Synthesis of new steroid analogues by samarium diiodide induced cyclisations of γ-naphthyl 1,3-diones

Article abstract of DOI:10.1016/j.tetasy.2010.04.036

We present the synthesis of new steroid analogues via samarium diiodide mediated intramolecular ketyl-aryl coupling reactions of γ-naphthyl- substituted 1,3-diones. From previous experiments with γ-naphthyl monoketones high stereoselectivities with the [unnatural] cis/cis annulation of rings B/C/D were expected. Surprisingly, we observed the formation of two diastereomers with cis- and trans-fused rings B and C of the tetracyclic skeleton. The diastereoselectivity proved to be strongly dependent on the amount of the proton source employed in the reaction. A rationale for this unexpected behaviour is discussed. In addition, we observed a smooth aluminium chloride induced cyclisation of one of the γ-naphthyl-substituted 1,3-diones to furnish an equilenine precursor. Another cyclisation product was converted by Grob-fragmentation into a naphthannulated cyclononane derivative.

Full text of DOI:10.1016/j.tetasy.2010.04.036

Tetrahedron: Asymmetry 21 (2010) 1601–1610
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new steroid analogues by samarium diiodide induced
cyclisations of
c-naphthyl 1,3-diones
*
Ulrike K. Wefelscheid , Hans-Ulrich Reissig
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
We present the synthesis of new steroid analogues via samarium diiodide mediated intramolecular
ketyl–aryl coupling reactions of c-naphthyl-substituted 1,3-diones. From previous experiments with c-
naphthyl monoketones high stereoselectivities with the ‘unnatural’ cis/cis annulation of rings B/C/D were
expected. Surprisingly, we observed the formation of two diastereomers with cis- and trans-fused rings B
and C of the tetracyclic skeleton. The diastereoselectivity proved to be strongly dependent on the amount
of the proton source employed in the reaction. A rationale for this unexpected behaviour is discussed. In
Received 10 March 2010
Accepted 21 April 2010
Available online 11 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday.
addition, we observed a smooth aluminium chloride induced cyclisation of one of the c-naphthyl-substi-
tuted 1,3-diones to furnish an equilenine precursor. Another cyclisation product was converted by Grob-
fragmentation into a naphthannulated cyclononane derivative.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
role of the proton source on the diastereoselectivity of samarium
diiodide mediated intramolecular ketyl–aryl couplings of
thyl-substituted 1,3-diones.
c
-naph-
Kagan et al. introduced samarium diiodide as a selective and
versatile electron-donating reagent for organic synthesis.1 It allows
for mild reaction conditions and often furnishes products with high
diastereoselectivity.2 Our group has discovered the ability of
samarium diiodide to promote intramolecular reductive ketyl–aryl
coupling reactions furnishing interestingly functionalised dearo-
matised products.3 Subsequently, we have systematically studied
H
2.2 eq. SmI2
n
2 eq. tBuOH
H
n
O
18 eq. HMPA
THF, RT, 1 d
H
OH
the scope and limitations of these processes.
nitrogen analogues prepared from aniline derivatives5 as well as
ketones with indole, pyrrole,6 and quinoline7 moieties in
-posi-
c
-Aryl ketones,4 their
n = 0 - 4
41% - 98%
1
2
protonation
from the
less hindered
exo -side
c
SmI2
tion were successfully employed in these samarium diiodide in-
duced intramolecular ketyl–aryl couplings. Furthermore, the
influence of substituents on the arene moiety has been explored
H
H
I2Sm
H
in detail.4a Reactions of simple
c-naphthyl monoketones 1 yielded
H
cyclisation, SmI2
OSmI2
OSmI2
steroid-like skeletons 2 as single diastereomers with ‘unnatural’
cis/cis annulation of rings B/C and C/D (Scheme 1).8 The excellent
diastereoselectivity in these reactions can be explained by a six-
membered chair-like transition state in which the bulky samarium
alcoholate group occupies an equatorial position. A second electron
transfer followed by regioselective protonation from the less hin-
dered exo-side affords compounds 2. Surprisingly, when we ex-
n
n
Scheme 1. Diastereoselective cyclisations of
analogues 2.8
c-naphthyl monoketones 1 to steroid
2. Results and discussion
posed
c-naphthyl 1,3-diones to our protocol, in addition to the
expected cis/cis-isomers we isolated significant amounts of the cor-
2.1. Synthesis of c-naphthyl-substituted 1,3-diones
responding trans/cis-isomers.9 Herein we describe in full detail the
Starting from commercially available tetralone 3a and 6-meth-
oxytetralone 3b -naphthyl-substituted 1,3-diones 7a, 7b and 7c
were prepared in four steps. Addition of vinylmagnesium bromide
to the tetralone derivative was followed by a Pd-catalysed allylic
substitution with 2-methylcyclopentane-1,3-dione or 2-methylcy-
c
* Corresponding author. Tel.: +49 30 838 55366; fax: +49 30 838 55367.
E-mail address: hans.reissig@chemie.fu-berlin.de (H.-U. Reissig).
Present address: Institut für Organische Chemie, Universität des Saarlandes,
Postfach 151150, 66041 Saarbrücken, Germany.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.036

1602
U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
O
O
O
O
HO
n
MgBr
n
THF, r.t., 16 h
cat. Pd(PPh3)4
O
reflux, 1-2 h
DMF, 80 °C, 1-4 d
R
R
R
3a R = H
3b R = OMe
4a R = H
4b R = OMe 68%
87%
5a R = H, n = 1
5b R = H, n = 2
47%
32%
5c R = OMe, n = 1 56%
O
n
O
O
cat. Pd/C, H2
EtOAc, r.t., 3-4 h
DDQ, PhCl
reflux, 1-2 h
n
O
R
R
7a R = H, n = 1
7b R = H, n = 2
97%
67%
6a R = H, n = 1
6b R = H, n = 2
87%
51%
7c R = OMe, n = 1 90%
6c R = OMe, n = 1 63%
Scheme 2. Synthesis of
c-naphthyl-substituted 1,3-diones 7a–7c.
clohexane-1,3-dione in DMF at 80 °C.10 Oxidation of 5 with DDQ11
and subsequent hydrogenation of the double bond in 6 yielded the
desired 1,3-diones 7 (Scheme 2). The outcome of the reduction
strongly depended on the amount and the reactivity of the palla-
dium catalyst as well as on the reaction time. Too much Pd/C or
long reaction times led to partial reduction of the naphthyl moiety.
To improve the yield for the Pd-catalysed allylic substitution, we
also used alternative reaction conditions with Et3B in THF at room
temperature.12 Reaction of the six-membered 1,3-dione proceeded
smoothly to give 5b in 69% yield (Scheme 3), whereas the five-
membered 1,3-dione did not show significant reactivity under
these conditions, presumably due to its lower solubility in THF.
O
O
O
O
HO
cat. Pd(OAc)2/PPh3
Et3B, THF, r.t., 4 d
87%
4a
5d
DDQ, PhCl
reflux, 1 h
35%
O
O
O
O
O
O
O
cat. Pd/C, H2
EtOH/THF
HO
cat. Pd(OAc)2/PPh3
r.t., 22 h
28%
Et3B, THF, r.t., 4 d
69%
O
4a
5b
Scheme 3. Alternative reaction conditions for the allylic substitution to product 5b.
7d
Scheme 4. Synthesis of
6d
,
c0-dinaphthyl-substituted 1,3-dione 7d.
We also prepared
c,
c0-dinaphthyl-substituted dione 7d by a
c
similar sequence (Scheme 4). The conditions for the oxidation
and reduction steps have not been optimised. In the latter we iso-
lated in addition to 28% of 7d 34% of the mono-hydrogenated com-
pound and 14% of starting material 6d.
dard procedure A (entries 5 and 6), which consisted in addition of a
solution of the starting material 7a and tBuOH in THF to a solution of
SmI2 and HMPA in THF. On the other hand, when we premixed the
SmI2/HMPA/THF-solution with tBuOH before adding a solution of
7a in THF the yield was maintained at approximately 70% and the
selectivity increased to 83:17 and 91:9, respectively (procedure B,
entries 7 and 8). Remarkably, with 6 equiv of H2O we found 11%
2.2. Reactions with samarium diiodide
The reaction of 1,3-dione 7a was conducted with 5.5 equiv of
SmI2, 36 equiv of HMPA and varying amounts of the respective
proton source (tBuOH, MeOH, PhOH or H2O) in THF (Table 1). With
8 equiv of tBuOH we isolated 74% of a 56:44-mixture of the epi-
mers cis-8 and trans-8 (entry 1). Herein cis and trans refer in all
products to the relative configuration of rings B and C of the tetra-
cyclic steroid-like skeleton. With 4 equiv of tBuOH the preference
for the cis-isomer could be improved to 64:36 (entry 2). Changing
the proton source to MeOH or PhOH did not show any positive ef-
fect on the selectivity (entries 3 and 4). With 2 or 1 equiv of tBuOH
the selectivity was enhanced, but the yield of steroid analogue 8
dropped to 43%à and 55%, respectively, when we employed our stan-
and 6% of two different isomers of ipso-coupling product
9
(Scheme 5), in addition to 26% of a 55:45-mixture of cis-8 and
trans-8.§ The relative configuration of compounds 9 could not be
determined with certainty. The ipso-attack of samarium-ketyls to
arenes has been observed before by Tanaka et al.13 and by our
group.4a With 1 equiv of water (entry 10) we obtained 8 with 73%
yield and a diastereomeric ratio of 90:10 a similar result as with
1 equiv of tBuOH. Nevertheless, we recommend the use of tBuOH
as a proton source, as the reaction proceeds slightly cleaner; since
less by-products are formed the purification is considerably easier.
Without any proton source a second intramolecular cyclisation is ob-
à
Only 20 equiv instead of 36 equiv of HMPA were applied. This may be the reason
§
for the lower yield of 43% compared with 55% for entry 6.
In this experiment we used 4.2 equiv of SmI2 and 28 equiv of HMPA.

U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
1603
Table 1
O
OH
5.8 eq. SmI2
4 eq. tBuOH, HMPA
Influence of the proton source on the diastereomeric ratio during the synthesis of
steroid analogues cis-8 and trans-8
H
THF, r.t., 2 d
O
H
OH
OH
7b
cis-10 and trans-10
33% and 20%
H
H
OH
OH
> 4 eq. SmI2
proton source
HMPA
O
Scheme 6. Synthesis of steroid analogues cis-10 and trans-10.
cis-8
+
OH
THF, r.t., 1-2 d
O
O
OH
H
H
5.5 eq. SmI2
7a
tBuOH, HMPA
H
THF, r.t., 1 d
O
H
OH
trans-8
MeO
MeO
7c
cis-11 and trans-11
4 eq. tBuOH
1 eq. tBuOH
16%, d.r. 57:43
9% and 4%
Scheme 7. Synthesis of methoxy-substituted steroid analogues cis-11 and trans-11.
and reduction.14 Longer reaction times did not lead to complete
conversion of the starting material; no simple reduction of 7b to
the corresponding b-hydroxyketones or 1,3-diols was observed in
this case.
