A practical route to a complex bis-steroidal diene intermediate using a microwave assisted Heck-reaction

Article abstract of DOI:10.1055/s-2002-33118

A very special set of Heck-conditions led reliably to a non-symmetric bis-steroidal diene which underwent regioselective high-pressure Diels-Alder cycloadditions with non-symmetric electron poor acetylenes. The cyclohexadienes thus obtained were aromatized to the corresponding benzene derivatives.

Full text of DOI:10.1055/s-2002-33118

PAPER
1373
A Practical Route to a Complex Bis-Steroidal Diene Intermediate Using a
Microwave Assisted Heck-Reaction
Microwave
Ass
.
istedHeck-R
F
eaction lessner,b V. Ludwig,a H. Siebeneicher,a E. Winterfeldt*a
a
Institut für Organische Chemie, Schneiderberg 1b, 30167 Hannover, Germany
Fax +490(511)7623011; E-mail: hosieben@gmx.de
b
BAYER AG, Central Research, 51368 Leverkusen, Germany
Received 30 November 2002; revised 25 April 2002
On the other hand, there is no doubt that the pyrazine ring
represents an electron-poor heteroaromatic system. Com-
pared to benzene, electrophilic substitution reactions on
suitably substituted pyrazines suffer from this low reactiv-
ity,5 while N-oxides, for example, are easily obtained via
simple oxidation reactions.
Abstract: A very special set of Heck-conditions led reliably to a
non-symmetric bis-steroidal diene which underwent regioselective
high-pressure Diels–Alder cycloadditions with non-symmetric
electron poor acetylenes. The cyclohexadienes thus obtained were
aromatized to the corresponding benzene derivatives.
Key words: natural products, Heck reaction, microwave condi-
tions, Diels Alder reactions, regioselectivity
Our attempts to selectively epoxidize the steroidal D-ring
double bonds in diketone 3 for instance, employing perac-
ids and hydroperoxides, simply afforded a mixture of the
quite polar mono- and bis-N-oxides 4 and 5 (see
Scheme 2) in a fast reaction.6
Along with our efforts to identify functional groups and
sub-structures essential for the biological activity of the
tumor inhibiting cephalostatin- (e.g. 1)1–4 and ritterazine-
type (e.g. 2) marine natural products (Scheme 1), we be-
came interested in the significance of the pyrazine-ring
connecting two steroidal moieties.
This result proves the important role of electron pairs on
nitrogen in the general chemical behaviour of these inter-
O
O
O
O
OH
OH
HO
H
H
N
N
12
H
O
OH
H
H
H
N
N
14
15
H
H
H
O
H
15'
14'
O
O
H
12'
H
3
O
O
O
1.3 eq m-CPBA
0°C / 30 min
CH2Cl2
cephalostatin 1 (1)
OH
OH
OH
HO
O
12
H
O
O
H
N
O
14
-
15
O
N
H
H
O
15'
H
H
14'
+
N
H
12'
H
O
H
H
O
N
OH
H
O
H
OH
HO
O
O
ritterazine K (2)
4
Scheme 1
+
O
H
-
O
O
As pyrazine formation is biogenetically certainly the most
simple way to link two steroids with an aromatic system,
one may speculate that any 6 -system, maybe even a sim-
ple benzene ring, could be in its place.
O
H
+
N
H
H
N
+
H
O
H
O
O
-
O
5
Synthesis 2002, No. 10, Print: 30 07 2002.
Art Id.1437-210X,E;2002,0,10,1373,1378,ftx,en;T11301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 2

1374
T. Flessner et al.
PAPER
esting molecules. It seemed worthwhile to elaborate a pro- Although the general idea looks simple there were a few
cedure which would allow the replacement of the important details to worry about.
heterocycle by other 6 -systems in order to obtain a deep-
er insight into the pharmacological relevance of this moi-
ety.
As the Diels–Alder cycloaddition employing acetylenes reaction10 of a non-activated terminal alkene and the prob-
represents a highly flexible route to cyclohexadienes7 (see lem of regioselectivity with a non-symmetric dienophile
Scheme 3), which themselves are ideal precursors for had to be taken into account11 in the cycloaddition pro-
benzene derivatives, we decided on an intermediate like 8 cess. The regioselectivity was by no means easy to predict
First of all a reliable and efficient approach to ring-A-
opened steroids of type 6 had to be identified.8,9 Further-
more, one had to find proper conditions for the Heck-
as the diene of choice for this project.
even if an electronic preference for the orientation given
in 8 appeared likely.
