rf ˆ 0.45( n-pentane/EtOAc 1:1); 1H NMR
(500 MHz, CD2Cl2): d ˆ 0.87 (s, 6H), 1.34 1.82 (m, 14H), 1.99 2.13 (m,
2H), 2.28 2.38 (m, 2H), 2.48 (ddd, J ˆ 16.1, 4.1, 4.1 Hz, 2H), 2.70 (ddd, J ˆ
16.1, 8.1, 8.1 Hz, 2H), 3.49 (brs, 2H), 3.69 (t, J ˆ 8.0 Hz, 2H), 5.97 (dd, J ˆ
10.0, 3.6 Hz, 2H), 6.01 (d, J ˆ 10.0 Hz, 2H), 6.98 (s, 2H); 13C NMR
(125MHz, CDCl 3): d ˆ 14.31, 22.88, 25.61, 25.66, 31.53, 31.96, 39.32, 42.77,
45.06, 78.10, 128.7, 130.2, 134.6, 135.2, 136.1; MS (70 eV, EI): m/z (%): 430.3
‡
‡
‡
(100) [M] , 364.9 (64) [M À Br] , 286.0 (39) [M À 2 Â Br] , 206.1 (15) [M À
‡
‡
2 Â BrÀ HBr] , 126.1 (30) [M À 4 Â Br] ; elemental analysis calcd (%) for
‡
‡
‡
C10H6Br4 (445.8): C 26.94, H 1.36; found C 27.18, H 1.40.
(100) [M] , 412.3 (4) [M À H2O] , 371.3 (2) [M À H2O À CH3 À C2H2] , 5 7.1
‡
‡
(16) [C3H5O] , 43.0 (11) [C2H3O] ; HRMS: calcd for C30H38O2: 430.2872;
found 430.2871.
(‡)-(1S,3aS,3bR,6bR,8aS,9S,11aS,11bR,14bR,16aS)-1,9-Di-tert-butoxy-
8a,16a-dimethyl-2,3,3a,3b,4,5,6b,7,8,8a,10,11,11a,11b,12,13,14b,15,16,16a-
eicosahydro-di-1H-indeno[4,5-a:4,5-h]-anthracene (18):
A solution of
2,4-Dibromo-5-[1,3]dioxolan-2-ylbenzaldehyde (23): Reaction of 2,4-di-
bromobenzene-1,5-dicarbaldehyde (55.0 g, 188 mmol), ethylene glycol
(10.5mL, 11.7 g, 188 mmol) and pTsOH ¥ H2O (0.5mol%, 179 mg, 9.41 Â
10À4 mol) in toluene (765mL) as described for 10 gave 23 (16.3 g,
48.5mmol, 26%) as a white solid together with the corresponding diacetal
(25.7 g, 67.7 mmol, 36%) and 2,4-dibromobenzene-1,5-dicarbaldehyde
(19.8 g, 67.8 mmol, 36%). Analytical data for 23: Rf ˆ 0.25( n-pentane/
CH2Cl2 2:1); m.p. 1128C; UV/Vis (CH3CN): lmax (lg e) ˆ 222.5(4.318),
freshly prepared 3 (9.0 mg, 17 mmol) and 10% Pd on charcoal (10 mol%
Pd, 1.8 mg, 1.7 mmol) in ethyl acetate (1 mL) was stirred under a hydrogen
atmosphere (3 bar) for 16 h at room temperature. The solvent was removed
in vacuo and the residue was purified by column chromatography (n-
pentane/CH2Cl2 5:1) to furnish 18 (7.3 mg, 13.3 mmol, 80%) as colorless oil.
Rf ˆ 0.32 (n-pentane/CH2Cl2 5:1); [a]2D0 ˆ ‡20.88 (c ˆ 0.4 in C6H6); 1H NMR
(500 MHz, C6D6): d ˆ 0.87 (s, 18H), 0.91 1.00 (m, 2H), 0.93 (s, 6H), 1.21
1.33 (m, 4H), 1.42 1.66 (m, 8H), 1.70 1.79 (m, 4H), 1.84 (ddt, J ˆ 14.5, 4.3,
4.3 Hz, 2H), 1.88 1.94 (m, 2H), 2.33 (d, J ˆ 14.5Hz, 2H), 2.56 (t, J ˆ
7.9 Hz, 2H), 2.64 (ddd, J ˆ 15.8, 4.0, 4.0 Hz, 2H), 2.79 2.89 (m, 2H), 2.90
(brs, 2H), 7.21 (s, 2H); 13C NMR (75MHz, CDCl 3): d ˆ 11.64, 23.94, 24.63,
26.26, 26.35, 28.71, 31.17, 33.22, 34.49, 38.23, 41.87, 43.30, 71.77, 80.53, 127.3,
263.5(4.170), 297.5nm (3.265); IR (KBr):
nÄ ˆ 2903, 2884, 1692 cmÀ1
;
1H NMR (200 MHz, CDCl3): d ˆ 4.02 4.23 (m, 4H), 6.04 (s, 1H), 7.91 (s,
1H), 8.11 (s, 1H), 10.30 (s, 1H); 13C NMR (75MHz, CDCl 3): d ˆ 65.57,
101.6, 127.2, 128.8, 129.8, 132.5, 137.55, 137.57; MS (70 eV, EI): m/z (%):
‡
‡
‡
335.9 (40) [M] , 334.9 (60) [M À H] , 306.9 (7) [M À CHO] , 290.9 (36)
‡
135.3, 136.0; MS (70 eV, EI): m/z (%): 546.4 (100) [M] , 489.3 (43) [M À
‡
‡
‡
[M À C2H5O] , 262.9 (33) [M À C3H5O2] , 73.1 (100) [C3H5O2] ; elemental
analysis calcd (%) for C10H8Br2O3 (336.0): C 35.75, H 2.40; found C 35.75;
H 2.25.
‡
‡
‡
C4H9] , 472.3 (18) [M À C4H10O] , 433.3 (7) [M À C4H8 À C4H9] , 415.3
‡
(22) [M À C4H9 À C4H10O] ; HRMS: calcd for C38H58O2: 546.4437; found
546.4436.