As most of physiologically active steroid derivatives bear an
oxygen substituent in 3-position of ring A, we applied our cyclisa-
Procedure A: a solution of 7a and the proton source in THF was added to a solution
of SmI2 and HMPA in THF. Procedure B: a solution of 7a in THF was added to a
solution of SmI2, HMPA and the proton source in THF.
tion protocol to methoxy-substituted
c-naphthyl 1,3-dione 7c
(Scheme 7). As expected for donor-substituted arenes,4a the yields
were considerably lower. With 4 equiv of tBuOH as proton source
we isolated only 16% of a 57:43-mixture of cis-11 and trans-11.
When we employed only 1 equiv tBuOH the preference for the
cis-isomer could be enhanced to 69:31. As by-products again b-
hydroxyketones and cis- and trans-1,3-diols were isolated.
OH
OH
O
4.2 eq. SmI2
6 eq. H2O, HMPA
cis-8
and
The relative configurations of tetracyclic products cis-8 and
trans-8 were determined via NOE NMR spectra and were unequiv-
ocally proven by X-ray analyses.15 To differentiate between cis-10
and trans-10 or cis-11 and trans-11 we compared the coupling con-
stants and the chemical shifts of the protons 8-H (4b-H) and 9-H
+
THF, r.t., 16 h
O
trans-8
9
7a
55:45
26%
2 isomers
11% and 6%
Table 2
Scheme 5. ipso-Coupling to 9 during transformation of 1,3-dione 7a with SmI2 in
Comparison of 1H and 13C NMR data of cis- and trans-configured steroid analogues 8,
10 and 11
the presence of water (Table 1, entry 9).
served leading to a novel pentacyclic skeleton (Fig. 1).9 In all these
reactions the mass balance was nearly quantitative and starting
material 7a was completely consumed. As by-products we isolated
uncyclised b-hydroxyketones and cis- and trans-1,3-diols, which
are formed by simple reduction of the two carbonyl groups.
9 (n = 1)
10b (n = 2)
OH
OH
H
H
n
n
H
OH
H
OH
R
R
8 (n = 1)
4b (n = 2)
R = H
R = H
n = 1
n = 2
R = OMe n = 1
trans-8
trans-10
trans-11
cis-8
cis-10
cis-11
HO
OH
H
Figure 1. Pentacyclic product generated by reactions of 7a with SmI2 without
proton source.9
Entry Compound 8/4b-H
(ppm)
9/10b-H
(ppm)
C-8/4b
(ppm)
C-9/10b
(ppm)
J8,9/
J4b,10b
(Hz)
The reaction of the homologous 1,3-dione 7b with SmI2 and
4 equiv of tBuOH proceeded more slowly. After 2 days we isolated
33% of cis-10, 20% of trans-10 and 25% of starting material 7b was
recovered (Scheme 6). Additionally, we found 13% and 7% of two
unknown diastereomeric by-products, which might occur from
intramolecular pinacol coupling and subsequent fragmentation
1
2
3
4
5
6
cis-8
trans-8
cis-10
trans-10
cis-11
trans-11
2.25
2.19
2.84
2.57
2.49
2.15
3.34
2.63
3.32
2.75
3.28
2.56
41.5
44.9
41.1
44.6
41.5
45.2
36.3
39.3
35.7
37.1
35.5
38.7
6.9
15.4
6.5
15.9
6.9
15.2

1604
U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
(10b-H) in the 1H NMR spectra as well as the chemical shifts of the
corresponding carbons in the 13C NMR spectra (Table 2). The cis-
isomers of 8, 10 and 11 show coupling constants of 6.5–6.9 Hz be-
tween 8-H and 9-H or 4b-H and 10b-H, respectively, which corre-
spond to dihedral angles of ꢀ30–50°, whereas the trans-
configuration with a dihedral angle of ꢀ180° is confirmed by cou-
pling constants in the range of 15.2–15.9 Hz. The chemical shifts of
the two protons in the cis-isomers are located more downfield than
in the corresponding trans-isomers, whilst the reverse is true for
the two carbons C-8 and C-9 or C-4b and C-10b.16
O
HO
3.0 eq. SmI2
20 eq. HMPA
THF, r.t., 1 d
74%
O
O
7a
13
Scheme 10. Reaction of 1,3-dione 7a with 3 equiv of SmI2 without proton source.
2.3. Discussion
A twofold intramolecular ketyl–aryl coupling of dione 7d may
generate an interesting product with eight annulated rings. Unfor-
tunately, treatment of 7d with SmI2 only gave the simple reduction
product 12 as a 7:3-mixture of two diastereomers in 87% yield
(Scheme 8). The fairly high steric hindrance might suppress a cyc-
lisation. Furthermore, the interaction of the SOMOradical/LUMOarene
might be less efficient in this example due to a higher energy gap:
the ketyl radical is in conjugation with the adjacent aryl group and
has thus a lower energy level.
The striking differences of the stereoselectivities of the mono-
ketone cyclisations (Scheme 1) with that of the 1,3-diones
described in this report must have its origin in the presence of
the second carbonyl group. In an attempt to explain the variation
of the diastereoselectivities– we should have a look at the conforma-
tions of the conceivable intermediates before cyclisation, ketyls A, B
or C (Scheme 11). In ketyl A the second carbonyl moiety is still pres-
ent, B is a diketyl||,17 or a radical/anion, whereas in C the second car-
bonyl group is already fully reduced to a samarium alcoholate or the
corresponding alcohol. After the cyclisation a second electron is
transferred by SmI2 to yield either benzylic anions D, E or F with
þ
SmI2 as ‘counterion’. Protonation of these anions from the less hin-
5.5 eq. SmI2
4 eq. tBuOH
HMPA, THF
dered exo-side (backside of the drawing in Scheme 11) leads to the
expected cis-8 as product.
O
O
OH
For endo-protonation, leading to the unexpected trans-product,
a pre-coordination of tBuOH via Sm(II) or Sm(III) to the carbonyl
oxygen in D or by the samarium alcoholates in E and F may be
decisive. Alternatively, intramolecular endo-protonation of alco-
hols E and F may also give trans-8. If more equivalents of tBuOH
or other proton sources are present in the reaction mixture the
equilibria are shifted to these pre-coordinated species or to the
alcohols E and F and hence endo-protonation is more likely than
with lower amounts of proton sources.
r.t., 2 d
2 Isomers
7:3, 87%
OH
7d
12
Scheme 8. Reaction of 1,3-dione 7d with SmI2.
To get further insight into the stereoselectivity of the proton-
ation step we synthesised b-hydroxyketone 13. Selective reduction
of one of the carbonyl moieties in 7a with NaBH4 afforded 68% of
13 (Scheme 9) and 18% of its diastereomer epi-13 (not shown).
The relative configuration was determined by NOE measurements.
Conversion of 13 with 2.8 equiv SmI2 and 2 equiv of tBuOH yielded
39% of a 1:1-mixture of cis-8 and trans-8 hence providing a result
similar to entry 1 (Table 1).
In the reaction of b-hydroxyketone 13 with SmI2, we can be sure
that F is an intermediate. Since 3 equiv of protons are present in
this reaction (two from tBuOH, one from 13) we would expect a
ꢀ2:1 mixture of cis-8 and trans-8 according to the results in Table 1.
Instead the ratio is 1:1, which supports the possibility of an intra-
molecular protonation of anion F.
The experiment with 1,3-dione 7a, 3 equiv of SmI2 and without
tBuOH (Scheme 10) provided almost no cyclisation product. Possi-
bly, the equilibrium is either at the side of anion G and 1 equiv of
SmI2 (which may be coordinated to the carbonyl group in G) or
at the side of anion/ketyl radical H (Scheme 12). Both, G and H,
can afford alcohols 13 or epi-13 after protonation during aqueous
work-up. Although our conclusions are still speculative this exper-
iment provides some evidence for the pathways via B/E or C/F as
illustrated in Scheme 11.
O
HO
NaBH4, MeOH
0 °C, 3 h
r.t., 17 h
68%
O
O
7a
13
2.4. Cyclisation with AlCl3 and Grob-fragmentation
2.8 eq. SmI2
2 eq. tBuOH
HMPA, THF
r.t., 1 d
OH
OH
In several unsuccessful attempts to remove the methyl group in
7c we observed the formation of steroid analogues 14 and 15. The
two products were obtained in good yield when 7c was subjected
to an excess of AlCl3 in MeCN (Scheme 13). Compounds 14 and 15
are known precursors of the mare hormone equilenine which is
H
H
+
39%
(1:1)
H
OH
H
OH
cis-8
trans-8
Scheme 9. Reaction of b-hydroxyketone 13 with SmI2.
–
We assume that the protonation at the discussed benzylic position is irreversible,
since the acidity of the proton sources should be considerably higher than that of the
benzylic C–H. Thus, the diastereoselectivity is not under thermodynamic but under
kinetic control.
The reaction of 1,3-dione 7a with 3.0 equiv samarium diiodide
without any proton source yielded 74% of b-hydroxyketone 13
(Scheme 10) together with 14% of a 2:1 mixture of 13 and epi-13
as well as 4% of the tetracyclic compound cis-8. Surprisingly, the
pentacyclic product (Fig. 1) was not formed in this experiment.
||
Experiments from Flowers17 indicate that tBuOH (other than MeOH, EtOH, PhOH)
may not be sufficiently acidic to protonate the samarium ketyl of acetophenone.
Nevertheless, we assume that in our case O-protonation of the samarium ketyl moiety
should be possible due to a slightly higher basicity of the involved alcoholate.

U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
1605
H
H
H
OSmI2
OSmI2
OSmI2
(
)
or
or
I2Sm / HO
O
I2Sm / HO
H
A
B
C
cyclisation, SmI2
cyclisation, SmI2
cyclisation, SmI2
H
H
H
I2Sm
I2Sm / HO
I2Sm
O
I2Sm
tBuOH
tBuOH
I2Sm
tBuOH
OSmI2
OSmI2
OSmI2
(
)
or
or
I2Sm / HO
H
E
D
F
OH
OH
via protonation
from the less
H
H
via inter- or intramolecular
endo-protonation
H
OH
H
OH
trans-8
Scheme 11. Possible mechanistic pathways for the cyclisation and stereoselective protonation of compound 7a.
hindered exo-side
cis-8
I2SmO
I2SmO
OH
OMs
SmI2
SmI2
MsCl, NEt3
CH2Cl2
H
H
0 °C, 2 h
85%
+
SmI2
H
OH
H
OH
O
OSmI2
cis-/trans-8
95:5
cis-/trans-16
G
H
95:5
Scheme 12. Supposed equilibrium in the reaction of 7a with 3 equiv of SmI2
without proton source.
NaH, THF, r.t.
2 h, 60 °C, 4 h
part of a commercially used steroid mixture for hormone replace-
ment therapy and isolated from the urine of pregnant mares.18
To investigate the ability of compounds with structure 8 to un-
dergo fragmentation reactions generating medium-sized rings we
H
H
O2
(workup)
2
2
H
30%
H
O
O
selectively mesylated the secondary hydroxyl group of
8
(Scheme 14). Grob-fragmentation of mesylate 16 promoted by
deprotonation with sodium hydride stereoselectively led to Z-con-
figured nine-membered ring compound 18 (reaction conditions
not optimised). Apparently, an aromatisation occurred during the
work-up of the reaction mixture. The Z-configuration of the double
bond in 18 is expected according to the fragmentation mechanism
and it was proved by NOE experiments.