O
6
[Pd]
O
X
+
H
8
TfO
7
H
O
O X
X
H
H
H
10
9
Scheme 3
O
O
O
O
O
O
O
O
O
H
H
a
HO
H
H
H
H
O
O
12
11
b, c, d
O
O
O
O
O
O
O
O
H
H
e, f
HO
O
H
H
O
H
H
O
O
14
13
Scheme 4 Reactions and conditions: (a) K2CO3 (3 equiv), NaIO4 (4.7 equiv), KMnO4 (0.4 equiv), t-BuOH–H2O (1:1), 30 min, 25 °C, 94%;
(b) CH2N2, CH2Cl2, 25 °C, >99%; (c) HO-(CH2)2-OH–CH2Cl2 (1:1), PTSA (2.1 equiv), 96 h, 25 °C, 91%; (d) LiAlH4 (2.5 equiv), THF, 10 min,
25 °C, >99%; (e) o-NO2PhSeCN (1.2 equiv), PBu3 (1.2 equiv), THF, 3 H, 25 °C, 82%;13 (f) H2O2 (35%), THF, 24 h, 25 °C, 90%.
Synthesis 2002, No. 10, 1373–1378 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Practical Route to a Complex Bis-Steroidal Diene Intermediate
1375
O
O
O
O
O
O
H
O
a
O
H
O
H
O
TfO
H
O
O
H
O
H
O
15
16
17
b
O
O
O
O
O
O
O
H
O
O
O
O
H
O
H
c, d
O
H
H
R
H
H
H
H
H
O
H
H
O
O
O
O
O
O
O
18
Scheme 5 19a: R = OCH3; 19b: R = CH3; 19c: R = H
19a-c
Reactions and conditions: (a) Pd(OAc)2 (11 mol%), n-Bu4NCl (1.4 equiv), K2CO3 (2.9 equiv), DMF, 65 h, 70 °C, 69%; (b) 14, n-Bu4NCl (1
equiv), Cs2CO3 (1.5 equiv), Pd(OAc)2 (1.1 equiv), microwave (20 min), 77%; (c) 19a: methyl propiolate (10 equiv), ZnCl2 (0.5 equiv), CH2Cl2,
14 kbar, 3 d, 67%; 19b: butynone (10 equiv), 14 kbar, 3 d, 59% yield, 82% de; 19c: propargylic aldehyde (10 equiv), 8 kbar, 3 d, 80%; d) DDQ
(2 equiv), dioxane (2.5 ml), 3 H, 90 °C, 67% (19a), 96% (19b), 80% (19c).
For the preparation of the ring-open steroid 13 we could Having access to diene 18 in multigram amounts, the
rely on the well established Lemieux-Rudloff-oxidation12 stage was set for cycloaddition experiments.
which performed best as compared to various other proto-
To finally arrive at a tetrasubstituted cyclohexadiene (see
cols and generated keto-acid 12 in 94% yield starting from
9, Scheme 3), the dienophiles chosen were methyl propi-
the unsatured ketone 11 (Scheme 4). This in turn was eas-
olate (R = OCH3), butynone (R = CH3) and propargylic
aldehyde (R = H), but even with this generally most reac-
ily available from hecogenin.
The 2,3-enoltriflate 15 needed for the Heck-coupling was tive aldehydes18 no cycloaddition was observed under
easily obtained from the corresponding 3-keto-precursor, thermal conditions or with the help of catalysts.
which had been prepared in our laboratory in connection
Finally, however, high pressure conditions gave rise to a
with investigations on the significance of the 14,15 double
3:1 mixture of isomers in the case of propargylic alde-
bond in the steroidal D-ring.1,2,18
hyde. The isomers were shown to be diastereoisomers,
As suspected, the subsequent Heck-reaction affording di- since subsequent dehydrogenation converted all the mate-
ene 18 turned out to be not trivial at all (Scheme 5). Al- rial into a single product.
though model compound 16 uneventfully afforded a 69%
In contrast to the aldehyde the corresponding propargylic
ester as well as butynone gave a substantially higher yield
of cycloadducts under these conditions. In the case of me-
thyl propiolate even weak Lewis acids (e. g. zinc dichlo-
ride) could be applied as catalysts without any harm. In all
cases NMR data proved these compounds to be the de-
sired tetrasubstituted benzene derivatives of type 19.
yield of diene 17 under Jeffery’s conditions14, the straight-
forward transfer of this technique to the steroidal deriva-
tive 14 only led to a meager 45% yield of the desired
coupling product 18. A significant improvement of the
yield up to 62% could be achieved by changing the base
from potassium carbonate to cesium carbonate15. When
this reaction was finally run under single mode micro-
It can be concluded from the data collected for 19a, 19b
and 19c that they correspond to the ortho-adduct o (see
Scheme 6). The most convincing arguments to prove
structure o are the following:
wave conditions16a,b a reliable yield of 77% was obtained.
