A new, efficient and stereoselective synthesis of tricyclic and tetracyclic compounds by samarium diiodide induced cyclisations of naphthyl-substituted arylketones-an easy access to steroid-like skeletons

Article abstract of DOI:10.1002/chem.200700057

In this report, we present the application of samarium diiodide induced cyclisations of naphthyl-substituted ketones towards an easy and stereoselective access to tri- and tetracyclic-functionalised compounds. Typical naphthalene derivatives were studied to investigate the scope and limitations of this novel cyclisation process. The model substrates studied demonstrate that the samarium ketyl cyclisations are essentially restricted to the formation of six-membered rings. The diastereoselectivity of these reactions is strongly influenced by the connection of the alkyl side chain to the naphthalene core. γ-Naphth-1-yl-substituted ketones furnished cyclisation products, such as 17 or 22-26, as single diastereomers, whereas γ-naphth-2-yl-substituted precursors gave mixtures of diastereomers - as demonstrated by the conversion of model compound 10 into tricyclic products 18 a/18 b, or that of cyclohexanone derivative 33 into tetracyclic diastereomers 34 a/34 b. Cyclic ketones as ketyl precursors furnished steroid-like tetracyclic skeletons; however, due to the cis/cis fusion of rings B/C and C/D these products have an "unnatural" bowl-like shape. Several of the cyclisation products have been identified by X-ray analyses, which not only proved the constitutions, but also the relative configurations and the preferred conformations. Steroid analogue 23 was subjected to subsequent transformations, which demonstrate that the styrene-like double bond of such compounds can be used for further structural diversification. First attempts to synthesise related azasteroids by incorporating nitrogen atoms into the ketone moiety are also reported. Thus, pyrrolidine derivatives 44 and 47 as well as piperidine derivatives 50 and 52 were subjected to samarium diiodide induced cyclisations. The expected tetracyclic products 48, 49 a/49 b, 51 and 53 a/53 b were obtained in moderate to good yields. The stereoselectivities observed follow the rules already established for the all-carbon precursors. The resulting products, bearing a nitrogen atom in ring D, are interesting azasteroid analogues with "unnatural" configuration.

Full text of DOI:10.1002/chem.200700057

FULL PAPER
DOI: 10.1002/chem.200700057
A New, Efficient and Stereoselective Synthesis of Tricyclic and Tetracyclic
Compounds by Samarium Diiodide Induced Cyclisations of Naphthyl-
Substituted Arylketones—An Easy Access to Steroid-Like Skeletons
Francesca Aulenta, Mathias Berndt, Irene Brüdgam, Hans Hartl, Sebastian Sçrgel, and
Hans-Ulrich Reißig*[a]
Dedicated to Professor Herbert Mayr on the occasion of his 60th birthday
Abstract: In this report, we present the
application of samarium diiodide in-
duced cyclisations of naphthyl-substi-
tuted ketones towards an easy and ste-
reoselective access to tri- and tetracy-
clic-functionalised compounds. Typical
naphthalene derivatives were studied
to investigate the scope and limitations
of this novel cyclisation process. The
model substrates studied demonstrate
that the samarium ketyl cyclisations
are essentially restricted to the forma-
tion of six-membered rings. The diaste-
reoselectivity of these reactions is
strongly influenced by the connection
of the alkyl side chain to the naphtha-
lene core. g-Naphth-1-yl-substituted ke-
tones furnished cyclisation products,
such as 17 or 22–26, as single diastereo-
mers, whereas g-naphth-2-yl-substituted
precursors gave mixtures of diastereo-
mers—as demonstrated by the conver-
sion of model compound 10 into tricy-
clic products 18a/18b, or that of cyclo-
hexanone derivative 33 into tetracyclic
diastereomers 34a/34b. Cyclic ketones
as ketyl precursors furnished steroid-
like tetracyclic skeletons; however, due
to the cis/cis fusion of rings B/C and C/
D these products have an “unnatural”
bowl-like shape. Several of the cyclisa-
tion products have been identified by
X-ray analyses, which not only proved
the constitutions, but also the relative
configurations and the preferred con-
formations. Steroid analogue 23 was
subjected to subsequent transforma-
tions, which demonstrate that the sty-
rene-like double bond of such com-
pounds can be used for further struc-
tural diversification. First attempts to
synthesise related azasteroids by incor-
porating nitrogen atoms into the
ketone moiety are also reported. Thus,
pyrrolidine derivatives 44 and 47 as
well as piperidine derivatives 50 and 52
were subjected to samarium diiodide
induced cyclisations. The expected tet-
racyclic products 48, 49a/49b, 51 and
53a/53b were obtained in moderate to
good yields. The stereoselectivities ob-
served follow the rules already estab-
lished for the all-carbon precursors.
The resulting products, bearing a nitro-
gen atom in ring D, are interesting
azasteroid analogues with “unnatural”
configuration.
Keywords:
electron transfer
·
ketyls · radical reactions · samarium
diiodide · steroids
Introduction
of carbon-centred radicals onto unsaturated functional
groups have been considered as one of the most useful syn-
ꢀ
It is well established that radical chemistry offers a wide
array of useful transformations for the construction of com-
plex molecular architectures.[1] Among all, the cyclisations
thetic tools for C C bond formation and have been used as
key steps in many natural product syntheses.[2] In the last 25
years, samarium diiodide has played a central role in radical
chemistry as a unique electron-transfer reagent,[3] and this
prominent position is witnessed by the ever-growing number
of original publications and reviews.[4] This reagent is partic-
ularly effective to induce reductive couplings of carbonyl
groups with carbon–carbon multiple bonds in high yield and
good stereoselectivity. Along this line, Molander and co-
workers[5] and other authors[6] have widely investigated the
intramolecular ketyl–olefin coupling, which leads to interest-
ingly functionalised cyclic compounds. In our group, samari-
[a] Dr. F. Aulenta, Dr. M. Berndt, I. Brüdgam,+ Prof. Dr. H. Hartl,+
Dr. S. Sçrgel, Prof. Dr. H.-U. Reißig
Institut für Chemie und Biochemie
Freie Universität Berlin, Takustrasse 3
14195 Berlin (Germany)
Fax : (+49)30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
[+] Responsible for X-ray crystal structure analysis.
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um diiodide was employed for new intramolecular couplings
of ketyls with alkenyl, alkynyl, aryl and hetaryl substituents,
yielding synthetically useful products, such as benzannulated
cyclooctane and cyclooctene derivatives,[7] hexahydronaph-
thalenes[8] and indoles.[9] These reactions are promoted by
the samarium diiodide–hexamethylphosphoramide (HMPA)
complex,[10] whereupon an electron is transferred from this
complex to the carbonyl group, thus generating a radical
anion (samarium ketyl). Intramolecular attack of this sama-
rium ketyl to the unsaturated functionality, followed by a
second electron transfer, generates an organosamarium spe-
cies, which, upon regioselective protonation, leads to the
final cyclised products. The use of an excess of HMPA as an
additive is in most of these cases a requirement to favour
the forward reaction and to control the outcome in terms of
product distribution and stereoselectivity.[11]
clic products which resemble steroids with unnatural cis/cis
fusion of rings B/C/D. We also reported that precursors E
underwent similar reductive cyclisations to products F, albeit
with low diastereoselectivity. In this full account, we de-
scribe in detail our efforts aimed at synthesising these poly-
cyclic compounds by means of the samarium diiodide pro-
moted reductive cyclisations. We also present the first appli-
cations of this methodology to the couplings of naphthyl-
substituted pyrrolidinone and piperidinone derivatives, ulti-
mately leading to highly functionalised nitrogen-containing
tetracyclic products, which may be regarded as azasteroids.
Results and Discussion
Tricyclic compounds: To investigate the applicability and
substrate-dependence of the samarium diiodide induced cyc-
lisations, we prepared a series of simple acyclic naphthyl-
substituted ketones (Scheme 2) differing in the chain length
(from b- to d-substituted ketones) and in the position of the
naphthyl ring, at which the aliphatic chain was connected
(C-1 or C-2). Ketones 3[17] and 5 were obtained by alkylation
of methyl 3-oxobutanoate (1) with bromomethylnaphtha-
lenes 2 or 4, followed by saponification and decarboxyla-
tion.[18] Syntheses of ketones 8 and 10[13b] were performed by
means of Heckreactions of the corresponding bromonaph-
The samarium diiodide intramolecular couplings of g-aryl
ketones A established a novel stereoselective route to hexa-
hydronaphthalene derivatives B.[8,12] With this method,[13] we
delivered a new solution to the challenging goal of dearoma-
tising benzene derivatives,[14] providing synthetically valua-
ble functionalised intermediates of type B (Scheme 1).
Scheme 1. Samarium diiodide promoted cyclisations of g-aryl ketones A
and g-naphthyl ketones C or E leading to the cyclisation products B, D
or F.
These results prompted us to investigate suitable naphthyl
ketones C and E, which should lead to tricyclic compounds
D or F. In general, naphthalene derivatives should be even
more favourable substrates compared to benzene deriva-
tives, due to the lower reduction potential of the fused 10p-
electron systems[15] and the “decreased loss of aromaticity”
during the cyclisation process. Furthermore, we expected
that these transformations would also occur with high dia-
stereoselectivity.
In a preliminary communication,[16] we demonstrated that
application of this methodology indeed allows stereoselec-
tive syntheses of compounds D and also of related tetracy-
Scheme 2. Synthesis of the naphthyl-substituted ketones 3, 5, 8, 10 and
12.
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Samarium Diiodide Induced Cyclisations
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thalenes 7 or 9 with 4-penten-2-ol (6) and subsequent iso-
merisation according to a literature procedure.[19] A Heck
coupling followed by hydrogenation was employed for the
preparation of compound 12.
thyl-substituted ketone 12 was subjected to the reductive
coupling which provided only alcohol 16[24] in 62% yield.
Very pleasingly, ketones 8 and 10 afforded the cyclised
products 17, 18a and 18b in excellent yields. These observa-
tions lead to the conclusion that the cyclisations are essen-
tially confined to the formation of six-membered rings
(Scheme 3). Similar results have been obtained for the relat-
ed benzene derivatives.[4b] It is interesting to note that 1-sub-
stituted naphthalene derivative 8 afforded only one diaste-
reomer with cis-annulated rings B and C as depicted. This
It was anticipated that cyclisations of b-, g-, and d-naph-
thyl-substituted ketones 3, 5, 8, 10, and 12 would occur by
means of 5-exo-trig, 6-exo-trig, and 7-exo-trig processes,[20]
leading to tricyclic compounds containing new five-, six-, or
seven-membered rings. However, rather surprisingly, the
cyclisation of ketone 3 under standard conditions (2.2 equiv
SmI2, 18 equiv HMPA, 2.2 equiv of tBuOH, RT) proceeded
via a 6-exo-trig pathway, affording tricyclic compound 13[13b]
in good yield and as a single diastereomer (Scheme 3).[21]
The final protonation of the organosamarium species oc-
curred regioselectively, affording product 13 with a deconju-
gated double bond and an intact aromatic ring.[22] In the
case of 5, in which a 6-exo-trig cyclisation is not feasible, the
main reaction pathway was the reduction of the carbonyl
group to deliver the corresponding alcohol 15[23] in 52%
yield; only traces of the cyclisation product 14 were identi-
fied. An analogous result was observed when the d-naph-
1
relative configuration was assigned by H NMR spectrosco-
py in which a coupling constant of J=5.4 Hz between the
two bridgehead protons clearly indicates their cis relation-
ship. The configuration at the hydroxyl group bearing
carbon was assigned in analogy to the related products 22–
26 (see below).
While tricyclic compound 17 was formed as a single dia-
stereomer, product 18 was isolated as a 60:40 mixture of
two diastereomers in very good yield. The relative configu-
1
rations of the two products were assigned by H NMR spec-
troscopy; in this case, the chemical shift of the bridgehead
proton is indicative for the cis
or trans relationship to the hy-
droxyl group. In the cis-config-
ured 18a, the signal of this
proton appeared at 3.24–
3.44 ppm, whereas for the other
isomer, the chemical shift was
2.47 ppm. A plausible explana-
tion for the loss of diastereose-
lectivity might be found in the
competing steric interaction be-
tween the naphthalene ring and
the bulky OSmI2 substituent
(Scheme 4). For this reason the
six-membered transition struc-
tures with an equatorially and
axially arranged OSmI2 group
have similar stability and thus
two diastereomers are formed.
When these factors are absent,
the samarium alcoholate for
steric reasons generally seems
to prefer an equatorial position,
a model which also operates in
the case of the highly stereose-
lective conversion of
8 into
17.[25]
It should also be noted that
the transformation of 10 into
18a/b is a highly regioselective
process. No products derived
from attackof the samarium
ketyl to C-1 of the naphthalene
ring were isolated. The consti-
tution of compounds 18a/b is
clearly shown by their NMR
Scheme 3. SmI2-induced cyclisation of ketones 3, 5, 12, 8 and 10.
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H.-U. Reißig et al.
Scheme 6. SmI2-induced cyclisations of the cyclic g-naphthyl-substituted
ketones 21a–e, leading to tetracyclic products 22–26.
Scheme 4. Proposed chair-like transition structures for the cyclisations of
substrates 8 and 10, leading to 17 and 18a/b (for clarity of the illustration,
we have depicted the enantiomers of the products drawn in Scheme 3;
HMPA ligands at samarium are omitted for simplicity).
eight-membered rings, the yields are only moderate. Howev-
er, these two experiments have only been performed in
small scale and are not yet optimised. In all cases, the rela-
tive configurations of products were assigned by two-dimen-
sional NMR spectroscopy (COSY, HMQC, NOESY), dem-
onstrating the expected cis/cis fusion of rings B/C and C/D.
This arrangement forces the molecules to adopt a bowl-like
shape and therefore to display steroid-like skeletons with
“unnatural” configuration and geometry.
We also examined the cyclisation of selected g-naphthyl-
substituted ketones already containing a functional group
that could provide a handle for subsequent modifications.
The first example is represented by the introduction of a
methoxy group in the 6-position of the naphthalene ring
(Scheme 7). An oxygen functionality in this position is pres-
ent in most naturally occurring steroids and it apparently
plays a crucial role for the interaction of these molecules
spectroscopic data and was strongly supported by the X-ray
crystal structure analysis of the closely related product 34a
(see below). The regioselectivity observed is in contradiction
to the result reported by Shono et al.[13] for the related elec-
trochemical reductive cyclisation of compound 10. We
assume that the higher steric hindrance involved with a sa-
marium ketyl causes this altered regioselectivity.
Tetracyclic compounds: The two acyclic g-naphthyl-substi-
tuted ketones 8 and 10 afforded tricycles in very good yields
with newly formed six-membered rings. We therefore ex-
pected that using cyclic g-naphthyl ketones of type 21 as
precursors of samarium diiodide induced cyclisations would
lead to tetracyclic products with steroid-like skeletons. The
synthesis of the precursor ketones 21a–e was achieved by a-
alkylation of Schiff-bases 19a–e (derived from the corre-
sponding ketones) with naphthyl-substituted alkyl iodide
20,[26] followed by hydrolysis of the resulting imine under
acidic conditions (Scheme 5).
Scheme 5. Synthesis of the precursor ketones 21a–e.
Most gratifyingly, tetracyclic products 22–26 were ob-
tained in good to excellent yield as single diastereomers
when ketones 21a–e underwent standard reductive coupling
conditions with samarium diiodide (Scheme 6). In the case
of compounds 22 and 26, incorporating four-membered and
Scheme 7. SmI2-induced cyclisations of ketones 27 and 29.
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Samarium Diiodide Induced Cyclisations
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with the respective receptors.[27] However, rather unfortu-
nately, the presence of an electron-releasing group at the
naphthyl ring has a negative influence on the cyclisation ef-
ficacy and compound 27[28] gave the expected tetracyclic
product 28 in approximately 28% yield only. The reaction
led in large extent to decomposition of the starting material
and/or of the product, which made the purification of the cy-
clised product very tedious. Hence, only characterisation by
1H NMR spectroscopy was possible. Oxygen substituents
with lower electron-donating properties at the naphthyl
group, such as acetoxy, may improve the cyclisation efficacy.
Introduction of a ketal group as a “masked” ketone, as in
precursor 29,[29] also resulted in impoverished yields of the
expected tetracyclic product 30, which was obtained in 19%
yield (Scheme 7). Surprisingly, the regioselectivity was also
reduced and a second product 31 was isolated in 7% yield.
In this case, the cyclisation occurred onto the 8-position of
the naphthalene ring, leading to the formation of a tetracy-
clic compound containing a seven-membered ring and a de-
conjugated double bond. Similar unexpected observations
have been made with other cyclohexanone derivatives bear-
ing additional substituents, in which compounds analogous
to 31 were formed in up to 30% yield.[16] The constitution
and relative configuration of 31 were assigned by X-ray
crystal structure analysis (Figure 1). Cleavage of the ketal
Scheme 8. SmI2-induced cyclisation of ketone 33.
Figure 2. Structure of compound 34a.
Figure 1. Structure of compound 31.
ative configuration of the bridgehead hydrogen sharing rings
B and C.
group in tetracycle 30 furnished the expected ketone 32 in
an excellent 95% yield. This product is crystalline and
hence again allowed relative configuration to be proved by
X-ray analysis.
Like the result reported above for the cyclisation of 10,
the cyclisation of the 2-substituted naphthalene derivative
33[29] also led to the formation of two diastereomers 34a and
34b (6:1) in a satisfactory overall yield (Scheme 8). Whereas
the minor isomer 34b is an oil, tetracycle 34a formed suita-
ble crystals and hence its relative configuration was un-
equivocally determined by X-ray crystal structure analysis
(Figure 2). Both diastereomers 34a and 34b show the ex-
pected cis annulation of rings C/D, but they differ in the rel-
Cleavage of the ketal groups of 34a and 34b afforded ke-
tones 35a in 77% yield and 35b in moderate 53% yield.
The hydroxyl group in 35b is arranged trans to one of the
bridgehead hydrogen atoms and therefore may have suf-
fered water elimination under the acidic conditions em-
ployed, eventually leading to undesired decomposed materi-
al. Compound 35a is crystalline and its structure was also
unambiguously proved by X-ray analysis (Figure 3).