1,5-Dibromo-2-(2,2-dibromovinyl)-4-[1,3]dioxolan-2-ylbenzene (24): Re-
action of CBr4 (32.2 g, 97.0 mmol) in CH2Cl2 (100 mL), PPh3 (50.9 g,
194 mmol) in CH2Cl2 (150 mL) and 23 (16.3 g, 48.5mmol) in CH 2Cl2
(150 mL) at À208C followed by reaction of the obtained mixture with
ethylene glycol (27.1 mL, 30.1 g, 485mmol) and pTsOH ¥ H2O (46 mg,
242 mmol) in toluene (350 mL) as described for 11 gave 24 as a white solid
(19.1 g, 38.8 mmol, 80%). Rf ˆ 0.19 (n-pentane/CH2Cl2 3:1); m.p. 558C;
UV/Vis (CH3CN): lmax (lg e) ˆ 209.0 (4.450), 266.0 nm (4.098); IR (KBr):
nÄ ˆ 3084, 2885, 1375 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ 4.01 4.20 (m,
4H), 6.05(s, 1H), 7.43 (s, 1H), 7.81 (s, 1H), 7.82 (s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 65.50, 93.90, 101.9, 123.1, 123.9, 129.2, 135.3, 135.5, 136.2, 136.3;
(À)-(1S,3aS,3bR,6bR,8aS,9S,11aS,11bR,14bR,16aS)-1,9-Dihydroxy-
8a,16a-dimethyl-2,3,3a,3b,4,5,6b,7,8,8a,10,11,11a,11b,12,13,14b,15,16,16a-
eicosahydro-di-1H-indeno[4,5-a:4,5-h]anthracene (19): A solution of 18
(7.2 mg, 13 mmol) and trimethylsilyliodide (TMSI) (4.7 mL, 6.9 mg,
34 mmol) in CH2Cl2 (1 mL) was stirred for 18 h at room temperature.
Methanol (0.1 mL) and brine (5mL) were added to the reaction mixture.
Then it was extracted with ethyl acetate (3 Â 5mL), the combined organic
layers were dried over Na2SO4, evaporated in vacuo and the residue was
purified by column chromatography (n-pentane/EtOAc 1:1) to furnish 19
(5.2 mg, 12 mmol, 90%) as colorless oil. Rf ˆ 0.34 (n-pentane/EtOAc 1:1);
1
[a]2D0 ˆ À96.48 (c ˆ 0.25in CHCl ); H NMR (500 MHz, CD2Cl2): d ˆ 0.83
3
‡
‡
MS (70 eV, EI): m/z (%): 491.8 (24) [M] , 446.7 (9) [M À C2H5O] , 410.8
(s, 6H), 1.00 (ddd, J ˆ 13.3, 13.3, 3.5Hz, 2H), 1.25 1.45(m, 6H), 1.53 (ddd,
J ˆ 13.3, 3.5, 3.5 Hz, 2H), 1.56 1.82 (m, 8H), 1.86 2.07 (m, 6H), 2.32 (dd,
J ˆ 14.6, 2.0 Hz, 2H), 2.55 (ddd, J ˆ 16.5, 5.4, 2.0 Hz, 2H), 2.73 (ddd, J ˆ
16.5, 12.7, 5.4 Hz, 2H), 2.90 (brs, 2H), 3.50 (t, J ˆ 8.2 Hz, 2H), 7.00 (s, 2H);
13C NMR (125MHz, CDCl 3): d ˆ 10.83, 23.57, 24.87, 25.85, 26.07, 30.31,
33.01, 34.59, 37.98, 41.99, 43.48, 82.20, 127.1, 135.3, 135.4; MS (70 eV, EI):
‡
‡
‡
(37) [M À Br] , 337.9 (8) [M À BrÀ C3H5O2] , 73.1 (100) [C3H5O2] ;
elemental analysis calcd (%) for C11H8Br4O2 (491.8): C 26.86, H 1.64;
found C 27.09, H 1.60.
1,5-Dibromo-2-[(Z)-2-bromovinyl]-4-[1,3]dioxolan-2-ylbenzene (25): Re-
action of 24 (15.0 g, 30.5 mmol), [Pd(PPh3)4] (4.00 mol%, 1.41 g,
1.22 mmol) and nBu3SnH (8.90 mL, 9.77 g, 33.6 mmol) in toluene
(180 mL) as described for 12 gave 25 (11.6 g, 28.1 mmol, 92%) as white
solid. Rf ˆ 0.17 (n-pentane/CH2Cl2 3:1); m.p. 658C; UV/Vis (CH3CN): lmax
‡
‡
m/z (%): 434.3 (100) [M] , 375.2 (3) [M À H2O À CH3 À C2H2] , 334.1 (2)
‡
[M À H2O À 2 Â CH3 À 2 Â C2H2] , 321.2 (4) [M À 2 Â CH3 À C2H2 À C3
‡
‡
H5O] , 57.0 (4) [C3H5O] ; HRMS: calcd for C30H42O2: 434.3185; found
434.3184.