The beneficial effect of microwave addition on the Heck-
reaction in general had been reported at this stage al-
ready,16a,b but only while we were investigating the forma-
tion of diene 18, did A. Hallberg and his colleagues17
apply this technique to a very similar coupling process.
First, there was no m-coupling visible for the two aromatic
protons, as should be the case with m. Second, a clear
coupling was observed between the carbonyl carbon and
Synthesis 2002, No. 10, 1373–1378 ISSN 0039-7881 © Thieme Stuttgart · New York

1376
T. Flessner et al.
PAPER
A three-necked flask with septum, three-way tap and gas inlet tube
(with joint) was filled with freshly prepared tris-(triphenylphos-
phine)rhodiumchloride (1.13 g, 1.22 mmol) and washed for several
times with hydrogen. The complex was dissolved in a mixture of
anhyd toluene anhyd EtOH (1:1, 58 ml) and prehydrogenated for
30 min. Then the A ring dienone (1.90 g, 4.05 mmol) was added as
a soln in the same solvent mixture (134 ml). The reaction mixture
was flushed with hydrogen for 8 h.22 After evaporating the solvent,
the catalyst was removed by column filtration (PE–EtOAc, 2:1).
The brown residue was purified by column chromatography (PE–
EtOAc, 2:1) to yield 11 (1.59 g, 3.37 mmol, 83%) as a white crys-
talline product; mp 175 °C.
R
O
H
O
R
H
H
30
31
H
2
3
32
33
H
H
H
H
o'
m'
R
O
IR (CHCl3): 2999, 2959, 2933, 2877, 1664, 1615, 1456, 1264, 1047
cm–1.
O
H
30
31
32
H
1H NMR: = 5.74 (s, 1 H, 4-H), 4.41–4.36 (m, 1 H, 16-H), 4.03–
3.99 (m, 2 H), 3.95–3.80 (m, 2 H), 3.50–3.46 (m, 1 H, 26 -H), 3.37
(t, 1 H, J = 10.9 Hz), 2.57–2.26 (m), 2.08–1.33 (m), 1.28–0.90 (m),
1.19 (s, 3 H, CH3-19), 0.97 (s, 3 H, CH3-18), 0.95 (d, 3 H, J = 7.0
Hz, CH3-21), 0.79 (d, 3 H, J = 6.4 Hz, 27-H).
R
2
3
33
H
H
m
o
13C NMR: = 199.3, 170.4, 124.1, 112.4, 109.4, 80.1, 66.9, 65.3,
64.3, 52.7, 51.7, 50.9, 47.9, 42.2, 38.3, 35.5, 34.5, 33.8, 32.7, 31.5,
31.4, 31.3, 30.4, 30.3, 28.8, 17.2, 17.1, 14.5, 13.8.
Scheme 6
MS: m/z (%) = 471 (34) [M+ + 1], 470 (100) [M+], 384 (25), 356
(23), 347 (93), 294 (17), 138 (24), 126 (13), 99 (14).
the proton at C33, which should not be the case with the 1,5
orientation in m, and finally the long-range coupling be-
tween the proton at C31 and C33 as expected for structure
m was completely absent. Having this very flexible and
reliable microwave assisted Heck-reaction in hand, as
well as the proof for a subsequent regioselective Diels–
HRMS: m/z calcd for C29H42O5: 470.3032; found: 470.3030.
12
The enone 11 (2.77 g, 5.88 mmol) was dissolved in boiling t-BuOH
(230 ml) together with K2CO3 (2.44 g, 17.6 mmol). After the addi-
Alder process one may envisage a number of options to tion of a soln of sodium periodate (5.91 g, 27.6 mmol) and KMnO4
(0.37 g, 2.35 mmol) in H2O (230 ml) and warmed up to 60 °C, the
‘substitute’ the pyrazine ring in the cephalostatins by var-
reaction mixture was stirred for 2 h at r.t. To destroy sodium hydro-
ious other 6 -systems including benzenes, pyridines or
gen sulfite the excess of oxidizing reagents the soln was treated with
1,2-pyrazines.
solid and acidified with dilute HCl. Extraction with Et2O (4 × 200
mL) was followed by washing the combined organic phases with
Na2S2O3 (aq, 2 × 150 mL). After treatment with brine, drying over
MgSO4 and evaporation of the solvent compound 12 (94%, 5.52
mmol, 2.71 g) was isolated as a white solid; mp 125 °C.
