Highly substituted benzannulated cyclooctanol derivatives by samarium diiodide-induced cyclizations

Article abstract of DOI:10.3762/bjoc.6.141

A series of γ-oxo esters suitably substituted with various styrene subunits was subjected to samarium diiodide-induced 8-endo-trig cyclizations. Efficacy, regioselectivity and stereoselectivity of these reactions via samarium ketyls strongly depend on the

Full text of DOI:10.3762/bjoc.6.141

Highly substituted benzannulated cyclooctanol
derivatives by samarium diiodide-induced
cyclizations
Jakub Saadi, Irene Brüdgam§ and Hans-Ulrich Reissig*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 1229–1245.
Freie Universität Berlin, Institut für Chemie und Biochemie,
Takustrasse 3, D-14195 Berlin, Germany
doi:10.3762/bjoc.6.141
Received: 18 August 2010
Accepted: 11 November 2010
Published: 28 December 2010
Email:
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
* Corresponding author
Associate Editor: J. Murphy
§ Responsible for X-ray analyses
© 2010 Saadi et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyclooctanes; ketones; ketyls; medium-sized rings; samarium
diiodide; single electron transfer; styrene derivatives; radicals
Abstract
A series of γ-oxo esters suitably substituted with various styrene subunits was subjected to samarium diiodide-induced 8-endo-trig
cyclizations. Efficacy, regioselectivity and stereoselectivity of these reactions via samarium ketyls strongly depend on the substitu-
tion pattern of the attacked alkene moiety. The stereoselectivity of the protonation of the intermediate samariumorganyl is also
influenced by the structural features of the substrates. This systematic study reveals that steric and electronic factors exhibited by
the alkene and ketone subunits are of high importance for the outcome of these cyclization reactions leading to highly substituted
benzannulated cyclooctanol derivatives. In exceptional cases, 7-exo-trig cyclizations to cycloheptanol derivatives have been
observed. In examples with high steric hindrance the ketyl–aryl coupling can be a competing process.
Introduction
Functionalized cyclooctane substructures are frequently found eight-membered rings has been developed [1,2,4-18].
in natural products and pharmacologically significant com- Successful approaches include ring-closing metathesis [4],
pounds. Because of their potential biological activity and rearrangements [5], and cycloadditions [6], transition metal-
intriguing geometrical features, the construction of cyclo- catalyzed cyclizations [7,8], nucleophilic and electrophilic
octanoid frameworks has challenged synthetic organic chemists substitution reactions [9] as well as ring expansion reactions
for a long time [1,2]. This task is quite challenging due to [10]. Among these approaches to carbocyclic compounds,
unfavourable enthalpic and entropic factors during the forma- samarium diiodide-mediated reactions play an important role
tion of medium-sized rings [3]. Nevertheless, in recent years a and have been described in a number of excellent review arti-
range of interesting solutions for the efficient formation of cles [19-21] and original publications [22-35]. In our previous
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reports we have described the efficient synthesis of cyclooc- nated with LDA and subsequently alkylated with 2-iodobenzyl
tanol and cyclooctenol derivatives by samarium diiodide- iodide, furnishing 2 in moderate yield. Intermediate 2 was then
induced 8-endo-trig and 8-endo-dig cyclizations of γ-styryl- treated with triethylamine trihydrofluoride, furnishing 2-iodo-
[20,31,33] and γ-phenyl-alkynyl-substituted [20,32] ketoesters. benzyl-substituted γ-ketoester 3. The following palladium-
Recently, we have also reported our preliminary results on catalyzed cross-coupling [38,39] with potassium 2-propenyl
cyclizations of analogous starting materials bearing alkyl and trifluoroborate afforded the cyclization precursor 4 in very good
aryl substituents at the styryl double bond, which furnished yield.
highly substituted cyclooctanol derivatives (Scheme 1) and in
some cases compounds with cycloheptanol substructure [34].
The transformation of A to B proceeds via the samarium ketyl
C followed by the 8-endo-trig cyclization to D. Subsequent
reduction of the radical D by the second equivalent samarium
diiodide and protonation furnishes the cyclooctanol derivative
B. The details of this mechanism have been discussed earlier
[31]. This method was also successfully applied to the syn-
thesis of cyclic compounds larger than cyclooctane derivatives
[35]. Here, we would like to present our detailed results
showing the scope and limitations of this method to the syn-
thesis of highly substituted cyclooctanol derivatives and the
influence of the substitution pattern of the precursors on the
regioselectivity and stereochemical outcome. First, the impact
Scheme 2: Three-step synthesis of precursor 4 starting from siloxycy-
clopropane derivative 1.
on the reaction by alkyl and aryl substituents at the α-styryl
carbon of the substrates will be described, then we discuss the
influence of analogous β-styryl substituents.