(lg e) ˆ 210.5(4.337), 257.5nm (4.021); IR (KBr): nÄ ˆ 2887, 1615, 1325 cmÀ1
;
1H NMR (200 MHz, CDCl3): d ˆ 4.02 4.22 (m, 4H), 6.09 (s, 1H), 6.63 (d,
J ˆ 8.4 Hz, 1H), 7.14 (d, J ˆ 8.4 Hz, 1H), 7.83 (s, 1H), 8.00 (s, 1H); 13C NMR
(50 MHz, CDCl3): d ˆ 65.46, 102.0, 110.3, 122.6, 124.5, 129.2, 131.3, 136.2,
(À)-(1S,3aS,3bS,6bR,8aS,9S,11aS,11bS,14bR,16aS)-1,9-Di-tert-butoxy-
8a,16a-dimethyl-2,3,3a,3b,4,5,6b,8a,10,11,11a,11b,12,13,14b,16a-hexadeca-
hydro-di-1H-indeno[4,5-a:4,5-h]anthracene (20): A solution of freshly
prepared 3 (20.6 mg, 38.2 mmol) and [(PPh3)3RhCl] (10 mol%, 3.54 mg,
3.83 mmol) in methanol/ethyl acetate (1:1, 2.75mL) was stirred under a
hydrogen atmosphere (3 bar) for 13 h at room temperature. The solvent
was removed in vacuo and the residue was purified by column chromatog-
raphy (n-pentane/CH2Cl2 5:1) to furnish 20 (14.5mg, 26.7 mmol, 70%) as
white solid. Rf ˆ 0.33 (n-pentane/CH2Cl2 5:1); m.p. 151 8C; [a]2D0 ˆ À271.88
(c ˆ 0.8 in C6H6); 1H NMR (500 MHz, C6D6): d ˆ 1.05(s, 18H), 1.09 (s, 6H),
1.27 1.39 (m, 2H), 1.44 1.61 (m, 6H), 1.61 1.69 (m, 2H), 1.70 1.82 (m,
4H), 2.27 (m, 2H), 2.52 (ddd, J ˆ 15.8, 4.4, 4.4 Hz, 2H), 2.75 (ddd, J ˆ 15.8,
11.5, 4.4 Hz, 2H), 3.21 (dd, J ˆ 7.5, 7.5 Hz, 2H), 3.48 (dd, J ˆ 4.4, 4.4 Hz,
‡
134.3, 136.0; MS (70 eV, EI): m/z (%): 411.7 (54) [M] , 366.9 (15) [M À
‡
‡
‡
C2H5O] , 333.0 (77) [M À Br] , 289.0 (9) [M À Br À C2H4O] , 260.9 (14)
‡
‡
[M À BrÀ C3H4O2] , 73.1 (100) [C3H5O2] ; elemental analysis calcd (%)
for C11H9Br3O2 (412.9): C 32.00, H 2.20; found C 32.36, H 2.11.
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,4-dibromo-5-([1,3]dioxolan-
2-yl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene (26): Re-
action of 25 (150 mg, 363 mmol), hydrindene
7 (151 mg, 727 mmol),
nBu4NOAc (274 mg, 908 mmol), PPh3 (20 mol%, 19.0 mg, 72.7 mmol) and
Pd(OAc)2 (10 mol%, 8.20 mg, 36.3 mmol) in DMF/CH3CN/H2O (1:1:0.2,
5mL) as described for 13 gave 23 as colorless oil (98.0 mg, 181 mmol, 50%).
2122
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0809-2122 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 9

Multiple Heck-Reactions
2116 2125
‡
‡
‡
Rf ˆ 0.22 (n-pentane/CH2Cl2 1:1); [a]2D0 ˆ À11.68 (c ˆ 0.5in CHCl 3); UV/
Vis (CH3CN): lmax (lg e) ˆ 208.5(4.482), 251.5nm (4.123); IR (KBr): nÄ ˆ
2971, 2876, 1584, 1389 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 0.63 (s, 3H),
1.11 (s, 9H), 1.17 1.26 (m, 1H), 1.29 1.44 (m, 2H), 1.60 1.69 (m, 1H),
1.79 1.89 (m, 2H), 1.99 (ddt, J ˆ 17.3, 5.2, 1.4 Hz, 1H), 2.87 2.95 (m, 1H),
3.47 (t, J ˆ 8.5Hz, 1H), 4.01 4.06 (m, 4H), 5.39 (d, J ˆ 9.8 Hz, 1H), 5.49
(dd, J ˆ 11.2, 11.2 Hz, 1H), 5.67 (ddt, J ˆ 10.0, 5.0, 2.5 Hz, 1H), 6.05 (s, 1H),
6.40 (d, J ˆ 11.2 Hz, 1H), 7.51 (s, 1H), 7.77 (s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 11.37, 24.69, 28.71, 30.41, 38.66, 38.68, 41.20, 46.14, 65.31, 65.57,
72.25, 80.52, 102.1, 121.1, 124.9, 127.6, 128.1, 128.4, 129.4, 135.8, 136.8, 135.9,
500.2 (4) [M À C4H10O] , 419.3 (4) [M À C4H10O À Br] , 57.1 (100) [C4H9] ;
HRMS: calcd for C24H29Br3O 569.9768; found 569.9768.
(‡)-1,5-Dibromo-2,4-bis{(Z)-2-[(1S,3aS,4S,7aS)-1-tert-butoxy-7a-methyl-
2,3,3a,4,7,7a-hexahydro-1H-inden-4-yl]vinyl}benzene (4): 1. Reaction of
vinyl bromide 27 (40.0 mg, 69.8 mmol), hydrindene 7 (29.0 mg, 140 mmol),
K2CO3 (24.0 mg, 174 mmol), nBu4NCl (19.0 mg, 69.8 mmol), PPh3
(20 mol%, 3.70 mg, 14.0 mmol) and Pd(OAc)2 (10 mol%, 1.60 mg,
6.98 mmol) in DMF/CH3CN/H2O (1:1:0.2, 1 mL) as described for 5 gave 4
(23.0 mg, 32.8 mmol, 47%) as colorless oil.
‡
‡
137.3; MS (70 eV, EI): m/z (%): 540.1 (10) [M] , 483.0 (19) [M À C4H9] ,
2. PPh3 (20 mol%, 4.70 mg, 17.9 mmol) was added at 508C to a stirred
solution of 30 (40.0 mg, 89.7 mmol), hydrindene 7 (75.0 mg, 359 mmol) and
nBu4NOAc (135mg, 449 mmol) in degassed DMF/CH3CN/H2O (1:1:0.2,
1 mL) and Pd(OAc)2 (10 mol%, 2.00 mg, 8.97 mmol), and the reaction
mixture was heated at 608C for 18 h. After cooling the solution was diluted
with Et2O (10 mL), washed with water (2 Â 5mL) and the combined
aqueous layers were extracted with Et2O (2 Â 5mL). Then, the combined
organic layers were washed with brine, dried over Na2SO4, the solvent was
removed in vacuo and the residue purified by column chromatography (n-
pentane/CH2Cl2 3:1) to give 4 (8.0 mg, 11.4 mmol, 13%) as colorless oil.