Unless otherwise noted, starting materials and solvents were ob-
tained from commercial suppliers and used after distillation. The
propargylic
aldehyde19
and
tris-(triphenylphosphine)-
rhodiumchloride20 were freshly prepared before use. Silica gel
60mesh size 0.04–0.063 mm (MN) was uzsed for flash chromatogr-
phy.
IR (CHCl3): 3690, 2960, 2931, 2877, 1705, 1603, 1457, 1230, 1048
cm–1.
1H NMR: = 4.42–4.36 (m, 1 H,), 4.02–3.80 (m, 4 H), 3.49–3.46
(m, 1 H), 3.49–3.47 (m, 1 H, 3.36 (t, 1 H, J = 11.1 Hz), 2.60–2.51
(m, 1 H), 2.37–1.82 (m), 1.78–1.37 (m), 1.25–0.83 (m), 1.12 (s, 3
H), 0.99 (s, 3 H), 0.95 (d, 3 H, J = 7.0 Hz), 0.79 (d, 3 H, J = 6.2 Hz).
13C NMR: = 214.6, 179.3, 112.4, 109.8, 80.3, 67.2, 65.6, 64.6,
53.0, 51.9, 50.4, 48.2, 42.6, 38.1, 34.2, 31.8, 31.7, 31.4, 30.9, 30.6,
29.5, 29.3, 29.1, 20.7, 17.4, 14.9, 14.1.
High-pressure-reactions were carried out with the Hofer high-pres-
sure-facility (14 kbar). The reactions under irradiation of focused
microwaves were performed in SynthewaveTM 402 (2.45 GHz) of
Prolabo. Melting points were determined on Gallenkamp MPD 350
1
melting point apparatus. H and 13C NMR spectra were taken in
CDCl3 solns using TMS as internal reference; chemical shifts are
given as values (ppm); the DEPT sequence was used for the 13
C
MS: m/z (%) = 491 (46) [M+ + 1], 490 (1) [M+], 348 (100), 233 (15),
139 (27), 127 (15), 99 (13).
NMR. Mass spectra were determined on a Finigan MAT 312 at an
ionizing voltage of 70 eV. FAB MS were performed on a VG-Au-
tospec in a matrix of nitrobenzyl alcohol. HRMS were measured on
a VG-Autospec using the peak-matching method. IR spectra were
obtained on the Perkin-Elmer FT 1710 spectrometer of Golden Gate
ATR. Petroleum ether (bp 50–70 °C) has been abbreviated as PE.
HRMS: m/z calcd for C28H42O7: 490.2931; found: 490.2933.
13
In the first step compound 12 was esterified quantitatively using di-
azomethane. The methyl ester (7.90 g, 15.7 mmol) was dissolved in
CH2Cl2 (40 ml), treated with p-toluenesulfonic acid (2.98 g, 15,7
mmol) and ethylene glycol (40 ml). After stirring for 24 h the layers
were separated and the ethylene glycol layer was extracted three
times with CH2Cl2 (50 mL). After evaporation the residue (40 ml)
was treated again with p-toluenesulfonic acid (1.49, 7.83 mmol) and
ethylene glycol (40 ml). The whole described procedure was repeat-
ed twice with varying amounts of p-toluenesulfonic acid (1.12 g,
5.87 mmol; 0.74 g, 3.91 mmol) so that after 96 h TLC monitored
complete conversion of the starting material. At this point the com-
11
A soln of hecogenin-12-acetal 11 (20.7 g, 43.6 mmol) and diphenyl
diselenide (4.1 g, 13.09 mmol) in toluene (420 ml) was heated to re-
flux. Iodosobenzene (76 g, 349 mmol) was added in portions within
8 h.21 After reflux for 24 h the reaction mixture was concentrated
and adsorbed on silica gel. After column filtration (PE EtOAc, 3:1)
the crude product was purified by silica gel chromatography (PE–
EtOAc, 2:1) to yield the A ring dienone (14.5 g, 31 mmol, 69%) as
a white solid.
Synthesis 2002, No. 10, 1373–1378 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Practical Route to a Complex Bis-Steroidal Diene Intermediate
1377
bined organic layers were washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was further purified by column
chromatography (PE–EtOAc, 3:1) to yield the methyl ester ketal
corresponding to 12 as a white powder (7.83 g, 14.26 mmol, 91%).
PE–EtOAc, 5:1) to yield diene 18 (938 mg, 0.98 mmol, 77%) as a
white solid.
IR: 2951, 2927, 2874, 1455, 1373, 1240, 1125, 1049, 980, 900 cm–1.