Subsequent transformations: The styrene-type double bond
in tetracyclic products 22–26, 28, 30 and 32 provide an at-
tractive handle for synthetic manipulations. Examples of
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H.-U. Reißig et al.
tively pentacyclic compound 39. The introduction of the
oxygen atom occurred entirely stereoselectively from the
less-hindered convex face of the molecule and cis to the
bridgehead hydroxyl group. X-ray crystal structure analysis
of 39 provided evidence of its relative configuration and
hence also that of the precursor 23.[32] Substitution of the
tertiary hydroxyl group of 23 by hydride was attempted by
treatment with triethylsilane and trifluoroboron-etherate.[33]
However, under these conditions, elimination of water was
observed instead, and by double-bond migration, naphtha-
lene derivative 40 was isolated in very good yield. Whereas
transformations, such as 23!21b and 23!40, deserve fur-
ther investigations to clarify their generality, the epoxidation
proceeded smoothly on several substrates of type 23[34] and
provides an excellent possibility for interesting structural di-
versifications of the steroid analogues.
Figure 3. Structure of compound 35a.
possible transformations of compounds employing steroid
analogue 23 as a substrate are represented in Scheme 9. Re-
duction of the conjugated double bond of 23 by hydrogen in
Nitrogen-containing tetracycles—synthesis of azasteroid de-
rivatives: Considering the growing importance of unnatural
azasteroid derivatives in pharmaceutical chemistry,[35] we
have also focused our efforts towards the synthesis of nitro-
gen-containing tetracycles by using samarium diiodide in-
duced cyclisations of naphthyl-substituted pyrrolidinone and
piperidinone derivatives 44, 47, 50 and 52.[36] Syntheses of
precursors 44 and 47 were carried out by a three-step proce-
[37]
dure involving an initial Heckreaction
between the naph-
thyl nonaflates 41 or 45 and homoallylic alcohol 42.[38] The
coupling products 43 and 46 were obtained in good yield
and without formation of conceivable double-bond isomers.
Hydrogenation of the double bonds and oxidation of the al-
cohols by the pyridine·SO3 complex in DMSO furnished the
required ketones 44 and 47 (Scheme 10).[39] The NMR spec-
tra of these compounds recorded at room temperature
showed the presence of two distinct amide rotamers—a phe-
nomenon well documented for amides and carbamate
groups and attributable to the presence of the Boc group.[40]
Gratifyingly, samarium diiodide induced couplings of ke-
tones 44, 47, 50 and 52 afforded the desired tetracyclic com-
pounds 48, 49a/b, 51 and 53a/b in moderate to good yields.
In accordance with the above-mentioned results, 1-substitut-
ed naphthalene derivatives 44 and 50 led to the formation
of 48 and 51 as single diastereomers with the expected cis-
junctions of rings B/C/D, whilst the 2-substituted naphtha-
lene derivatives 47 and 52 afforded mixtures of diastereo-
mers 49a/b (dr: 1.2:1) and 53a/b (dr: 2:1). It is also interest-
ing to note that the reactions of substrates 44 and 47 were
less efficient—when compared to 50 and 52—leading to the
cyclised compounds 48 and 49 only in moderate yields
(Scheme 11).[41] Compounds 51 and 53a/b were rather unsta-
ble due to the presence of a tertiary amine moiety which
causes rapid oxidation by the air. Purification of the minor
isomer 53b was not completely successful, and the identifi-
cation of this product was carried out in the mixture of the
two isomers by 1H NMR spectroscopy.
Scheme 9. Examples of chemical transformations of tetracyclic compound
23.
the presence of Pd/C proceeded uneventfully and afforded
compound 36 in almost quantitative yield. Oxidation of 23
with MnO2 in THF furnished naphthalene derivative 37 in
73% yield.[30] Very surprisingly, oxidation with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) did not provide the
expected product 37, but instead afforded cyclisation precur-
sor 21b in 71% yield. The detailed mechanism of this un-
usual fragmentation is not clear; however, a related oxida-
tive transformation was reported by Singh et al.[31] Smooth
epoxidation of 23 was achieved under standard conditions
with m-chloroperbenzoic acid (mCPBA) affording quantita-
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Samarium Diiodide Induced Cyclisations
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products. The biological activity
of the steroid analogues is cur-
rently being investigated and
will be reported in due
course.[43]
Experimental Section
General information: Reactions were
performed under argon in flame-dried
flasks, and solvents and reagents were
added by syringes. 1,2-Diiodoethane
was purified by sublimation under
vacuum (0.2 mbar, 508C). THF and di-
ethyl ether were freshly distilled from
sodium/benzophenone under argon.
Hexamethylphosphoramide and tert-
butanol were distilled from calcium
hydride (HMPA: 1308C, 12 mbar;
tBuOH: 558C, 1013 mbar) and stored
over molecular sieves (4 Š) under
argon. Argon was purged through the
solution to eliminate residual oxygen
prior to use. Warning: HMPA has
been identified as a carcinogenic re-
agent. Use of gloves is required during
handling. Reactions and chromatogra-
phy should be performed in well-venti-
lated hoods. Triethylamine and diiso-
propylamine were distilled from potas-
sium hydroxide and stored over KOH
under argon. Dichloromethane was
distilled over calcium hydride and
stored over molecular sieves (4 Š)
under argon. Ethanol was distilled
from magnesium oxide and stored
over molecular sieves (4 Š) under
argon. Dry DMF and dry dimethylsulf-
oxide were purchased from Aldrich
and used as obtained under an atmos-
phere of argon.
Scheme 10. Synthesis of the pyrrolidinone derivatives 44 and 47.
Methyl acetylacetate (1), 1-(bromome-
thyl)naphthalene (2), 2-(bromome-
thyl)naphthalene (4), 1-bromonaph-
Conclusion
thalene (7), 2-bromonaphthalene (9), 4-penten-2-ol (6) and 5-hexen-2-
one (11) were purchased from Fluka, Aldrich, Acros, or Merck and used
as received. N-Cyclohexyl-N-cycloalkylidenamines (19a–e)[44] and 1-(2-io-
doeth-1-yl)naphthalene (20)[45] were synthesised according to literature
procedures.
We have demonstrated that g-naphthyl-substituted ketones
are very good substrates for samarium diiodide promoted
reductive couplings. These reactions afforded tri- and tetra-
cyclic compounds in moderate to excellent yields and often
with high diastereoselectivity. Several of these tetracycles
present steroid-like skeletons but with “unnatural” configu-
ration. Our new approach nicely complements alternative
strategies for the de novo synthesis of steroidal com-
pounds.[42] The presence of a styrene-type double bond
allows many chemical transformations and the introduction
of additional functional groups, thus leading to structurally
highly diversified compounds. Using this methodology, it
was also possible to synthesise nitrogen-containing tetracy-
cles, some of which also display steroid-type skeletons. The
methods described here not only contribute to the evalua-
tion of scope and limitations of the samarium–ketyl-arene
cyclisations, but they also lead to synthetically interesting
Products were purified by flash chromatography on silica gel (230–400
mesh, Merck) or neutral alumina (activity III, Fluka). Preparative HPLC
was carried out on a nucleosil 50–5 column (diameter 16 mm, length
244 mm) and a Knauer variable UV detector (l=255 nm) and a Knauer
refractometer were used. Unless otherwise stated, yields refer to analyti-
cally pure samples.
1H and 13C NMR spectra were recorded on Bruker AC 250 (250 MHz),
Bruker AC 270 (270 MHz), AC 500 (500 MHz) and Joel Eclipse 500
(500 MHz) spectrometers. Integrals are in accordance with assignments;
coupling constants are given in Hz. IR spectra were measured with an
FTIRD spectrometer Nicolet5 SXC. MS and HRMS analyses were per-
formed on Finnigan MAT 711 (EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV,
3 kV) instruments. Elemental analyses were recorded with an “Elemen-
tal-Analyzer” (Perkin–Elmer). Melting points were measured with a
Reichert apparatus and are uncorrected. Single-crystal X-ray data were
collected on a Bruker SMART CCD diffractometer (MoKa radiation, l=
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H.-U. Reißig et al.
rification by column chromatography
on silica gel (hexane/ethyl acetate 9:1)
provided 5 as a pale-yellow oil (1.52 g,
76%). 1H NMR (CDCl3, 270 MHz):
d=7.84–7.74 (m, 3H; Ar), 7.61 (brs,
1H; Ar), 7.50–7.41 (m, 2H; Ar), 7.31
(d, J=8.8 Hz, 1H; Ar), 3.04 (t, J=
7.6 Hz, 2H; CH2), 2.78 (t, J=7.6 Hz,
2H; CH2), 2.11 ppm (s, 3H; CH3);
13C NMR (CDCl3, 67.9 MHz): d=
207.8 (s; CO), 138.5, 133.5, 132.0 (3s;
Ar), 128.0, 127.6, 127.4, 127.0, 126.3,
126.0, 125.3 (7d; Ar), 44.8 (t; CH2),
30.0 (q; CH3), 29.9 ppm (t; CH2); IR
ꢀ
ꢀ
(film): n˜ =3050–2900 (=C H, C H),
1700 (C=O), 1605 cmꢀ1 (C=C); ele-
mental analysis calcd (%) for C14H14O
(198.3):
84.52, H 6.70.
5-(1-Naphthyl)-2-pentanone (8): 1-
Bromonaphthalene (7) (2.07 g,
C 84.81, H 7.12; found: C
10.0 mmol), 4-penten-2-ol (6) (1.29 g,
15.0 mmol), palladium(II) acetate
(1.00 g, 4.50 mmol), tetra-n-butylam-
monium chloride (5.56 g, 20.0 mmol),
LiCl (0.424 g, 10.0 mmol) and lithium
acetate-dihydrate (2.60 g, 25.0 mmol)
were suspended in DMF (20 mL) and
the mixture was stirred for 72 h at
1008C. After cooling, the reaction was
quenched with brine (50 mL) and the
Scheme 11. Synthesis of the nitrogen-containing tetracyclic products 48, 49, 51 and 53.
product was extracted with Et2O (3”
50 mL). The combined organic layers
were dried with Na2SO4, filtered, and
0.71073 Š, graphite monochromator), empirical absorption correction by
using symmetry-equivalent reflections (SADABS),[46] structure solution
and refinement by SHELXS-97[47] and SHELXL-97[48] in the WINGX
System.[49] The hydrogen atoms were located by difference Fourier syn-
theses. CCDC-606010, -606011 and -606013 contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
the solvent was removed under reduced pressure to afford the crude
product, which was purified by column chromatography on silica gel
(hexane/ethyl acetate 4:1) to yield 8 as a colourless oil (1.75 g, 83%).
1H NMR (CDCl3, 270 MHz): d=8.06 (d, J=8.1 Hz, 1H; Ar), 7.84 (d, J=
7.4 Hz, 1H; Ar), 7.71 (d, J=8.1 Hz, 1H; Ar), 7.55–7.42 (m, 2H; Ar),
7.38 (t, J=8.1 Hz, 1H; Ar), 7.29 (d, J=7.4 Hz, 1H; Ar), 3.07 (t, J=
7.4 Hz, 2H; CH2), 2.51 (t, J=7.4 Hz, 2H; CH2), 2.12 (s, 3H; CH3),
2.03 ppm (quint., Jꢁ7.4 Hz, 2H; CH2); 13C NMR (CDCl3, 67.9 MHz):
d=207.0 (s; CO), 137.7, 137.6, 133.9 (3s; Ar), 128.7, 126.7, 126.1, 125.8,
Syntheses of cyclisation precursors
125.5, 125.4, 123.8 (7d; Ar), 43.1, 32.2 (2t; CH2), 30.0 (q; CH3), 24.5 ppm
Typical procedure for the synthesis of ketones 3 and 5: Methyl acetylace-
tate (1, 10.0 mmol) was added to a solution of lithium diisopropylamide
(20.0 mmol) in THF (50 mL) at 08C. The solution was stirred at 08C for
20 min then a solution of 1-(bromomethyl)naphthalene (2) or 2-(bromo-
methyl)naphthalene (4) (10.0 mmol) in THF (20 mL) was added drop-
wise. The mixture was stirred for an additional 20 min at 08C, then
quenched by addition of 10% aq HCl (35 mL) and the product was ex-
tracted with Et2O. The organic phase was washed with water until a neu-
tral pH was reached and then dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The crude product and sodium hy-
droxide (15.0 mmol) were suspended in distilled water (12 mL) and
stirred at RT for 10 h, then at reflux for 4 h. The mixture was then cooled
down and the product extracted in Et2O. The combined organic layers
were dried with MgSO4, filtered, and the solvent was removed under re-
duced pressure. The crude product was purified by column chromatogra-
phy on silica gel.
ꢀ1
ꢀ
ꢀ
(t; CH2); IR (film): n˜ =3100–2850 (=C H, C H), 1715 (C=O), 1595 cm
(C=C); elemental analysis calcd (%) for C15H16O (212.3): C 84.87, H
7.60; found: C 84.76, H 7.36.
6-(1-Naphthyl)-2-hexanone (12): 1-Bromonaphthalene (7) (4.14 g,
20.0 mmol), 5-hexen-2-one (11) (2.95 g, 30.0 mmol), LiCl (1.27 g,
29.9 mmol), K2CO3 (10.4 g, 75.0 mmol) and palladium(II) acetate
(0.673 g, 3.00 mmol) were suspended in DMF (20 mL) and stirred at
1008C for 4 h. After cooling, the reaction was quenched with brine
(50 mL) and the product was extracted with Et2O (3”50 mL). The com-
bined organic layers were dried with Na2SO4, filtered and the solvent was
removed under reduced pressure to leave the crude product, which was
filtered over silica gel (hexane/ethyl acetate 4:1). The crude product was
dissolved in MeOH (50 mL) and added to a suspension of Pd/C (10%,
1.00 g) in MeOH (100 mL) under an atmosphere of H2. The mixture was
stirred at RT for 24 h, then filtered over a pad of Celite and the solvent
was removed under reduced pressure. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate 9:1 to 4:1) to
afford 12 as a colourless oil (3.14 g, 69%). 1H NMR (CDCl3, 270 MHz):
d=7.97 (brd, J=7.8 Hz, 1H; Ar), 7.81 (brd, J=7.8 Hz, 1H; Ar), 7.67 (d,
J=8.3 Hz, 1H; Ar), 7.50–7.25 (m, 4H; Ar), 3.04 (t, J=7.2 Hz, 2H; CH2),
2.43 (t, J=7.2 Hz, 2H; CH2), 2.08 (s, 3H; CH3), 1.74–1.64 ppm (m, 4H;
CH2); 13C NMR (CDCl3, 67.9 MHz): d=208.8 (s; CO), 138.2, 133.8, 131.7
(3s; Ar), 128.7, 126.5, 125.8, 125.6, 125.4, 125.3, 123.7 (7d; Ar), 43.4, 32.8,
30.1 (3t; CH2), 29.8 (q; CH3), 23.8 ppm (t; CH2); IR (film): n˜ =3050–
4-(1-Naphthyl)-2-butanone (3): Compound 1 (1.16 g, 10.0 mmol) and 2
(2.21 g, 10.0 mmol) afforded 2.78 g of crude alkylation product which was
treated with sodium hydroxide (0.60 g, 15.0 mmol). Purification by
column chromatography on silica gel (hexane/ethyl acetate 9:1) furnished
3 as a pale-yellow oil (1.69 g, 85%). The analytical data is in agreement
with those reported in the literature.[50]
4-(2-Naphthyl)-2-butanone (5): Compound 1 (1.16 g, 10.0 mmol) and 4
(2.21 g, 10.0 mmol) afforded 2.94 g of crude alkylation product, which
was subsequently treated with sodium hydroxide (0.60 g, 15.0 mmol). Pu-
6054
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6047 – 6062

Samarium Diiodide Induced Cyclisations
FULL PAPER
ꢀ1
1
ꢀ
ꢀ
2800 (=C H, C H), 1720 (C=O), 1600 cm (C=C); elemental analysis
90%). H NMR (CDCl3, 270 MHz): d=8.02 (d, J=8.3 Hz, 1H; Ar), 7.81
(d, J=8.3 Hz, 1H; Ar), 7.68 (d, J=7.5 Hz, 1H; Ar), 7.55–7.23 (m, 4H;
Ar), 3.09–2.81 (m, 2H; CH2), 2.77–0.81 ppm (m, 15H; CH, CH2);
13C NMR (CDCl3, 67.9 MHz): d=219.8 (s; CO), 138.0, 133.8, 131.7 (3s;
Ar), 128.6, 126.6, 125.9, 125.8, 125.5, 125.4, 123.7 (7d; Ar), 50.3 (d; CH),
calcd (%) for C16H18O (226.3): C 84.91, H 8.02; found: C 84.55, H 7.81.
Typical procedure for the synthesis of ketones 21: n-Butyllithium
(1.8 equiv) was added to a solution of diisopropylamine (1.6 equiv) in
THF (2 mLmmolꢀ1) at 08C. The solution was stirred for 20 min at 08C
and then a solution of the imine 19 (1.5 equiv) in THF (0.5 mLmmolꢀ1
)
42.3, 33.7, 33.1, 31.0, 27.4, 25.5, 25.3, 24.7 ppm (8t; CH2); IR (film): n˜ =
ꢀ1
ꢀ
ꢀ
3050–2800 (=C H, C H), 1710 (C=O), 1605 cm (C=C); elemental anal-
ysis calcd (%) for C20H24O (280.4): C 85.67, H 8.63; found: C 84.81, H
8.66.
was added and the mixture was stirred for a further 30 min at this tem-
perature. A solution of 1-(2-iodoeth-1-yl)naphthalene (20) (1 equiv) in
THF (0.5 mLmmolꢀ1) was finally added and the mixture was stirred for
30 min at 08C. After this time, a HCl (2n) solution was added and the
product was extracted with ethyl acetate. The combined organic phases
were washed with brine, dried with Na2SO4 and filtered. The solvent was
evaporated under reduced pressure and the residue purified by column
chromatography on silica gel.