18
cis-/trans-17
Scheme 14. Synthesis and stereoselective Grob-fragmentation of mesylate 16
leading to naphthannulated cyclononane derivative 18.
effect on the protonation step of the reaction. While the samarium
intermediates derived from
monoketones were exclusively protonated from the less hindered
exo-side, with -naphthyl-substituted 1,3-diones protonation can
c-aryl- and c-naphthyl-substituted
c
3. Conclusion
occur from both sides. We attempted to analyse the role of the pro-
ton source with regard to exo- versus endo-protonation. The highest
diastereomeric ratios were achieved with only 1 equiv of tBuOH
providing the cis/cis-annulated products in ratios up to 95:5. The
reductive cyclisation protocol described here allowed a smooth
and fairly efficient entry to novel steroid analogues. It should be
mentioned that this method induces dearomatisation19 of one of
the two rings of the naphthyl moiety leading to compounds with
a styrene subunit which allows smooth further functionalisa-
tions.8,9 The briefly studied Grob-fragmention of compounds such
as 8 deserves further investigation since it may allow a straightfor-
ward route to functionalised medium-sized ring compounds like 18.
In samarium diiodide mediated intramolecular ketyl–aryl cou-
pling reactions of
c-naphthyl-substituted 1,3-diones the second
carbonyl group (or the resulting hydroxyl group) has a remarkable
O
H
O
MeO
AlCl3
MeCN
14 57%
+
O
50 °C, 2 d
O
4. Experimental section
4.1. General
MeO
7c
MeO
15 31%
Reactions were generally performed under argon in flame dried
flasks. Solvents and reagents were added by syringe. Solvents were
Scheme 13. Cyclisation of 7c with AlCl3 to steroid derivatives 14 and 15.

1606
U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
dried using standard procedures. Tetrahydrofuran (THF) was
freshly distilled from sodium/benzophenone under argon. 1,2-
Diiodoethane was dried at 50 °C for 3 h in vacuo and stored at
4 °C. Hexamethylphosphoramide was distilled from calcium hy-
dride and stored over molecular sieves (4 Å) under an atmosphere
of argon. (CAUTION: HMPA has been identified as a carcinogenic re-
agent. Appropriate glove protection is required during handling. Reac-
tions and chromatography should be performed in a well-vented
hood.) SmI2 was either freshly prepared (see procedure for cis-8/
trans-8) or taken from a previously prepared 0.1 M stock solution.
Products were purified by flash chromatography on silica gel (230–
400 mesh, Merck or Fluka) or HPLC (Nucleosil 50-5). Unless other-
wise stated, yields refer to analytical pure samples. NMR spectra
were recorded on Bruker (AC 250, AC 500) and JOEL (Eclipse 500)
instruments. Chemical shifts are reported relative to TMS (1H:
d = 0.00 ppm) and CDCl3 (13C: d = 77.0 ppm). Integrals are in accor-
dance with assignments; coupling constants are given in Hertz. All
13C spectra are proton-decoupled. For detailed peak assignments
2D spectra were measured. IR spectra were measured with an
FT-IRD spectrometer Nicolet 5 SXC. MS and HRMS analyses were
performed with Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT CH7A
(EI, 80 eV, 3 kV), CH5DF (FAB, 3 kV) and Varian Ionspec QFT-7
(ESI-FT ICRMS) instruments. Elemental analyses were carried out
with CHN-Analyzer 2400 (Perkin Elmer), Vario EL or Vario EL III
(Elementar). Melting points were measured with a Reichert appa-
ratus Thermovar and are uncorrected.
(1.50 g, 8.61 mmol), Pd(PPh3)4 (99 mg, 0.086 mmol), DMF (17 mL),
80 °C, 4 d. Product 5b (770 mg, 32%) was isolated as a yellow solid,
starting material 4a (822 mg, 55%) was reisolated as a colourless
oil.
Method 2: To a solution of tetralone derivative 4a (2.00 g,
11.5 mmol) in THF (57 mL) was added 2-methylcyclohexane-1,3-
dione (1.74 g, 13.8 mmol), Pd(OAc)2 (128 mg, 0.570 mmol), PPh3
(307 mg, 1.17 mmol) and Et3B (1 M in THF, 27.6 mL, 27.6 mmol).
The reaction mixture was stirred at rt for 4 d. Then satd aq NaHCO3
solution (65 mL) was added, the organic layer was separated and
the aqueous layer was extracted with Et2O (3 ꢁ 65 mL). The com-
bined organic layers were washed with brine (1 ꢁ 10 mL) and
dried with Na2SO4. Column chromatography on silica gel (hex-
ane/EtOAc 9:1) afforded 5b (2.22 g, 69%) as a yellow solid. Mp:
65 °C. 1H NMR (500 MHz, CDCl3): d = 1.27 (s, 3H, Me), 1.78 (quint.,
J = 6 Hz, 2H, 300-H), 1.81–1.87 (m, 1H, 5-H1), 1.90–1.98 (m, 1H, 5-
H2), 2.46 (t, J = 5.7 Hz, 2H, 200-H), 2.56–2.64 (m, 4H, 4-H, 6-H),
2.68 (d, J = 7.7 Hz, 2H, 10-H), 2.72 (t, J = 6.3 Hz, 2H, 400-H), 5.70 (t,
J = 7.6 Hz, 1H, 20-H), 7.02–7.05 (m, 1H, Ar), 7.08–7.11 (m, 2H, Ar),
7.42–7.45 (m, 1H, Ar) ppm. 13C NMR (126 MHz, CDCl3): d = 17.3
(t, C-5), 19.5 (q, Me), 22.9 (t, C-300), 26.3 (t, C-200), 30.0 (t, C-400),
35.6 (t, C-10), 38.0 (t, C-4, C-6), 64.9 (s, C-2), 117.1 (d, C-20),
123.5, 125.7, 126.7, 128.5 (4d, Ar), 135.4, 137.2, 137.4 (3s, Ar, C-
100), 210.0 (s, C@O) ppm. IR (KBr):
m = 3060–2835 (@CH, C–H),
1725 (C@O), 1695 (C@O), 1485–1025 (@C–H, C–H) cmꢂ1. HRMS
(ESI): Calcd for C19H22O2ꢃH+: 283.1698. Found: 283.1691.
4.2. Preparation of a 0.1 M stock solution of SmI2
4.5. 2-[(2E)-2-(6-Methoxy-3,4-dihydronaphthalen-1(2H)-ylidene)-
ethyl]-2-methylcyclopentane-1,3-dione 5c
Sm metal (40 mesh, 2.71 g, 18.0 mmol) and I2 (3.81 g,
15.0 mmol) were placed under argon in a flame dried 250 mL flask
equipped with a three way adapter. THF (150 mL) was added and
the mixture was vigorously stirred until the deep blue colour of
SmI2 appeared (2–5 h). For storage in the dark, the flask was
wrapped by an alumina foil.
Similar to the procedure described for 5a; tetralone derivative
4b (1.87 g, 9.16 mmol), 2-methylcyclopentane-1,3-dione (1.23 g,
11.0 mmol), Pd(PPh3)4 (106 mg, 0.092 mmol), DMF (25 mL), 80 °C,
3 d. 5c (1.54 g, 56%) was isolated as a yellow solid. 1H NMR
(250 MHz, CDCl3): d = 1.17 (s, 3H, Me), 1.26 (t, J = 6.8 Hz, 2H, 200-
H), 1.77 (quint., J = 6.4 Hz, 2H, 300-H), 2.43 (t, J = 5.9 Hz, 2H, 400-H),
2.55 (d, J = 8.2 Hz, 2H, 10-H), 2.68–2.78 (m, 4H, 4-H, 5-H), 5.64 (t,
J = 8.2 Hz, 1H, 20-H), 6.60 (d, J = 2.7 Hz, 1H, 500-H), 6.69 (dd, J = 2.7,
8.7 Hz, 1H, 700-H), 7.40 (d, J = 8.7 Hz, 1H, 800-H) ppm.20
4.3. 2-[(2E)-2-(3,4-Dihydronaphthalen-1(2H)-ylidene)ethyl]-2-
methylcyclopentane-1,3-dione 5a
Tetralone derivative 4a (9.76 g, 56.0 mmol) and 2-methylcy-
clopentane-1,3-dione (7.53 g, 67.2 mmol) were dissolved in DMF
(112 mL) under an atmosphere of argon, Pd(PPh3)4 (575 mg,
0.560 mmol) was added and the mixture was stirred at 80 °C for
24 h. CH2Cl2 (800 mL) was added and the solution was washed with
water (3 ꢁ 100 mL) and brine (2 ꢁ 100 mL) and dried with Na2SO4.
The solvent was removed under reduced pressure to afford the crude
product as a solution in DMF. The solution was diluted with EtOAc
(300 mL), washed with brine (5 ꢁ 20 mL) and dried with Na2SO4.
The solvent was removed under reduced pressure. Column chroma-
tography on silica gel (hexane/EtOAc 8:1) afforded 7.10 g (47%) of 5a
as a yellow oil. 1H NMR (250 MHz, CDCl3): d = 1.18 (s, 3H, Me), 1.79
(quint., J = 6.6 Hz, 2H, 300-H), 2.46 (t, J = 6.6 Hz, 2H, 200-H), 2.57 (d,
J = 8.2 Hz, 2H, 10-H), 2.69–2.79 (m, 6H, 4-H, 5-H, 400-H), 5.77 (t,
J = 8.2 Hz, 1H, 20-H), 7.05–7.18 (m, 3H, Ar), 7.42–7.47 (m, 1H, Ar)
ppm. 13C NMR (63 MHz, CDCl3): d = 18.9 (q, Me), 23.2, 26.3, 30.2,
34.9 (4t, C-10, C-200, C-300, C-400), 35.5 (t, C-4, C-5), 56.9 (s, C-2), 116.1
(d, C-20), 123.7, 125.9, 127.2, 128.9 (4d, Ar), 135.4, 137.6, 138.5 (3s,
4.6. 2,2-Bis[(2E)-2-(3,4-dihydronaphthalen-1(2H)-ylidene)-
ethyl]-1H-indene-1,3(2H)-dione 5d
Similar to the procedure described in method 2 for 5b; tetralone
derivative 4a (2.50 g, 14.3 mmol), indane-1,3-dione (1.05 g,
7.17 mmol), Pd(OAc)2 (162 mg, 0.722 mmol), PPh3 (378 mg,
1.44 mmol) Et3B (1 M in THF, 17.2 mmol, 17.2 mL), THF (36 mL),
rt, 4 d. 5d (2.87 g, 87%) was isolated as a yellow solid. 1H NMR
(500 MHz, CDCl3): d = 1.75 (quint., J = 6.4 Hz, 4H, 300-H), 2.49, 2.67
(dt and t, J = 1.6, 6.4 Hz, J = 6.4 Hz, 4H each, 200-H, 400-H), 2.82 (d,
J = 8.0 Hz, 4H, 10-H), 5.68 (t, J = 8.0 Hz, 2H, 20-H), 6.93–6.98 (m,
4H, Ar), 7.02 (dt, J = 1.3, 7.3 Hz, 2H, Ar), 7.10 (dd, J = 1.0, 7.9 Hz,
2H, Ar), 7.68–7.72 (m, 2H, Ar), 7.87–7.91 (m, 2H, Ar) ppm. 13C
NMR (126 MHz, CDCl3): d = 23.1 (t, C-300), 26.2, 30.1 (2t, C-200, C-
10), 33.4 (t, C-400) 59.0 (s, C-2), 116.8 (d, C-20), 122.8, 123.7, 125.7,
126.8, 128.6, 135.6 (6d, Ar), 135.7 (s, C-100), 137.4, 138.0, 142.2
(3s, Ar), 203.9 (s, C@O) ppm. IR (KBr):
m = 3060–2835 (@CH, C–H),
C-100, Ar), 216.7 (s, C@O) ppm. IR (neat):
m
= 3060–2840 (@CH, C–
1745 (C@O), 1710 (C@O), 1595 (C@C), 1480 (C@C) cmꢂ1. EA: Calcd
H), 1725 (C@O), 1640–1570 (C@C) cmꢂ1. EA: Calcd for C18H20O2
for C33H30O2 (458.6): C, 86.43; H, 6.59. Found: C, 86.36; H, 6.44.