1H NMR: = 5.86 (d, 1 H, J = 15.7 Hz), 5.39 (m, 3 H), 4.84 (dd,
1 H, J = 8.2 Hz, 1.4 Hz), 4.36–4.29 (dd, 1 H, J = 9.0 , 7.8 Hz), 4.05–
3.94 (m, 4 H), 3.93–3.73 (m, 8 H), 3.55–3.30 (m), 2.59 (dd, 1 H,
J = 9.5 Hz, 8.2 Hz), 2.34 (dd, 1 H, J = 9.0 Hz, 7.0 Hz), 1.23 (s, 3 H),
1.16 (s, 3 H), 1.13 (m, 3 H), 0.98 (d, 3 H, J = 6.8 Hz), 0.96 (s, 3 H),
2.31–0.83 (m), 0.78 (d, 3 H, J = 6.3 Hz), 0.75 (d, 3 H, J = 6.3 Hz),
0.73 (s, 3 H).
13C NMR: = 156.1, 135.1, 132.7, 126.5, 124.0, 120.0, 113.7,
113.5, 112.6, 109.4, 106.7, 85.3, 80.2, 67.1, 66.8, 65.1, 65.0, 64.7,
64.4, 64.2, 64.1, 55.4, 52.5, 51.9, 51.1, 50.8, 47.8, 44.4, 44.1, 44.0,
42.2, 41.0, 40.1, 38.9, 35.1, 33.9, 31.5, 31.4, 31.4, 30.4, 30.4, 30.3,
30.0, 29.7, 29.5, 29.2, 28.8, 28.7, 28.4, 27.7, 18.4, 18.1, 17.5, 17.1,
17.1, 14.5, 13.8, 11.7.
A suspension of LiAlH4 (173 mg, 4.56 mmol) in anhyd THF (5 ml)
was cooled to 0 °C and addition of a soln of the above product (1.05
g, 1.82 mmol) in anhyd THF (5 ml) followed. The reaction was
monitored by TLC. At the end the reaction mixture was quenched
with H2O (173 L), 15% NaOH soln (173 L) and H2O (520 L).
The product was filtered through a cotton plug, the residue was
washed with CH2Cl2 several times (500 ml), and the combined con-
centrated filtrates were washed with brine and dried over MgSO4.
After solvent evaporation the residue was purified by column chro-
matography (PE–EtOAc, 1:1) over silica gel to obtain compound 13
as a white solid (0.94 g, 1.81 mmmol, >99%); mp: 179 °C.
IR (CHCl3): 3625, 2958, 2932, 2879, 1456, 1379, 1241, 1148, 1048
cm–1.
1H NMR: 4.40–4.34 (m, 1 H), 4.03–3.81 (m, 8 H), 3.49–3.46 (m, 1
H), 3.37 (t, 1 H, J = 11.0 Hz), 2.38–2.34 (m, 1 H), 2.07–1.97 (m),
1.85–1.09 (m), 0.98 (s, 3 H), 0.94 (d, 3 H, J = 7.0 Hz), 0.93 (s, 3 H),
0.78 (d, 3 H, J = 6.4 Hz).
FAB MS: m/z (%) = 955 (100) [M+], 893 (8), 493 (14), 462 (23),
431 (7), 345 (8), 307 (6).
19a; Typical Procedure
Diene 18 (100 mg, 0.105 mmol) was dissolved in anhyd CH2CL2
(1.5ml) and transfered into a teflon tube. Methyl propiolate (95 L,
1.05 mmol) and ZnCl2 (7 mg, 0.05 mmol) were added and the
closed tube was pressurized at 14 kbar for 3 d. The solvent was
evaporated at r.t. Finally the residue was purified by column chro-
matography (silica gel, PE–EtOAc, 5:1). This provided the cyclo-
hexadiene adduct as a white foam (27 mg, 0.03 mmol, 25%). This
adduct (27 mg, 0.03 mmol) and DDQ (12 mg, 0.05 mmol, 2 eq)
were dissolved in anhyd dioxane (2.5 ml) and heated for 3 h at
90 °C. The reaction was monitored by TLC. After adding H2O (1
mL) and extracting with methyl-tert-butyl ether (4 × 5 mL), the or-
ganic phase was washed with brine and dried over MgSO4. Finally
the residue was purified by column chromatography on silica gel
(PE–EtOAc, 3:1) to provide 19a (18 mg, 0.02 mmol, 67%) as a yel-
low foam.
13C NMR: = 113.8, 112.7, 109.5, 80.3, 66.9, 65.2, 64.4, 64.2,
64.0, 63.7, 52.7, 52.1, 48.0, 43.8, 42.9, 42.3, 33.9, 31.5, 31.4, 31.2,
30.8, 30.3, 30.3, 28.8, 28.6, 27.8, 18.3, 17.2, 14.6, 13.8.
MS: m/z (%) = 520 (42) [M+], 334 (11), 185 (30), 99 (100).