The cyclization reactions were generally performed with
2.2 equiv of samarium diiodide in THF and in the presence of
18 equiv of HMPA and 2 equiv of tert-butanol. HMPA is
crucial for the success of most of the described cyclizations
because of its unique influence on the reactivity of samarium
diiodide [40-44]. For control experiments and an add-on to our
previous observations [33], we started our experiments with the
cyclization of ketoesters 5a/b containing a cycloheptanone
subunit. Here only the unlike-configured [45] 5a furnished the
expected benzannulated tricyclic compound 6 in moderate yield
(Scheme 3). The like-configured precursor 5b is unable to
arrange the reacting moieties (carbonyl group and alkene) in
appropriate proximity while retaining an energetically
favourable conformation of the molecule. The impact of the
relative configuration of cyclic ketones as starting materials on
Scheme 1: SmI2-induced cyclizations of styryl-substituted γ-ketoesters
A to benzannulated cyclooctanol derivatives B via samarium ketyl C
and radical D (HMPA ligands at the samarium are omitted for simplicity
in all Schemes, but certainly can play an important role for the
outcome).
Results and Discussion
Starting materials were prepared from readily available siloxy-
cyclopropanes in analogy to our previously described modular
Scheme 3: Attempted cyclizations of diastereomeric cycloheptanone
derivatives 5a and 5b.
approach [33]. As a typical example, the synthesis of precursor
4 is depicted in Scheme 2. Cyclopropane 1 [36,37] was deproto-
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the 8-endo-trig process is in full agreement with our previous Cyclization of acyclic starting material 4, bearing a methyl
observations for the corresponding cyclohexanone derivatives substituent at the α-styryl carbon, furnished a mixture of trans-
[33].
and cis-cyclization products 9 and 10 in very good combined
yield, but practically no stereochemical preference. The
Because of the observed sensitivity of this reaction to steric precursor 11, bearing the more bulky iso-propyl ketone subunit,
factors, it was necessary to study the tolerance and limitations provided cyclooctanol derivatives 12 and 13 with similarly
for the substitution pattern of the starting materials in more good combined yield and a clear preference for trans-product
detail. At first, the influence of a methyl substituent at the 12 (Scheme 5).
α-styryl carbon was investigated. Cyclization of the unlike-
configured cyclohexanone derivative 7a afforded the expected The relative configurations of lactone-bridged compounds 10
tricyclic cyclooctanol derivative 8 in good yield and excellent and 13 were deduced from NOESY-correlations and the
trans-stereoselectivity (Scheme 4). The terms cis and trans refer assumption was confirmed that the five-membered lactone
in this report to the position of the methoxycarbonyl group and bridge, which is quite constrained and rigid, can be formed only
the hydroxyl group. In general, cis-configured products directly when carboxyl and hydroxyl groups are at the same face of the
undergo a subsequent cyclization to the corresponding eight-membered ring (Figure 1). This analysis was further
γ-lactones. It is noteworthy that the additionally introduced supported by high similarity of NMR-spectroscopic data (1H
stereogenic centre bearing the methyl group is also generated and 13C NMR shifts and relative signal patterns) with those of
stereoselectively.
compound 17a and at the same time rather big differences to
those of the epimeric compound 17b.
Scheme 4: Samarium diiodide-induced cyclization of γ-ketoester 7a to
tricyclic compound 8.
In part, the configuration of 8 was assigned based on the rela-
tive configuration of the starting material. The lack of lactone
formation indicates that the bridgehead hydroxyl group is trans
located with respect to the methoxycarbonyl group. The config-
uration at the methyl-substituted stereocenter was assigned
Figure 1: NOESY-correlation for compound 10.
based on NOESY-correlations and careful comparison of spec- The NOESY-experiments also indicated the proton correlations
troscopic data with those of related compounds. The analogous across the eight-membered ring in compounds 9 and 12. The
cyclopentanone-derived starting material was also tested in the assignment was further supported by the correlations between
cyclization reaction; however, it afforded a complex mixture of the protons at carbons with one substituent at the ring and their
products.
neighbouring protons. The cis-vicinal protons indicated strong
Scheme 5: Samarium diiodide-induced cyclizations of methyl ketone 4 and iso-propyl ketone 11.
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correlations, while the trans-vicinal protons, where the dihedral group at the newly formed third stereogenic centre, which arises
angle was close to 180°, show none or almost no correlations during the protonation of the samariumorganyl intermediate,
between each other (Figure 2).
was always trans to the hydroxyl group, arising from the ketone
moiety. This interesting observation indicates that the protona-
tion is highly stereoselective and the protons are coming from
the same face of the ring where the samariumoxy group is situ-
ated after the completed cyclization. Since samarium(III) is very
oxophilic, it is possible that the samariumoxy group coordi-
nates tert-butanol, which is then a more acidic proton source
(intermediates B and C, Scheme 6). This template effect would
then be responsible for the stereoselective protonation governed
by the samariumoxy moiety. An intermediate similar to C
(covalent C–Sm bond or contact ion pair) may be a plausible
alternative, which is then protonated under retention by the
proton source [46].
The introduction of two additional methyl substituents between
the ketone and ester moieties in the bulky diisopropyl ketone
derived substrate 14, suppressed the 8-endo-trig cyclization
completely and only the fragmentation product 15 was isolated
from the reaction mixture (Scheme 7). It is not clear whether the
mechanism of SmI2-induced fragmentation of 1,4-dicarbonyl
compounds is of anionic or radical nature, but it has been
observed in several cases [33,47-50]. It is possible that, due to
Figure 2: NOESY-correlation for compound 9.