General procedure for the synthesis of ketones 29, 33, 50 and 52:[52] n-Bu-
tyllithium (1.0–1.5 equiv) was added to a solution of diisopropylamine
(2.0–3.2 equiv) in THF (3 mLmmolꢀ1) at ꢀ788C and the solution was
stirred for 30 min. A solution of the corresponding SAMP hydrazone
(1.0–1.3 equiv) in THF (1.6 mLmmolꢀ1) was then slowly added at ꢀ788C
and the mixture was stirred for 4 h and allowed to warm to 08C. The re-
action vessel was again cooled to ꢀ788C and a solution of 1-(2-bromoe-
thyl)naphthalene or 2-(2-bromoethyl)naphthalene[53] (1.0 equiv) in THF
(1.6 mLmmolꢀ1) was added. The solution was stirred overnight whilst al-
lowing the temperature to rise to RT. The mixture was then quenched by
careful addition of a saturated aqueous solution of ammonium chloride
and the product was repeatedly extracted with Et2O. The combined or-
ganic layers were dried with MgSO4, filtered, and the solvent was re-
moved under reduced pressure. The crude product was dissolved in Et2O
and stirred vigorously with a saturated aqueous solution of oxalic acid
(3 mL) at 08C for 4 h. The aqueous layer was separated, the product ex-
tracted with Et2O, and the combined organic layers were dried with
MgSO4. The mixture was then filtered and the solvent removed under re-
duced pressure to leave the crude product, which was purified by column
chromatography.
2-(1-Naphthylethyl)-1-cyclobutanone (21a): N-Cyclohexyl-N-cyclobutyl-
idenamine (19a) (0.800 g, 5.30 mmol), diisopropylamine (0.8 mL,
A
5.60 mmol), n-butyllithium (2.5 mL, 6.25 mmol; 2.5m in hexane) and 20
(0.987 g, 3.50 mmol) afforded, after purification by column chromatogra-
phy (hexane/ethyl acetate 9.5:0.5), 21a as a colourless oil (0.340 g, 43%).
1H NMR (CDCl3, 270 MHz): d=8.15 (d, J=8.3 Hz, 1H; Ar), 7.87 (d, J=
8.3 Hz, 1H; Ar), 7.75 (d, J=8.3 Hz, 1H; Ar), 7.65–7.29 (m, 4H; Ar),
3.36–2.89 (m, 5H; CH, CH2), 2.22–2.05 (m, 2H; CH2), 2.00–1.84 (m, 1H;
CH2), 1.62 ppm (quint., Jꢁ9.5 Hz, 1H; CH2); 13C NMR (CDCl3,
67.9 MHz): d=211.9 (s; CO), 137.4, 133.8, 131.7 (3s; Ar), 128.8, 126.7,
126.1, 125.8, 125.5, 125.4, 123.1 (7d; Ar), 59.9 (d; CH), 44.4, 30.6, 30.3,
16.9 ppm (4t; CH2); IR (film): n˜ =3050–2850 (=C H, C H), 1750 (C=O),
1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 224 (28) [M]+, 141 (100)
[MꢀC5H7O]+; HRMS (80 eV): calcd for C16H16O: 224.1201; found:
224.1224; elemental analysis calcd (%) for C16H16O (224.3): C 85.68, H
7.19; found: C 85.11, H 7.03.
ꢀ
ꢀ
7-[2-(1-Naphthyl)ethyl]-1,4-dioxaspiro
to the sequence described above, (2S)-2-(methoxymethyl)-N-[1,4-
dioxaspiro[4.5]dec-8-ylidene]pyrrolidin-1-amine (1.10 g, 4.08 mmol), dii-
sopropylamine (1.47 mL, 10.5 mmol), n-butyllithium (1.98 mL,
[4.5]decan-8-one (29): According
2-(1-Naphthylethyl)-1-cyclopentanone (21b): N-Cyclohexyl-N-cyclopen-
tylidenamine (19b) (12.4 g, 75.0 mmol), diisopropylamine (11.2 mL,
80.0 mmol), n-butyllithium (34.9 mL, 87.3 mmol; 2.5m in hexane) and 20
(14.1 g, 50.0 mmol) afforded, after purification by column chromatogra-
phy (hexane/ethyl acetate 9:1), 21b as a colourless oil (9.16 g, 77%). The
analytical data are in agreement with those reported in the literature.[51]
AHCTREUNG
4.95 mmol; 2.5m in hexane) and 1-(2-bromoethyl)naphthalene (0.764 g,
3.25 mmol) afforded after column chromatography on neutral alumina
(hexane/ethyl acetate 3:1) 29 as a colourless oil (0.925 g, 92%). 1H NMR
(CDCl3, 270 MHz): d=8.18 (d, J=8.5 Hz, 1H; Ar), 7.82 (d, J=8.0 Hz,
1H; Ar), 7.69 (d, J=7.3 Hz, 1H; Ar), 7.54–7.25 (m, 4H; Ar), 4.02–3.95
(m, 4H; OCH2), 3.15, 2.98 (2ddd, J=13.3, 11.1, 5.3 Hz, 1H each; CH2),
2.78, 2.67 (2m, 1H each; CH, CH2), 2.39 (ddd, J=14.7, 4.3, 3.7 Hz, 1H;
CH2), 2.28–1.90 (m, 4H; CH2), 1.81 (t, J=13.1 Hz, 1H; CH2), 1.60 ppm
(m, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=211.4 (s; CO), 138.6,
134.0, 132.1 (3s; Ar), 128.8, 126.8, 126.1, 125.9, 125.7, 125.6, 124.2 (7d;
Ar), 107.5 (s; C-5), 64.8, 64.7 (2t; C-2, C-3), 46.4 (d; C-7), 41.1, 38.5, 35.9,
2-(1-Naphthylethyl)-1-cyclohexanone (21c): N-Cyclohexyl-N-cyclohexyli-
denamine (19c) (0.902 g, 5.00 mmol), diisopropylamine (0.8 mL,
5.60 mmol), n-butyllithium (2.5 mL, 6.25 mmol; 2.5m in hexane) and 20
(0.987 g, 3.50 mmol) afforded, after purification by column chromatogra-
phy (hexane/ethyl acetate 19:1), 21c as a colourless oil (0.731 g, 83%).
1H NMR (CDCl3, 270 MHz): d=8.05 (d, J=8.1 Hz, 1H; Ar), 7.84 (d, J=
8.1 Hz, 1H; Ar), 7.70 (d, J=7.8 Hz, 1H; Ar), 7.56–7.30 (m, 4H; Ar),
3.15 (t, J=8.0 Hz, 2H; CH2), 2.39–1.53 ppm (m, 11H; CH, CH2);
13C NMR (CDCl3, 67.9 MHz): d=213.6 (s; CO), 134.0, 132.8, 128.6 (3s;
Ar), 128.8, 126.7, 125.9, 125.8, 125.6, 125.5, 123.7 (7d; Ar), 58.7 (d; CH),
ꢀ
ꢀ
30.9, 30.8 ppm (5t; CH2); IR (film): n˜ =3060–2880 (=C H, C H), 1710
(C=O), 1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 310 (17) [M]+, 155
(100) [C8H11O3+C12H11]+, 141 (21) [C11H9]+; HRMS (EI, 80 eV): calcd
for C20H22O3: 310.1568; found: 310.1557.
38.2, 30.8, 30.7, 29.8, 20.7, 16.1 ppm (6t; CH2); IR (film): n˜ =3050–2850
(=C H, C H), 1715 (C=O), 1600 cm (C=C); elemental analysis calcd
(%) for C18H20O (252.4): C 85.67, H 7.99; found: C 85.12, H 7.63.
ꢀ1
ꢀ
ꢀ
7-[2-(2-Naphthyl)ethyl]-1,4-dioxaspiro
to the sequence described above, (2S)-2-(methoxymethyl)-N-[1,4-
dioxaspiro[4,5]dec-8-ylidene]pyrrolidin-1-amine (1.33 g, 4.95 mmol), dii-
sopropylamine (1.79 mL, 12.7 mmol), n-butyllithium (2.40 mL,
A
2-(1-Naphthylethyl)-1-cycloheptanone (21d): N-Cyclohexyl-N-cyclohep-
tylidenamine (19d) (5.79 g, 30.0 mmol), diisopropylamine (4.5 mL,
32.1 mmol), n-butyllithium (14.1 mL, 35.3 mmol; 2.5m in hexane) and 20
(5.63 g, 20.0 mmol) afforded, after purification by column chromatogra-
phy (hexane/ethyl acetate 19:1), 21d as a colourless oil (4.10 g, 77%).
1H NMR (CDCl3, 270 MHz): d=8.05 (d, J=8.3 Hz, 1H; Ar), 7.85 (d, J=
8.3 Hz, 1H; Ar), 7.72 (d, J=7.8 Hz, 1H; Ar), 7.57–7.29 (m, 4H; Ar),
3.13–2.82 (m, 2H; CH, CH2), 2.69–2.31 (m, 2H; CH2), 2.22–2.03 (m, 1H;
CH2), 1.95–1.12 (m, 8H; CH2), 0.98–0.79 ppm (m, 2H; CH2); 13C NMR
(CDCl3, 67.9 MHz): d=215.8 (s; CO), 133.8, 128.5 (2s; Ar), 128.9, 127.7,
126.5, 126.4, 125.7, 125.5, 123.7 (7d; Ar), 51.6 (d; CH), 43.0, 33.4, 31.7,
AHCTREUNG
6.00 mmol; 2.5m in hexane) and 2-(2-bromoethyl)naphthalene (0.927 g,
3.94 mmol) afforded, after column chromatography on silica gel (hexane/
1
ethyl acetate 4:1), 33 as a colourless oil (0.976 g, 80%). H NMR (CDCl3,
500 MHz): 7.76–7.73 (m, 2H; Ar), 7.72 (d, J=8.4 Hz, 1H; Ar), 7.59 (s,
1H; Ar), 7.42–7.36 (m, 2H; Ar), 7.30 (dd, J=8.4, 1.6 Hz, 1H; Ar), 3.93–
3.92 (m, 4H; OCH2), 2.80–2.70 (m, 2H; CH2), 2.65 (sept, J=6.6 Hz, 1H;
CH), 2.58 (dd, J=14.1, 6.6 Hz, 1H; CH2), 2.34 (ddd, J=14.1, 5.0, 3.4 Hz,
1H; CH2), 2.20–2.16 (m, 1H; CH2), 2.13 (ddd, J=13.2, 5.8, 3.4 Hz, 1H;
CH2), 1.99–1.92 (m, 2H; CH2), 1.74 (t, J=13.2 Hz, 1H; CH2), 1.60–
1.52 ppm (m, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=211.3 (s; CO),
139.6, 133.8, 132.1 (3s; Ar), 127.9, 127.6, 127.5, 127.4, 126.4, 125.9, 125.1
(7d; Ar), 107.4 (s, C-5), 64.7, 64.6 (2t; C-2, C-3), 45.8 (d; C-7), 40.7, 34.7,
ꢀ
ꢀ
30.6, 29.3, 28.6, 24.2 ppm (7t; CH2). IR (film): n˜ =3045–2850 (=C H, C
H), 1700 (C=O), 1595 cmꢀ1 (C=C); elemental analysis calcd (%) for
C19H22O (266.4): C 85.67, H 8.32; found: C 85.55, H 8.25.
2-(1-Naphthylethyl)-1-cyclooctanone (21e): N-Cyclohexyl-N-cyclooctyl-
idenamine (19e) (6.22 g, 30.0 mmol), diisopropylamine (4.5 mL,
ꢀ
ꢀ
33.9, 33.3, 30.8 ppm (5t; CH2); IR (film): n˜ =3050–2885 (=C H, C H),
1715 (C=O), 1600 cmꢀ1 (C=C); elemental analysis calcd (%) for C20H22O3
(310.4): C 77.39, H 7.14; found: C 76.79, H 6.74.
32.1 mmol), n-butyllithium (14.1 mL, 35.3 mmol; 2.5m in hexane) and 20
(5.63 g, 20.0 mmol) afforded, after purification by column chromatogra-
phy (hexane/ethyl acetate 9:1 to 7:3), 21e as a pale-yellow oil (5.05 g,
Chem. Eur. J. 2007, 13, 6047 – 6062
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6055

H.-U. Reißig et al.
1-Methyl-3-[2-(1-naphthyl)ethyl]piperidin-4-one (50): According to the
sequence described above, (2S)-2-(methoxymethyl)-N-(1-methylpiperi-
din-4-ylidene)pyrrolidin-1-amine (0.475 g, 2.10 mmol), diisopropylamine
(0.60 mL, 4.27 mmol), n-butyllithium (0.84 mL, 2.10 mmol; 2.5m in
hexane) and 1-(2-bromoethyl)naphthalene (0.51 g, 2.17 mmol) afforded,
after column chromatography on neutral alumina (hexane/ethyl acetate
3:1), the alkylation product as a colourless oil (0.559 g, 70%). 1H NMR
(CDCl3, 500 MHz): d=8.04 (d, J=8.4 Hz, 1H; Ar), 7.83 (dd, J=8.0,
1.0 Hz, 1H; Ar), 7.69 (dd, J=6.7, 2.6 Hz, 1H; Ar), 7.51–7.43 (m, 2H;
Ar), 7.38–7.37 (m, 2H; Ar), 3.44 (m, 1H; CH), 3.37 (m, 1H; CH2), 3.25
(s, 3H; OCH3), 3.23–3.19 (m, 1H; CH), 3.12–3.09 (m, 2H; CH2), 3.04–
3.00 (m, 3H; CH2), 2.93 (dd, J=11.5, 2.0 Hz, 1H; CH2), 2.73 (dt, J=13.3,
5.5 Hz, 1H; CH2), 2.48 (d, J=8.8 Hz, 1H; CH2), 2.25 (s, 3H; NCH3),
2.24–2.14 (m, 2H; CH2), 2.08–2.00 (m, 3H; CH2), 1.99 (dd, J=10.9,
2.9 Hz, 1H; CH2), 1.85–1.79 (m, 2H; CH2), 1.64–1.57 ppm (m, 1H; CH2).
at RT under argon for 10 min, then a solution of 42 (0.700 g, 3.29 mmol)
in DMF (2 mL) was added. The vessel was sealed and heated to 908C for
48 h. After cooling to RT, the mixture was quenched with distilled water.
The product was extracted with ethyl acetate (3”10 mL), the combined
organic layers were washed with brine (2”10 mL), dried with MgSO4
and the solvent was removed under reduced pressure to give the crude
product, which was further purified by column chromatography on silica
gel (hexane/ethyl acetate 6:1) and preparative HPLC (hexane/iso-propa-
nol 95:5) to afford 43 as a colourless oil (0.294 g, 87%).[54] 1H NMR
(CDCl3, 500 MHz): d=8.06, 7.83 (2d, J=7.7 Hz, 1H each; Ar), 7.76 (d,
J=8.1 Hz, 1H; Ar), 7.53 (d, J=7.1 Hz, 1H; Ar), 7.49–7.47 (m, 2H; Ar),
7.42–7.40 (m, 1H; Ar), 7.25 (d, J=15.5 Hz, 1H; =CH), 6.05 (dd, J=15.5,
8.1 Hz, 1H; =CH), 4.18 (m, 1H; CH), 3.81–3.67 (m, 2H; CH2), 3.41 (dd,
J=11.0, 6.9 Hz, 0.5H; CH2), 3.33 (m, 1H; CH2), 3.27 (dd, J=11.3,
5.4 Hz, 1H; CH2), 2.95 (m, 2H; CH, OH), 1.48 ppm (s, 9H; tBu);
13C NMR (CDCl3, 126 MHz): d=154.6 (s; CO), 134.6, 133.6, 131.2 (3s;
Ar), 131.0, 129.6 (2d; CH=CH), 128.6, 128.1, 126.2, 125.9, 125.7, 123.9,
123.7 (7d; Ar), 79.6 (s; tBu), 75.2, 74.5 (2d; CH), 52.4, 52.2 (2t; CH2),
The alkylation product (0.080 g, 0.21 mmol) was dissolved in Et2O
(1 mL) and stirred vigorously with a saturated aqueous solution of oxalic
acid (1 mL) at 08C for 4 h. The aqueous layer was separated, the product
was extracted with Et2O (3”2 mL), and the combined organic layers
were dried with MgSO4. The mixture was then filtered and the solvent
removed under reduced pressure to afford 50 as a colourless oil (0.052 g,
93%). 1H NMR (CDCl3, 500 MHz): d=8.13 (m, 1H; Ar), 7.83 (dt, J=
8.0, 0.7 Hz, 1H; Ar), 7.69 (d, J=8.3 Hz, 1H; Ar), 7.51 (ddd, J=8.3, 6.8,
1.4 Hz, 1H; Ar), 7.45 (ddd, J=8.0, 6.9, 1.4 Hz, 1H; Ar), 7.37 (dd, J=8.0,
6.9 Hz, 1H; Ar), 7.30 (m, 1H; Ar), 3.17 (ddd, J=13.9, 10.3, 5.7 Hz, 1H;
CH2), 3.07 (ddd, J=11.2, 5.7, 2.5 Hz, 1H; CH2), 3.01 (ddd, J=13.9, 10.3,
6.6 Hz, 2H; CH2), 2.70–2.60 (m, 2H; CH2), 2.42 (dd, J=11.2, 3.6 Hz, 1H;
CH2), 2.39 (dd, J=4.7, 3.6 Hz, 1H; CH2), 2.36 (s, 3H; NCH3), 2.28–2.21
(m, 1H; CH2), 2.18 (t, J=11.2 Hz, 1H; CH2), 1.57 ppm (ddt, J=13.9,
10.3, 5.7 Hz, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=210.4 (s; CO),
138.2, 134.0, 131.9 (3s; Ar), 128.2, 126.8, 126.1, 126.0, 125.6, 125.5, 124.0
(7d; Ar), 61.7, 56.3 (2t; CH2), 49.3 (d, CH), 45.4 (q; CH3), 41.3, 30.8,
50.3 (d; CH), 49.7, 49.4 (2t; CH2), 28.5 ppm (q; tBu); IR (film): n˜ =3400
ꢀ1
ꢀ
(OH), 3060–2885 (=CH, C H), 1670 (C=O), 1600 cm (C=C); MS (EI,
80 eV): m/z (%): 340 (6) [M+H]+, 339 (23) [M]+, 283 (39) [MꢀC4H9]+,
57 (100) [C4H9]+; HRMS (80 eV): calcd for C21H25NO3: 339.18344;
found: 339.18288.
tert-Butyl 3-[2-(1-naphthyl)ethyl]-4-oxopyrrolidine-1-carboxylate (44):
Hydrogen was bubbled through a suspension of Pd/C (10%, 44 mg) in
EtOH (5 mL) for 2 h, then a solution of 43 (220 mg, 0.65 mmol) in EtOH
(1 mL) was added and the mixture was stirred at RT under an atmos-
phere of hydrogen for 3 h. The solid residue was filtered through a pad
of silica and thoroughly washed with EtOH. The organic solvent was re-
moved under reduced pressure to afford the reduction product as a col-
ourless oil (0.168 g, 76%).[54] 1H NMR (CDCl3, 500 MHz): d=7.98 (d, J=
8.2 Hz, 1H; Ar), 7.84, 7.70 (2m, 1H each; Ar), 7.51–7.46 (m, 2H; Ar),
7.38 (m, 1H; Ar), 7.30 (d, J=6.0 Hz, 1H; Ar), 4.01 (brs, 1H; CH), 3.64–
3.56 (m, 2H; CH2), 3.24–3.14 (m, 1H; CH2), 3.11–3.08 (m, 3H; CH2),
2.70, 2.66 (2s, 1H; OH), 2.20–2.08 (m, 1H; CH), 1.96–1.91 (m, 1H;
CH2), 1.65–1.62 (m, 1H; CH2), 1.46 ppm (s, 9H; tBu); 13C NMR (CDCl3,
126 MHz): d=154.7 (s; CO), 137.6, 133.8, 131.6 (3s; Ar), 128.8, 126.7,
125.9, 125.8, 125.5, 125.4, 123.3 (7d; Ar), 79.4 (s; tBu), 75.3, 74.5 (2d;
CH), 52.7, 52.4, 49.4, 48.9 (4t; CH2), 46.1, 45.5 (2d; CH), 32.5, 31.1 (2t;
ꢀ
28.7 ppm (3t; CH2); IR (film): n˜ =3060–2785 (=CH, C H), 1715 (C=O),
1595 cmꢀ1 (C=C); elemental analysis calcd (%) for C18H21NO (267.4): C
80.86, H 7.92, N 5.24; found: C 80.99, H 8.03, N 5.09.