(268.4): C, 80.56; H, 7.51. Found: C, 80.21; H, 7.52.
4.7. 2-Methyl-2-[(E)-2-(1-naphthyl)ethenyl]cyclopentane-1,3-
4.4. 2-[(2E)-2-(3,4-Dihydronaphthalen-1(2H)-ylidene)ethyl]-2-
dione 6a
methylcyclohexane-1,3-dione 5b
Compound 5a (7.10 g, 26.5 mmol) and DDQ (12.1 g, 53.2 mmol)
were suspended in chlorobenzene (140 mL) and stirred under re-
flux for 90 min. The mixture was filtered through a pad of silica
Method 1: Similar to the procedure described for 5a; 2-methyl-
cyclohexane-1,3-dione (1.30 g, 10.3 mmol), tetralone derivative 4a

U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
1607
gel (hexane/EtOAc 4:1) and the solvent was removed under re-
duced pressure. The crude product was purified by column chro-
matography (hexane/EtOAc 9:1) to afford 5.11 g (77%) of 6a as
yellow oil. A small scale reaction (2.15 mmol) yielded 6a in 87%.
1H NMR (250 MHz, CDCl3): d = 1.41 (s, 3H, Me), 2.70–3.11 (m, 4H,
4-H, 5-H), 6.02 (d, J = 16.4 Hz, 1H, 10-H), 7.25 (d, J = 16.4 Hz, 1H,
20-H), 7.41 (t, J = 7.7 Hz, 1H, Ar), 7.45–7.56 (m, 3H, Ar), 7.75–7.87
(m, 2H, Ar), 7.95–8.03 (m, 1H, Ar) ppm. 13C NMR (68 MHz, CDCl3):
d = 18.9 (q, Me), 35.0 (t, C-4, C-5), 59.9 (s, C-2), 123.4, 123.8, 125.3,
125.8, 126.2, 128.4, 128.5, 128.8, 129.9 (9d, Ar, CH@), 130.9, 133.4,
Hydrogen was bubbled through the mixture for 40 min, then it
was stirred for additional 155 min under H2 atmosphere. Filtration
through a pad of Celite followed by column chromatography on sil-
ica gel (hexane/EtOAc 9:1?3:1) afforded 5.01 g (97%) of dione 7a
as a yellow oil. 1H NMR (250 MHz, CDCl3): d = 1.21 (s, 3H, Me),
2.04–2.13 (m, 2H, 10-H), 2.66–2.96 (m, 6H, 20-H, 4-H, 5-H), 7.25
(d, J = 6.4 Hz, 1H, Ar), 7.36 (t, J = 7.7 Hz, 1H, Ar), 7.43–7.59 (m,
2H, Ar), 7.71 (d, J = 7.3 Hz, 1H, Ar), 7.84 (d, J = 8.2 Hz, 1H, Ar),
7.95 (d, J = 8.2 Hz, 1H, Ar) ppm. 13C NMR (63 MHz, CDCl3):
d = 20.0 (q, Me), 28.2 (t, C-10), 35.2 (t, C-4, C-5), 36.1 (t, C-20), 56.8
(s, C-2), 123.4, 125.4, 125.6, 126.16, 126.22, 127.2, 128.7 (7d, Ar),
131.6, 133.8, 136.9 (3s, Ar), 216.3 (s, C@O) ppm. IR (neat):
133.5 (3s, Ar), 213.3 (s, C@O) ppm. IR (neat):
m = 3100–2940 (@CH,
C–H), 1720 (C@O) cmꢂ1. MS (EI, 80 eV, 110 °C): m/z (%) = 264 (100)
[M]+, 208 (48), 179 (70), 178 (57), 165 (94), 155 (35), 152 (38), 128
(32), 127 (31), 89 (35), 55 (38), 43 (45). HRMS (EI): Calcd for
m
= 3060–2870 (@CH, C–H), 1720 (C@O), 1595, 1510 (C@C) cmꢂ1
.
MS (EI, 80 eV, 80 °C): m/z (%) = 266 (12) [M]+, 155 (17), 154
C18H16O2: 264.11503. Found: 264.11387.
(100), 153 (20), 141 (33), 129 (14), 115 (18), 69 (11), 43 (13), 41
(19). HRMS (EI): Calcd for
C18H18O2: 266.13068. Found:
4.8. 2-Methyl-2-[(E)-2-(1-naphthyl)ethenyl]cyclohexane-1,3-
dione 6b
266.13107. EA: Calcd for C18H18O2 (266.3): C, 81.17; H, 6.81.
Found: C, 81.09; H, 6.90.
Similar to the procedure described for 6a; 5b (382 mg,
1.35 mmol), DDQ (613 mg, 2.70 mmol), chlorobenzene (7.6 mL),
4.12. 2-Methyl-2-[2-(1-naphthyl)ethyl]cyclohexane-1,3-dione
7b
reflux, 135 min. Product 6b was isolated as
a yellow solid
(192 mg, 51%). 1H NMR (500 MHz, CDCl3): d = 1.52 (s, 3H, Me),
1.85 (ttd, J = 4.9, 9.6, 14.1 Hz, 1H, 5-H1), 2.21 (quint.d, J = 6.2,
14.1 Hz, 1H, 5-H2), 2.63 (ddd, J = 4.9, 6.4, 16.2 Hz, 2H, 4-H1, 6-H1),
2.96 (ddd, J = 5.9, 10.2, 16.2 Hz, 2H, 4-H2, 6-H2), 6.22 (d,
J = 15.9 Hz, 1H, 10-H), 7.14 (d, J = 15.9 Hz, 1H, 20-H), 7.42 (t,
J = 7.8 Hz, 1H, Ar), 7.47–7.53 (m, 3H, Ar), 7.79 (d, J = 8.1 Hz, 1H,
Ar), 7.84 (dd, J = 2.3, 7.2 Hz, 1H, Ar), 7.94 (dd, J = 1.2, 7.8 Hz, 1H,
Ar) ppm. 13C NMR (126 MHz, CDCl3): d = 17.7, 18.0 (q and t, 2-
Me, C-5), 38.2 (t, C-4, C-6), 69.4 (s, C-1), 123.4, 123.9, 125.4,
126.0, 126.4, 128.6, 128.7, 130.0, 131.5 (9d, Ar, C-10, C-20), 131.0,
Similar to the procedure described for 7a; 6b (141 mg,
0.507 mmol), Pd/C (10% wt, 27 mg, 0.025 mmol Pd), EtOAc
(17 mL), 4 h. Product 7b (95 mg, 67%) was isolated as a yellow
oil. 1H NMR (500 MHz, CDCl3): d = 1.34 (s, 3H, Me), 1.90–1.96 (m,
2H, 5-H), 2.15–2.20 (m, 2H, 10-H), 2.61–2.71 (m, 4H, 4-H, 6-H),
2.82–2.87 (m, 2H, 20-H), 7.27 (dd, J = 1.1, 7.0 Hz, 1H, Ar), 7.35 (dd,
J = 7.0, 8.2 Hz, 1H, Ar), 7.44 (ddd, J = 1.1, 7.0, 8.2 Hz, 1H, Ar), 7.53
(ddd, J = 1.1, 7.0, 8.2 Hz, 1H, Ar), 7.68 (d, J = 8.2 Hz, 1H, Ar), 7.81
(dd, J = 1.1, 8.2 Hz, 1H, Ar), 8.05 (d, J = 8.2 Hz, 1H, Ar) ppm. 13C
NMR (126 MHz, CDCl3): d = 17.5, 21.0 (q and t, 2-Me, C-5), 28.4
(t, C-10), 37.5 (t, C-20), 38.0 (t, C-4, C-6), 65.3 (s, C-2), 123.5,
125.5*, 126.0, 126.1, 126.8, 128.6 (6d, Ar), 131.6, 133.8, 137.4 (3s,
Ar), 210.1 (s, C@O) ppm; *signal has higher intensity. IR (neat):
133.5, 133.7 (3s, Ar), 207.4 (s, C@O) ppm. IR (KBr):
m = 3050–
2940 (@CH, C–H), 1710 (C@O) cmꢂ1. HRMS (ESI): Calcd for
C
19H18O2ꢃH+: 279.1385. Found: 279.1403.
m
= 3065–2875 (@CH, C–H), 1725 (C@O), 1695 (C@O), 1595
4.9. 2-[(E)-2-(6-Methoxy-1-naphthyl)ethenyl]-2-methylcyclo-
(C@C), 1510 (C@C) cmꢂ1. EA: Calcd for C19H20O2 (280.4): C,
pentane-1,3-dione 6c
81.40; H, 7.19. Found: C, 80.82; H, 7.09.
Similar to the procedure described for 6a; 5c (1.30 g,
4.38 mmol), DDQ (1.99 g, 8.76 mmol) chlorobenzene (23 mL), re-
flux, 60 min. Product 6c was isolated as a yellow solid (812 mg,
63%). 1H NMR (250 MHz, CDCl3): d = 1.41 (s, 3H, Me), 2.75–3.08
(m, 4H, 4-H, 5-H), 3.92 (s, 3H, OMe), 6.01 (d, J = 15.5 Hz, 1H, 10-
H), 7.12–7.21* (m, 2H, Ar), 7.21* (d, J = 15.5 Hz, 1H, 20-H), 7.34–
7.42 (m, 2H, Ar), 7.68 (dd, J = 2.7, 6.4 Hz, 1H, Ar), 7.90 (d,
4.13. 2-[2-(6-Methoxy-1-naphthyl)ethyl]-2-methylcyclo-
pentane-1,3-dione 7c
Similar to the procedure described for 7a; 6c (859 mg,
2.92 mmol), Pd/C (10% wt, 124 mg, 0.177 mmol Pd), EtOAc
(30 mL), 3 h. Product 7c (781 mg, 90%) was isolated as a pale yel-
low solid. Mp: 91 °C. 1H NMR (250 MHz, CDCl3): d = 1.20 (s, 3H,
Me), 2.08 (mc, 2H, 10-H), 2.65–2.92 (m, 6H, 4-H, 5-H, 20-H), 3.92
(s, 3H, OMe), 7.09* (d, J = 7.1 Hz, 1H, 200-H), 7.13 (d, J = 2.6 Hz, 1H,
500-H), 7.21 (dd, J = 2.6, 9.3 Hz, 1H, 700-H), 7.31 (t, J = 7.7 Hz, 1H,
300-H), 7.61* (d, J = 8.4 Hz, 1H, 400-H), 7.85 (d, J = 9.3 Hz, 1H, 800-H)
*
J = 9.1 Hz, 1H, Ar) ppm; signals overlap.
4.10. 2,2-Bis[(E)-2-(1-naphthyl)ethenyl]-1H-indene-1,3(2H)-
dione 6d
*
ppm; assignment interchangeable.