In cyclizations of the (2-propenyl)phenyl-substituted ketoesters, the high steric hindrance of the initially formed samarium ketyl,
trans-products are preferred; however the cis/trans stereoselec- the coupling to the alkene is very slow. The ketyl or the anion
tivity was generally lower than that observed for the formed by its further reduction with SmI2 fragments to the
cyclizations of their styrene analogues [33]. It seems that the samarium enolate of diisopropyl ketone and the radical or anion
previously observed correlation between the bulkiness of a
ketone subunit and the increase in stereoselectivity is also effec-
tive here. This result is in accordance to the proposed eight-
membered pseudo-chair-like transition structure [33], where the
methoxycarbonyl group occupies a preferred pseudo-equatorial
position and the ketyl substituent is competing with the bulky
samariumoxy group for the other pseudo-equatorial position.
Therefore, ketones with bulkier substituents preferentially react
through a transition structure A (Scheme 6) leading to the trans-
Scheme 7: Reductive fragmentation of highly hindered ketoester 14.
cyclization product. Remarkably, the orientation of the methyl
Scheme 6: Assumed transition structures and intermediates A, B, or C for the cyclizations of (2-propenyl)phenyl-substituted ketones 4 and 11 leading
to products of type D (HMPA ligands at the samarium are omitted for simplicity).
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
Scheme 8: Samarium diiodide-induced cyclization of phenyl-substituted substrate 16 leading to lactones 17a and 17b.
stabilized by the methoxycarbonyl group. Very surprisingly in additionally stabilized by the phenyl substituent, occurred with
this reaction, small amounts of the n-propyl ester of 15 were lower stereochemical preference in this case. However, if an
also found. At this moment, the origin of the n-propyl group is intermediate such as C (Scheme 6) is also involved in this trans-
not clear.
formation a less covalent C-Sm bond may lead to a decreased
stereoselectivity of the protonation step.
The modulation analysis of the electronic properties of the
reacting alkene was evaluated by the introduction of a phenyl We have subsequently investigated the influence of alkyl
substituent to the α-styryl position. The samarium diiodide- substituents at the β-styryl carbon. In this series, (E)-1-
induced cyclization of ketoester 16 afforded two epimeric propenyl-substituted acyclic ketones 18, 21, and 24 gave the
lactone bridged cis-products, 17a and 17b, in ca. 1.7:1 ratio and expected trans-cyclooctanol derivatives 19, 22, and 25 in
in good combined yield (Scheme 8).
moderate to good yields and with excellent stereoselectivities
(Scheme 9). In case of cyclization of methyl-substituted ketone
The relative configuration of 17b was unambiguously assigned 18, the side-product 20 was obtained as a result of a ketyl–aryl
by X-ray crystal structure (Figure 3) [51]. Assuming that the coupling [20,53-58] in addition to the desired cyclooctanol
lactone bridge is formed only when carboxyl and hydroxyl derivative 19. Also minor amounts of fragmentation product 23
groups are at the same face of the eight-membered ring, the were detected in the cyclization of ethyl ketone 21 (Scheme 9).
configuration of 17a with the inverted phenyl-substituted These two observations indicate that the transition structures of
stereocenter was assigned as the only alternative to 17b.
the cyclizations leading to eight-membered rings are more
constrained and that the reactions are slower than those where a
terminally unsubstituted alkene is attacked.
Figure 3: Molecular structure (Diamond [52]) of compound 17b.
The exclusive cis-selectivity of cyclization, observed in this
case, may be attributed to a high level of the steric repulsions
between the bulky phenyl group at the alkene moiety and the
iso-propyl group at the samarium ketyl in the usually preferred
trans-transition structure (compare A, Scheme 6). It is unclear,
why the protonation of the samariumorganyl species, which is
Scheme 9: Samarium diiodide-induced cyclizations of (E)-(1-
propenyl)phenyl-substituted γ-ketoesters 18, 21, and 24.
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The assignment of the configuration of product 20 is based on only low quantities of cyclooctanol products, 27 and 29, res-
that of numerous earlier described examples of SmI2-induced pectively, along with the recovered starting material and either
ketyl–aryl coupling products [57]. The configurations of prod- the ketyl-aryl coupling product 28 or the fragmentation product
ucts 19, 22, and 25 were assigned on the basis of NOESY- 23 (Scheme 10).
correlations.
The stereochemical assignments for products 27 and 29 are
The transition structure for the SmI2-mediated 8-endo-trig based on the relative configuration of their precursors. The exis-
cyclizations of these (E)-1-propenyl-substituted substrates is tence or lack of lactone formation allows for assigning the con-
proposed in accordance to the previously postulated eight- figuration of the bridgehead carbon bearing the hydroxyl group.
membered pseudo-chair-like transition structures (Figure 4). The assignment of the centre with the methyl group is based on
The methoxycarbonyl group and substituent R at the ketyl a strong NOESY-correlation between the methyl protons and
moiety are both occupying preferred pseudo-equatorial posi- the bridgehead proton. It is noteworthy that the stereoselec-
tions. In our drawing, the olefin approaches the samarium ketyl tivity of the cyclization for cyclic ketones is clearly controlled
from the backside perpendicularly to the bulky samariumoxy by the relative configuration of the precursors and that the
group. The methyl substituent at the alkene moiety prefers a hydroxyl group is generated trans to the vicinal substituents.
staggered position in between the bulky samariumoxy group The reactivity of the sterically more demanding β-styryl-substi-
and substituent R.
tuted substrates was strongly retarded due to rigidity and bulki-
ness of the integrated cyclohexane ring, which in the previous
cyclization examples afforded cyclooctanol products with good
yield and excellent stereoselectivity.