1-Methyl-3-[2-(2-naphthyl)ethyl]piperidin-4-one (52): According to the
sequence described above, (2S)-2-(methoxymethyl)-N-(1-methylpiperi-
din-4-ylidene)pyrrolidin-1-amine (0.823 g, 3.66 mmol), diisopropylamine
(1.32 mL, 9.39 mmol), n-butyllithium (1.77 mL, 4.43 mmol; 2.5m in
hexane), and 2-(2-bromoethyl)naphthalene (0.685 g, 2.91 mmol) afforded,
after column chromatography on aluminium oxide (hexane/ethyl acetate
3:1), the alkylation product as a colourless oil (0.806 g, 73%). 1H NMR
(CDCl3, 500 MHz): d=7.79–7.73 (m, 3H; Ar), 7.63 (s, 1H; Ar), 7.44–7.37
(m, 2H; Ar), 7.34 (dd, J=8.4, 1.7 Hz, 1H; Ar), 3.48–3.46 (m, 1H; CH2),
3.36 (s, 3H; OCH3), 3.30–3.25 (m, 3H; CH2), 3.09–3.03 (m, 1H; CH2),
2.83–2.77 (m, 2H; CH2), 2.67–2.59 (m, 2H; CH2), 2.49–2.42 (m, 4H; CH2,
CH), 2.25 (s, 3H; CH3), 2.22–2.17 (m, 1H; CH2), 2.16–2.14 (m, 1H;
CH2), 2.04–2.00 (m, 1H; NCH2), 1.93–1.90 (m, 1H; CH2), 1.85–1.80 (m,
2H; CH2), 1.70–1.67 ppm (m, 1H; CH2).
ꢀ
CH2), 28.4 ppm (q; tBu); IR (film): n˜ =3420 (OH), 3060–2880 (=CH, C
H), 1670 (C=O), 1595 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 341 (7)
[M]+, 285 (42) [MꢀC4H9]+, 240 (10) [MꢀC5H9O2]+, 154 (9) [C12H11]+,
141 (27) [C11H9]+, 85 (27) [C5H9O]+, 57 (100) [C4H9]+; HRMS (80 eV):
calcd for C21H27NO3: 341.19910; found: 341.19866.
A solution of this reduction product (0.168 g, 0.49 mmol) and triethyla-
mine (0.129 mL, 0.93 mmol) in DMSO (4 mL) was cooled to 08C and
Py·SO3 complex (0.131 g, 0.84 mmol) was added. The mixture was stirred
for 10 min at this temperature and then allowed to warm to RT and
stirred for a further 2 h. Distilled water was added and the product was
extracted with CH2Cl2 (3”5 mL). The combined organic phases were
washed with brine (3”5 mL), dried with MgSO4, filtered and the solvent
was removed under reduced pressure. The crude product was purified by
column chromatography on silica gel (hexane/ethyl acetate 5:1) to afford
44 as colourless oil (0.128 g, 77%). 1H NMR (CDCl3, 500 MHz): d=8.04
(d, J=8.4 Hz, 1H; Ar), 7.88 (d, J=7.4 Hz, 1H; Ar), 7.75 (d, J=8.4 Hz,
1H; Ar), 7.55–7.50 (m, 2H; Ar), 7.41 (t, J=7.4 Hz, 1H; Ar), 7.34 (d, J=
6.6 Hz, 1H; Ar), 4.20–4.00 (m, 1H; CH2), 3.89, 3.71 (2brd, J=19.2 Hz,
1H each; NCH2), 3.38–3.27 (m, 1H; CH2), 3.18 (brs, 2H; CH2), 2.61
(brs, 1H; CH), 2.30–2.26 (m, 1H; CH2), 1.86 (m, 1H; CH2), 1.52 ppm (s,
9H; tBu); 13C NMR (CDCl3, 126 MHz): d=212.6 (s; CO), 154.4 (s; CO),
137.0, 134.1, 131.8 (3s; Ar), 129.0, 127.2, 126.3, 126.2, 125.8, 125.6, 123.7
(7d; Ar), 80.2 (s; tBu), 52.9, 52.5 (2t; CH2), 48.5, 48.2 (2d; CH), 47.1,
Acid treatment of the alkylation product (0.100 g, 0.26 mmol) afforded
52 as a colourless oil (0.067 g, 96%). 1H NMR (CDCl3, 500 MHz): d=
7.79–7.75 (m, 3H; Ar), 7.60 (s, 1H; Ar), 7.46–7.39 (m, 2H; Ar), 7.32 (dd,
J=8.4, 1.6 Hz, 1H; Ar), 3.10 (ddd, J=11.3, 5.6, 2.2 Hz, 1H; CH2), 3.04–
2.99 (m, 1H; CH2), 2.84–2.74 (m, 2H; CH2), 2.66–2.59 (m, 2H; CH,
CH2), 2.46 (dt, J=11.3, 3.6 Hz, 1H; CH2), 2.39 (s, 3H; NCH3), 2.38–2.35
(m, 1H; CH2), 2.29–2.20 (m, 2H; CH2), 1.57 ppm (m, 1H; CH2);
13C NMR (CDCl3, 126 MHz): d=209.7 (s; CO), 139.1, 133.6, 132.0 (3s;
Ar), 127.9, 127.5, 127.4, 127.1, 126.3, 125.8, 125.1 (7d; Ar), 61.2, 56.0 (2t;
CH2), 48.5 (d; CH), 45.2 (q; CH3), 40.8, 33.3, 28.7 ppm (3t; CH2); IR
ꢀ1
ꢀ
(film): n˜ =3050–2785 (=CH, C H), 1715 (C=O), 1600 cm (C=C); MS
(EI, 80 eV): m/z (%): 267 (27) [M]+, 141 (22) [C11H9]+, 126 (100)
[MꢀC11H9]+; HRMS (80 eV): calcd for C18H21NO: 267.16232; found:
267.16366.
46.8, 30.2, 29.6 (4t; CH2), 28.3 ppm (q; tBu); IR (film): n˜ =3060–2875 (=
tert-Butyl 3-hydroxy-4-[(E)-2-(1-naphthyl)vinyl]pyrrolidine-1-carboxylate
(43): A high-pressure tube was loaded with sodium hydrogencarbonate
(0.335 g, 4.00 mmol), triethylbenzylammonium chloride (0.340 g,
1.50 mmol), 1-naphthyl nonaflate 41 (0.426 g, 1.00 mmol), palladium(II)
acetate (45 mg, 0.20 mmol) and DMF (4 mL). The suspension was stirred
ꢀ1
ꢀ
CH, C H), 1755–1670 (C=O), 1595 cm (C=C); MS (EI, 80 eV): m/z
(%): 339 (14) [M]+, 283 (31) [MꢀC4H9]+, 239 (5) [MꢀC5H9O2]+, 141
(30) [C11H9]+, 57 (100) [C4H9]+; HRMS (80 eV): calcd for C21H25NO3:
339.18344; found: 339.18266.
6056
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6047 – 6062

Samarium Diiodide Induced Cyclisations
FULL PAPER
tert-Butyl 3-hydroxy-4-[(E)-2-(2-naphthyl)vinyl]pyrrolidine-1-carboxylate
(46): According to the procedure described above, 2-naphthyl nonaflate
45 (0.374 g, 0.88 mmol), sodium hydrogencarbonate (0.294 g, 3.51 mmol),
triethylbenzylammonium chloride (0.298 g, 1.32 mmol), palladium(II)
acetate (39 mg, 0.17 mmol) and 42 (0.560 g, 2.63 mmol) afforded after pu-
rification by column chromatography on silica gel (hexane/ethyl acetate
5:1) 46 as a colourless solid (0.195 g, 66%).[54] M.p. 152–1548C; 1H NMR
(CDCl3, 500 MHz): d=7.81–7.76 (m, 3H; Ar), 7.68 (s, 1H; Ar), 7.55 (dd,
J=8.6, 1.4 Hz, 1H; Ar), 7.47–7.43 (m, 2H; Ar), 6.67 (d, J=15.9, 1H;
CH=CH), 6.17 (dd, J=15.9, 8.3 Hz, 1H; CH=CH), 4.19 (dd, J=11.8,
5.9 Hz, 1H; CH), 3.78 (dd, J=10.6, 5.5 Hz, 1H; CH2), 3.72 (dd, J=10.4,
7.4 Hz, 1H; CH2), 3.37 (dd, J=10.4, 7.4 Hz, 1H; CH2), 3.26 (dd, J=10.6,
5.5 Hz, 1H; CH2), 2.89 (m, 1H; CH), 2.36 (brs, 1H; OH), 1.48 ppm (s,
9H; tBu); 13C NMR (CDCl3, 126 MHz): d=154.6 (s; CO), 134.1, 133.5
(2s; Ar), 132.9 (d; =CH), 132.5 (s; Ar), 128.2 (d; Ar), 128.0 (d; =CH),
127.9, 127.6, 126.3, 126.1, 125.9, 123.3 (6d; Ar), 79.6 (s; tBu), 76.0, 74.5
(2d; CH), 52.3, 52.0 (2t; CH2), 50.1, 49.5 (2d; CH), 49.3, 48.7 (2t; CH2),
28.5 ppm (q; tBu); IR (KBr): n˜ =3475–3440 (OH), 2975–2870 (=CH,
CH), 1690 (C=O), 1595 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 339 (28)
[M]+, 283 (49) [MꢀC4H8]+, 57 (100) [C4H9]+; HRMS (80 eV): calcd for
C21H25NO3: 339.18344; found: 339.18358.
dried with MgSO4, filtered and the solvent was removed under reduced
pressure to give the crude cyclisation product.
rac-(1R,9aR)-1-Methyl-2,3,7,9a-tetrahydro-1H-phenalen-1-ol (13): Ac-
cording to the general procedure, samarium (0.361 g, 2.40 mmol), 1,2-
diiodoethane (0.620 g, 2.20 mmol), HMPA (3.23 g, 18.0 mmol), 3 (0.198 g,
1.00 mmol) and tBuOH (0.148 g, 2.00 mmol) afforded after purification
by column chromatography on silica gel (hexane/ethyl acetate 9:1 to 8:2)
13 as a colourless solid (0.161 g, 81%). The analytical data are in agree-
ment with those reported in the literature.[13b]
rac-(1S,4aS,10aS)-1-Methyl-1,2,3,4,5a,10a-hexahydrophenanthren-1-ol
(17): According to the general procedure, samarium (0.361 g, 2.40 mmol),
1,2-diiodoethane (0.620 g, 2.20 mmol), HMPA (3.23 g, 18.0 mmol),
8
(0.212 g, 1.00 mmol) and tBuOH (0.148 g, 2.00 mmol) afforded after pu-
rification by column chromatography on silica gel (hexane/ethyl acetate/
triethylamine 9.4:0.5:0.1) 17 as a colourless oil (0.198 g, 93%). 1H NMR
(CDCl3, 500 MHz): d=7.16–7.09 (m, 3H; Ar), 7.06–7.01 (m, 1H; Ar),
6.46 (dd, J=9.7, 3.2 Hz, 1H; =CH), 5.68 (brd, J=9.7 Hz, 1H; =CH), 3.11
(td, J=12.1, 5.4 Hz, 1H; CH), 2.57 (m, 1H; CH), 1.75–1.44 (m, 6H; CH2,
OH), 1.34 (s, 3H; CH3), 1.38–1.31 ppm (m, 1H; CH2); 13C NMR (CDCl3,
126 MHz): d=140.6, 132.7 (2s; Ar), 128.8, 128.7, 128.3, 128.2, 127.6,
126.3 (6d; Ar, =CH), 71.5 (s; C-1), 46.4, 36.7 (2d; CH), 35.0 (t; CH2),
28.7 (q; CH3), 27.3, 20.0 ppm (2t; CH2); IR (film): n˜ =3420 (OH), 3100–
tert-Butyl 3-[2-(2-naphthyl)ethyl]-4-oxopyrrolidine-1-carboxylate (47):
According to the procedure described above, 46 (0.170 g, 0.50 mmol) and
Pd/C (10%, 34 mg) afforded the reduction product as a colourless oil
(0.168 g, 98%). 1H NMR (CDCl3, 500 MHz): d=7.77 (m, 3H; Ar), 7.60
(s, 1H; Ar), 7.43 (m, 2H; Ar), 7.30 (d, J=8.2 Hz, 1H; Ar), 4.00 (m, 1H;
CH), 3.60–3.57 (m, 2H; CH2), 3.19–3.16 (m, 1H; CH2), 3.06 (dd, J=10.5,
6.0 Hz, 1H; CH2), 2.83–2.78 (m, 2H; CH2), 2.70 (brs, 1H; OH), 2.10–
1.93 (m, 1H; CH), 1.90 (m, 1H; CH2), 1.60 (dtd, J=13.6, 9.1, 5.8 Hz, 1H;
CH2), 1.42 ppm (s, 9H; tBu); 13C NMR (CDCl3, 126 MHz): d=154.7 (s;
CO), 139.0, 133.5, 131.8 (3s; Ar), 128.0, 127.5, 127.3, 127.0, 126.3, 125.9,
125.2 (7d; Ar), 79.4 (s; tBu), 75.3, 74.5 (2d; CH), 52.7, 52.4, 49.4, 48.8
(4t; CH2), 45.7, 45.0 (2d; CH), 34.0, 33.0 (2t; CH2), 28.4 ppm (q; tBu);
ꢀ1
ꢀ
ꢀ
2900 (=C H, C H), 1600 cm (C=C); elemental analysis calcd (%) for
C15H18O (214.3): C 84.07, H 8.47; found: C 84.22, H 8.33.
rac-(1S,9aS)- and rac-(1R,9aS)-1-Methyl-1,2,3,4,9,9a-hexahydroanthra-
cen-1-ol (18a) and (18b): According to the general procedure, samarium
(0.361 g, 2.40 mmol), 1,2-diiodoethane (0.620 g, 2.20 mmol), HMPA
(3.23 g, 18.0 mmol), 10 (0.212 g, 1.00 mmol) and tBuOH (0.148 g,
2.00 mmol) afforded after purification by column chromatography on
silica gel (hexane/ethyl acetate/triethylamine 9.4:0.5:0.1) 18a (0.117 g,
55%) and 18b (0.078 g, 36%) as colourless oils.
1
Compound 18a: H NMR (CDCl3, 500 MHz): d=7.39 (d, J=7.3 Hz, 1H;
Ar), 7.20–7.12 (m, 3H; Ar), 5.63 (s, 1H, 5-H), 3.44–3.24 (m, 3H; CH2,
CH), 2.33–2.28 (m, 1H; CH2), 2.07–1.98 (m, 1H; CH2), 1.93–1.74 (m,
4H; CH2, OH), 1.52–1.41 (m, 1H; CH2), 0.84 ppm (s, 3H; CH3);
13C NMR (CDCl3, 126 MHz): d=137.8, 135.0, 133.7 (3s; C-4a, Ar), 129.4,
128.3, 126.2, 125.5 (4d; Ar), 117.9 (d; C-5), 76.5 (s; C-1), 53.0 (d; C-9a),
ꢀ
IR (film): n˜ =3485 (OH), 3045–2900 (=CH, C H), 1680 (C=O),
1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 341 (2) [M]+, 285 (9)
[MꢀC4H8]+, 154 (8) [C12H11]+, 141 (22) [C11H9]+, 57 (100) [C4H9]+;
HRMS (80 eV): calcd for C21H27NO3: 341.19910; found: 341.19869.
41.0, 35.4, 30.3, 25.6 (4t; CH2), 20.9 ppm (q; CH3); IR (film): n˜ =3450
According to the procedure described above, the reduction product
(0.150 g, 0.44 mmol), triethylamine (0.115 mL, 0.83 mmol) and the
Py·SO3 complex (0.117 g, 0.75 mmol) afforded, after column chromatog-
raphy on silica gel (hexane/ethyl acetate 5:1), 47 as a colourless solid
ꢀ1
ꢀ
ꢀ
(OH), 3100–2850 (=C H, C H), 1600 cm (C=C); elemental analysis
calcd (%) for C15H18O (214.3): C 84.07, H 8.47; found: C 84.34, H 8.47.