Similar to the procedure described for 6a; 5d (301 mg,
0.656 mmol) DDQ (596 mg, 2.63 mmol), chlorobenzene (6.5 mL),
reflux, 2 h. Product 6d (104 mg, 35%) was isolated as a red-brown
viscous oil. 1H NMR (250 MHz, CDCl3): d = 6.47 (d, J = 15.5 Hz, 2H,
10-H), 7.42 (t, J = 7.7 Hz, 2H, Ar), 7.44–7.54 (m, 4H, Ar), 7.61 (d,
J = 6.4 Hz, 2H, Ar), 7.65 (d, J = 15.5 Hz, 2H, 20-H), 7.78 (d,
J = 8.2 Hz, 2H, Ar), 7.83 (dd, J = 2.5, 6.7 Hz, 2H, Ar), 7.95 (dd,
J = 3.2, 5.9 Hz, 2H Ar), 8.09 (dd, J = 2.7, 6.4 Hz, 2H, Ar), 8.15 (dd,
J = 3.6, 5.9 Hz, 2H, Ar) ppm.
4.14. 2,2-Bis[2-(1-naphthyl)ethyl]-1H-indene-1,3(2H)-dione 7d
To a suspension of Pd/C (10% wt, 12 mg, 0.012 mmol Pd) in
EtOH (2 mL) was added a solution of 6d (104 mg, 0.231 mmol) in
EtOH (3 mL) und THF (3 mL). Hydrogen was bubbled through the
mixture for 20 min, then stirring was continued under an atmo-
sphere of H2 for 22 h. Filtration over Celite and purification by pre-
parative HPLC yielded 7d (29 mg, 28%) as a yellow solid. Starting
material 6d (15 mg, 14%) was recovered and 36 mg (34%) of the
mono-hydrogenated compound was isolated. Mp: 139–141 °C. 1H
NMR (500 MHz, CDCl3): d = 2.30 (mc, 4H, 10-H), 2.84 (mc, 4H, 20-
H), 7.17 (dd, J = 1.0, 7.0 Hz, 2H, Ar), 7.29 (dd, J = 7.1, 8.2 Hz, 2H,
Ar), 7.43 (ddd, J = 1.1, 6.9, 8.1 Hz, 2H, Ar), 7.51 (ddd, J = 1.4, 6.9,
8.4 Hz, 2H, Ar), 7.65 (br d, J = 8.2 Hz, 2H, Ar), 7.79 (dd, J = 0.7,
4.11. 2-Methyl-2-[2-(1-naphthyl)ethyl]cyclopentane-1,3-dione
7a
Compound 6a (5.11 g, 19.3 mmol) was dissolved in EtOAc
(250 mL) and Pd/C (10% wt, 411 mg, 0.368 mmol Pd) was added.

1608
U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
8.2 Hz, 2H, Ar), 7.88 (br d, J = 8.4 Hz, 2H, Ar), 7.91 (dd, J = 3.0,
5.6 Hz, 2H, Ar), 8.11 (dd, J = 3.1, 5.7 Hz, 2H, Ar) ppm. 13C NMR
(126 MHz, CDCl3): d = 28.5 (t, C-10), 36.3 (t, C-20), 58.7 (s, C-2),
123.2, 123.4, 125.4, 125.5, 126.1, 126.2, 127.0, 128.7, 131.5 (9d,
Ar), 133.8, 136.0, 137.0, 142.5 (4s, Ar), 204.5 (s, C@O) ppm. IR
4.16. rac-(1S,4aR,4bS,10bS,12aS)-12a-Methyl-
1,3,4,4b,10b,11,12,12a-octahydrochrysene-1,4a(2H)-diol cis-10
and rac-(1S,4aR,4bS,10bR,12aS)-12a-methyl-
1,3,4,4b,10b,11,12,12a-octahydrochrysene-1,4a(2H)-diol trans-
10
(KBr):
m = 3060–2835 (@CH, C–H), 1740, 1705 (C@O), 1595
(C@C), 1510 (C@C) cmꢂ1. HRMS (ESI): Calcd for C33H26O2ꢃH+:
According to the procedure described for cis-8/trans-8; dione 7b
(48 mg, 0.17 mmol), Sm (163 mg, 1.08 mmol), ICH2CH2I (279 mg,
0.99 mmol), tBuOH (66 lL, 53 mg, 0.72 mmol), HMPA (1.14 mL,
455.2011. Found: 455.2024.
4.15. rac-(8
diol cis-8 and rac-(8
tetraene-14,17-diol trans-8
a
,9
a
,13
a
,14
a
,17b)-Estra-1(10),2,4,6-tetraene-14,17-
1.12 g, 6.49 mmol), THF (15 mL for preparation of SmI2, 10 mL for
the solution of 7b and tBuOH), rt, 2 d. The crude product was fil-
tered through silica gel, subsequent preparative HPLC afforded
16 mg (33%) of cis-10 and 10 mg (20%) of trans-10 as colourless
solids.
a,9b,13
a
,14 ,17b)-estra-1(10),2,4,6-
a
Sm (180 mg, 1.20 mmol) and ICH2CH2I (310 mg, 1.10 mmol)
were suspended in THF (8 mL) at rt and vigorously stirred until
the deep blue colour of SmI2 appeared; then HMPA (1.26 mL,
1.29 g, 7.20 mmol) and tBuOH (0.20 mL, 1 M in THF, 0.20 mmol)
were added. Dione 7a (52 mg, 0.20 mmol) was dissolved in THF
(8 mL) and the solution was purged with argon for 30 min. The
solution of 7a was added via syringe to the SmI2/HMPA/tBuOH
solution. The mixture was stirred at rt over night. Satd aq. NaHCO3
solution was added, the organic layer was separated and the aque-
ous layer was extracted with Et2O. The combined organic layers
were washed with water and brine and dried with Na2SO4. The sol-
vents were removed under reduced pressure. Column chromatog-
raphy on silica gel (hexane/EtOAc 2:1) afforded a 91:9 mixture of
isomers cis-8 and trans-8 (38 mg, 70%) as a colourless solid. Analyt-
ically pure samples of cis-8 and trans-8 were obtained by prepara-
tive HPLC.
cis-10: Mp: 166–169 °C. 1H NMR (500 MHz, CDCl3): d = 1.08–
1.16 (m, 3H, 12-H1, 3-H1, 4-H1), 1.34 (s, 3H, Me), 1.43–1.48 (m,
1H, 4-H2), 1.50–1.56 (m, 1H, 2-H1), 1.63 (ddt, J = 2.4, 3.7, 13.7 Hz,
1H, 2-H2), 1.68–1.79 (m, 2H, 12-H2, 3-H2), 2.12 (ddt, J = 4.1, 6.5,
14.7 Hz, 1H, 11-H1), 2.38 (br d, J = 14.7 Hz, 1H, 11-H2), 2.66 (br s,
1H, OH), 2.84 (t, J = 6.5 Hz, 1H, 4b-H), 2.88 (s, 1H, OH), 3.32 (t,
J = 6.5 Hz, 1H, 10b-H), 3.43 (br s, 1H, 1-H), 6.07 (dd, J = 6.5,
9.8 Hz, 1H, 5-H), 6.64 (d, J = 9.8 Hz, 1H, 6-H), 7.02 (dd, J = 1.3,
7.4 Hz, 1H, Ar), 7.15 (br t, J = 7.4 Hz, 1H, Ar), 7.20 (dt, J = 1.5,
7.4 Hz, 1H, Ar), 7.24 (br d, J = 7.4 Hz, 1H, Ar) ppm. 13C NMR
(126 MHz, CDCl3): d = 15.0 (t, C-3), 17.1 (q, Me), 19.6 (t, C-11),
28.0 (t, C-4), 28.4 (t, C-2), 29.2 (t, C-12), 35.7 (d, C-10b), 40.9 (s,
C-12a), 41.1 (d, C-4b), 77.5 (s, C-4a), 77.7 (d, C-1), 122.6, 125.9,
126.5, 127.7 (4d, Ar), 129.1 (d, C-5), 130.5 (d, C-6), 134.8, 137.4
(2s, Ar) ppm. IR (KBr):
m = 3235 (O–H), 3060–2835 (@CH, C–H),
cis-8: Mp: 167–169 °C. 1H NMR (500 MHz, CDCl3): d = 1.12–1.21
(m, 2H, 16-H1, OH), 1.16 (s, 3H, Me), 1.26* (ddd, J = 4.5, 10.1,
14.7 Hz, 1H, 15-H1), 1.26* (s, 1H, OH), AB-signal (dA = 1.38,
dB = 1.42, JA,B = 13.8 Hz, additional couplings of A, J = 3.1, 13.8 Hz,
and B, J = 3.6, 3.6 Hz, 1H each, 12-H2), 1.53 (ddd, J = 5.9, 12.5,
14.7 Hz, 1H, 15-H2), 1.87–2.01 (m, 2H, 16-H2, 11-H1), 2.43 (qd,
J = 3, 14.6 Hz, 1H, 11-H2), 2.52 (dd, J = 6.1, 6.9 Hz, 1H, 8-H), 3.34
(br dd, J = 6, 6.9 Hz, 1H, 9-H), 4.17 (t, J = 8.5 Hz, 1H, 17-H), 6.14
(dd, J = 6.1, 9.8 Hz, 1H, 7-H), 6.59 (d, J = 9.8 Hz, 1H, 6-H), 7.02 (dd,
J = 1.2, 7.4 Hz, 1H, 4-H), 7.14 (br t, J = 7.4 Hz, 1H, 3-H), 7.19 (dt,
1670–1570 (C@C) cmꢂ1. MS (EI, 80 eV, 140 °C): m/z (%) = 284 (24)
[M]+, 154 (37), 141 (49), 129 (34), 128 (100), 55 (38), 43 (59), 41
(35).
trans-10: Mp: 187–188 °C. 1H NMR (500 MHz, CDCl3): d = 1.21
(s, 3H, Me), 1.33–1.42 (m, 1H, 12-H1), 1.54–1.66 (m, 2H, 3-H1,
4-H1), 1.69–1.75 (m, 1H, 2-H1), 1.80–1.96 (m, 4H, 2-H2, 4-H2,
11-H1, 12-H2), 2.05 (tq, J = 3.8, 13.5 Hz, 1H, 3-H2), 2.21–2.27 (m,
1H, 11-H2), 2.51 (br s, 1H, OH), 2.57 (td, J = 2.5, 15.9 Hz, 1H,
4b-H), 2.71–2.78 (m, 1H, 10b-H), 3.34 (br s, 1H, OH), 3.57 (br s,
1H, 1-H), 6.17 (dd, J = 2.1, 9.8 Hz, 1H, 5-H), 6.53 (dd, J = 2.9,
9.8 Hz, 1H, 6-H), 7.04–7.07 (m, 1H, Ar), 7.16–7.22 (m, 2H, Ar),
7.23–7.26 (m, 1H, Ar) ppm. 13C NMR (126 MHz, CDCl3): d = 15.4
(t, C-3), 17.5 (q, Me), 23.4 (t, C-11), 28.4 (t, C-2), 29.4 (t, C-4),
32.1 (t, C-12), 37.1 (d, C-10b), 40.8 (s, C-12a), 44.6 (d, C-4b),
75.9 (s, C-4a), 77.6 (d, C-1), 123.6, 125.9, 126.3, 127.0 (4d, Ar),
128.1 (d, C-6), 129.5 (d, C-5), 134.1, 138.2 (2s, Ar) ppm. IR
*
J = 1.2, 7.4 Hz, 1H, 2-H), 7.26 (br d, J = 7.4 Hz, 1H, 1-H) ppm; sig-
nals overlap. 13C NMR (126 MHz, CDCl3): d = 16.5 (q, Me), 19.9 (t,
C-11), 24.6 (t, C-12), 28.3 (t, C-16), 31.4 (t, C-15), 36.3 (d, C-9),
41.5 (d, C-8), 47.2 (s, C-13), 80.9 (d, C-17), 83.8 (s, C-14), 123.5
(d, C-1), 126.1 (d, C-3), 126.5 (d, C-4), 127.7 (d, C-2), 129.1 (d, C-
7), 129.8 (d, C-6), 134.1, 136.3 (2s, C-5, C-10) ppm. IR (KBr):
m
= 3325 (O–H), 3060–2830 (@CH, C–H), 1655–1570 (C@C) cmꢂ1
.