The cyclopentanone-derived analogues of 26a/b were also
examined in this samarium diiodide-promoted transformation,
but among the isolated products only the starting materials
could be unequivocally identified. Not surprisingly, the (E)-1-
propenyl analogue of the bulky diisopropyl ketone-derived sub-
strate 14 only afforded the corresponding fragmentation pro-
duct. In this case again small amounts of the n-propyl ester were
detected (compare Scheme 7).
Figure 4: Proposed transition structure for the cyclization of (E)-1-
propenyl-substituted substrates (HMPA ligands and proton donors
ROH at the samarium are omitted for simplicity).
Another indication of the considerable steric repulsion intro-
duced by the methyl substituent at the β-styryl position is The influence of the configuration of the reacting alkene was
provided by the cyclizations of sterically more constrained also studied. The cyclization of (Z)-1-propenyl-substituted 30,
cyclohexanone derivatives 26a and 26b (Scheme 10). In these which is isomeric to already examined (E)-1-propenyl-ketoester
two cases both the usually preferred unlike-configured 24, afforded the corresponding cyclooctanol 31 with consider-
precursor 26a and the disfavoured like-configured 26b gave ably lower efficacy (Scheme 11, compare Scheme 9). The
Scheme 10: Attempted samarium diiodide-induced cyclizations with (E)-1-propenyl-substituted precursors 26a and 26b.
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
Scheme 11: Attempted samarium diiodide-induced cyclization of (Z)-1-propenyl-substituted precursor 30.
reaction mixture afforded considerable amounts of fragmenta- is an interesting observation that the 8-endo-trig cyclization
tion product 32 along with unchanged starting material.
mode is preferred over the possible 7-exo-trig mode for the
reaction of compound 36.
The configuration of product 31 is based on the comparison
with the isomeric product 25. Analysis of a possible transition The configurations of products 34 and 37 are assigned with the
structure analogous to that proposed for the cyclization of (E)- aid of NOESY-correlations and by comparison with the NMR-
1-propenyl-substituted γ-ketoesters (compare Figure 4) reveals spectroscopic data of analogous compounds obtained after
that the Z-configured alkene has to arrange the methyl cyclizations of (E)-1-propenyl-substituted γ-ketoesters.
substituent in a highly unfavourable endo-cyclic position of the
newly formed ring. This apparently causes high steric repulsion In contrary to the reaction of acyclic ketone 36, stilbenyl-substi-
and thus strongly suppressed reactivity.
tuted cyclohexanone derivatives 38a and 38b both preferred to
undergo a 7-exo-trig cyclization, yielding tricyclic cyclohep-
In order to further define the scope and limitations of the tanol derivative 39 and tetracyclic lactone 40, respectively
samarium diiodide-induced reaction we then studied the (Scheme 13). Similarly as in cyclizations of the cyclohexanone-
cyclization of β-styryl-substituted γ-ketoester 33. This precursor
has the preferred (E)-configured alkene substructure, but is
equipped with branched substituents at the ketone and alkene
moieties (Scheme 12). The starting material was completely
consumed in this reaction, affording a moderate yield of the
eight-membered carbocycle 34 together with a fairly high
amount of fragmentation product 35. The obtained product ratio
suggests that in this example, the cyclization is roughly two
times slower than the fragmentation. When a phenyl group was
introduced to the β-styrene position the cyclization of
γ-ketoester 36 mainly afforded the desired cyclooctanol deriva-
tive 37, along with several undefined side products in low quan-
tities and 20% of unconsumed starting material (Scheme 12). It
has to be emphasized here, that the 1,2-diarylalkene unit can
Scheme 13: Samarium diiodide-induced cyclizations of diastereo-
meric stilbenyl-substituted γ-ketoesters 38a and 38b.
potentially react with the samarium ketyl at both carbon atoms
affording two different stabilized benzylic radicals. Therefore it
Scheme 12: Samarium diiodide-induced cyclizations of γ-ketoesters 33 and 36.
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
derived ketoesters with terminally substituted alkenes 26a/b, the the unlike-configured precursor should be transferred to the pro-
8-endo-trig cyclization pathway may be quite hampered in the duct and the bridgehead hydroxyl group should be in trans-rela-
cases of 38a and 38b. However, due to the radical stabilizing tionship to the methoxycarbonyl group since no lactone forma-
properties of the terminal phenyl substituent, the 7-exo-trig tion was observed. The configuration of the stereogenic centre
pathway is now possible. It is probable that the restricted con- with the phenyl group of 39 is based on NOESY-correlations
formational flexibility of the cyclic ketones leads to higher between the exocyclic benzylic protons and the bridgehead
steric and torsional strain in an alternative eight-membered tran- proton.
sition structure. This assumption is supported by the observa-
tion that conformationally more flexible acyclic γ-ketoesters, An attempt to cyclize γ-ketoester 41 featuring a β-dialkyl-
such as 36, prefer the 8-endo-trig cyclization mode. Further- substituted styryl moiety furnished only minor amounts of the
more, the like-configured starting material 38b, which is ketyl–aryl coupling products 42 and 43 (Scheme 14). Similar to
disfavoured in 8-endo-trig cyclizations, afforded the cyclohep- some other reactions leading mainly to side products, trace
tanol derivative with even better efficacy than the unlike-config- amounts of n-propyl ester of 42 of unknown origin were
ured 38a.
detected. Although the precursor was completely consumed, the
missing material could not be identified. The relative configura-
The constitution and the relative configuration of compound 40, tion of the hexahydronaphthalene derivatives was assigned by
featuring a tetracyclic lactone-bridged core, were unambigu- the comparison of spectroscopic data with that of the previ-
ously determined by an X-ray crystal structure (Figure 5) [59]. ously described analogous compounds [57].