Rf ˆ 0.31 (n-pentane/CH2Cl2 5:1); [a]2D0 ˆ ‡6.38 (c ˆ 1 in CHCl3); UV/Vis
(CH3CN): lmax (lg e) ˆ 239.0 nm (4.340); IR (KBr): nÄ ˆ 2972, 1197,
‡
‡
‡
461.2 (34) [M À Br] , 403.1 (100) [M À BrÀ C4H8] , 73.0 (56) [C3H5O2] ,
‡
57.0 (88) [C4H9] ; HRMS: calcd for C25H32Br2O3: 538.0718; found 538.0718.
(À)-2,4-Dibromo-5-{(Z)-2-[(1S,3aS,4S,7aS)-1-tert-butoxy-7a-methyl-
2,3,3a,4,7,7a-hexahydro-1H-inden-4-yl]vinyl}benzaldehyde (26a): A solu-
tion of 26 (4.19 g, 7.76 mmol) and pyridinium p-toluenesulfonate (585 mg,
2.33 mmol) in acetone/water (2:1, 100 mL) was heated under reflux for
4.5d. The solvents were removed in vacuo and diethyl ether (100 mL) was
added. The organic phase was washed with brine, dried over Na2SO4 and
evaporated in vacuo. Purification by column chromatography (n-pentane/
Et2O 30:1) furnished 26a (3.21 g, 6.47 mmol, 83%) as colorless oil and 26
(163 mg, 302 mmol, 4%). Rf ˆ 0.28 (n-pentane/Et2O 30:1); [a]2D0 ˆ À11.08
(c ˆ 0.8 in CHCl3); UV/Vis (CH3CN): lmax (lg e) ˆ 202.5 (4.259), 245.0
1079 cmÀ1
;
1H NMR (500 MHz, CDCl3): d ˆ 0.61 (s, 6H), 1.02 1.17 (m,
2H), 1.11 (s, 18H), 1.22 1.47 (m, 4H), 1.57 1.66 (m, 2H), 1.75 1.88 (m,
4H), 1.98 (dd, J ˆ 17.2, 5.0 Hz, 2H), 2.76 2.85(m, 2H), 3.45(t, J ˆ 8.4 Hz,
2H), 5.40 (d, J ˆ 10.0 Hz, 2H), 5.44 (dd, J ˆ 11.0, 11.0 Hz, 2H), 5.66 (ddt,
J ˆ 10.0, 5.4, 2.1 Hz, 2H), 6.34 (d, J ˆ 11.2 Hz, 2H), 7.13 (s, 1H), 7.78 (s,
1H); 13C NMR (75MHz, CDCl 3): d ˆ 11.49, 24.76, 28.74, 30.37, 38.71, 38.97,
41.12, 46.35, 72.22, 80.58, 122.5, 127.7, 128.1, 128.4, 131.6, 135.5, 136.8, 137.0;
(4.331), 314.5nm (3.350); IR (KBr): nÄ ˆ 2972, 1698, 1575 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d ˆ 0.60 (s, 3H), 1.11 (s, 9H), 1.12 1.21 (m, 1H), 1.27
1.50 (m, 2H), 1.56 1.67 (m, 1H), 1.77 1.88 (m, 2H), 1.98 (dd, J ˆ 17.2,
5.3 Hz, 1H), 2.73 2.81 (m, 1H), 3.46 (t, J ˆ 8.3 Hz, 1H), 5.40 (d, J ˆ 9.6 Hz,
1H), 5.55 (dd, J ˆ 11.2, 11.2 Hz, 1H), 5.68 (ddt, J ˆ 9.7, 5.0, 2.6 Hz, 1H), 6.35
(d, J ˆ 11.2 Hz, 1H), 7.76 (s, 1H), 7.88 (s, 1H), 10.27 (s, 1H); 13C NMR
(50 MHz, CDCl3): d ˆ 11.33, 24.77, 28.71, 30.42, 38.66, 38.89, 41.18, 46.11,
72.24, 80.48, 124.8, 127.1, 127.9, 128.0, 130.9, 131.2, 132.0, 137.0, 138.1, 138.4,
‡
‡
MS (70 eV, EI): m/z (%): 700.2 (8) [M] , 643.2 (10) [M À C4H9] , 587.1 (36)
‡
‡
‡
[M À C4H8 À C4H9] , 569.1 (34) [M À C4H9 À C4H10O] , 57.1 (100) [C4H9] ;
HRMS: calcd for C38H52Br2O2: 698.2334; found 698.2334; elemental
analysis calcd (%) for C38H52Br2O2 (700.6): C 65.14, H 7.48; found C
65.02, H 7.31.
‡
‡
190.8; MS (70 eV, EI): m/z (%): 496.1 (4) [M] , 440.0 (41) [M À C4H8] ,
‡
‡
343.1 (26) [M À C4H9O À Br] , 57.1 (100) [C4H9] ; HRMS: calcd for
C23H28Br2O2: 494.0456; found 494.0456; elemental analysis calcd (%) for
C23H28Br2O2 (496.3): C 55.66, H 5.69; found C 55.70, H 5.31.
(À)-(1S,3aS,3bS,8aS,8bS,11S,11aS,13aR,14bR,16aS)-1,11-Di-tert-butoxy-
11a,16a-dimethyl-2,3,3a,3b,8a,8b,9,10,11a,13a,14b,16a-dodecahydro-di-1H-
indeno[4,5-a:4,5-j]anthracene (2): A solution of 4 (20.0 mg, 28.5 mmol),
Ag3PO4 (31.0 mg, 74.2 mmol) and trans-di(m-acetato)-bis[orto-(di-ortho-
tolylphosphino)benzyl]dipalladium(ii) 15 (5.00 mol%, 1.30 mg, 1.43 mmol)
in degassed DMF/CH3CN/H2O (1:1:0.2, 1 mL) was heated for 1.5h at
1308C in a preheated oil bath. After the reaction mixture was cooled, water
(10 mL) was added and the reaction mixture was extracted with Et2O (2 Â
10 mL). The combined organic layers were washed with brine and dried
over Na2SO4. Removal of the solvent and chromatographic purification (n-
pentane/CH2Cl2 5:1) yielded 2 (12.4 mg, 23.0 mmol, 81%) as colorless oil.