(KBr): m = 3375 (O–H), 3060–2855 (@CH, C–H), 1660–1570
MS (EI, 80 eV, 90 °C): m/z (%) = 270 (82) [M]+, 156 (31), 154 (72),
142 (40), 141 (55), 129 (59), 128 (100), 28 (51). HRMS (EI): Calcd
for C18H22O2: 270.16199. Found: 270.16256.
(C@C) cmꢂ1. MS (EI, 80 eV, 100 °C): m/z (%) = 284 (73) [M]+, 181
(20), 154 (64), 142 (51), 141 (80), 129 (41), 128 (100), 111 (21),
84 (21), 55 (25), 43 (30), 41 (18). HRMS (EI): Calcd for
trans-8: Mp: 176–178 °C. 1H NMR (500 MHz, CDCl3): d = 1.07 (s,
3H, Me), 1.41 (dt, J = 3.8, 13.6 Hz, 1H, 12-H1), 1.56–1.72 (m, 6H, 11-
H1, 12-H2, 15-H2, 16-H1, OH), 2.16–2.34 (m, 4H, 8-H, 11-H2, 16-H2,
OH), 2.63 (ddd, J = 3.7, 11.9, 15.4 Hz, 1H, 9-H), 4.32 (t, J = 8.6 Hz,
1H, 17-H), 6.17 (dd, J = 2.0, 9.7 Hz, 1H, 7-H), 6.57 (dd, J = 2.9,
9.7 Hz, 1H, 6-H), 7.08 (dd, J = 1.6, 7.1 Hz, 1H, 4-H), 7.17–7.21 (m,
1H, 3-H), 7.22 (dt, J = 1.6, 6.9 Hz, 1H, 2-H), 7.25–7.29 (m, 1H, 1-
H) ppm. 13C NMR (126 MHz, CDCl3): d = 16.6 (q, Me), 23.2 (t, C-
11), 28.4 (t, C-12), 28.8 (t, C-15), 30.0 (t, C-16), 39.3 (d, C-9), 44.9
(d, C-8), 47.7 (s, C-13), 80.9 (d, C-17), 83.1 (s, C-14), 123.5 (d, C-
1), 126.0 (d, C-4), 126.4 (d, C-3), 127.3 (d, C-2), 129.0 (d, C-6),
129.4 (d, C-7), 134.1, 138.4 (2s, C-5, C-10) ppm. IR (KBr):
C19H24O2: 284.17763. Found: 284.17778.
4.17. rac-(8
tetraene-14,17-diol cis-11 and rac-(8
a
,9
a
,13
a
,14
a
,17b)-3-Methoxyestra-1(10),2,4,6-
,9b,13 ,14 ,17b)-3-
a
a
a
methoxyestra-1(10),2,4,6-tetraene-14,17-diol trans-11
According to the procedure described for cis-8/trans-8; SmI2
was taken from a previously prepared stock solution. Dione 7c
(190 mg, 0.641 mmol), SmI2 (0.1 M in THF, 35 mL, 3.50 mmol),
HMPA (4.1 mL, 4.1 g, 23 mmol), tBuOH (1 M in THF, 0.64 mL,
0.64 mmol; tBuOH was added to the SmI2–HMPA solution before
a solution of 7c in THF was added), THF (10 mL, for the solution
of 7c). Column chromatography on silica gel (hexane/EtOAc 1:1)
and preparative HPLC afforded 17 mg (9%) of cis-11 and 7 mg
(4%) of trans-11 as colourless solids.
m
= 3315 (O–H), 3060–2830 (@CH, C–H), 1660–1600 (C@C) cmꢂ1
.
MS (EI, 80 eV, 150 °C): m/z (%) = 270 (81) [M]+, 157 (73), 155
(75), 142 (87), 141 (100), 129 (59), 128 (95), 115 (30), 97 (60),
43 (41), 41 (32), 28 (69). HRMS (EI): Calcd for
270.16199. Found: 270.16114.
C
18H22O2:
cis-11: Mp: 144–146 °C. 1H NMR (500 MHz, CDCl3): d = 1.15 (s,
3H, 13-Me), 1.14–1.28 (m, 3H, OH, 15-H1, 16-H1), 1.32–1.44 (m,

U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
1609
3H, 12-H2, OH), 1.57 (ddd, J = 5.7, 12.4, 14.9 Hz, 1H, 15-H2), 1.89
(tdd, J = 5.1, 13.2, 14.6 Hz, 1H, 11-H1), 1.96 (dtd, J = 5.7, 9,
13.2 Hz, 1H, 16-H2), 2.39 (qd, J = 2.3, 14.6 Hz, 1H, 11-H2), 2.49 (t,
J = 6.5 Hz, 1H, 8-H), 3.28 (br t, J = 6 Hz, 1H, 9-H), 3.79 (s, 3H,
OMe), 4.17 (t, J = 8.5 Hz, 1H, 17-H), 6.16 (dd, J = 6.5, 9.8 Hz, 1H, 7-
H), 6.54 (d, J = 9.8 Hz, 1H, 6-H), 6.61 (d, J = 2.7 Hz, 1H, 4-H), 6.71
(dd, J = 2.7, 8.3 Hz, 1H, 2-H), 7.15 (d, J = 8.3 Hz, 1H, 1-H) ppm. 13C
NMR (126 MHz, CDCl3): d = 16.4 (q, 13-Me), 20.0 (t, C-11), 24.4 (t,
C-12), 28.1 (t, C-16), 31.3 (t, C-15), 35.5 (d, C-9), 41.5 (d, C-8),
47.1 (s, C-13), 55.2 (q, OMe), 80.8 (d, C-17), 83.8 (s, C-14), 112.1
(d, C-2), 112.6 (d, C-4), 124.4 (d, C-1), 128.3 (s, Ar), 129.8, 129.9
(31), 41 (28), 28 (56). EA: Calcd for C18H20O2 (268.4): C, 80.56; H,
7.51. Found: C, 80.18; H, 7.43.
Epi-13: 1H NMR (500 MHz, CDCl3): d = 1.18 (s, 3H, Me), 1.79–
1.88 (m, 2H, 10-H), 1.89–1.96 (m, 1H, 5-H1), 2.02 (br s, 1H, OH),
2.23 (mc, 2H, 4-H1, 5-H2), 2.47–2.58 (m, 1H, 4-H2), 2.96–3.06 (m,
1H, 20-H1), 3.08–3.17 (m, 1H, 20-H2), 4.33 (t, J = 5.7 Hz, 1H, 3-H),
7.30 (d, J = 6.9 Hz, 1H, Ar), 7.38 (t, J = 7.5 Hz, 1H, Ar), 7.48 (ddd,
J = 1.2, 6.8, 7.6 Hz, 1H, Ar), 7.53 (ddd, J = 1.2, 6.8, 8.5 Hz, 1H, Ar),
7.71 (d, J = 8.2 Hz, 1H, Ar), 7.85 (d, J = 7.6 Hz, 1H, Ar), 8.00 (d,
J = 8.5 Hz, 1H, Ar) ppm. 13C NMR (126 MHz, CDCl3): d = 14.8 (q,
Me), 27.5 (t, C-20), 27.9 (t, C-5), 34.9 (t, C-4), 36.4 (t, C-10), 53.4
(s, C-2), 75.8 (d, C-3), 123.4, 125.51, 125.54, 125.9, 126.0, 126.8,
128.8 (7d, Ar), 131.6, 133.9, 137.9 (3s, Ar), 220.3 (s, C-1) ppm. IR
(2d, C-6, C-7), 135.7 (s, Ar), 158.0 (s, C-3) ppm. IR (KBr):
m = 3440,
3335 (O–H), 3045–2830 (@CH, C–H, OMe), 1640–1495 (C@C)
cmꢂ1. MS (EI, 80 eV, 160 °C): m/z (%) = 300 (30) [M]+, 171 (15),
159 (100), 158 (45), 144 (11), 128 (12), 115 (25), 55 (12), 43
(19), 41 (15). HRMS (EI): Calcd for C19H24O3: 300.17254. Found:
300.17312.
(neat):
m = 3450 (O–H), 3095–2875 (@CH, C–H), 1730 (C@O),
1595 (C@C), 1510 (C@C) cmꢂ1. HRMS (ESI): Calcd for C18H20O2ꢃH+:
269.1542. Found: 269.1541.
trans-11: Mp: 169–171 °C. 1H NMR (500 MHz, CDCl3): d = 1.06
(s, 3H, 13-Me), 1.40 (dt, J = 3.7, 13.7 Hz, 1H, 12-H1), 1.52–1.70 (m,
6H, 11-H1, 12-H2, 15-H1, 16-H1, 2 ꢁ OH), 2.15 (td, J = 2.5, 15.2 Hz,
1H, 8-H), 2.17–2.34 (m, 3H, 11-H2, 15-H2, 16-H2), 2.56 (ddd,
J = 3.6, 11.9, 15.2 Hz, 1H, 9-H), 3.80 (s, 3H, OMe), 4.31 (t,
J = 8.5 Hz, 1H, 17-H), 6.19 (dd, J = 2.1, 9.7 Hz, 1H, 7-H), 6.52 (dd,
J = 2.9, 9.7 Hz, 1H, 6-H), 6.66 (d, J = 2.7 Hz, 1H, 4-H), 6.75 (dd,
J = 2.7, 8.4 Hz, 1H, 2-H), 7.17 (d, J = 8.4 Hz, 1H, 1-H) ppm. 13C
NMR (126 MHz, CDCl3): d = 16.6 (q, 13-Me), 23.4 (t, C-11), 28.3
(t, C-12), 28.7 (t, C-16), 29.8 (t, C-15), 38.7 (d, C-9), 45.2 (d, C-8),
47.6 (s, C-13), 55.3 (q, OMe), 80.8 (d, C-17), 83.0 (s, C-14), 111.9,
112.0 (2d, C-2, C-4), 124.4 (d, C-1), 128.9 (d, C-6), 130.1 (d, C-7),
4.19. 3-Methoxyestra-1,3,5(10),6,8,15-hexaen-17-one 14 and 3-
methoxyestra-1,3,5(10),6,8,14-hexaen-17-one 15
Compound 7c (24 mg, 0.081 mmol) was added to a suspension
of AlCl3 (125 mg, 0.937 mmol) in acetonitrile (2.5 mL) and the mix-
ture was stirred in a sealed tube at 50 °C for 2 d. Then EtOAc
(50 mL) was added, the solution was washed with water
(1 ꢁ 5 mL) and brine (1 ꢁ 5 mL) and dried with Na2SO4. Column
chromatography (hexane/EtOAc 4:1) yielded 14 (13 mg, 57%) and
15 (7 mg, 31%) as colourless solids.