HRMS: m/z calcd for C30H48O7: 520.3400; found: 520.3402.
14
Compound 13 (1.88 g, 3.16 mmol) was dissolved together with p-
nitrophenyl selenocyanate (986 mg, 4.34 mmol) in anhyd THF (15
ml). Tributyl phosphine (1.08 ml, 4.34 mmol) was added while stir-
ring. After 3 h the solvent was removed, the residue was adsorbed
on silica gel and then purified by chromatography (PE–EtOAc, 8:1)
to obtain a yellow solid (1.83 g, 2.59 mmol, 82%). This phenylsele-
nyl product (2.22 g, 3.15 mmol) was redissolved in anhyd THF (30
ml) and a H2O2 soln (35%; 1.24 ml) was added dropwise at r.t. After
24 h stirring the reaction mixture was diluted with H2O, extracted
with methyl-tert-butyl ether, washed with brine and dried over
MgSO4. After column filtration (PE–EtOAc, 12:1) a white crystal-
line product (1.42 g, 2.82 mmol, 90%) was obtained; mp 181 °C.
IR: 2951,2925, 2874, 1720, 1455, 1241, 1145, 1052, 980 899 cm–1.
1H NMR: = 7.36 (s, 1 H), 7.01 (s, 1 H), 5.45 (m, 1 H), 4.32 (m, 1
H), 3.81 (s, 3 H), 4.10–3.68 (m, 12 H), 3.38 (m, 1 H), 2.60 (m, 1 H),
2.39 (m, 1 H), 1.23 (s, 3 H), 1.20–1.16 (m, 3 H), 1.01 (s, 3 H), 0.99
(d, 3 H, J = 6.7 Hz), 0.86 (s, 3 H), 2.90–0.80 (m), 0.79 (d, 3 H,
J = 6.3 Hz), 0.76 (d, 3 H, J = 6.4 Hz), 0.74 (s, 3 H)
13C NMR: (100 MHz, CDCl3, TMS): = 169.7, 155.9, 139.2, 138.1,
133.2, 132.6, 130.9, 129.5, 120.2, 113.6, 113.2, 112.6, 109.4, 106.8,
85.3, 80.2, 67.1, 66.8, 65.2, 65.1, 65.1, 64.1, 63.8, 63.1, 55.4, 51.9,
51.7, 51.1, 50.6, 47.9, 46.9, 46.2, 44.4, 42.8, 42.2, 41.4, 36.1, 35.5,
34.6, 33.8, 33.6, 31.6, 31.5, 31.4, 30.4, 30.3, 29.8, 29.7, 29.0, 29.0,
28.8, 28.7, 28.4, 27.4, 18.5, 17.2, 17.1, 16.4, 15.3, 14.6, 13.8, 13.8.
IR (CHCl3): 2957, 2931, 2883, 1457, 1379, 1241, 1180, 1149, 1126,
1049 cm–1.
1H NMR: = 6.13–6.02 (m, 1 H), 4.90 (m, 1 H), 4.87 (m, 1 H),
4.40–4.33 (m, 1 H), 3.96–3.81 (m, 8 H), 3.49–3.45 (m, 1 H), 3.37 (t,
1 H, J = 10.9 Hz), 2.93–2.87 (m, 1 H), 2.39–2.28 (m, 2 H), 2.03–
1.92 (m, 2 H), 1.87–1.80 (m, 1 H), 1.69–1.14 (m), 0.99 (s, 3 H), 0.94
(d, 3 H, J = 7.1 Hz), 0.93 (s, 3 H), 0.78 (d, 3 H, J = 6.4 Hz).
HRMS: m/z calcd for C63H88O12: 1036.6276; found: 1036.6238.
13C NMR: = 138.3, 113.7, 113.3, 112.6, 109.4, 80.3, 66.9, 65.0,
64.4, 64.1, 64.0, 52.3, 51.9, 47.9, 44.0, 44.0, 42.3, 39.8, 33.9, 31.5,
31.4, 30.4, 30.3, 30.2, 28.8, 27.8, 17.9, 17.2, 14.6, 13.8.
19b
As described for 19a the diene 18 (73 mg, 0.76 mmol) was treated
with butynone (60 l, 0.76 mmol, 10 eq) at 14 kbar to give butynone
adduct (10:1 diastereomeres) after 3 d as a white foam (46 mg,
59%). This adduct (25 mg, 0.02 mmol) was treated with DDQ (11
mg, 0.05 mmol), worked up and purified according to the general
procedure to yield the desired product 19b as a yellow foam (24 mg,
0.02 mmol, 96%).
MS: m/z (%) = 502 (37) [M+], 415 (11), 167 (18), 99 (100).