Rf ˆ 0.33 (n-pentane/CH2Cl2 5:1); [a]2D0 ˆ À338.38 (c ˆ 0.3 in CHCl3); UV/
Vis (CH3CN): lmax (lg e) ˆ 222.0 (4.133), 250.5 (4.508), 257.0 (4.538), 270.0
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,4-dibrom-5-(2,2-dibromovi-
nyl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene (26b): Re-
action of CBr4 (4.28 mg, 12.9 mmol) in CH2Cl2 (20 mL), PPh3 (6.77 g,
25.8 mmol) in CH2Cl2 (20 mL) and benzaldehyde 26a (3.20 g, 6.45mmol)
in CH2Cl2 (10 mL) at À208C as described for 13b gave 26b as colorless oil
(3.14 g, 4.82 mmol, 75%). Rf ˆ 0.34 (n-pentane/CH2Cl2 6:1); [a]2D0 ˆ À5.28
(c ˆ 0.5in CHCl 3); UV/Vis (CH3CN): lmax (lg e) ˆ 253.3 nm (4.283); IR
(KBr): nÄ ˆ 2971, 1196, 1078 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 0.58 (s,
3H), 1.04 1.16 (m, 1H), 1.10 (s, 9H), 1.26 1.40 (m, 2H), 1.56 1.65 (m,
1H), 1.76 1.87 (m, 2H), 1.97 (dd, J ˆ 17.2, 5.2 Hz, 1H), 2.89 2.96 (m, 1H),
3.45(t, J ˆ 8.5Hz, 1H), 5.44 (d, J ˆ 9.6 Hz, 1H), 5.48 (dd, J ˆ 11.0, 11.0 Hz,
1H), 5.69 (ddt, J ˆ 9.6, 5.4, 2.6 Hz, 1H), 6.35 (d, J ˆ 11.2 Hz, 1H), 7.40 (s,
1H), 7.46 (s, 1H), 7.80 (s, 1H); 13C NMR (75MHz, CDCl 3): d ˆ 11.73, 24.60,
28.72, 30.36, 38.67, 38.92, 41.23, 46.27, 72.27, 80.50, 93.40, 121.5, 124.4, 127.9,
127.9, 128.3, 131.5, 134.8, 137.2, 135.7, 137.6; MS (70 eV, EI): m/z (%): 652.1
(4.287), 281.5nm (4.167); IR (KBr): nÄ ˆ 2972, 1362, 1198 cmÀ1
;
1H NMR
(500 MHz, CDCl3): d ˆ 0.85(s, 6H), 1.10 (s, 18H), 1.34 1.53 (m, 6H),
1.68 1.77 (m, 2H), 1.78 1.88 (m, 2H), 2.63 (ddd, J ˆ 11.8, 6.9, 6.9 Hz, 2H),
3.47 (dd, J ˆ 8.7, 6.5Hz, 2H), 3.70 (dd, J ˆ 6.9, 6.9 Hz, 1H), 5.82 (dd, J ˆ 9.7,
6.1 Hz, 2H), 6.04 (d, J ˆ 10.1 Hz, 2H), 6.15(dd, J ˆ 10.1, 4.7 Hz, 2H), 6.30
(d, J ˆ 9.7 Hz, 2H), 6.60 (s, 1H), 7.18 (s, 1H); 13C NMR (150 MHz, CDCl3):
d ˆ 14.93, 22.82, 28.73, 31.80, 33.83, 38.20, 41.62, 44.74, 72.39, 76.21, 124.2,
125.4, 126.2, 129.5, 130.7, 136.1, 136.3; MS (70 eV, EI): m/z (%): 538.6 (56)
‡
‡
‡
(5) [M] , 594.9 (23) [M À C4H9] , 577.9 (30) [M À C4H10O] , 497.0 (12)
‡
‡
[M À C4H10O À Br] , 57.1 (100) [C4H9] ; HRMS: calcd for C24H28Br4O:
647.8874; found 647.8874; elemental analysis calcd (%) for C24H28Br4O
(652.1): C 44.20, H 4.33; found C 43.95, H 4.06.
‡
‡
‡
[M] , 481.5(54) [ M À C4H9] , 425.5 (20) [M À C4H9 À C4H8] , 407.4 (34)
(À)-(1S,3aS,4S,7aS)-1-tert-Butoxy-4-{(Z)-2-[2,4]-dibromo-5-((Z)-2-bromo-
‡
‡
[M À C4H9 À C4H8 À H2O] , 57.1 (100) [C4H9] ; HRMS: calcd for C38H50O2:
vinyl)phenyl]vinyl}-7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-indene
(27):
538.3811; found 538.3811.