The constitution of compound 39 was assigned as a cyclohep-
tanol derivative based on the similarities of its 13C NMR data Conclusion
with those of 40 rather than those of the analogous eight- Samarium diiodide-mediated 8-endo-trig cyclizations of styryl-
membered carbocycles. The configuration of 39 was assigned substituted γ-ketoesters bearing alkyl or aryl substituents at the
by using the following arguments: the relative configuration of α- or β-styryl carbon were systematically studied. The stereose-
lectivity of these transformations was strongly influenced by the
steric bulk at the ketone and alkene moieties. Acyclic
γ-ketoesters such as A cyclized very efficiently, affording
mixtures of cis- and trans-products B and C with improving cis/
trans stereoselectivity by increase of the size of the ketone
substituents (Scheme 15).
Scheme 15: Typical products of samarium diiodide-induced 8-endo-
Figure 5: Molecular structure (Diamond [52]) of compound 40.
trig cyclizations of α-styryl-substituted γ-ketoesters.
Scheme 14: Attempted cyclization of β-dialkyl-substituted styrene derivative 41.
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
γ-Ketoesters with substituents at the β-styryl carbon such as D CDCl3 signal (δH = 7.26 ppm. δC = 77.16 ppm). IR spectra
cyclized with similar efficiency, affording in most cases the were measured with a Nicolet 205 5SXC FTIR-interferometer,
8-endo-trig-cyclization products E. Only cyclohexanone equipped with a DTGS-detector. Melting points are uncorrected
derived γ-ketoesters F preferred the 7-exo-trig over the 8-endo- and determined with a melting point microscope Büchi 510. MS
trig-cyclization mode (Scheme 16).
and HRMS analyses were performed with Finnigan MAT 711
(EI = 80 eV, 8 kV), MAT 95 (EI = 70 eV), MAT CH7A (EI =
80 eV, 3 kV) and CH5DF (FAB = 80 eV, 3 kV) instruments.
Elemental analyses were performed with Perkin-Elmer and
Vario EL Elementar analytical equipment.
Preparation of all cyclization precursors analogously to known
procedures is described in Supporting Information File 1.
SmI2-induced cyclization
General procedure A [60,61]: Samarium metal (2.4 equiv) and
1,2-diiodoethane (2.2 equiv) were placed under a flow of argon
in a flame-dried, two-necked round-bottomed flask containing a
magnetic stirring bar and a septum inlet. THF (12 mL/mmol of
1,2-diiodoethane) was added and the mixture was vigorously
stirred at rt for 2 h. HMPA (18 equiv) was added to this solu-
tion of SmI2 (2.2 equiv), and after 10 min of stirring, a solution
of the substrate (1 equiv) and t-BuOH (2 equiv) in THF
(40 mL/mmol of substrate) was added over 2 h. The mixture
was stirred at rt for 16 h and quenched with satd. aqueous
NaHCO3 solution (20 mL/mmol of substrate). The phases were
separated, and the aqueous layer was extracted with diethyl
ether (3 × 15 mL/mmol of substrate). The combined organic
Scheme 16: Typical products of samarium diiodide-induced 8-endo-
trig cyclizations of β-styryl-substituted γ-ketoesters D and of 7-exo-trig
cyclizations of β-styryl-substituted γ-ketoesters F.
A typical side reaction, which was observed for methyl ketones layers were washed with water and brine (10 mL/mmol of sub-
or cyclohexanone derivatives, was the ketyl-aryl coupling strate) and dried (Na2SO4).
reaction leading to hexahydronaphthalene derivatives in low
yields.
General procedure B [62,63]: Samarium metal (2.48 g,
16.5 mmol) and iodine (3.81 g, 15.0 mmol) were placed under a
In conclusion, the intramolecular 8-endo-trig samarium ketyl- flow of argon in a flame-dried, 250 mL round-bottomed flask
alkene coupling reaction is a flexible tool for the construction of containing a magnetic stirring bar. Then 150 mL of dry and
highly substituted cyclooctanol derivatives. A careful design of oxygen-free THF was added and the mixture was covered from
the precursors following the rules determined in this study light, and stirred at rt for 24 h to give a 0.1 M solution of SmI2
allows the synthesis of functionalized benzannulated cyclooc- in THF. This solution was stored in the dark under argon at rt
tanol derivatives with a high degree of regio- and stereocontrol. and aliquots were transferred with a syringe (2.2 equiv) into the
two-necked reaction flask, and the solution was then used as
Experimental
General: All reactions were carried out under argon in flame-
described in General procedure A.