1
Compound 18b: H NMR (CDCl3, 500 MHz): d=7.09–7.04 (m, 3H; Ar),
1
6.91 (d, J=6.5 Hz, 1H; Ar), 6.17 (s, 1H, 5-H), 3.19 (dd, J=17.3, 3.5 Hz,
1H; CH2), 3.08 (dd, J=17.3, 10.4 Hz, 1H; CH2), 2.47 (dd, J=10.4,
3.5 Hz, 1H; CH), 2.39–2.34 (m, 1H; CH2), 2.15 (dt, J=13.2, 5.0 Hz, 1H;
CH2), 1.86–1.75 (m, 3H; CH2, OH), 1.61 (dt, J=13.2, 5.2 Hz, 1H; CH2),
1.45 (qt, J=13.2, 4.4 Hz, 1H; CH2), 1.01 ppm (s, 3H; CH3); 13C NMR
(CDCl3, 126 MHz): d=140.8, 133.37, 133.35 (3s; C-4a, Ar), 127.2, 126.5,
126.0, 125.5 (4d; Ar), 121.7 (d; C-5), 75.2 (s; C-1), 48.3 (d; C-9a), 42.8,
(0.109 g, 73%). M.p. 77–798C; H NMR (CDCl3, 500 MHz): d=7.81–7.77
(m, 3H; Ar), 7.62 (s, 1H; Ar), 7.44 (m, 2H; Ar), 7.31 (dd, J=8.3, 1.6 Hz,
1H; Ar), 4.13–4.10 (m, 1H; CH2), 3.87–3.81 (m, 1H; CH2), 3.69–3.65 (m,
1H; CH2), 3.31 (m, 1H; CH2), 2.90–2.79 (m, 2H; CH2), 2.53 (brs, 1H;
CH), 2.27–2.22 (m, 1H; CH2), 1.79–1.75 (m, 1H; CH2), 1.48 ppm (s, 9H;
tBu); 13C NMR (CDCl3, 126 MHz): d=212.9 (s; CO), 154.4 (s; CO),
138.2, 133.6, 132.3 (3s; Ar), 128.3, 127.7, 127.5, 127.2, 126.7, 126.2, 125.5
(7d; Ar), 80.4 (s; tBu), 53.1, 52.9 (2t; CH2), 49.0, 48.3 (2d; CH), 47.0,
46.6, 33.4, 30.3 (4t; CH2), 28.5 ppm (q; tBu); IR (KBr): n˜ =3050–2870
35.0, 26.2, 25.0 (4t; CH2), 20.6 ppm (q; CH3); IR (film): n˜ =3450 (OH),
ꢀ1
ꢀ
ꢀ
3100–2850 (=C H, C H), 1600 cm (C=C); elemental analysis calcd (%)
for C15H18O (214.3): C 84.07, H 8.47; found: C 84.08, H 8.25.
ꢀ1
ꢀ
A
rac-(2aR,2bR,8bR,10aR)-1,2b,8b,9,10,10a-Hexahydrocyclobuta[a]phen-
anthren-2a(2H)-ol (22): According to the general procedure, samarium
calcd (%) for C21H25NO3 (339.4): C 74.31, H 7.42, N 4.13; found: C 73.97,
H 7.50, N 3.93.
(0.161 g, 1.07 mmol), 1,2-diiodoethane (0.277 g, 0.981 mmol), HMPA
(1.44 g, 8.03 mmol), 21a (0.100 g, 0.446 mmol) and tBuOH (0.066 g,
0.89 mmol) afforded after purification by column chromatography on
silica gel (hexane/ethyl acetate 19:1) product 22 (0.041 g, 41%) as a col-
ourless oil. 1H NMR (CDCl3, 500 MHz): d=7.17–7.13 (m, 3H; Ar), 7.03
(d, J=7.5 Hz, 1H; Ar), 6.47 (dd, J=9.6, 2.5 Hz, 1H; =CH), 6.18 (dd, J=
9.6, 4.9 Hz, 1H; =CH), 3.02 (m, 1H; CH), 2.67 (m, 1H; CH), 2.26 (m,
1H; CH), 2.14–2.06 (m, 2H; CH2), 1.91–1.78 (m, 2H; CH2), 1.74–1.67
(m, 1H; CH2), 1.63 (brs, 1H; OH), 1.52–1.45 (m, 1H; CH2), 1.39 (m,
1H; CH2), 1.27–1.20 ppm (m, 1H; CH2); 13C NMR (CDCl3, 126 MHz):
d=139.0, 133.4 (2s; Ar), 128.4, 128.0 (2d; =CH), 127.5, 126.4, 126.3,
126.2 (4d; Ar), 75.2 (s; C-2a), 43.5, 43.3, 36.3 (3d; CH), 33.2, 24.5, 23.0,
Cyclisation experiments
General experimental procedure for the samarium diiodide induced cyc-
lisations: Samarium (2.4–2.9 equiv) and 1,2-diiodoethane (2.2–2.5 equiv)
were suspended in THF (25 mL/2.4 mmol SmI2) under an atmosphere of
argon and stirred at RT until the colour of the solution turned into dark
blue (approximately 2 h). The flaskwas then gently evacuated, purged
with argon and HMPA (18 equiv) was added. The corresponding ketone
(1.0 equiv) and tBuOH (2.0 equiv) were dissolved in THF (15 mLmmolꢀ1
of ketone), argon was purged through for 10 min and the solution was
then added to the deep violet solution of SmI2 in THF/HMPA. The mix-
ture was stirred for 16 h at RT and then quenched by addition of saturat-
ed aqueous sodium hydrogencarbonate solution (15 mL). The aqueous
phase was extracted with Et2O (3”20 mL) and the combined organic
layers were washed once with distilled water and twice with brine, then
ꢀ
ꢀ
18.9 ppm (4t; CH2); IR (film): n˜ =3380 (OH), 3035–2830 (=C H, C H),
1630 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 226 (20) [M]+, 196 (100)
[MꢀCH2O]+, 181 (16) [MꢀC2H5O]+; HRMS (80 eV): calcd for C16H18O:
Chem. Eur. J. 2007, 13, 6047 – 6062
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6057

H.-U. Reißig et al.
226.13577; found: 226.13655; elemental analysis calcd (%) for C16H18O
(226.3): C 84.91, H 8.02; found: C 84.71, H 7.97.
26.2, 26.0, 23.1 ppm (8t; CH2); IR (film): n˜ =3435 (OH), 3025–2850 cmꢀ1
+
ꢀ
ꢀ
(=C H, C H); MS (EI, 80 eV): m/z (%): 264 (6) [MꢀH2O] , 207 (100),
128 (70) [C10H8]+.
rac-(3aR,3bR,9bR,11aS)-1,2,3,3b,9b,10,11,11a-Octahydro-3aH-cyclopen-
ta[a]phenanthren-3a-ol (23): According to the general procedure, samari-
um (0.361 g, 2.40 mmol), 1,2-diiodoethane (0.620 g, 2.20 mmol), HMPA
(3.23 g, 18.0 mmol), 21b (0.238 g, 1.00 mmol) and tBuOH (0.148 g,
2.00 mmol) afforded after purification by column chromatography on
silica gel (hexane/ethyl acetate 19:1 to 9:1) 23 (0.193 g, 80%) as a colour-
less solid. M.p.=114–1168C; 1H NMR (CDCl3, 500 MHz): d=7.22–7.09
(m, 3H; Ar), 7.02 (d, J=7.7 Hz, 1H; Ar), 6.52 (d, J=9.5 Hz, 1H; =CH),
6.18 (dd, J=9.5, 5.2 Hz, 1H; =CH), 3.30–3.22 (m, 1H; CH), 2.65 (dd, J=
7.0, 5.2 Hz, 1H; CH), 2.42–2.28 (m, 1H; CH2), 2.04–1.89 (m, 1H; CH2),
1.80–1.70 (m, 1H; CH), 1.65–1.60 (m, 1H; CH2), 1.60–1.55 (m, 2H;
CH2), 1.55–1.20 ppm (m, 5H; CH2); 13C NMR (CDCl3, 126 MHz): d=
137.2, 134.4 (2s; Ar), 129.9, 128.5 (2d; =CH), 127.4, 126.2, 126.0, 124.1
(4d; Ar), 84.1 (s; C-3a), 47.6, 44.2, 36.5 (3d; CH), 33.2, 29.1, 28.0, 24.4,
rac-(3aR,3bR,9bR,11aS)-7-Methoxy-1,2,3,3b,9b,10,11,11a-octahydro-3aH-
cyclopenta[a]phenanthren-3a-ol (28): According to the general proce-
dure, samarium (0.180 g, 1.20 mmol), 1,2-diiodoethane (0.310 g,
1.10 mmol), HMPA (1.61 g, 9.00 mmol), 27 (0.134 g, 0.50 mmol) and
tBuOH (0.074 g, 1.00 mmol) afforded, after purification by column chro-
matography on silica gel (hexane/ethyl acetate 19:1 to 9:1), 28 as a pale-
1
yellow oil (0.038 g, ꢁ28%, purity 80–90%). H NMR (CDCl3, 270 MHz):
d=7.19–7.05 (m, 3H; Ar), 6.44 (dd, Jꢁ9.5, 2.7 Hz, 1H; =CH), 6.20 (brd,
Jꢁ9.5 Hz, 1H; =CH), 3.20–3.00 (m, 1H; CH), 3.75 (s, 3H; OCH3), 2.49
(m, 1H; CH), 2.37–1.01 ppm (m, 12H; CH, CH2, OH).
rac-(4aR,10bR,12aR)-1,3,4,4b,10b,11,12,12a-Octahydro-4aH-spiro[chry-
sene-2,2’-[1,3]dioxolan-4a-ol
3,7,8,8a,9,11,12,12b-octahydro-12aH-spiro
(30)
and
[benzo
rac-(8aR,12aS,12bS)-
[4,5]cyclohepta[1,2,3-
G
G
ACHTREUNG
19.8 ppm (5t; CH2); IR (KBr): n˜ =3380 (OH), 3050–2800 cmꢀ1 (=C H,
ꢀ
de]naphthalene-10,2’-[1,3]dioxolan]-12a-ol (31): According to the general
procedure, samarium (1.13 g, 7.52 mmol), 1,2-diiodoethane (1.79 g,
6.37 mmol), HMPA (8.93 g, 49.9 mmol), 29 (0.860 g, 2.77 mmol) and
tBuOH (0.406 g, 5.48 mmol) afforded, after column chromatography on
silica gel (hexane/ethyl acetate 3.5:1 to 3:1) and preparative HPLC
(hexane/ethyl acetate 7:3), 30 (0.166 g, 19%) and 31 (0.060 g, 7%), both
as a colourless solid.
Compound 30: M.p. 123–1258C; 1H NMR (CDCl3, 500 MHz): d=7.25
(d, J=7.4 Hz, 1H; Ar), 7.20 (dt, J=7.4, 1.3 Hz, 1H; Ar), 7.14 (m, 1H;
Ar), 7.02 (dd, J=7.4, 1.0 Hz, 1H; Ar), 6.63 (d, J=9.7 Hz, 1H; CH=CH),
6.16 (dd, J=9.7, 5.9 Hz, 1H; CH=CH), 3.90–3.78 (m, 4H; OCH2), 3.27
(m, 1H; CH2), 2.48 (m, 2H; CH2, CH), 2.16 (dd, J=13.8, 5.7 Hz, 1H;
CH2), 1.99 (qd, J=13.8, 2.6 Hz, 1H; CH2), 1.77–1.68 (m, 3H; CH2, CH),
1.52 (ddd, J=13.8, 6.7, 3.4 Hz, 1H; CH2), 1.45 (dt, J=13.8, 2.6 Hz, 1H;
CH2), 1.42–1.38 (m, 1H; CH2), 1.35–1.30 (m, 2H; CH2), 1.19 ppm (td, J=
13.8, 4.1 Hz, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=137.6, 134.7
(2s; Ar), 130.3, 128.8 (2d; =CH), 127.8, 126.3, 125.9, 123.6 (4d; Ar),
+
+
ꢀ
C H); MS (EI, 80 eV): m/z (%): 240 (52) [M] , 223 (3) [MꢀH2O] , 154
(49), 129 (62), 128 (100) [C10H8]+; HRMS (80 eV): calcd for C17H20O:
240.1514; found: 240.1537. elemental analysis calcd (%) for C17H20O
(240.4): C 84.96, H 8.39; found: 84.67, H 8.25.
rac-(4aR,4bR,10bR,12aS)-1,3,4,4b,10b,11,12,12a-Octahydrobenzo[a]phen-
anthren-4a(2H)-ol (24): According to the general procedure, samarium
(0.361 g, 2.40 mmol), 1,2-diiodoethane (0.620 g, 2.20 mmol), HMPA
(3.23 g, 18.0 mmol), 21c (0.252 g, 1.00 mmol) and tBuOH (0.148 g,
2.00 mmol) afforded, after purification by column chromatography on
silica gel (hexane/ethyl acetate from 19:1 to 9:1), product 24 (0.245 g,
96%) as
a
colourless solid. M.p. 106–1088C; 1H NMR (CDCl3,
500 MHz): d=7.20–7.10 (m, 3H; Ar), 7.01 (d, J=7.5 Hz, 1H; Ar), 6.51
(d, J=9.8 Hz, 1H; =CH), 6.18 (dd, J=9.8, 5.7 Hz, 1H; =CH), 3.25 (m,
1H; CH), 2.63 (dd, J=7.0, 5.7 Hz, 1H; CH), 2.37–2.30 (m, 1H; CH2),
2.00–1.90 (m, 1H; CH2), 1.79–1.72 (m, 1H; CH), 1.68–1.54 (m, 5H; CH2,
OH), 1.46–1.20 ppm (m, 6H; CH2); 13C NMR (CDCl3, 126 MHz): d=
137.2, 134.4 (2s; Ar), 129.9, 128.4 (2d; =CH), 127.3, 126.2, 125.9, 124.1
(4d; Ar), 84.0 (s; C-4a), 47.5, 44.1, 36.5 (3d; CH), 33.2, 29.0, 26.4, 24.4,
19.8, 19.7 ppm (6t; CH2); IR (KBr): n˜ =3365 (OH), 3000–2800 cmꢀ1 (=
ꢀ ꢀ
108.6 (s, O C O), 74.0 (s; C-4a), 64.3, 63.6 (2t; OCH2), 47.7, 44.7, 37.0
(3d; CH), 35.7, 30.3, 26.4, 26.0, 25.6 ppm (5t; CH2); IR (KBr): n˜ =3460
(OH), 3030–2870 (=CH, CH), 1595 cmꢀ1 (C=C); MS (EI, 80 eV): m/z
(%): 312 (49) [M]+, 294 (25) [MꢀH2O]+, 99 (100); HRMS (80 eV): calcd
for C20H24O3: 312.17255; found: 312.17355.
ꢀ
ꢀ
C H, C H); elemental analysis calcd (%) for C18H22O (254.4): C 84.99,
H 8.72; found: C 84.90, H 8.58.
1
Compound 31: M.p. 143–1488C; H NMR (CDCl3, 500 MHz): d=7.09 (t,
rac-(4bR,6aS,11aR,11bR)-4b,5,6,6a,7,8,9,10,11,11b-Decahydro-11aH-cy-
clohepta[a]phenanthren-11a-ol (25): According to the general procedure,
samarium (0.361 g, 2.40 mmol), 1,2-diiodoethane (0.620 g, 2.20 mmol),
HMPA (3.23 g, 18.0 mmol), 21d (0.266 g, 1.00 mmol) and tBuOH
(0.148 g, 2.00 mmol) afforded, after purification by column chromatogra-
phy on silica gel (hexane/ethyl acetate 19:1 to 9:1), 25 (0.263 g, 98%) as
a colourless solid. M.p. 109–1118C; 1H NMR (CDCl3, 500 MHz): d=
7.16–7.08 (m, 3H; Ar), 7.03–6.98 (m, 1H; Ar), 6.45 (dd, J=9.9, 2.7 Hz,
1H; =CH), 6.06 (dd, J=9.9, 3.3 Hz, 1H; =CH), 3.17 (m, 1H; CH), 2.53
(m, 1H; CH), 1.97–1.15 ppm (m, 16H; CH, CH2, OH); 13C NMR
(CDCl3, 126 MHz): d=139.9, 133.1 (2s; Ar), 129.0, 127.8, 127.4, 126.2*,
125.9 (5d; Ar, =CH), 76.5 (s; C-11a), 46.5, 44.6, 37.3 (3d; CH), 33.3, 29.8,
29.5, 29.1, 24.4, 20.8, 19.7 ppm (7t; CH2), *=signal with higher intensity;
J=7.5 Hz, 1H; Ar), 6.97 (m, 2H; Ar), 6.11 (dddd, J=10.0, 4.9, 2.2,
0.7 Hz, 1H; CH2), 6.06 (dddd, J=10.0, 4.9, 3.0, 0.5 Hz, 1H; CH2), 3.86–
3.76 (m, 4H; OCH2), 3.73–3.71 (m, 1H; CH), 3.33 (m, 1H; CH2), 3.28
(m, 1H; CH2), 3.06 (ddd, J=14.9, 11.0, 7.3 Hz, 1H; CH2), 2.75 (ddd, J=
14.9, 11.0, 1.9 Hz, 1H; CH2), 1.85–1.84 (m, 1H; CH2), 1.82–1.75 (m, 3H;
CH2), 1.65 (brs, 1H; OH), 1.57–1.52 (m, 1H; CH2), 1.50–1.41 (m, 2H;
CH2, CH), 1.29 (dt, J=13.1, 3.1 Hz, 1H; CH2), 1.17 ppm (td, J=13.9,
4.5 Hz, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=139.1, 134.2, 133.8
(3s; Ar), 127.3 (d; =CH), 126.8, 126.6, 126.5 (3d; Ar), 126.3 (d; =CH),
ꢀ ꢀ
108.9 (s; O C O), 64.3, 64.2 (2t; OCH2), 48.3, 38.9 (2d; CH), 37.7, 31.4,
ꢀ
31.0, 30.5, 30.4, 25.5 ppm (6t; CH2). IR (KBr): n˜ =3540–3470 (O H),
ꢀ1
ꢀ
3030–2820 (=CH, C H), 1590 cm (C=C); elemental analysis calcd (%)
IR (KBr): n˜ =3435 (OH), 3060–2800 cmꢀ1 (=C H, C H); elemental anal-
ysis calcd (%) for C19H24O (268.4): C 85.03, H 9.01; found: C 84.90, H
8.58.
for C20H24O3 (312.4): C 76.89, H 7.74; found C 76.55, H 7.45.