Reaction of 26b (3.20 g, 6.45mmol), [Pd(PPh 3)4] (4.00 mol%, 223 mg,
1.93 Â 10À4 mol) and nBu3SnH (1.34 mL, 1.47 g, 5.06 mmol) in degassed
toluene (26 mL) as described for 14 gave 27 (2.53 g, 4.41 mmol, 92%) as
colorless oil. Rf ˆ 0.28 (n-pentane/CH2Cl2 6:1); [a]2D0 ˆ À36.38 (c ˆ 0.8 in
CHCl3); UV/Vis (CH3CN): lmax (lg e) ˆ 252.5 nm (4.622); IR (KBr): nÄ ˆ
2972, 1576, 1197 cmÀ1; 1H NMR (500 MHz, CDCl3): d ˆ 0.62 (s, 1H), 1.05
1.16 (m, 1H), 1.11 (s, 9H), 1.26 1.41 (m, 2H), 1.57 1.65 (m, 1H), 1.76
1.87 (m, 2H), 1.97 (dd, J ˆ 17.2, 5.2 Hz, 1H), 2.98 3.04 (m, 1H), 3.46 (t, J ˆ
8.5Hz, 1H), 5.45(d, J ˆ 9.8 Hz, 1H), 5.48 (dd, J ˆ 11.0, 11.0 Hz, 1H), 5.68
(ddt, J ˆ 9.7, 5.5, 2.2 Hz, 1H), 6.37 (d, J ˆ 11.2 Hz, 1H), 6.58 (d, J ˆ 8.0 Hz,
1H), 7.09 (d, J ˆ 8.0 Hz, 1H), 7.65(s, 1H), 7.81 (s, 1H); 13C NMR (50 MHz,
CDCl3): d ˆ 11.71, 24.60, 28.73, 30.39, 38.71, 38.85, 41.25, 46.36, 72.22, 80.56,
110.0, 122.1, 123.9, 127.6, 128.0, 128.5, 131.4, 131.6, 133.9, 136.8, 135.6,
(1S,3aS,3bS,8bR,11S,11aS,14bR,16aS)-1,11-Di-tert-butoxy-11a,16a-dimeth-
yl-2,3,3a,3b,8b,9,10,11a,12,13,14b,16a-dodecahydro-di-1H-indeno[4,5-a:
4,5-j]anthracene (28): Rf ˆ 0.18 (n-pentane/CH2Cl2 5:1); 1H NMR (5 00 MHz,
CDCl3): d ˆ 0.66 (s, 3H), 0.90 (s, 3H), 1.10 (s, 9H), 1.18 (s, 9H), 1.38 1.88
(m, 8H), 2.07 2.20 (m, 3H), 2.69 2.77 (m, 2H), 3.11 3.30 (m, 2H), 3.47
(dd, J ˆ 8.9, 6.2 Hz, 1H), 3.64 (t, J ˆ 7.8 Hz, 1H), 3.82 (t, J ˆ 5.5 Hz, 1H),
5.95 (dd, J ˆ 9.6, 6.0 Hz, 1H), 6.10 (d, J ˆ 10.0 Hz, 1H), 6.30 (dd, J ˆ 10.0,
4.3 Hz, 1H), 6.55 (d, J ˆ 9.6 Hz, 1H), 7.09 (d, J ˆ 8.4 Hz, 1H), 7.34 (s, 1H),
7.53 (d, J ˆ 8.4 Hz, 1H), 7.77 (s, 1H); 13C NMR (150 MHz, CDCl3): d ˆ
10.81, 15.08, 22.87, 23.84, 24.52, 28.71, 28.77, 31.79, 31.85, 34.33, 34.35, 38.79,
42.38, 42.45, 45.22, 46.53, 72.34, 72.39, 76.19, 79.96, 121.1, 124.4, 125.0,
125.51, 125.54, 127.0, 130.2, 130.5, 130.8, 131.5, 130.6, 136.1, 136.3, 136.4; MS
‡
‡
‡
‡
137.42; MS (70 eV, EI): m/z (%): 574.3 (2) [M] , 517.3 (4) [M À C4H9] ,
(70 eV, EI): m/z (%): 538.3 (100) [M] , 481.2 (96) [M À C4H9] , 464.2 (36)
Chem. Eur. J. 2002, 8, No. 9 ¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0809-2123 $ 20.00+.50/0
2123

L. F. Tietze and W.-R. Krahnert
FULL PAPER
‡
‡
[M À C4H8 À H2O] , 407.2 (6) [M À C4H9 À C4H8 À H2O] , 57.0 (54)
consisting of 33 (8.5mg, 15.9 mmol, 29%) and 2 (8.6 mg, 15.9 mg, 29%).
Analytical data for 33: Rf ˆ 0.24 (n-pentane/CH2Cl2 3:1); 1H NMR
(500 MHz, CDCl3): d ˆ 0.71 (s, 6H), 1.25(s, 18H), 1.67 1.80 (m, 2H),
1.95 2.13 (m, 4H), 2.20 2.32 (m, 2H), 3.09 (dd, J ˆ 12.5, 7.3 Hz, 2H), 4.02
(dd, J ˆ 8.5, 7.5 Hz, 2H), 6.54 (d, J ˆ 9.8 Hz, 2H), 7.26 (d, J ˆ 8.6 Hz, 2H),
7.36 (d, J ˆ 9.8 Hz, 2H), 7.87 (d, J ˆ 8.6 Hz, 2H), 8.36 (s, 1H), 8.89 (s, 1H);
13C NMR (150 MHz, CDCl3): d ˆ 10.46, 23.69, 28.84, 32.49, 44.92, 46.35,
72.61, 75.62, 115.2, 122.2, 123.5, 127.3, 127.4, 128.3, 129.0, 130.2, 135.1, 139.2;
‡
[C4H9] ; HRMS: calcd for C38H50O2: 538.3811; found 538.3810.
1,5-Dibromo-2,4-di(2,2-dibromovinyl)benzene (29): Reaction of CBr4
(2.67 g, 8.04 mmol) in CH2Cl2 (15mL), PPh 3 (4.22 g, 16.1 mmol) in CH2Cl2
(15mL) and 2,4-dibromobenzene-1,5-dicarbaldehyde ( 22; 587 mg,
2.01 mmol) as described for 16 gave 29 (694 mg, 1.15mmol, 57%) as white
solid. Rf ˆ 0.54 (n-pentane); m.p. 1758C; UV/Vis (CH3CN): lmax (lg e) ˆ
207.5(3.948), 262.5nm (3.908); IR (KBr): nÄ ˆ 3080, 1595, 1574, 1444 cmÀ1
;
‡
‡
MS (70 eV, EI): m/z (%): 534.4 (87) [M] , 459.2 (12) [M À C4H9 À H2O] ,
1H NMR (200 MHz, CDCl3): d ˆ 7.43 (s, 2H), 7.79 (s, 1H), 7.84 (s, 1H);
‡
57.0 (100) [M] ; C38H46O2 (534.8).
13C NMR (50 MHz, CDCl3): d ˆ 94.15, 123.3, 131.3, 135.3, 135.4, 136.0; MS
‡
‡
(70 eV, EI): m/z (%): 603.7 (70) [M] , 522.7 (2) [M À Br] , 443.9 (10) [M À
‡
‡
‡
2 Â Br] , 364.9 (2) [M À 3 Â Br] , 284.0 (10) [M À 4 Â Br] ; elemental
analysis calcd (%) for C10H4Br6 (603.6): C 19.90, H 0.67; C 20.22, H 0.67.