dried flasks, and the components were added by syringe. All SmI2-induced cyclization of 5a
solvents were dried by standard methods. Thin layer chroma- General procedure B: 5a (0.300 g, 1.00 mmol), SmI2
tography (TLC) was carried out on commercial Polygram Sil G/ (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and
UV254 or Polygram Alox N/UV254 (Macherey & Nagel). t-BuOH (0.148 g, 2.00 mmol). The crude product was purified
Column chromatography was performed with 70–230 mesh by column chromatography (silica gel, ethyl acetate/hexane 1:9)
silica gel (Merck) or neutral aluminium oxide (activity grade to furnish 6 (0.126 g, 42%) as colourless crystals (mp
III; Fluka or Merck). Unless stated otherwise, 1H NMR and 126–127 °C) and 5a (0.069 g, 23%).
13C NMR spectra were determined with Bruker AC 200, AC
300, DRX 500, Avance III 700 or Jeol Eclipse 500 instruments Methyl (6RS,6aSR,11aRS)-11a-hydroxy-6,6a,7,8,9,10,11,11a,
in CDCl3 solution. The chemical shifts refer to TMS or to the 12,13-decahydro-5H-benzo[a]cyclohepta[e][8]annulene-6-
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
carboxylate (6): 1H NMR (CDCl3, 700 MHz): δ = 1.11–1.15, furnish 9 (0.080 g, 40%) as a colourless oil and 10 (0.067 g,
1.20–1.33, 1.52–1.75, 1.77–1.81 (4 m, 2 H, 3 H, 6 H, 1 H, 6a-H, 38%) as colourless crystals (mp 130–132 °C).
7-H, 8-H, 9-H, 10-H, 11-H, OH), 1.88 (ddd, J = 2.2, 8.0, 14.4
Hz, 1 H, 12-H), 2.06 (ddd, J = 2.6, 11.6, 14.4 Hz, 1 H, 12-H), Methyl (6RS,8RS,10RS)-8-hydroxy-8,10-dimethyl-
2.68 (ddd, J = 2.6, 8.0, 14.0 Hz, 1 H, 13-H), 2.85 (dd, J = 4.6, 5,6,7,8,9,10-hexahydro-benzo-[8]annulene-6-carboxylate (9):
14.2 Hz, 1 H, 5-H), 3.01 (ddd, J = 4.6, 5.2, 10.6 Hz, 1 H, 6-H), Compound 9 shows temperature-dependent NMR spectra. At rt
3.18 (ddd, J = 2.2, 11.6, 14.0 Hz, 1 H, 13-H), 3.62 (dd, J = 5.2, some signals appear broad; however, for measurements at
14.2 Hz, 1 H, 5-H), 3.69 (s, 3 H, CO2Me), 6.89–6.91, 7.12–7.18 55 °C, the signals are more clearly seen. 1H NMR (CDCl3,
(2 m, 1 H, 3 H, Ar) ppm. 13C NMR (CDCl3, 175 MHz): δ = 500 MHz, 55 °C): δ = 1.20 (s, 3 H, 8-Me), 1.33 (dd, J = 11.5,
23.6, 29.1, 29.4, 29.5 (4 t, C-7, C-8, C-9, C-10), 31.5 (t, C-13), 14.7 Hz, 1 H, 7-H), 1.33 (d, J = 7.1 Hz, 3 H, 10-Me), 1.62 (dd,
34.9 (t, C-5), 45.0 (d, C-6a), 46.9, 47.0 (2 t, C-11, C-12), 51.4 J = 11.4, 14.3 Hz, 1 H, 9-H), 1.67 (dd, J = 3.8, 14.7 Hz, 1 H,
(d, C-6), 126.1, 127.0, 129.1, 130.5, 136.8, 142.0 (4 d, 2 s, Ar), 7-H), 1.79–1.83 (m, 1 H, 9-H), 3.10 (dddd, J = 2.9, 3.8, 7.5,
51.2, 176.1 (q, s, CO2Me) ppm. Signal for C-11a is not clearly 11.5 Hz, 1 H, 6-H), 3.16 (dd, J = 2.9, 13.9 Hz, 1 H, 5-H),
visible. IR (KBr): = 3500 (O–H), 3060–2855 (=C–H, C–H), 3.36–3.43 (m, 1 H, 10-H), 3.43 (dd, J = 7.5, 13.9 Hz, 1 H, 5-H),
1715 (C=O) cm–1. C19H26O3 (302.4): calcd. C 75.46, H 8.67; 3.68 (s, 3 H, CO2Me), 6.97–6.99, 7.06–7.10, 7.17–7.25 (3 m, 1
found: C 75.36, H 8.78.