HRMS: m/z calcd for C30H46O6: 502.3294; found: 502.3294.
18
In the reaction vessel 15 (768 mg, 1.27 mmol), 14 (640 mg, 1.27
mmol), Bu4NCl (353 mg, 1.27 mmol), Cs2CO3 (621 mg, 1.91
mmol) palladium (II) acetate (86 mg, 0.38 mmol) and anhyd DMF
(20 ml) were suspended under argon. The contents of the flask were
irradiated with focused microwaves (5 min –24 W, 5 min –32 W).
Further palladium (II) acetate (120 mg, 0.53 mmol) was added and
the irradiation was repeated as described. After cooling, the reaction
mixture was filtered over silica gel (PE–EtOAc, 1:1). The residue
was concd and was purified by column chromatography (silica gel,
IR: 2952, 2926, 2874, 1724, 1681, 1453, 1124, 1056, 980, 899 cm–1.
1H NMR: = 7.11 (s, 1 H), 7.01 (s, 1 H), 5.40 (m, 1 H), 4.84 (dd, 1
H, J = 8.2, 1.9 Hz), 4.32 (m, 1 H), 4.38–3.68 (m, 12 H), 3.51–3.39
(m), 3.34 (t, 1 H, J = 10.9 Hz), 2.60 (m, 1 H), 2.51 (s, 3 H), 2.35 (m,
1 H), 1.23 (s, 3 H), 1.17 (s, 3 H), 1.21–1.16 (m, 3 H), 0.99 (d, 3 H,
Synthesis 2002, No. 10, 1373–1378 ISSN 0039-7881 © Thieme Stuttgart · New York

1378
T. Flessner et al.
PAPER
J = 6.7 Hz), 0.86 (s, 3 H), 2.80–0.85 (m), 0.79 (d, 3 H, J = 6.3 Hz),
0.76 (d, 3 H, J = 6.4 Hz), 0.74 (s, 3 H).
References
(1) Kramer, A.; Ullmann, U.; Winterfeldt, E. J. Chem. Soc.,
Perkin Trans. 1 1993, 2865.
(2) Jautelat, R.; Müller-Fahrnow, A.; Winterfeldt, E. J. Prakt.
Chem. 1996, 338, 695.
(3) Drögemüller, M.; Jautelat, R.; Winterfeldt, E. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1572; Angew. Chem. 1996,
108, 1669.
13C NMR: = 203.9, 155.9, 138.7, 137.5, 137.2 133.8, 132.4, 128.9,
120.3, 113.6, 113.3, 112.5, 109.4, 106.8, 85.3, 80.2, 67.1, 66.8,
65.8, 65.2, 65.1, 65.1, 64.1, 63.9, 63.0, 55.4, 52.6, 51.9, 51.1, 50.6,
47.9, 47.2, 46.0, 44.4, 43.0, 42.2, 41.5, 35.6, 35.3, 34.6, 33.8, 33.6,
31.5, 31.4, 30.4, 30.3, 30.3, 29.9, 29.7, 29.1, 28.8, 28.8, 28.8, 28.4,
27.4, 18.5, 17.2, 17.1, 16.6, 14.6, 13.8, 13.8, 11.4.
(4) Drögemüller, M.; Flessner, T.; Jautelat, R.; Scholz, U.;
Winterfeldt, E. Eur. J. Org. Chem. 1998, 2811.
(5) Cheeseman, G. W. H.; Cookson, R. F. In Chemistry of
Heterocyclic Compounds, Vol. 35; Weissberger A., Taylor
E. C., John Wiley & Sons: New York, 1979, 3.
(6) Nawasreh, M. In Stereoselective Synthesis of Cephalostatin
Analogues as anti-Cancer Agents; Dissertation: Hannover,
2000.
(7) Behar, V.; Danishefsky, S. J. Am. Chem. Soc. 1993, 115,
7017.
(8) Hasse-Held, M.; Hatzis, M.; Mann, J. J. Chem. Soc., Perkin
Trans. 1 1992, 2999.
(9) Hanson, J. R.; Uyanik, C. J. Chem. Res. 1998, 221; and
references therein.
(10) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
(11) Crimmins, M. T.; Al Awar, R. S.; Vallin, J. M.; Hollis, W.
G. Jr.; O’Mahony, R.; Lever, J. G.; Bankaitis-Davis, D. M.
J. Am. Chem. Soc. 1996, 118, 7513.
(12) Rudloff, V. Can. J. Chem. 1965, 4, 2660.
(13) (a) Grieco, P. A.; Gilman, S.; Nishizawa, N. J. Org. Chem.