1,5-Dibromo-2,4-di[(Z)-2-bromovinyl]benzene (30): Reaction of 29
(623 mg, 1.03 mmol), [Pd(PPh3)4] (8.00 mol%, 95.0 mg, 82.6 mmol) and
nBu3SnH (0.57 mL, 631 g, 0.57 mmol) in toluene (62 mL) as described for
17 gave 30 (354 mg, 794 mmol, 77%) as white solid. Rf ˆ 0.39 (n-pentane);
m.p. 1088C; UV/Vis (CH3CN): lmax (lg e) ˆ 256.5 nm (4.313); IR (KBr):
Acknowledgement
We thank the Deutsche Forschungsgemeinschaft (Sonderforschungsber-
eich 416) and the Fonds der Chemischen Industrie for financial support. We
also thank Schering AG and Degussa AG for generous gifts of chemicals.
nÄ ˆ 3080, 1620, 1572, 1318, 1045, 864, 666 cmÀ1
;
1H NMR (200 MHz,
CDCl3): d ˆ 6.65(d, J ˆ 8.0 Hz, 2H), 7.15(d, J ˆ 8.0 Hz, 2H), 7.86 (s, 1H),
8.14 (s, 1H); 13C NMR (50 MHz, CDCl3): d ˆ 110.3, 123.6, 131.2, 131.3,
‡
134.2, 135.8; MS (70 eV, EI): m/z (%): 445.9 (100) [M] , 365.0 (64) [M À
[1] G. R. Petit, M. Inoue, Y. Kamano, D. L. Herald, C. Arm, C. Dufresne,
N. D. Christie, J. M. Schmidt, D. L. Doubek, T. S. Krupa, J. Am. Chem.
Soc. 1988, 110, 2006 2007.
[2] G. R. Pettit, R. Tan, J.-P.Xu, Y. Ichihara, M. D. Williams, M. R. Boyd,
J. Nat. Prod. 1998, 61, 955 958.
‡
‡
‡
Br] , 286.0 (40) [M À 2 Â Br] , 206.1 (21) [M À 2 Â BrÀ HBr] , 126.1 (40)
‡
[M À 4 Â Br] ; elemental analysis calcd (%) for C10H6Br4 (445.8): C 26.94,
H 1.36; found C 27.15, H 1.49.
(À)-(1S,3aS,3bR,8aR,8bR,11S,11aS,13aR,14bR,16aS)-1,11-Di-tert-butoxy-
11a,16a-dimethyl-2,3,3a,3b,4,5,7,8,8a,8b,9,10,11a,12,13,13a,14b,15,16,16a-
eicosahydro-di-1H-indeno[4,5-a:4,5-j]anthracene (31): A solution of fresh-
ly prepared 2 (54.3 mg, 101 mmol) and PtO2 ¥ H2O (10 mol%, 2.50 mg,
10.2 mmol) in methanol/ethyl acetate (1:1, 4 mL) was stirred under a
hydrogen atmosphere (50 bar) for 15 h at room temperature. The solvent
was removed in vacuo and the residue was purified by column chromatog-
raphy (n-pentane/CH2Cl2 5:1) to furnish 31 (54 mg, 98.7 mmol, 98%) as
white solid. Rf ˆ 0.14 (n-pentane/CH2Cl2 5:1); m.p. 188 8C; [a]2D0 ˆ À95.08
(c ˆ 0.5in CHCl 3); UV/Vis (CH3CN): lmax (lg e) ˆ 204.0 (4.730), 248.0
(2.932), 254.0 (2.970), 260.5 (2.970), 275.5 (3.204), 284.5 (3.235), 308.0 nm
(2.447); IR (KBr): nÄ ˆ 2971, 2925, 1198 cmÀ1; 1H NMR (500 MHz, CDCl3):
d ˆ 0.96 (s, 24H), 1.06 1.16 (m, 2H), 1.21 1.42 (m, 4H), 1.48 1.59 (m,
4H), 1.60 1.77 (m, 8H), 1.86 1.97 (m, 4H), 2.47 (d, J ˆ 14.5Hz, 2H), 2.57
(dd, J ˆ 16.8, 4.7 Hz, 2H), 2.82 (m, 2H), 3.01 (t, J ˆ 8.0 Hz, 4H), 6.88 (s,
1H), 7.67 (s, 1H); 13C NMR (150 MHz, CDCl3): d ˆ 11.40, 23.74, 24.96,
25.25, 25.67, 28.54, 30.86, 33.30, 34.20, 38.24, 41.41, 42.96, 71.68, 80.82, 123.9,
[3] S. Fukuzawa, S. Matsunaga, N. Fusetani, Tetrahedron 1995, 51, 6707
6716.
[4] S. Fukuzawa, S. Matsunaga, N. Fusetani, J. Org. Chem. 1997, 62, 4484
4491.
[5] Y. Li, J. R. Dias, Chem. Rev. 1997, 97, 283 304.
[6] T. G. LaCour, C. Guo, S. Bhandaru, M. R. Boyd, P. L. Fuchs, J. Am.
Chem. Soc. 1998, 120, 692 707.
[7] a) C. H. Heathcock, S. C. Smith, J. Org. Chem. 1994, 59, 6828 6839.
[8] M. Drˆgem¸ller, R. Jautelat, E. Winterfeldt, Angew. Chem. 1996, 108,
1669 1671; Angew. Chem. Int. Ed. Engl. 1996, 35, 1572 1574.
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1993, 2865 2867.
[10] M. Drˆgem¸ller, T. Flessner, R. Jautelat, U. Scholz, E. Winterfeldt,
Eur. J. Org. Chem. 1998, 2811 2831.
[11] E. Winterfeldt, Pure Appl. Chem. 1998, 71, 1095 1099.
[12] J. U. Jeong, S. C. Sutton, S. Kim, P. L. Fuchs, J. Am. Chem. Soc. 1995,
117, 10157 10158.