Compound 14: Mp: 88–90 °C. 1H NMR (500 MHz, CDCl3):
d = 1.30 (s, 3H, Me), 1.65 (ddd, J = 4.1, 11.2, 13.2 Hz, 1H, 12-H1),
2.24 (ddd, J = 4.2, 5.5, 13.2 Hz, 1H, 12-H2), 2.53 (ddd, J = 4.2, 11.2,
16.1 Hz, 1H, 11-H1), 3.17 (ddd, J = 4.1, 5.5, 16.1 Hz, 1H, 11-H2),
3.92 (s, 3H, OMe), 3.93 (t, J = 2.5 Hz, 1H, 14-H), 6.14 (dd, J = 2.5,
5.6 Hz, 1H, 16-H), 7.13 (d, J = 2.7 Hz, 1H, 4-H), 7.17 (dd, J = 2.7,
9.2 Hz, 1H, 2-H), 7.38* (d, J = 8.4 Hz, 1H, 7-H), 7.59 (dd, J = 2.5,
5.6 Hz, 1H, 15-H), 7.65* (d, J = 8.4 Hz, 1H, 6-H), 7.88 (d, J = 9.2 Hz,
130.6, 135.2 (2s, Ar), 158.3 (s, C-3) ppm. IR (KBr):
m = 3460 (O–
H), 3030–2830 (@CH, C–H, OMe), 1630–1495 (C@C) cmꢂ1. MS
(EI, 80 eV, 170 °C): m/z (%) = 300 (25) [M]+, 184 (23), 172 (26),
171 (31), 159 (44), 158 (30), 115 (27), 97 (30), 57 (26), 55 (42),
43 (100), 41 (52). HRMS (EI): Calcd for C19H24O3: 300.17254.
Found: 300.17224.
1H, 1-H) ppm; assignment interchangeable. 13C NMR (126 MHz,
*
4.18. rac-(2S,3S)-3-Hydroxy-2-methyl-2-[2-(1-naphthyl)-
ethyl]cyclopentanone 13 and rac-(2R,3S)-3-hydroxy-2-methyl-
2-[2-(1-naphthyl)ethyl]cyclopentanone epi-13
CDCl3): d = 22.1 (t, C-11), 23.8 (q, Me), 33.2 (t, C-12), 47.2 (d, C-
14), 54.7 (s, C-13), 55.3 (q, OMe), 106.6 (d, C-4), 118.7 (d, C-2),
124.9 (d, C-1), 125.9, 127.2 (2d, C-6, C-7), 129.3 (s, Ar), 130.5* (d,
C-16), 130.5*, 133.6, 133.7 (3s, Ar), 157.3 (s, C-3), 165.3 (d, C-15),
To a solution of 7a (350 mg, 1.31 mmol) in MeOH (8 mL) was
added NaBH4 (50 mg, 1.32 mmol) at 0 °C in portions of 10 mg over
3 h. After warming up to rt over night satd aq NH4Cl solution
(5 mL) was added. The organic layer was separated and the aque-
ous phase was extracted with Et2O. The combined organic layers
were dried with Na2SO4 and the solvent was removed in vacuo. Fil-
tration over silica gel (hexane/EtOAc 2:1) and subsequent separa-
tion of the diastereomers with preparative HPLC (hexane/EtOAc
4:1) yielded 237 mg (68%) of 13 as a colourless solid and 64 mg
(18%) of epi-13 as a colourless oil.
214.7 (s, C@O) ppm; *signals overlap. IR (ATR):
m = 2980–2840
(@CH, C–H), 1700 (C@O), 1605 (C@C) cmꢂ1. HRMS (ESI): Calcd
for C19H18O2ꢃNa+: 301.1205. Found: 301.1212.
Compound 15: Mp: 148–150 °C. 1H NMR (500 MHz, CDCl3):
d = 1.19 (s, 3H, Me), 1.76 (dt, J = 6.3, 12.5 Hz, 1H, 12-H1), 2.22
(ddd, J = 1.2, 5.9, 13.0 Hz, 1H, 12-H2), 3.06 (dd, J = 3.0, 23.3 Hz, 1H,
16-H1), 3.22 (ddd, J = 5.9, 12.3, 17.9 Hz, 1H, 11-H1), 3.33–3.40* (m,
1H, 11-H2), 3.37* (dd, J = 2.3, 23.3 Hz, 1H, 16-H2), 3.93 (s, 3H,
OMe), 6.27 (br t, J = 2.5 Hz, 1H, 15-H), 7.14 (d, J = 2.7 Hz, 1H, 4-H),
7.19 (dd, J = 2.7, 9.2 Hz, 1H, 2-H), 7.62, 7.64 (2d, J = 8.7 Hz, 1H each,
Compound 13: Mp: 102–103 °C. 1H NMR (500 MHz, CDCl3):
d = 1.21 (s, 3H, Me), 1.46 (s, 1H, OH), 1.88–1.99 (m, 2H, 10-H1, 4-
H1), 2.02 (ddd, J = 5.6, 12.0, 14.0 Hz, 1H, 10-H2), 2.22–2.30 (m, 1H,
4-H2), 2.35 (ddd, J = 4.4, 9.2, 19.0 Hz, 1H, 5-H1), 2.51 (ddd, J = 8.9,
9.7, 19.0 Hz, 1H, 5-H2), 3.10 (ddd, J = 5.6, 12.0, 13.4 Hz, 1H, 20-H1),
3.21 (ddd, J = 4.8, 12.0, 13.4 Hz, 1H, 20-H2), 4.16 (t, J = 4.1 Hz, 1H,
3-H), 7.35 (d, J = 7.0 Hz, 1H, Ar), 7.39 (dd, J = 7.0, 8.1 Hz, 1H, Ar),
7.47 (ddd, J = 1.4, 7.0, 8.1 Hz, 1H, Ar), 7.51 (ddd, J = 1.4, 7.0,
8.1 Hz, 1H, Ar), 7.72 (d, J = 8.1 Hz, 1H, Ar), 7.85 (d, J = 8.1 Hz, 1H,
Ar), 8.08 (d, J = 8.1 Hz, 1H, Ar) ppm. 13C NMR (126 MHz, CDCl3):
d = 19.3 (q, Me), 27.4, 28.1, 31.7, 34.0 (4t, C-4, C-5, C-10, C-20),
53.1 (s, C-2), 77.6 (d, C-3), 123.7, 125.4, 125.5, 125.86, 125.88,
126.7, 128.7 (7d, Ar), 131.7, 133.9, 138.5 (3s, Ar), 220.8 (s, C-1)
7-H, 6-H), 7.93 (d, J = 9.2 Hz, 1H, 1-H) ppm; signals overlap. 13C
*
NMR (126 MHz, CDCl3): d = 19.6 (q, Me), 22.9, 28.0 (2t, C-11, C-
12), 42.2 (t, C-16), 49.2 (s, C-13), 55.3 (q, OMe), 107.1 (d, C-4),
115.0 (d, C-15), 118.6 (d, C-2), 123.2 (d, C-6), 125.3 (d, C-1),
125.9* (d, C-7), 125.9*, 127.4, 130.7, 134.6 (4s, Ar), 146.1 (s, C-14),
157.6 (s, C-3), 220.2 (s, C@O) ppm; *signals overlap. IR (ATR):
m
= 3010–2850 (@CH, C–H), 1735 (C@O), 1600 (C@C) cmꢂ1. HRMS
(ESI): Calcd for C19H18O2ꢃNa+: 301.1205. Found: 301.1205.
4.20. rac-(8
tetraen-17-yl methane sulfonate cis-16 and rac-
(8 ,9b,13 ,14 ,17b)-14-hydroxyestra-1(10),2,4,6,tetraen-17-yl
a,9a,13a,14a,17b)-14-Hydroxyestra-1(10),2,4,6,-
a
a
a
methane-sulfonate trans-16
ppm. IR (KBr):
m = 3425 (O–H), 3060–2860 (@C–H, C–H), 1720
(C@O), 1595 (C@C), 1510 (C@C) cmꢂ1. MS (EI, 80 eV, 90 °C): m/z
To a solution of cis-8 and trans-8 (95:5, 122 mg, 0.451 mmol) in
CH2Cl2 (7 mL) were added NEt3 (0.29 mL, 0.23 g, 2.3 mmol) and
(%) = 268 (29) [M]+, 154 (100), 141 (54), 115 (32), 113 (96), 43

1610
U. K. Wefelscheid, H.-U. Reissig / Tetrahedron: Asymmetry 21 (2010) 1601–1610
MsCl (45
l
L, 67 mg, 0.59 mmol) at 0 °C. After stirring for 2 h at 0 °C
script, Dr. M. Berndt for preliminary experiments, L. Schefzig for
her experimental assistance and W. Münch for HPLC separations.
water (2 mL), brine (2 mL) and CH2Cl2 (20 mL) were added. The or-
ganic layer was separated and dried with Na2SO4. The solvent was
removed under reduced pressure. Column chromatography (hex-
ane/EtOAc 2:1) yielded a 95:5-mixture of cis-16 and trans-16
(133 mg, 85%) as colourless foam.
References
1. (a) Namy, J.-L.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5–7; (b) Girard, P.; Namy, J.-
L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693–2698.
cis-16: 1H NMR (500 MHz, CDCl3, 95:5-mixture with trans-16):
d = 1.23 (s, 3H, Me), 1.33 (ddd, J = 3.6, 9.9, 14.0 Hz, 1H, 15-H1), 1.39
(br s, 1H, OH), 1.43–1.56 (m, 3H, 12-H2, 16-H1), 1.61 (ddd, J = 5.9,
12.6, 14.0 Hz, 1H, 15-H2), 1.90 (dtd, J = 5.0, 9.9, 13.1 Hz, 1H, 11-
H1), 2.11 (dtd, J = 5.9, 9.6, 13.4 Hz, 1H, 16-H2), 2.39–2.45 (m, 1H,
11-H2), 2.53 (dd, J = 6.2, 7.4 Hz, 1H, 8-H), 2.95 (s, 3H, OSO2Me),
3.35 (t, J = 6.5 Hz, 1H, 9-H), 4.96 (dd, J = 6.8, 9.6 Hz, 1H, 17-H),
6.11 (dd, J = 6.2, 9.8 Hz, 1H, 7-H), 6.60 (d, J = 9.8 Hz, 1H, 6-H),
7.03 (dd, J = 1.2, 7.4 Hz, 1H, Ar), 7.15 (tt, J = 1.2, 7.3 Hz, 1H, Ar),
7.20 (dt, J = 1.2, 7.4 Hz, 1H, Ar), 7.25 (d, J = 7.4 Hz, 1H, Ar) ppm.
13C NMR (126 MHz, CDCl3, 95:5-mixture with trans-16): d = 16.0
(q, Me), 19.5 (t, C-11), 25.3 (t, C-12), 25.6 (t, C-16), 31.3 (t, C-15),
35.9 (d, C-9), 37.9 (q, OSO2Me), 40.7 (d, C-8), 47.4 (s, C-13), 82.5
(s, C-14), 90.3 (d, C-17), 123.3, 126.2, 126.6, 127.9 (4d, Ar), 128.2
(d, C-7), 130.2 (d, C-6), 134.3, 135.9 (2s, Ar) ppm.