ꢀ
ꢀ
rac-(4a’R,12a’R,12b’R)
(34a)
and
rac-(4a’R,12a’S,12b’R)-
1’,2’,4’,4a’,5’,6’,12’,12a’-Octahydro-12b’H-spiro[1,3-dioxolane-2,3’-tetra-
phen]-12b’-ol (34b): According to the general procedure, samarium
(1.01 g, 6.72 mmol), 1,2-diiodoethane (1.75 g, 6.20 mmol), HMPA (8.00 g,
44.6 mmol), 33 (0.771 g, 2.48 mmol) and tBuOH (0.363 g, 4.89 mmol) af-
forded 34a as a colourless solid (0.473 g, 61%) and 34b as a colourless
oil (0.087 g, 11%), after column chromatography on silica gel (hexane/
ethyl acetate 3:1). Compound 34a was further purified by repeated wash-
ing of the solid with cold Et2O. Compound 34b was purified by prepara-
tive HPLC (hexane/ethyl acetate 4:1).
Compound 34a: M.p. 151–1538C; 1H NMR (CDCl3, 500 MHz): d=7.04–
7.03 (m, 3H; Ar), 6.90 (dd, J=6.4, 1.3 Hz, 1H; Ar), 6.16 (s, 1H; =CH),
3.90–3.81 (m, 4H; OCH2), 3.20 (dd, J=17.3, 2.1 Hz, 1H; CH2), 3.10 (dd,
J=17.3, 10.4 Hz, 1H; CH2), 2.43 (d, J=10.4 Hz, 1H; CH), 2.37 (ddd, J=
12.2, 4.3, 2.2 Hz, 1H; CH2), 2.22 (dd, J=14.1, 5.9 Hz, 1H; CH2), 2.16 (dd,
J=13.1, 5.0 Hz, 1H; CH2), 2.03 (dd, J=13.1, 4.3 Hz, 1H; CH2), 1.80–1.74
rac-(4bR,6aS,11aR,12bR)-4b,6,6a,7,8,9,10,11,12,12b-Decahydrocyclooc-
ta[a]phenanthren-12(5H)-ol (26): According to the general procedure,
samarium (0.180 g, 1.20 mmol), 1,2-diiodoethane (0.310 g, 1.10 mmol),
HMPA (1.61 g, 9.00 mmol), 21e (0.140 g, 0.50 mmol) and tBuOH
(0.074 g, 1.00 mmol) afforded after purification by column chromatogra-
phy on silica gel (hexane/ethyl acetate 9:1 to 7:3) and preparative HPLC
(hexane/ethyl acetate 17:3) 26 (0.073 g, 52%, purity ꢁ90%) as a colour-
less oil. 1H NMR (CDCl3, 500 MHz): d=7.26 (brd, Jꢁ7.5 Hz, 1H; Ar),
7.16 (td, J=7.5, 1.3 Hz, 1H; Ar), 7.09, 6.99 (2tt, J=7.3, 1.3 Hz, 1H each;
Ar), 6.56 (d, J=9.8 Hz, 1H; =CH), 6.12 (dd, J=9.8, 6.0 Hz, 1H; =CH),
3.19 (m, 1H; CH), 2.56–2.50 (m, 2H; CH2), 2.38 (m, 1H; CH), 1.85–
0.86 ppm (m, 16H; CH, CH2, OH); 13C NMR (CDCl3, 126 MHz): d=
138.9, 135.4 (2s; Ar), 131.2, 129.8, 127.5, 125.9, 125.5, 122.9 (6d; Ar, =
CH), 63.1 (s; C-12), 42.8, 42.0, 35.6 (3d; CH), 32.3, 30.0, 29.6, 28.4, 26.6,
6058
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6047 – 6062

Samarium Diiodide Induced Cyclisations
FULL PAPER
1
(m, 2H; CH2, CH), 1.70–1.60 (m, 2H; CH2), 1.45–1.41 (m, 2H; CH2),
1.38 (brs, 1H; OH), 1.35 ppm (dq, J=14.1, 2.2 Hz, 1H; CH2); 13C NMR
(CDCl3, 126 MHz): d=140.3 (s; C=CH), 133.5, 133.3 (2s; Ar), 127.1,
Compound 49b: M.p. 187–1908C; H NMR (CD3OD, 500 MHz): d=7.62
(d, J=7.7 Hz, 1H; Ar), 7.17–7.10 (m, 3H; Ar), 5.77 (m, 1H; =CH), 3.64
(td, J=10.3, 5.7 Hz, 1H; NCH2), 3.60–3.57 (m, 1H; CH2), 3.50–3.35 (m,
2H; CH2, CH), 3.16 (dd, J=12.5, 11.7 Hz, 1H; CH2), 3.12 (dd, J=10.3,
7.1 Hz, 1H; CH2), 2.65 (d, J=11.7 Hz, 1H; CH2), 2.35 (ddd, J=12.5, 3.9,
2.8 Hz, 1H; CH2), 2.20 (quint., Jꢁ6 Hz, 1H; CH), 2.14 (m, 1H; CH2),
2.02–1.97 (m, 1H; CH2), 1.40, 1.35 (2s, ꢁ4.5H each; tBu), 1.20 ppm (dt,
J=12.9, 3.9 Hz, 1H; CH2); 13C NMR (CD3OD, 126 MHz): d=155.8 (s;
CO), 136.6, 133.6, 133.5, 133.1, 133.0 (5s; C=CH, Ar), 130.3, 130.2, 127.9,
127.8, 126.2, 126.1, 125.2, 125.1, 119.1, 119.0 (10 d; =CH, Ar), 83.9, 83.2
ꢀ ꢀ
126.6, 126.1, 125.6 (4d; Ar), 121.3 (d; =CH), 108.5 (s; O C O), 75.8 (s;
C-12b’), 64.3, 63.4 (2t; OCH2), 48.9, 45.3 (2d; CH), 35.5, 35.4, 31.4, 29.5,
ꢀ
26.2, 23.7 ppm (6t; CH2); IR (KBr): n˜ =3430 (OH), 3075–2840 (=CH, C
H), 1595 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 312 (14) [M]+, 294 (7)
[MꢀH2O]+, 156 (100); HRMS (80 eV): calcd for C20H24O3: 312.17255;
found: 312.17325; elemental analysis calcd (%) for C20H24O3 (312.4): C
76.89, H 7.74; found: C 76.17, H 7.56.
Compound 34b: 1H NMR (CDCl3, 500 MHz): d=7.38 (m, 1H; Ar),
7.20–7.15 (m, 3H; Ar), 5.68–5.67 (m, 1H; =CH), 4.00–3.82 (m, 4H;
OCH2), 3.44–3.27 (m, 3H; CH2, CH), 2.36–2.33 (m, 1H; CH2), 2.28 (dd,
J=13.6, 5.2 Hz, 1H; CH2), 2.13–2.04 (m, 3H; CH2, CH), 1.86 (dt, J=
14.0, 3.8 Hz, 1H; CH2), 1.77 (dd, J=13.1, 4.2 Hz, 1H; CH2), 1.74–1.71
(m, 1H; CH2), 1.64 (brs, 1H; OH), 1.48–1.42 (m, 2H; CH2), 0.81 ppm
(m, 1H; CH2); 13C NMR (CDCl3, 126 MHz): d=137.7 (s; C=CH), 135.8,
133.7 (2s; Ar), 129.1, 128.6, 126.5, 125.9 (4d; Ar), 117.8 (d; =CH), 108.9
ꢀ
(2s; tBu), 79.5, 79.4 (2s; C O), 51.5, 50.9, 47.7 (3t; CH2), 46.7 (d; CH),
34.3, 32.2, 32.1 (3t; CH2), 29.8 (d; CH), 27.4, 27.3 ppm (2q; tBu); IR
ꢀ
(KBr): n˜ =3435 (OH), 3065–2860 (=CH, C H), 1700–1695 (C=O),
1615 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 341 (3) [M]+, 285 (17)
[MꢀC4H8]+, 57 (100) [C4H9]+; HRMS (80 eV): calcd for C21H27NO3:
341.19910; found: 341.19855.
rac-(4aS,4bR,10bR,12aR)-2-Methyl-1,3,4,4b,10b,11,12,12a-octahydro-
A
N
ꢀ ꢀ
(s; O C O), 77.0 (s; C-12b’), 64.4, 63.6 (2t; OCH2), 53.4, 43.7 (2d; CH),
dure, samarium (0.537 g, 3.57 mmol), 1,2-diiodoethane (0.919 g,
3.28 mmol), HMPA (4.22 g, 23.6 mmol), 50 (0.350 g, 1.31 mmol) and
tBuOH (0.200 g, 2.69 mmol) afforded, after column chromatography on
neutral alumina (hexane/ethyl acetate 3:1), 51 as a colourless solid. The
product was further purified by repeated washing with cold Et2O
(0.199 g, 56%). M.p. 124–1288C; 1H NMR (CD3OD, 500 MHz): d=7.28
(d, J=7.5 Hz, 1H; Ar), 7.17 (td, J=7.5, 1.2 Hz, 1H; Ar), 7.10 (t, J
ꢁ7.3 Hz, 1H; Ar), 7.01 (brd, J=7.3 Hz, 1H; Ar), 6.63 (d, J=9.7 Hz, 1H;
=CH), 6.16 (dd, J=9.7, 6.1 Hz, 1H; =CH), 3.25 (m, 1H; CH), 2.60–2.54
(m, 1H; CH2), 2.54 (dd, J=11.4, 3.5 Hz, 1H; CH2), 2.45 (t, Jꢁ6.5 Hz,
1H; CH), 2.37 (m, 1H; CH2), 2.27–2.23 (m, 1H; CH2), 2.12–2.07 (m, 1H;
CH2), 2.05 (s, 3H; NCH3), 2.02–1.95 (m, 1H; CH2), 1.82–1.75 (m, 1H;
CH2), 1.55 (m, 2H; CH, CH2), 1.32 (m, 1H; CH2), 1.19 ppm (dt, J=13.4,
3.9 Hz, 1H; CH2); 13C NMR (CD3OD, 126 MHz): d=134.8, 132.7 (2s;
Ar), 127.4, 126.8 (2d; =CH), 125.1, 123.8, 123.5, 121.0 (4d; Ar), 69.0 (s;
COH), 54.4, 49.2 (2t; CH2), 44.7 (d; CH), 43.1 (q; NCH3), 42.1, 34.7 (2d;
35.6, 35.5, 31.9, 30.7, 29.8, 24.8 ppm (6t; CH2); IR (film): n˜ =3465 (OH),
3055–2875 (=CH, CH), 1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 313
(3) [M+H]+, 312 (13) [M]+, 294 (8) [MꢀH2O]+, 156 (100); HRMS
(80 eV): calcd for C20H24O3: 312.17255; found: 312.17366.
tert-Butyl rac-(3aS,3bR,9bR,11aR)-3a-hydroxy-1,3,3a,3b,9b,10,11,11a-oc-
tahydro-2H-naphtho[2,1-e]isoindole-2-carboxylate (48): According to the
N
general procedure, samarium (0.159 g, 1.06 mmol), 1,2-diiodoethane
(0.250 g, 0.90 mmol), HMPA (1.16 g, 6.46 mmol), 44 (0.122 g, 0.36 mmol)
and tBuOH (0.055 g, 0.74 mmol) afforded, after column chromatography
on silica gel (hexane/ethyl acetate 3:1 to 1:1) and preparative HPLC
(hexane/isopropanol 95:5), 48 as a colourless solid (0.035 g, 29%).[54]
M.p.=157–1608C; 1H NMR (CD3CN, 500 MHz): d=7.29–7.24 (m, 1H;
Ar), 7.23–7.16 (m, 2H; Ar), 7.08 (td, J=7.0, 1.3 Hz, 1H; Ar), 6.57 (dd,
J=9.9, 3.6 Hz, 1H; =CH), 6.20–6.11 (m, 1H; =CH), 3.46 (dd, J=10.5,
6.3 Hz, 1H; CH2), 3.27 (m, 1H; CH), 3.01 (m, 2H; OH, CH2), 2.93 (d,
J=12.0 Hz, 1H; CH2), 2.78 (m, 1H; CH2), 2.68–2.65 (m, 1H; CH), 2.45–
2.36 (m, 1H; CH2), 2.05–1.95 (m, 1H; CH), 1.70–1.67 (m, 2H; CH2),
1.35, 1.27 (2s, ꢁ4.5H each; tBu), 1.23–1.20 ppm (m, 1H; CH2); 13C NMR
(CD3CN, 126 MHz): d=155.5, 155.4 (2s; CO), 135.2, 130.4 (2s; Ar),
130.2, 129.4 (2d; =CH), 128.8, 127.4, 127.3, 125.5 (4d; Ar), 80.1 (s; C-3a),
79.3 (s; tBu), 54.8, 54.1, 51.7, 51.1 (4t; NCH2), 46.7, 46.0, 44.0, 43.9, 37.2,
37.1 (6d; CH), 28.6, 28.5 (2q; tBu), 25.9, 25.5 (2d; CH), 24.8, 24.4 ppm
CH), 25.6, 22.8, 22.7 ppm (3t; CH2); IR (KBr): n˜ =3390 (OH), 3030–2800
ꢀ1
(=CH, C H), 1595 cm (C=C); MS (EI, 80 eV): m/z (%): 269 (17) [M]+,
ꢀ
268 (8) [MꢀH]+, 28 (100); HRMS (80 eV): calcd for C18H23NO:
269.17798; found: 269.17844.
rac-(4aR,12aR,12bS)-
2,3,4,4a,5,6,12,12a-octahydronaphtho
and
rac-(4aR,12aS,12bS)-3-Methyl-
[2,3-f]isoquinolin-12b(1H)ol (53a)
AHCTREUNG
ꢀ
(2t; CH2); IR (KBr): n˜ =3360 (OH), 3055–2850 (=CH, C H), 1670–
and (53b): According to the general procedure, samarium (0.316 g,
2.10 mmol), 1,2-diiodoethane (0.544 g, 1.93 mmol), HMPA (2.48 g,
13.9 mmol), 52 (0.205 g, 0.77 mmol) and tBuOH (0.109 g, 1.47 mmol) af-
forded, after column chromatography on neutral alumina (hexane/ethyl
acetate from 3:1 to 2:1), 53a as a colourless solid, which was further puri-
fied by repeated washing with cold Et2O (0.080 g, 39%) and 53b as a col-
ourless oil (0.041 g, 20%).
Compound 53a: M.p. 160–1658C; 1H NMR (CDCl3, 500 MHz): d=7.26–
7.02 (m, 3H; Ar), 6.90 (m, 1H; Ar), 6.19 (s, 1H; =CH), 3.19 (dd, J=17.4,
2.3 Hz, 1H; CH2), 3.07 (dd, J=17.4, 10.5 Hz, 1H; CH2), 2.48–2.37 (m,
5H; CH2, CH), 2.22 (dd, J=13.3, 5.0 Hz, 1H; CH2), 2.16 (s, 3H; NCH3),
2.08–1.94 (m, 2H; CH2), 1.80–1.71 (m, 2H; CH2), 1.69 (brs, 1H; OH),
1.57 (m, 1H; CH), 1.23 ppm (dd, J=14.2, 2.3 Hz, 1H; CH2); 13C NMR
(CDCl3, 126 MHz): d=140.3, 133.4, 133.3 (3s, C=CH; Ar), 127.0, 126.5,
126.1, 125.5 (4d; Ar), 121.5 (d; =CH), 73.8 (d; C-12b), 57.0, 51.5 (2t;
CH2), 48.6 (d; CH), 46.5 (q; NCH3), 45.1 (d; CH), 34.9, 30.4, 26.7,
1660 cmꢀ1 (C=O); MS (EI, 80 eV): m/z (%): 341 (6) [M]+, 57 (100)
[C4H9]+; HRMS (80 eV): calcd for C21H27NO3: 341.19910; found:
341.19879.
tert-Butyl rac-(3aR,11aR,11bS)- and rac-(3aR,11aS,11bS)-11b-hydroxy-
1,3,3a,4,5,11,11a,11b-octahydro-2H-naphtho[2,3-e]isoindole-2-carboxylate
G
(49a) and (49b): According to the general procedure, samarium (0.113 g,
0.75 mmol), 1,2-diiodoethane (0.203 g, 0.72 mmol), HMPA (0.93 g,
5.20 mmol), 47 (0.098 g, 0.29 mmol) and tBuOH (0.041 g, 0.56 mmol) af-
forded after purification by column chromatography on silica gel
(hexane/ethyl acetate 3:1 to 1:1) 49a (0.027 g, 27%) and 49b as colour-
less solids (0.022 g, 22%).
Compound 49a: M.p. 185–1888C; 1H NMR (CD3OD, 500 MHz): d=
7.06–7.04 (m, 3H; Ar), 6.93 (m, 1H; Ar), 6.27 (s, 1H; =CH), 3.61 (td, J=
9.9, 5.6 Hz, 1H; NCH2), 3.15–2.92 (m, 5H; CH2), 2.73–2.67 (m, 1H; CH),
2.41 (dt, J=13.3, 3.1 Hz, 1H; CH2), 2.24 (td, J=13.3, 4.4 Hz, 1H; CH2),
2.05 (m, 1H; CH), 1.94 (m, 1H; CH2), 1.41, 1.35 (2s, ꢁ4.5H each; tBu),
1.23–1.12 ppm (m, 1H; CH2); 13C NMR (CD3OD, 126 MHz): d=155.8 (s,
CO), 139.7, 139.6, 134.5, 134.4, 133.6, 133.5 (6s; C=CH, Ar), 128.1, 128.0,
127.6, 127.5, 127.2, 127.1, 126.4, 126.3 (8d; Ar), 123.4, 123.3 (2d; =CH),
83.3, 82.6 (2s; tBu), 80.5, 80.4 (2s; C-11b), 52.3, 51.8, 51.2 (3t; NCH2),
47.7, 46.9, 45.4, 45.3 (4d; CH), 34.0, 33.9, 32.0, 31.8 (4t; CH2), 28.4, 28.3
ꢀ
25.8 ppm (4t; CH2); IR (KBr): n˜ =3310 (OH), 2930–2800 (=CH, C H),
1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 269 (53) [M]+, 268 (10)
[MꢀH]+, 58 (100); HRMS (80 eV): calcd for C18H23NO: 269.17798;
found: 269.17758.