1976, 41, 1485. (b) Grieco, P. A.; Yokoyama, Y. J. Am.
Chem. Soc. 1977, 99, 5210.
HRMS: m/z calcd for C63H88O11: 1020.6327; found: 1020.6310.
19c
Diene 18 (100 mg, 0.105 mmol) was treated with propargylic alde-
hyde (57 mg, 0.105 mmol) at 8 kbar for 3 d. The reaction was mon-
itored by TLC. The solvent was evaporated at r.t. and the residue
was purified by column chromatography on silica gel (PE–EtOAc,
5:1) to provide the cycloadduct (3:1 diastereomers, 1H NMR) as a
white foam (40 mg, 38%). According to the general procedure the
adduct (25 mg, 0.02 mmol) was treated with DDQ (11 mg, 0.05
mmol) in dioxane (2.5 ml) at 90 °C for 3 h. After work-up and pu-
rification (general procedure) resulted product 19c was obtained as
a yellow foam (20 mg, 0.02 mmol, 80%).
IR: 2951, 2926, 2874, 1680, 1454, 1123, 1050, 980, 900 cm–1.
1H NMR: (400 MHz, CDCl3, TMS): = 10.43 (s, 1 H), 7.54 (s, 1
H), 6.99 (s, 1 H), 5.46 (t, 1 H, J = 1.8 Hz), 4.87 (dd, 1 H, J = 8.3,
1.9 Hz), 4.35–4.28 (m, 1 H), 4.09–3.58 (m, 12 H), 3.52–3.20 (m),
3.33 (t, 1 H, J = 10.9 Hz), 2.95–2.91 (m), 2.70–2.59 (m), 2.48–2.29
(m), 2.25 (dd, 1 H, J = 9.0, 7.2 Hz), 1.18 (s, 3 H), 1.18 (d, 3 H,
J = 7.0 Hz), 1.12 (s, 3 H), 0.89 (d, 3 H, J = 6.9 Hz), 0.87 (s, 3 H),
2.15–0.82 (m), 0.79 (d, 3 H, J = 6.3 Hz), 0.76 (d, 3 H, J = 6.2 Hz),
0.73 (s, 3 H).
13C NMR: = 192.2, 155.9, 141.8, 141.5, 133.7, 132.9, 132.6,
128.9, 120.3, 113.6, 113.1, 112.5, 109.4, 106.8, 85.3, 80.1, 67.1,
66.8, 65.5, 65.2, 65.1, 64.2, 63.7, 63.2, 55.4, 52.8, 51.9, 51.1, 50.5,
48.0, 46.8, 45.9, 44.4, 42.8, 42.1, 41.3, 35.4, 34.9, 34.3, 33.8, 33.8,
32.4, 31.4, 31.4, 30.4, 30.3, 29.8, 29.7, 29.1, 28.9, 28.8, 28.7, 28.3,
27.1, 18.5, 17.2, 17.1, 16.9, 14.6, 13.9, 13.8, 11.4.
(14) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(15) Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 186.
(16) (a) Loupry, A.; Petit, A.; Hamelin, J.; Texier-Boullet, F.;
Jacquault, P.; Mathé, D. Synthesis 1998, 1213.
(b) Lidström, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(17) (a) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem.
2001, 66, 4340. (b) Vallin, K. S. A.; Zhang, Q.; Curran, D.
P.; Larhed, M.; Hallberg, A. Poster displayed at Drug
Discovery Technology 2001 Boston.
(18) Flessner, T. Beiträge zur chemischen Diversität der
Cephalostatine; Dissertation: Hannover, 1999.
(19) Sauer, J. C. Org. Synth. 1962, 4, 813.
(20) Osborn, J. A.; Wilkinson, G. Inorg. Synth. 1981, 28, 77.
(21) Barton, D. H. R.; Godfrey, C. R. A.; Morzycki, J. W.;
Motherwell, W. B.; Ley, S. V. J. Chem. Soc., Perkin Trans.
1 1982, 1947.
HRMS: m/z calcd for C62H86O11: 1006.6170; found: 1006.6183.
Acknowledgement
Continuous funding of this work by the Fonds der Chemischen In-
dustrie is gratefully acknowledged and we are thankful to the Deut-
sche Forschungsgemeinschaft for providing high-pressure
facilities. We particularly thank our colleagues at the Schering
Company, Berlin for providing starting materials and for constant
encouragement.
(22) (a) Birch, A. J.; Williamson, D. H. Org. React. 1976, 24, 1.
(b) Djerassi, C.; Grutzwiller, J. J. Am. Chem. Soc. 1966, 88,
4537.
Synthesis 2002, No. 10, 1373–1378 ISSN 0039-7881 © Thieme Stuttgart · New York