2. Selected reviews: (a) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic
Synthesis using Samarium Diiodide; The Royal Society of Chemistry: Cambridge,
2010; (b) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem. 2009, 121, 7276–
7301. Angew. Chem., Int. Ed. 2009, 48, 7140–7165; (c) Rudkin, I. M.; Miller, L. C.;
Procter, D. J. Organomet. Chem. 2008, 34, 19–45; (d) Gopalaiah, K.; Kagan, H. B.
New J. Chem. 2008, 32, 607–637; (e) Ebran, J.-P.; Jensen, C. M.; Johannesen, S. A.;
Karaffa, J.; Lindsay, K. B.; Taaning, R.; Skrydstrup, T. Org. Biomol. Chem. 2006, 4,
3553–3564; (f) Berndt, M.; Gross, S.; Hölemann, A.; Reissig, H.-U. Synlett 2004,
422–438; (g) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104,
3371–3403; (h) Concellón, J. M.; Rodriguez-Solla, H. Chem. Soc. Rev. 2004, 33,
599–609; (i) Kagan, H. B. Tetrahedron 2003, 59, 10351–10372; (j) Krief, A.;
Laval, A.-M. Chem. Rev. 1999, 99, 745–777; (k) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321–3354; (l) Khan, F. A.; Zimmer, R. J. Prakt. Chem.
1997, 339, 101–104; (m) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307–
338.
3. Dinesh, C. U.; Reissig, H.-U. Angew. Chem. 1999, 111, 874–876. Angew. Chem.,
Int. Ed. 1999, 38, 789–791; For related examples of ketyl–aryl couplings see: (a)
Schmalz, H.-G.; Siegel, S.; Bats, J. W. Angew. Chem. 1995, 107, 2597–2599.
Angew. Chem., Int. Ed. 1995, 34, 2383–2385; (b) Kuo, C.-W.; Fang, J. M. Synth.
Commun. 2001, 31, 877–892; (c) Kise, N.; Suzumoto, T.; Shono, T. J. Org. Chem.
1994, 59, 1407–1413; (d) Gorny, R.; Schäfer, H. J.; Fröhlich, R.; Wibbeling, B.
Eur. J. Org. Chem. 2003, 2919–2932.
4. (a) Wefelscheid, U. K.; Berndt, M.; Reissig, H.-U. Eur. J. Org. Chem. 2008, 3635–
3646; (b) Berndt, M.; Reissig, H.-U. Synlett 2001, 1290–1292; (c) Nandanan, E.;
Dinesh, C. U.; Reissig, H.-U. Tetrahedron 2000, 56, 4267–4277.
5. (a) Kumaran, R. S.; Brüdgam, I.; Reissig, H.-U. Synlett 2008, 991–994; (b) Gross,
S.; Reissig, H.-U. Synlett 2002, 2027–2030.
6. (a) Beemelmanns, C.; Blot, V.; Gross, S.; Lentz, D.; Reissig, H.-U. Eur. J. Org. Chem.
2010, 2716–2732; (b) Beemelmanns, C.; Reissig, H.-U. Org. Biomol. Chem. 2009,
7, 4475–4480; (c) Blot, V.; Reissig, H.-U. Eur. J. Org. Chem. 2006, 4989–4992; (d)
Blot, V.; Reissig, H.-U. Synlett 2006, 2763–2766; (e) Gross, S.; Reissig, H.-U. Org.
Lett. 2003, 5, 4305–4307; (f) Shiue, J.-S.; Lin, M.-H.; Fang, J. M. J. Org. Chem.
1997, 62, 4643–4649; For electroreductive intramolecular coupling of 1-
indolealkanones see: (g) Kise, N.; Mano, T.; Sakurai, T. Org. Lett. 2008, 10, 4617–
4620.
trans-16: 13C NMR (126 MHz, CDCl3, 5:95-mixture with cis-16):
d = 16.2 (q, Me), 22.8, 26.2, 28.9, 29.9 (4t, C-11, C-12, C-15, C-16),
37.9 (q, OSO2Me), 38.9 (d, C-9), 44.2 (d, C-8), 47.9 (s, C-13), 81.9
(s, C-14), 90.0 (d, C-17), 123.4, 126.0, 126.5, 127.3 (4d, Ar), 128.5
(d, C-7), 129.2 (d, C-6), 133.8, 137.8 (2s, Ar) ppm.
cis-16/trans-16: IR (KBr):
m = 3550 (O–H), 3090–2800 (@CH, C–
H), 1485–1175 (@CH, S@O, O–H, C–H) cmꢂ1. MS (EI, 80 eV,
70 °C): m/z (%) = 348 (100) [M+], 252 (62), 250 (17), 235 (19), 234
(22), 219 (17), 209 (19), 154 (12), 141 (15), 43 (11). HRMS (EI):
Calcd for C19H24O4S: 348.13953. Found: 348.14110.
4.21. 11-Methyl-8,9,12,13-tetrahydro-7H-
cyclonona[a]naphthalen-7-one 18
7. Aulenta, F.; Wefelscheid, U. K.; Reissig, H.-U. Eur. J. Org. Chem. 2008, 2325–
2335.
8. (a) Aulenta, F.; Berndt, M.; Brüdgam, I.; Hartl, H.; Sörgel, S.; Reissig, H.-U. Chem.
Eur. J. 2007, 13, 6047–6062; (b) Berndt, M.; Hlobilová, I.; Reissig, H.-U. Org. Lett.
2004, 6, 957–960.
9. Wefelscheid, U. K.; Reissig, H.-U. Adv. Synth. Catal. 2008, 350, 65–69.
10. Sakakibara, M.; Ogawa, A. Tetrahedron Lett. 1994, 35, 8013–8014.
11. Fu, P. P.; Harvey, R. G. Chem. Rev. 1978, 78, 317–361.
A 95:5 mixture of cis-16 and trans-16 (14 mg, 0.040 mmol) was
dissolved in THF (1 mL), then NaH (ꢀ50% wt, 9 mg, 0.19 mmol) was
added. The mixture was stirred at rt for 2 h, then at 60 °C for 2 h.
NaH (ꢀ50% wt, 13 mg, 0.31 mmol) was added again and stirring
was continued for additional 2 h at 60 °C. Water (1 mL) and EtOAc
(35 mL) were added, the organic layer was separated, washed with
brine (1 ꢁ 2 mL) and dried with Na2SO4. The solvent was removed
under reduced pressure. Column chromatography (hexane/EtOAc
10:1) yielded 18 (3 mg, 30%) as colourless oil. 1H NMR (500 MHz,
CDCl3): d = 1.54 (s, 3H, Me), 2.31 (dt, J = 8.3, 12.6 Hz, 2H 9-H),
2.42 (t, J = 6.2 Hz, 2H, 12-H), 2.83–2.86 (m, 2H, 8-H), 3.29 (t,
J = 6.2 Hz, 2H, 13-H), 5.25 (t, J = 8.3 Hz, 1H, 10-H), 7.24 (d,
J = 8.4 Hz, 1H, 6-H), 7.50–7.59 (m, 2H, 2-H, 3-H), 7.73 (d,
J = 8.4 Hz, 1H, 5-H), 7.85 (d, J = 8.0 Hz, 1H, 4-H), 8.10 (d,
J = 8.4 Hz, 1H, 1-H) ppm. 13C NMR (126 MHz, CDCl3): d = 25.1 (q,
Me), 25.4 (t, C-9), 26.1 (t, C-13), 31.1 (t, C-12), 45.7 (t, C-8), 121.5
(d, C-6), 122.7 (d, C-10), 124.3 (d, C-1), 126.2 (d, C-3), 126.4 (d,
C-5), 126.8 (d, C-2), 128.8 (d, C-4), 131.8, 133.7, 135.2, 138.6 (4 s,
12. Kimura, M.; Horino, Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2001,
123, 10401–10402.
13. (a) Ohno, H.; Okumura, M.; Maeda, S.-I.; Iwasaki, H.; Wakayama, R.; Tanaka, T.
J. Org. Chem. 2003, 68, 7722–7732; (b) Ohno, H.; Wakayama, R.; Maeda, S.-I.;
Iwasaki, H.; Okumura, M.; Iwata, C.; Mikamiyama, H.; Tanaka, T. J. Org. Chem.
2003, 68, 5909–5916; (c) Ohno, H.; Maeda, S.-I.; Okumura, M.; Wakayama, R.;
Tanaka, T. Chem. Commun. 2002, 316–317.
14. Wefelscheid, U. K. Dissertation, Freie Universität Berlin, 2007.
15. Crystallographic data for cis-8: Wefelscheid, U. K.; Brüdgam, I.; Hartl, H.;
Reissig, H.-U. Z. Kristallogr.—New Cryst. Struct. 2007, 222, 467–468. For trans-8:
CCDC 659638, the data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
16. For other examples of 1H NMR and 13C NMR data of cis- and trans-fused 6/6-
ring systems, see: Frey, B.; Schnaubelt, J.; Reissig, H.-U. Eur. J. Org. Chem. 1999,
1377–1384.
17. (a) Review: Flowers, R. A., II Synlett 2008, 1427–1439; (b) Chopade, P. R.;
Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2004, 126, 44–45.
18. Daniewski, A. R.; Kowalczyk-Przewloka, T. Tetrahedron Lett. 1982, 23, 2411–
2414.
Ar), 139.8 (s, C-11), 212.3 (s, C-7) ppm. IR (neat):
m = 3065–2855
19. Reviews dealing with synthetic applications of dearomatising processes: for
reductive dearomatisations see: (a) Mander, L. N. Synlett 1991, 134–144; (b)
Donohoe, T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asymmetry 1996, 7, 317–
344; (c) Schultz, A. Chem. Commun. 1999, 1263–1271; For nucleophilic
dearomatisations see: (d) Clayden, J.; Kenworthy, M. N. Synthesis 2004,
1721–1736; (e) López-Ortiz, F.; Iglesias, M. J.; Fernández, I.; Sánchez, C. M.
A.; Gómez, G. R. Chem. Rev. 2007, 107, 1580–1691; (f) Barbe, G.; Pelletier, G.;
Charette, A. B. Org. Lett. 2009, 11, 3398–3401; For transition metal mediated
dearomatisations see: (g) Bach, T. Angew. Chem. 1996, 108, 795–796. Angew.
Chem., Int. Ed. 1996, 35, 729–730; (h) Pape, A. R.; Kaliappan, K. P.; Kündig, E. P.
Chem. Rev. 2000, 100, 2917–2940; For oxidative dearomatisations see: (i)
Quideau, S.; Pouységu, L.; Deffieux, D. Synlett 2008, 467–495. and references
cited therein.
(@CH, C–H), 1695 (C@O), 1595 (C@C), 1510 (C@C) cmꢂ1. MS (EI,
80 eV, 40 °C): m/z (%) = 250 (100) [M+], 194 (24), 193 (27), 28
(26). HRMS (EI): Calcd for C18H18O: 250.13577. Found: 250.13670.
Acknowledgements
Generous support of this work by the Deutsche Forschungs-
gemeinschaft, the Fonds der Chemischen Industrie and the Bayer
Schering Pharma AG is most gratefully acknowledged. We also
thank Dr. R. Zimmer for his help during preparation of this manu-
20. Haffer, G.; Eder, U.; Sauer, G.; Wiechert, R. Chem. Ber. 1975, 108, 2665–2672.