1
Compound 53b: H NMR (CDCl3, 250 MHz): d=7.19–7.13 (m, 1H; Ar),
7.05–7.00 (m, 3H; Ar), 5.68 (s, 1H; =CH), 3.22–3.15 (m, 1H; CH2), 3.07
(dd, J=17.4, 10.5 Hz, 1H; CH2), 2.57–2.34 (m, 5H; CH2, CH), 2.37–2.22
(m, 1H; CH2), 2.20 (s, 3H; NCH3), 2.09–1.88 (m, 2H; CH2), 1.86–1.67
(m, 3H; OH, CH2), 1.23 (d, J=14.0 Hz, 1H; CH2), 0.67 ppm (brd,
Jꢁ12.0 Hz, 1H; CH).
(2q; tBu), 28.2, 28.0 ppm (2t; CH2); IR (KBr): n˜ =3400 (OH), 3095–2885
ꢀ1
ꢀ
(=CH, C H), 1690–1670 (C=O), 1600 cm (C=C); MS (EI, 80 eV): m/z
(%): 341 (6) [M]+, 285 (23) [MꢀC4H8]+, 240 (10) [MꢀC5H9O2]+, 57
(100) [C4H9]+; HRMS (80 eV): calcd for C21H27NO3: 341.19910; found:
341.19877.
Chem. Eur. J. 2007, 13, 6047 – 6062
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6059

H.-U. Reißig et al.
Subsequent reactions of cyclisation products
(CDCl3, 270 MHz): d=7.24–7.09 (m, 4H; Ar), 3.14 (m, 1H; CH), 2.96–
2.74 (m, 3H; CH, CH2), 2.19–1.48 ppm (m, 14H; CH, CH2, OH);
13C NMR (CDCl3, 67.9 MHz): d=141.2, 137.1 (2s; Ar), 128.4, 127.7,
125.8, 125.6 (4d; Ar), 82.6 (s; C-3a), 46.1, 44.2, 37.2 (3d; CH), 36.8, 30.0,
General procedure for the ketal cleavage: To a solution of the corre-
sponding ketal (30, 34a, 34b) in Et2O (10 mLmmolꢀ1) was added a 50%
aq solution of H2SO4 (10 mLmmolꢀ1). The mixture was vigorously stirred
for 2 h at RT and then neutralized with a saturated solution of sodium
hydrogencarbonate. The product was then repeatedly extracted with
ethyl acetate and the combined organic layers were dried with MgSO4,
filtered and the solvent was removed under reduced pressure.
28.3, 26.7, 25.2, 22.0, 20.5 ppm (7t; CH2); IR (KBr): n˜ =3380 (OH),
+
3050–2800 cmꢀ1 (=C H, C H); MS (EI, 80 eV): m/z (%): 242 (45) [M] ,
224 (100) [MꢀH2O]+, 200 (26) [MꢀC2H2O]+; HRMS (80 eV): calcd for
C17H22O: 242.1670; found: 242.1666.
ꢀ
ꢀ
rac-(3aR,11aS)-1,2,3,10,11,11a-Hexahydro-3aH-cyclopenta[a]phenanth-
ren-3a-ol (37): A mixture of 23 (0.100 g, 0.417 mmol) and MnO2 (0.869 g,
10.0 mmol) in THF (25 mL) was stirred and heated under reflux. After
2 h, a second portion of MnO2 (0.869 g, 10.0 mmol) was added, and the
suspension heated further for 2 h. After cooling to RT, the mixture was
filtered through Celite, evaporated and the residue dissolved in CH2Cl2.
The solution was washed with HCl (1N) and distilled water, dried with
MgSO4, filtered and the solvent was evaporated. The crude residue was
purified by column chromatography on silica gel (hexane/ethyl acetate
9:1) to afford 37 as a colourless solid (0.073 g, 73%). M.p. 93–958C;
1H NMR (CDCl3, 270 MHz): d=7.97, 7.79 (2d, J=8.1, 1H each; Ar),
7.73–7.63 (m, 2H; Ar), 7.54–7.42 (m, 2H; Ar), 3.72 (m, 1H; CH), 3.31
(dt, J=16.7, 4.6 Hz, 1H; CH2), 2.97 (ddd, J=16.7, 10.7, 5.5 Hz, 1H;
CH2), 2.35–1.22 ppm (m, 9H; CH2, OH); 13C NMR (CDCl3, 67.9 MHz):
d=138.7, 132.4, 131.5, 131.2 (4s; Ar), 128.3, 126.7, 126.0, 125.4*, 123.7
(5d; Ar), 82.2 (s; C-3a), 47.9 (d; CH), 40.5, 30.3, 28.4, 24.8, 22.1 ppm (5t;
rac-(4aR,4bR,10bR,12aR)-4a-Hydroxy-3,4,4a,4b,10b,11,12,12a-octahydro-
chrysen-2(1H)one (32): According to the general procedure above, 30
(0.166 g, 0.531 mmol) afforded, after column chromatography on silica
gel (hexane/ethyl acetate 3:1), 32 as a colourless solid (0.136 g, 95%).
M.p. 178–1808C; 1H NMR (CD3CN, 500 MHz): d=7.25 (d, J=7.3 Hz,
1H; Ar), 7.20 (td, Jꢁ7.3, J=1.3 Hz, 1H; Ar), 7.15 (td, Jꢁ7.3, J=1.0 Hz,
1H; Ar), 7.06 (m, 1H; Ar), 6.67 (d, J=9.8 Hz, 1H; =CH), 6.25 (dd, J=
9.8, 6.0 Hz, 1H; =CH), 3.31 (brt, Jꢁ6.3 Hz, 1H; CH), 2.99 (dd, J=14.0,
6.4 Hz, 1H; CH2), 2.83 (s, 1H; OH), 2.57 (m, 1H; CH), 2.54–2.52 (m,
1H; CH2), 2.48 (m, 1H; CH2), 2.00–1.95 (m, 1H; CH), 1.84 (dt, J=14.0,
2.2 Hz, 1H; CH2), 1.83–1.81 (m, 1H; CH2), 1.70–1.68 (m, 2H; CH2), 1.61
(m, 1H; CH2), 1.34–1.26 (m, 1H; CH2), 1.23 ppm (dd, J=14.2, 5.2 Hz,
1H; CH2); 13C NMR (CD3CN, 126 MHz): d=212.3 (s; CO), 138.2, 135.8
(2s; Ar), 130.8, 130.4, 128.6, 127.2, 127.0, 124.1 (6d; =CH, Ar), 73.7 (s;
C-4a), 48.1, 47.6 (2d; CH), 44.1 (t; CH2), 37.5 (d; CH), 37.3, 28.7, 27.7,
ꢀ
25.6 ppm (4t; CH2); IR (KBr): n˜ =3510 (OH), 3070–2835 (=CH, C H),
1690 cmꢀ1 (C=O); elemental analysis calcd (%) for C18H20O2 (268.4): C
CH2), *=signal with higher intensity; IR (KBr): n˜ =3380 (OH), 3050–
+
2800 cmꢀ1 (=C H, C H); MS (EI, 80 eV): m/z (%): 238 (100) [M] , 209
(99) [MꢀC2H5]+, 196 (90) [MꢀC2H2O]+; elemental analysis calcd for
C17H18O (238.3): C 85.67, H 7.61; found: C 85.15, H 7.47.
ꢀ
ꢀ
80.56, H 7.51; found: C 80.23, H 7.15.
rac-(4aR,12aR,12bR)-12b-Hydroxy-1,4,4a,5,6,12,12a,12b-octahydrotetra-
phen-3(2H)one (35a): According to the general procedure above, 34a
(0.400 g, 1.28 mmol) afforded, after column chromatography on silica gel
(hexane/ethyl acetate 4:1), 35a as a colourless solid (0.264 g, 77%). M.p.
144–1468C; 1H NMR (CD3CN, 500 MHz): d=7.10–7.02 (m, 3H; Ar),
6.90 (m, 1H; Ar), 6.19 (s, 1H; =CH), 3.25 (dd, J=17.5, 2.5 Hz, 1H;
CH2), 3.15 (dd, J=17.5, 10.5 Hz, 1H; CH2), 3.08 (dd, J=14.2, 6.1 Hz,
1H; CH2), 2.60–2.52 (m, 2H; CH2, CH), 2.40 (ddd, J=13.0, 4.5, 2.2 Hz,
1H; CH2), 2.23 (dt, J=13.0, 4.9 Hz, 1H; CH2), 2.14–2.10 (m, 1H; CH),
2.04–2.02 (m, 1H; CH2), 2.00 (dt, J=14.2, 2.0 Hz, 1H; CH2), 1.91 (s, 1H;
OH), 1.90–1.80 (m, 2H; CH2), 1.71 (ddt, J=14.6, 7.1, 2.0 Hz, 1H; CH2),
1.28 ppm (dq, J=13.3, Jꢁ4.5 Hz, 1H; CH2); 13C NMR (CD3CN,
126 MHz): d=211.8 (s; CO), 139.0, 133.1, 132.7 (3s; C=CH, Ar), 127.1,
126.9, 126.3, 125.8 (4d; Ar), 122.2 (d; =CH), 74.2 (s; C-12b), 48.4, 48.0
(2d; CH), 43.5, 36.2, 34.8, 31.8, 26.2, 26.0 ppm (6t; CH2); IR (KBr): n˜ =
3425–3385 (OH), 3060–2845 (=CH, CH), 1690 (C=O), 1600 cmꢀ1 (C=C);
MS (EI, 80 eV): m/z (%): 268 (28) [M]+, 250 (2) [MꢀH2O]+, 156 (100);
HRMS (80 eV): calcd for C18H20O2: 268.14633; found: 268.14533.
DDQ oxidation of 23: Compound 23 (0.100 g, 0.417 mmol) and DDQ
(0.191 g, 0.841 mmol) were dissolved in benzene (3 mL) and stirred at
reflux for 2 h. The reaction was then cooled to RT, and the solvent re-
moved under reduced pressure to leave the crude product, which was pu-
rified by column chromatography (hexane/ethyl acetate 9:1) to afford
21b as a colourless oil (0.071 g, 71%).
rac-(1aS,5bR,7aS,10aR,10bS,10cR)-1a,5b,6,7,7a,8,9,10,10b,10c-Decahy-
dro-10aH-cyclopenta
A
ACHTREUNG
(70%, 0.257 g, 1.05 mmol) was added to
a
1.00 mmol) in CH2Cl2 (1.5 mL) and the mixture was stirred at 08C for
30 min, then at RT. After 8 h, the solution was diluted with CH2Cl2
(10 mL), washed with NaOH (4N) and with distilled water. The organic
layer was separated, dried with MgSO4, filtered and the solvent was
evaporated to afford pure 39 as a colourless solid (0.256 g, quant.). M.p.
1
109–1108C; H NMR (CDCl3, 500 MHz): d=7.37 (d, J=7.4 Hz, 1H; Ar),
7.31–7.24 (m, 1H; Ar), 7.23–7.15 (m, 2H; Ar), 4.00 (dd, J=4.3, 2.6 Hz,
1H; CH), 3.85 (d, J=4.3 Hz, 1H; CH), 3.17–3.10 (m, 1H; CH), 2.75 (dd,
J=7.0, 2.6 Hz, 1H; CH), 2.45 (qd, J=14.0, 3.2 Hz, 1H; CH2), 2.01–1.91
(m, 1H; CH2), 1.79–0.94 (m, 8H; CH2, CH, OH), 0.82–0.69 ppm (m, 1H;
CH2); 13C NMR (CDCl3, 126 MHz): d=137.0, 133.1 (2s; Ar), 129.7,
128.8, 125.6, 124.3 (4d; Ar), 82.9 (s; C-10a), 55.6, 53.9, 49.5, 42.8 (4d;
CH), 31.8 (t; CH2), 31.1 (d; CH), 29.5, 28.3, 24.6, 20.0 ppm (4t; CH2); IR
rac-(4aR,12aS,12bR)-12b-Hydroxy-1,4,4a,5,6,12,12a,12b-octahydrotetra-
phen-3(2H)one (35b): According to the general procedure above, 34b
(0.087 g, 0.28 mmol) afforded, after column chromatography on silica gel
(hexane/ethyl acetate 4:1), 35b as a colourless solid (0.040 g, 53%).
M.p.=122–1248C; 1H NMR (CD3CN, 500 MHz): d=7.52–7.48 (m, 1H;
Ar), 7.20 (m, 1H; Ar), 7.18 (m, 1H; Ar), 7.15–7.12 (m, 1H; Ar), 5.70 (m,
1H; =CH), 3.44 (m, 1H; CH), 3.33 (m, 2H; CH2), 3.12 (d, J=0.8 Hz,
1H; OH), 3.09 (dd, J=14.1, 6.5 Hz, 1H; CH2), 2.46 (m, 1H; CH2), 2.36–
2.21 (m, 2H; CH, CH2), 2.19–2.15 (m, 1H; CH2), 2.01–1.96 (m, 1H;
CH2), 1.89–1.85 (m, 2H; CH2), 1.83–1.75 (m, 1H; CH2), 1.26 (dq, J=
13.3, 4.5 Hz, 1H; CH2), 1.12 ppm (ddt, J=14.3, 7.0, 2.1 Hz, 1H; CH2);
13C NMR (CD3CN, 126 MHz): d=212.1 (s; CO), 138.2, 136.0, 134.6 (3s;
C=CH; Ar), 131.5, 128.9, 127.2, 126.3 (4d; Ar), 119.6 (d; =CH), 77.0 (s;
C-12b), 53.5, 48.0 (2d; CH), 44.3, 36.9, 35.9, 33.2, 30.9, 27.5 ppm (6t;
CH2); IR (KBr): n˜ =3470 (OH), 3060–2850 (=CH, CH), 1700 (C=O),
1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 268 (65) [M]+, 250 (4)
[MꢀH2O]+, 156 (100); HRMS (80 eV): calcd for C18H20O2: 268.14633;
found: 268.14596; elemental analysis calcd for C18H20O2 (268.4): C 80.56,
H 7.51; found: C 79.87, H 7.35.
(KBr): n˜ =3365 (OH), 3065–2850 cmꢀ1 (=C H, C H); elemental analysis
calcd (%) for C17H20O2 (256.4): C 79.65, H 7.86; found: C 79.88, H 7.84.
ꢀ
ꢀ
rac-(3aS,11aS)-2,3,3a,10,11,11a-Hexahydro-1H-cyclopenta[a]phenan-
threne (40): Triethylsilane (0.027 g, 0.23 mmol) was added to a solution
of 23 (0.050 g, 0.21 mmol) in CH2Cl2 (2 mL) at ꢀ788C. Boron trifluoride
etherate (0.032 g, 0.23 mmol) was then added dropwise and the mixture
was stirred for 45 min at ꢀ788C and then for 3 h at RT. It was quenched
by addition of distilled water, the product was extracted in CH2Cl2, the
combined organic layers were dried with MgSO4, filtered and the solvent
was removed under reduced pressure. The crude product was purified by
column chromatography on silica gel (hexane 100%) to afford 40 as
pale-yellow oil (0.043 g, 93%). 1H NMR (CDCl3, 500 MHz): d=8.03,
7.82 (2d, J=8.1 Hz, 1H each; Ar), 7.67 (d, J=8.4 Hz, 1H; Ar), 7.52
(ddd, J=8.4, 6.8, 1.5 Hz, 1H; Ar), 7.45 (ddd, J=8.1, 6.8, 1.1 Hz, 1H;
Ar), 7.33 (d, J=8.4 Hz, 1H; Ar), 3.25 (dt, J=16.5, 4.6 Hz, 1H; CH2),
3.24–3.17 (m, 1H; CH), 2.97 (ddd, J=16.5, 10.8, 5.3 Hz, 1H; CH2), 2.37
(m, 1H; CH), 2.28 (m, 1H; CH2), 2.09–2.01 (m, 1H; CH2), 1.94–1.86 (m,
1H; CH2), 1.84–1.78 (m, 1H; CH2), 1.75–1.65 ppm (m, 4H; CH2);
rac-(3aR,3bR,9bR,11aS)-1,2,3,3b,4,5,9b,10,11,11a-Decahydro-3aH-cyclo-
penta[a]phenanthren-3a-ol (36): Compound 23 (0.240 g, 1.00 mmol) and
Pd/C (10%, 0.100 g) in MeOH (12 mL) were stirred at RT for 24 h under
a hydrogen atmosphere. Filtration through Celite and evaporation afford-
ed 36 as a colourless solid (0.238 g, 98%). M.p. 108–1118C; 1H NMR
6060
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 6047 – 6062

Samarium Diiodide Induced Cyclisations
FULL PAPER
13C NMR (CDCl3, 126 MHz): d=137.7, 131.9, 131.8, 131.3 (4s; Ar),
128.5, 128.3, 128.2, 125.8, 124.6, 123.2 (6d; Ar), 43.8, 36.9 (2d; CH), 34.4,
[9] a) S. Gross, H.-U. Reißig, Org. Lett. 2003, 5, 4305–4307; b) V. Blot,
H.-U. Reißig, Synlett 2006, 2763–2766; c) V. Blot, H.-U. Reißig, Eur.
J. Org. Chem. 2006, 4989–4992.
[10] a) Z. Hou, H. Aihara, A. Hosomi, J. Am. Chem. Soc. 1996, 118,
3533–3534; b) R. J. Enemaerke, T. Hertz, T. Skrydstrup, K. Daasb-
jerg, Chem. Eur. J. 2000, 6, 3747–3754.
ꢀ
ꢀ
32.0, 26.7, 24.8, 24.1 ppm (5t; CH2); IR (film): n˜ =3050–2870 (=C H, C
H), 1600 cmꢀ1 (C=C); MS (EI, 80 eV): m/z (%): 222 (100) [M]+, 194 (52)
[MꢀC2H2]+, 179 (60) [MꢀC3H7]+; HRMS (80 eV): calcd for C17H18
:
222.1409; found: 222.1413.
[11] The use of HMPA raises the reducing potential of samarium diio-
dide and is required for many ketyl coupling reactions. See: a) K.
Otsububo, J. Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986, 27,
5763–5764; b) J. Inanaga, M. Ishikawa, M. Yamaguchi, Chem. Lett.