[13] S. Bhandaru, P. L. Fuchs, Tetrahedron Lett. 1995, 36, 8347 8350.
[14] S. Bhandaru, P. L. Fuchs, Tetrahedron Lett. 1995, 36, 8351 8354.
[15] S. Kim, P. L. Fuchs, Tetrahedron Lett. 1994, 35, 7163 7166.
[16] a) L. F. Tietze, T. Nˆbel, M. Spescha, Angew. Chem. 1996, 108, 2259
2261; Angew. Chem. Int. Ed. Engl. 1996, 35, 2674 2675.
[17] L. F. Tietze, T. Nˆbel, M. Spescha, J. Am. Chem. Soc. 1998, 120, 8971
8977.
[18] L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2000, 1827 1830.
[19] L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2001, 1619 1624.
[20] L. F. Tietze, W.-R. Krahnert, Synlett 2001, 560 562.
[21] L. F. Tietze, P. S. V. Subba Rao, Synlett 1993, 291 293.
[22] T. Mandai, T. Matsumoto, M. Kwada, J. Tsuji, Tetrahedron 1993, 49,
5483 5493.
‡
130.2, 134.4, 136.0; MS (70 eV, EI): m/z (%): 546.6 (100) [M] , 489.5(88)
‡
‡
[M À C4H9] , 471.5(27)
[
M À C4H9 À H2O] , 433.4 (14) [M À C4H8 À
‡
‡
C4H9] , 415.4 (40) [M À C4H9 À C4H8 À H2O] ; HRMS: calcd for
C38H58O2: 546.4437; found 546.4436.
(À)-(1S,3aS,3bR,8aR,8bS,11S,11aS,13aR,14bR,16aS)-1,11-Dihydroxy-
11a,16a-dimethyl-2,3,3a,3b,4,5,7,8,8a,8b,9,10,11a,12,13,13a,14b,15,16,16a-
eicosahydro-di-1H-indeno[4,5-a:4,5-j]anthracene (32): Reaction of 31
(20.0 mg, 36.6 mmol) with TMSI (10.0 mL, 14.6 mg, 73.1 mmol) as described
for 19 gave 32 (16 mg, 36.8 mmol, 100%) as colorless oil. Rf ˆ 0.52 (n-
pentane/EtOAc 1:1); [a]2D0 ˆ À90.88 (c ˆ 1.16 in CHCl3); 1H NMR
(500 MHz, CD2Cl2): d ˆ 0.83 (s, 6H), 0.92 (dd, J ˆ 13.1, 3.3 Hz, 2H),
1.18 1.28 (m, 4H), 1.28 1.41 (m, 2H), 1.43 (brs, 2H), 1.52 (ddd, J ˆ 12.6,
3.3, 3.3 Hz, 2H), 1.59 1.66 (m, 2H), 1.71 1.81 (m, 4H), 1.88 1.98 (m,
4H), 2.04 (ddd, J ˆ 11.8, 8.0, 3.8 Hz, 2H), 2.36 (dddd, J ˆ 14.7, 5.4, 2.5,
2.5Hz, 2H), 2.56 (d, J ˆ 16.5Hz, 2H), 2.66 2.76 (m, 2H), 2.96 (brs, 2H),
3.45(dd, J ˆ 8.6, 7.8 Hz, 2H), 6.75(s, 1H), 7.31 (s, 1H); 13C NMR
(125MHz, CDCl 3): d ˆ 11.27, 23.96, 25.28, 25.74, 26.22, 30.67, 33.44, 35.00,
38.60, 42.43, 43.92, 82.59, 124.6, 130.2, 135.2, 136.3; MS (70 eV, EI): m/z
[23] J. Tsuji, T. Mandai, Synthesis 1996, 1 24.
[24] Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1974, 39, 1615 1621.
[25] U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492 493;
Angew. Chem. Int. Ed. Engl. 1971, 10, 496 497.
[26] J. R. Naylor, J. Chem. Soc. 1952, 4085 4086.
‡
‡
(%): 434.3 (100) [M] , 375.2 (3) [M À H2O À CH3 À C2H2] , 334.2 (3) [M À
[27] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769 3772.
[28] G. J. Hollingworth, J. B. Sweeney, Synlett 1993, 463 465.
[29] J. Morris, D. G. Wishka, Synthesis 1994, 43 46.
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[31] J. Uenishi, R. Kawahama, O. Yonemitsu, J. Tsuji, J. Org. Chem. 1996,
61, 5716 5717.
[32] J. Uenishi, R. Kawahama, Y. Shiga, O. Yonemitsu, J. Tsuji, Tetrahe-
dron Lett. 1996, 37, 6759 6762.
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Chem. 1998, 110, 334 336; Angew. Chem. Int. Ed. 1998, 37, 320 323.
‡
‡
H2O À 2 Â CH3 À 2 Â C2H2] , 321.2 (7) [M À 2 Â CH3 À C2H2 À C3H5O]
; HRMS: calcd for C30H42O2: 434.3185; found 434.3184.
(1S,3aS,8bS,11S,11aS,16aS)-1,11-Di-tert-butoxy-11a,16a-dimethyl-
2,3,3a,8b,9,10,11a,16a-octahydro-di-1H-indeno[4,5-a:4,5-j]anthracene
(33): A solution of freshly prepared 2 (30.0 mg, 55.7 mmol) and 10%
palladium on charcoal (20 mol% Pd, 1.17 mg, 11.4 mmol) in methanol
(1 mL) was stirred for 6 d at 508C. The catalyst was removed by filtration
through a short pad of celite. Evaporation of the solvent and purification of
the residue by column chromatography gave an inseparable 1:1 mixture
2124
¹ WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002
0947-6539/02/0809-2124 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 9

Multiple Heck-Reactions
2116 2125
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M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989 1992; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1844 1846.
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4133.
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: (‡44)1223-336-033; or deposit@ccdc.cam.uk).
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the simplified analogues of cephalostatin described in this manuscript
is also included in the 60 human cancer cell line panel from the NCI.
Received: November 22, 2001 [F3701]
Chem. Eur. J. 2002, 8, No. 9
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