H, 1 H, 2 H, Ar) ppm, the signal for the OH group could not be
assigned unambiguously. 13C NMR (CDCl3, 125 MHz, 55 °C):
δ = 23.2 (q, 10-Me), 30.2 (d, C-10), 32.3 (t, C-5), 36.0 (q,
SmI2-induced cyclization of 7a
General Procedure A: 7a (0.296 g, 0.99 mmol), SmI2 8-Me), 36.5 (t, C-7), 42.2 (d, C-6), 55.1 (t, C-9), 71.5 (s, C-8),
(2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and 125.1, 125.9, 127.1, 129.6, 136.5, 146.3 (4 d, 2 s, Ar), 51.7,
t-BuOH (0.148 g, 2.00 mmol). The crude product was purified 176.1 (q, s, CO2Me) ppm. IR (neat):
= 3500 (br, O-H),
by column chromatography (silica gel, ethyl acetate/hexane 1:9) 3100–2840 (=C-H, C-H), 1715 (C=O) cm–1. HRMS (ESI) calcd
then HPLC (iso-propanol/hexane 7:93) to furnish 8 (0.187 g, for C16H22O3: [M+H]+ = 217.1255, [M+Na]+ = 239.1074,
63%) as colourless crystals (mp 74–75 °C).
[M+K]+ = 255.0813; found: 217.1267, 239.1095, 255.0844.
Methyl (4aSR,5RS,11RS,12aRS)-12a-hydroxy-11-methyl- (2RS,5SR,7SR)-5,7-Dimethyl-1,5,6,7-tetrahydro-2,5-
1,2,3,4,4a,5,6,11,12,12a-decahydro-dibenzo[a,e][8]annulene- methano-4-benzoxonin-3(2H)-one (10): 1H NMR (CDCl3,
5-carboxylate (8): 1H NMR (CDCl3, 500 MHz): δ = 1.14–1.18 500 MHz): δ = 1.34 (d, J = 6.9 Hz, 3 H, 7-Me), 1.36 (s, 3 H,
(m, 2 H, 3-H, 4-H), 1.28 (d, J = 7.0 Hz, 3 H, 11-Me), 1.30–1.34, 5-Me), 1.43 (dd, J = 1.1, 13.9 Hz, 1 H, 12-H), 1.55 (dd, J =
1.38–1.46, 1.54–1.58, 1.63–1.70 (4 m, 1 H, 3 H, 1 H, 2 H, 1-H, 11.3, 14.6 Hz, 1 H, 6-H), 1.74–1.79 (m, 1 H, 12-H), 2.05–2.09
2-H, 3-H, 4-H, 4a-H), 1.96 (dd, J = 4.9, 15.2 Hz, 1 H, 12-H), (m, 1 H, 6-H), 2.76 (dqd, J = 1.3, 6.9, 11.3 Hz, 1 H, 7-H), 3.15
2.08 (dd, J = 11.5, 15.2 Hz, 1 H, 12-H), 2.63 (ddd, J = 4.7, 5.8, (dddd, J = 1.1, 2.5, 10.3, 12.8 Hz, 1 H, 2-H), 3.20 (dd, J = 12.8,
10.6 Hz, 1 H, 5-H), 3.13–3.20 (m, 2 H, 6-H), 3.35 (dqd, J = 4.9, 14.5 Hz, 1 H, 1-H), 3.31 (dd, J = 2.5, 14.5 Hz, 1 H, 1-H),
7.0, 11.5 Hz, 1 H, 11-H), 3.73 (s, 3 H, CO2Me), 6.98–7.00, 7.00–7.02, 7.15–7.18, 7.28–7.36 (3 m, 1 H, 1 H, 2 H, Ar) ppm.
7.12–7.21 (2 m, 1 H, 3 H, Ar) ppm, the signal for the OH group 13C NMR (CDCl3, 125 MHz): δ = 22.5 (q, 7-Me), 29.6 (q,
could not be assigned unambiguously. 13C NMR (CDCl3, 5-Me), 30.0 (d, C-7), 34.2 (t, C-12), 34.5 (t, C-1), 39.3 (d, C-2),
125 MHz): δ = 21.3 (t, C-2), 24.3 (q, 11-Me), 24.9 (t, C-3), 29.6 51.4 (t, C-6), 86.3 (s, C-5), 125.4, 126.7, 127.9, 130.4, 136.8,
(t, C-4), 33.7 (d, C-11), 34.1 (t, C-6), 44.3 (t, C-1), 45.0 (d, 146.2 (4 d, 2 s, Ar), 181.5 (s, C-3) ppm. IR (KBr):
=
C-4a), 53.2 (d, C-5), 54.0 (t, C-12), 73.2 (s, C-12a), 126.4, 3065–2825 (=C-H, C-H), 1755 (C=O) cm–1. C15H18O2 (230.3):
127.4, 127.6, 131.0, 137.3, 144.8 (4 d, 2 s, Ar), 51.7, 176.6 (q, calcd. C 78.23, H 7.88; found: C 78.49, H 7.93.
s, CO2Me) ppm. IR (KBr): = 3510 (br, O-H), 3060–2860
(=C-H, C-H), 1725 (C=O) cm−1. MS (EI, 70 eV): m/z (%) = SmI2-induced cyclization of 11
302 (21) [M]+, 284 (100), 224 (64), 169 (57), 131 (53), 117 General procedure A: Compound 11 (0.290 g, 1.01 mmol),
(60), 91 (44), 43 (46). C19H26O3 (302.4): calcd. C 75.46, H SmI2 (2.22 mmol), HMPA (3.16 mL, 18.0 mmol) and t-BuOH
8.67; found: C 75.23, H 8.71.