1987, 1485–1486; c) M. Shabangi, R. A. Flowers II, Tetrahedron
Lett. 1997, 38, 1137–1140; d) J. B. Shotwell, J. M. Sealy, R. A. Flow-
ers II, J. Org. Chem. 1999, 64, 5251–5255; e) R. S. Miller, J. M.
Sealy, M. Shabangi, M. L. Kuhlman, J. Fuchs, R. A. Flowers II, J.
Am. Chem. Soc. 2000, 122, 7718–7722; f) E. Prasad, R A. . Flowers
II, J. Am. Chem. Soc. 2002, 124, 6895–6899; g) R. A. Flowers II, X.
Xu, C. Timmons, G. Li, Eur. J. Org. Chem. 2004, 2988–2990; h) A.
DahlØn, G. Hilmersson, Eur. J. Inorg. Chem. 2004, 3393–3404.
There has been no general success by replacing HMPA with less
toxic cosolvents.
[12] For related samarium ketyl cyclisations see: a) H.-G. Schmalz, S.
Siegel, J. W. Bats, Angew. Chem. 1995, 107, 2597–2599; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2383–2385; b) C.-W. Kuo, J. M. Fang,
Synth. Commun. 2001, 31, 877–892, and earlier workof this group.
c) H. Ohno, R. Wakayama, S. Maeda, H. Iwasaki, M. Okumura, C.
Iwata, H. Mikamiyama, T. Tanaka, J. Org. Chem. 2003, 68, 5909–
5916; d) H. Ohno, M. Okumura, S. Maeda, H. Iwasaki, R. Wakaya-
ma, T. Tanaka, J. Org. Chem. 2003, 68, 7722–7732.
Acknowledgements
Support of this workby the Deutsche Forschungsgemeinschaft, the Euro-
pean Community (Marie Curie fellowship for F.A.), the Fonds der Chem-
ischen Industrie and the Schering AG is most gratefully acknowledged.
We thankDr. R. Zimmer, M. Brasholz and Professor F. A. Khan for dis-
cussions and help during preparation of the manuscript.
[1] a) B. Giese, Radicals in Organic Synthesis: Formation of Carbon–
Carbon Bonds; Pergamon Press, New York, 1986; b) C. P. Jasperse,
D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237–1286; c) G. A.
Molander, Acc. Chem. Res. 1998, 31, 603–609.
[2] For few selected reviews in the area see: a) G. S. C. Srikanth, S. L.
Castle, Tetrahedron 2005, 61, 10377–10441; b) G. Nagendrappa,
Resonance 2005, 10, 80–90; c) W. Zhang, Curr. Org. Chem. 2004, 8,
757–780; d) P. Renaud, Chimia 2001, 55, 1045–1048; e) S. C. Roy, J.
Indian Inst. Sci. 2001, 81, 477–482; f) P. J. Parsons, C. S. Penkett,
A. J. Shell, Chem. Rev. 1996, 96, 195–206.
[13] Related electrochemical investigations: a) T. Shono, N. Kise, T. Su-
zumoto, T. Marimoto, J. Am. Chem. Soc. 1986, 108, 4676–4677;
b) N. Kise, T. Suzumoto, T. Shono, J. Org. Chem. 1994, 59, 1407–
1413; c) R. Gorny, H. J. Schäfer, R. Frçhlich, B. Wibbeling, Eur. J.
Org. Chem. 2003, 2919–2932.
[14] Reviews summarizing synthetically useful dearomatising methods:
a) L. N. Mander, Synlett 1991, 134–144; b) T. Bach, Angew. Chem.
1996, 108, 795–796; Angew. Chem. Int. Ed. Engl. 1996, 35, 729–730;
c) A. R. Pape, P. P. Kaliappan, E. P. Kündig, Chem. Rev. 2000, 100,
2917–2940; d) J. Clayden, M. N. Kenworthy, Synthesis 2004, 1721–
1736.
[15] For a recent collection of ꢀE1/2 values see: A. DahlØn, A. Nilsson,
G. Hilmersson, J. Org. Chem. 2006, 71, 1576–1580; thus, the half re-
duction potential of naphthalene is roughly 0.9 V lower than that of
benzene (R. S. Ruoff, K. M. Kadish, P. Boulas, E. C. M. Chen, J.
Phys. Chem. 1995, 99, 8843–8850).
[16] a) M. Berndt, I. Hlobilovµ, H.-U. Reißig, Org. Lett. 2004, 6, 957–
960; b) M. Berndt, Dissertation, Freie Universität Berlin, Germany,
2003.
[17] For alternative syntheses of ketone 3 see reference [13b] and C. S.
Cho, S. I. Motofusa, K. Ohe, S. Uemuda, Bull. Chem. Soc. Jpn. 1996,
69, 2341–2348.
[18] S. N. Huckin, L. Weiler, J. Am. Chem. Soc. 1974, 96, 1082–1087.
Autorenkollektiv, Organikum, 18th ed., Deutscher Verlag der Wis-
senschaften, Berlin, 1990, p. 519.
[19] E. C. Taylor, Y. Wang, Heterocycles 1998, 48, 1537–1553.
[20] For benzene derivatives and related arenes as ketyl acceptors, the
use of the terms exo- and endo-cyclisation may not be appropriate.
Nevertheless, as exo-processes are generally more favourable for
stereoelectronic reasons (see reference [25]) and a similar geometri-
cal arrangement is possible for arenes, we prefer to use the term
exo-trig also for these reactions.
[3] a) J.-L. Namy, P. Girard, H. B. Kagan, Nouv. J. Chim. 1977, 1, 5–7;
b) J.-L. Namy, P. Girard, H. B. Kagan, J. Am. Chem. Soc. 1980, 102,
2693–2698.
[4] Reviews concerning samarium diiodide induced reactions: a) D. J.
Edmonds, D. Johnston, D. J. Procter, Chem. Rev. 2004, 104, 3371–
3404; b) J. M. Concellón, H. Rodriguez-Solla, Chem. Soc. Rev. 2004,
33, 599–609; c) M. Berndt, S. Groß, A. Hçlemann, H.-U. Reißig,
Synlett 2004, 422–438; d) H. B. Kagan, Tetrahedron 2003, 59,
10351–10372; e) A. Hçlemann, Synlett 2002, 1497–1498; f) B. K.
Banik, Eur. J. Org. Chem. 2002, 2431–2444; g) P. G. Steel, J. Chem.
Soc. Perkin Trans. 1 2001, 2727–2751; h) A. Krief, A.-M. Laval,
Chem. Rev. 1999, 99, 745–777; i) H. B. Kagan, J. L. Namy, Top. Or-
ganomet. Chem. 1999, 2, 155–198; j) G. A. Molander, C. R. Harris,
Tetrahedron 1998, 54, 3321–3354; k) F. A. Khan, R. Zimmer, J.
Prakt. Chem. 1997, 339, 101–104; l) G. A. Molander, C. R. Harris,
Chem. Rev. 1996, 96, 307–338; m) G. A. Molander, Chem. Rev.
1992, 92, 29–68; n) H. B. Kagan, New J. Chem. 1990, 14, 453–460;
o) H. B. Kagan, J. L. Namy, Tetrahedron 1986, 42, 6573–6614.
[5] a) G. A. Molander, C. Kenny, J. Org. Chem. 1990, 55, 6171–6176;
b) G. A. Molander, C. Kenny, J. Am. Chem. Soc. 1989, 111, 8236–
8246; c) G. A. Molander, J. A. McKie, J. Org. Chem. 1992, 57, 3132–
3139; d) G. A. Molander, C. Kenny, J. Org. Chem. 1994, 59, 3186–
3192.
[6] For selected examples see: a) S. Fukuzawa, A. Nakanishi, T. Fujina-
mi, S. Sakai, J. Chem. Soc. Perkin Trans. 1 1988, 1669–1675; b) S.
Fukuzawa, M. Iida, A. Nakanishi, T. Fujinami, S. Sakai, J. Chem.
Soc. Chem. Commun. 1987, 920–921; c) E. J. Enholm, A. Trivellas,
Tetrahedron Lett. 1989, 30, 1063–1066; d) M. Kito, T. Sakai, K.
Yamada, F. Matsuda, H. Shirahama, Synlett 1993, 158–162; e) D.
Johnston, C. F. McCuster, K. Muir, D. J. Procter, J. Chem. Soc.
Perkin Trans. 1 2000, 681–695; f) H. Villar, F. GuibØ, Tetrahedron
Lett. 2002, 43, 9517–9520.
[21] All chiral compounds presented in this study are racemic; the de-
picted formulas describe the relative configurations of precursors
and products.
[22] The final two steps (second electron transfer and protonation) of
the reaction occur in full analogy to the Birch reduction. Review:
P. W. Rabideau, Z. Marcinow, Org. React. 1992, 42, 1–334.
[23] For analytical data of compound 15 see: A. G. M. Barrett, D. C.
Braddock, R. A. James, N. Koike, P. A. Pocopiu, J. Org. Chem. 1998,
63, 6273–6280.
[7] a) F. A. Khan, R. Czerwonka, R. Zimmer, H.-U. Reißig, Synlett
1997, 995–997; b) H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U.
Dinesh, A. L. Shaikh, R. Zimmer, Eur. J. Org. Chem. 2006, 4419–
4428; c) E. Nandanan, C. U. Dinesh, H.-U. Reißig, Tetrahedron
2000, 56, 4267–4277.
[8] a) C. U. Dinesh, H.-U. Reißig, Angew. Chem. 1999, 111, 874–876;
Angew. Chem. Int. Ed. 1999, 38, 789–791; b) M. Berndt, H.-U.
Reißig, Synlett 2001, 1290–1292; c) S. Gross, H.-U. Reißig, Synlett
2002, 2027–2030.
Chem. Eur. J. 2007, 13, 6047 – 6062
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6061

H.-U. Reißig et al.
[24] For analytical data of compound 16 see: S. Toda, T. Higashii, I. Kuri-
moto, M. Minai, C. Sekine, T. Tani, K. Fujisawa, Eur. Pat. Appl. EP
416946, 1991.
[25] For the transition structures of radical cyclisations see: a) A. L. J.
Beckwith, Tetrahedron 1981, 37, 3073–3100; b) D. C. Spellmeyer,
K. N. Houk, J. Org. Chem. 1987, 52, 959–974.
mide, followed by cleavage of the hydrazone under mild acidic con-
ditions.
[37] A. Padwa, A. Zanka, J. M. Harris, Tetrahedron 2003, 59, 4939–4944.
[38] For the synthesis of rac-tert-butyl (3S,4R)-3-hydroxy-4-vinylpyrroli-
dine-1-carboxylate (42) see: S. U. Hansen, M. Bols, Acta Chem.
Scand. 1998, 52, 1214–1222.
[39] J. R. Parikh, W. v. E. Doering, J. Am. Chem. Soc. 1967, 89, 5505–
5507.
[40] D. Marcovici-Mizrahi, H. E. Gottlieb, V. Marks, A. Nudelman, J.
Org. Chem. 1996, 61, 8402–8406.
[26] a) I. Fleming, J. Godhill, J. Chem. Soc. Perkin Trans. 1 1980, 1493–
1498; b) I. Fleming, J. Godhill, J. Chem. Soc. Perkin Trans. 1 1982,
1563–1570; c) P. Wallace, S. Warren, J. Chem. Soc. Perkin Trans. 1
1992, 3169–3171.
[41] The NMR spectroscopic analysis of tetracycles 48 and 49 carried out
at RT also revealed the presence of two distinct rotamers, as already
observed in the case of the ketone precursors.
[27] a) C. A. Strott, Endocr. Rev. 1996, 17, 670–697; b) R. Hobkirk, Can.
J. Biochem. Cell Biol. 1985, 63, 1127–1144; c) J. Liu, C. C. Y. Chang,
E. J. Wesover, D. F. Covey, T.-Y. Chang, Biochem. J. 2005, 391, 389–
397.
[28] Precursor 27 was obtained in 38% yield according to the method
described above for the synthesis of ketones 21a–e, for details see
reference [16b].
[29] The synthesis of ketones 29 and 33 was carried out by a-alkylation
of the cyclohexyl imines or of the SAMP-hydrazones of the corre-
sponding ketones with the appropriate alkyl bromide, followed by
cleavage of the hydrazones under mild acidic conditions, according
to a method reported in the literature: a) D. Enders, A. Nuhring, J.
Runsik, Chirality 2000, 12, 374–377; b) D. Enders, T. Hundertmark,
R. Lazny, Synlett 1998, 721–722.
[30] B. Bonnaud, D. C. H. Bigg, Synthesis 1994, 465–467.
[31] T. V. Singh, R. Kaur, K. R. Agnihotri, M. Bali, ARKIVOC 2002, 82–
90.
[42] For selected recent examples: a) L. F. Tietze, S. Petersen, Eur. J.
Org. Chem. 2001, 1619–1624; b) L. F. Tietze, K. M. Sommer, G.
Schneider, P. Tapolcsµny, J. Wçlfling, P. Müller, M. Noltemeyer, H.
Terlau, Synlett 2003, 1494–1496; c) L. F. Tietze, J. M. Wiegand, C.
Vock, J. Organomet. Chem. 2003, 687, 895–897; d) L. F. Tietze, J. M.
Wiegand, C. Vock, Eur. J. Org. Chem. 2004, 4107–4112; e) H. W.
Sünnemann, A. Hofmeister, J. Magull, M. G. Banwell, A. de Mei-
jere, Org. Lett. 2007, 9, 517–520; f) H. W. Sünnemann, A. de Mei-
jere, Angew. Chem. 2004, 116, 913–915; Angew. Chem. Int. Ed.
2004, 43, 895–897; g) J. O. Bunte, S. Rinne, C. Schäfer, B. Neumann,
H.-G. Stammler, J. Mattay, Tetrahedron Lett. 2003, 44, 45–48;
h) J. O. Bunte, S. Rinne, J. Mattay, Synthesis 2004, 619–633; i) For a
recent review dealing with ring C closures in the syntheses of ste-
roids: F. C. E. Sarabꢁr, A. de Groot, Tetrahedron 2006, 62, 5363–
5383.
[43] Compounds such as 48 show a surprisingly high estrogenic activity:
I. Ott, R. Gust, Institut für Pharmazie, Freie Universität Berlin,
2006, unpublished results.
[44] S. M. Gingerich, P. W. Jennings, J. Org. Chem. 1983, 48, 2606–2608.
[45] P. L. Ornstein, T. J. Bleisch, M. B. Arhold, R. A. Wright, B. G. John-
son, D. D. Schoepp, J. Med. Chem. 1998, 41, 346–357.
[46] Area-Detector Absorption Correction, Siemens Industrial Automa-
tion, Madison, WI, 1996.
[47] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467–473.
[48] G. M. Sheldrick, University of Gçttingen, Germany, 1997.
[49] J. Appl. Crystallogr. 1999, 32, 837–838.
[32] M. Berndt, I. Brüdgam, H. Hartl, H.-U. Reißig, Z. Kristallogr. New
Cryst. Struct. 2004, 219, 49–50.
[33] a) G. A. Kraus, K. A. Frazier, B. D. Roth, M. J. Taschner, K. Neu-
enschwander, J. Org. Chem. 1981, 46, 2417–2419; C. Brückner, H.
Holzinger, H.-U. Reißig, J. Org. Chem. 1988, 53, 2450–2456.
[34] Unpublished results of F. Aulenta, I. Hlobilovµ, U. Wefelscheid„ H.-
U. Reißig, Freie Universität Berlin.
[35] a) H. Singh, V. K. Kapoor, D. Paul, Heterosteroids and Drug Re-
search, Vol. 16: Progress in Medicinal Chemistry, 1979, 1635–1649;
b) F. Cachoux, M. Ibrahim-Ouali, M. Santelli, Tetrahedron Lett.
2001, 42, 843–845; c) W. Xie, H. Peng, D. I. Kim, M. Kunkel, G.
Powis, L. H. Zalkow, Bioorg. Med. Chem. 2001, 9, 1073–1083; d) K.
Oumzil, M. Ibrahim-Ouali, M. Santelli, Synlett 2005, 1695–1698;
e) R. W. Chesnut, N. N. Durham, R. A. Brown, E. A. Mawdsley,
K. D. Berlin, Steroids 1976, 27, 525–541; f) R. E. Dolle, H. S. Al-
laudeen, L. I. Kruse, J. Med. Chem. 1990, 33, 877–880; g) C. Lange,
N. Holzhey, B. Schçnecker, R. Beckert, U. Mçllmann, H.-M. Dahse,
Bioorg. Med. Chem. 2004, 12, 3357–3362; h) L. F. Tietze, L. P.
Lücke, F. Major, P. Müller, Aust. J. Chem. 2004, 57, 635–640; i) A.
Jacobi von Wangelin, H. Neumann, D. Gçrdes, S. Hübner, C. Wen-
dler, S. Klaus, D. Strübing, A. Spannenberg, H. Jiao, L. El Firdoussi,
K. Thurow, N. Stoll, M. Beller, Synthesis 2005, 2029–2038; j) C. I.
Turner, R. M. Williamson, P. Turner, M. S. Sherburn, Chem.
Commun. 2003, 1610–1611.
[50] C. S. Cho, S. I. Motofusa, K. Ohe, S. Uemura, Bull. Chem. Soc. Jpn.
1996, 69, 2341–2348.
[51] H. Lee, R. G. Harvey, Tetrahedron Lett. 1988, 29, 3207–3210.
[52] After alkylation, the corresponding SAMP hydrazones were purified
by column chromatography on aluminium oxide and these purified
intermediates were treated under acid conditions to hydrolyse the
hydrazones as reported above.
[53] 2-(2-Bromoethyl)naphthalene was synthesised according to a litera-
ture procedure: S. Nishizawa, Y.-Y. Cui, M. Minagawa, K. Morita,
Y. Kato, S. Taniguchi, R. Kato, N. Teramae, J. Chem. Soc. Perkin
Trans. 2 2002, 866–870.
[54] Due to the presence of two rotamers the signal of several protons
and carbon atoms are doubled in the NMR spectra.
[36] The synthesis of these piperidinone substrates was carried out in a
two-step procedure by alkylation of the SAMP hydrazone of the
corresponding N-methylpiperidinone with the appropriate alkyl bro-
Received: January 14, 2007
Published online: May 8, 2007
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