(0.150 g, 2.02 mmol). The crude product was purified by
column chromatography (silica gel, ethyl acetate/hexane 1:9) to
furnish 12 (0.157 g, 54%) as a colourless oil and 13 (0.072 g,
SmI2-induced cyclization of 4
General Procedure A: 4 (0.200 g, 0.77 mmol), SmI2 28%) as colourless crystals (mp 117–119 °C).
(1.70 mmol), HMPA (2.43 mL, 13.8 mmol) and t-BuOH
(0.114 g, 1.54 mmol). The crude product was purified by Methyl (6RS,8RS,10SR)-8-hydroxy-8-isopropyl-10-methyl-
column chromatography (silica gel, ethyl acetate/hexane 1:9) to 5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carboxylate
1238

Beilstein J. Org. Chem. 2010, 6, 1229–1245.
(12): Compound 12 shows temperature-dependent NMR MHz): δ = 25.3 [q, =C(Ar)Me], 28.3 (t, C-3), 35.9 (t, C-2),
spectra. At rt most signals appear very broad; however, for 115.3 (t, =CH2), 126.3, 127.2, 128.4, 129.0, 137.0, 143.9, 145.4
measurements at 50 °C, the signals are clearly seen. [4 d, 3 s, =C(Ar)Me], 51.7, 173.6 (q, s, CO2Me) ppm. IR (neat):
1H NMR (CDCl3, 500 MHz, 50 °C): δ = 0.85, 0.86 (2 d, J = 6.9
= 3065–2845 (=C-H, C-H), 1735 (C=O), 1640 (C=C) cm–1.
Hz, 2 × 3 H, CHMe2), 1.08 (dd, J = 12.5, 14.7 Hz, 1 H, 7-H), MS (EI = 70 eV): m/z (%) = 204 (23) [M]+, 130 (47), 129 (100),
1.23 (br. s, 1 H, OH), 1.35 (d, J = 7.0 Hz, 3 H, 10-Me), 1.55 115 (42), 91 (29), 28 (47). HRMS (80 eV) calcd for C13H16O2:
(sept, J = 6.9 Hz, 1 H, CHMe2), 1.62–1.69, 3.07–3.13 (2 m, 3 [M]+ = 204.11504; found: 204.11522.
H, 2 H, 5-H, 6-H, 7-H, 9-H), 3.45 (dqd, J = 3.1, 7.0, 9.9 Hz, 1
H, 10-H), 3.54 (dd, J = 7.6, 14.0 Hz, 1 H, 5-H), 3.71 (s, 3 H, SmI2-induced cyclization of 16
CO2Me), 6.99–7.01, 7.09–7.12, 7.21–7.30 (3 m, 1 H, 1 H, 2 H, General procedure A: Compound 16 (0.170 g, 0.49 mmol),
Ar) ppm. 13C NMR (CDCl3, 125 MHz, 50 °C): δ = 16.7, 17.2 SmI2 (1.08 mmol), HMPA (1.54 mL, 8.77 mmol) and t-BuOH
(2 q, CHMe2), 23.3 (q, 10-Me), 29.1 (d, C-10), 31.9 (t, C-7), (0.073 g, 0.98 mmol). The crude product was purified by
32.7 (t, C-5), 42.2 (d, C-6), 43.2 (d, CHMe2), 50.3 (t, C-9), 74.8 column chromatography (silica gel, ethyl acetate/hexane 7:93 to
(s, C-8), 124.7, 125.8, 127.1, 129.7, 136.6, 146.9 (4 d, 2 s, Ar), 25:75) then HPLC (ethyl acetate/hexane 1:4) to furnish 17a
51.6, 176.2 (q, s, CO2Me) ppm. IR (neat): = 3515 (br, O-H), (0.058 g, 37%, mp 162–165 °C) and 17b (0.035 g, 22%, mp
3100–2845 (=C-H, C-H), 1720 (C=O) cm–1. MS (EI, 70 eV): 180–182 °C) as colourless crystals.
m/z (%) = 290 (13) [M]+, 247 (70), 215 (85), 187 (54), 145
(73), 117 (40), 71 (26), 43 (100). C18H26O3 (290.4): calcd: C (2RS,5SR,7RS)-5-Isopropyl-7-phenyl-1,5,6,7-tetrahydro-2,5-
74.45, H 9.02; found: C 74.71, H 8.83.
methano-4-benzoxonin-3(2H)-one (17a): 1H NMR (CDCl3,
500 MHz): δ = 0.89, 0.98 (2 d, J = 6.9 Hz, 2 × 3 H, CHMe2),
(2RS,5SR,7SR)-5-Isopropyl-7-methyl-1,5,6,7-tetrahydro-2,5- 1.37 (dd, J = 1.3, 14.0 Hz, 1 H, 12-H), 1.84 (ddd, J = 1.3, 11.0,
methano-4-benzoxonin-3(2H)-one (13): 1H NMR (CDCl3, 14.0 Hz, 1 H, 12-H), 1.93 (sept, J = 6.9 Hz, 1 H, CHMe2), 2.13
500 MHz): δ = 0.79, 0.89 (2 d, J = 6.9 Hz, 2 × 3 H, CHMe2), (dd, J = 11.6, 14.0 Hz, 1 H, 6-H), 2.57 (td, J = 1.3, 14.0 Hz, 1
1.27 (dd, J = 1.3, 13.9 Hz, 1 H, 12-H), 1.35 (d, J = 7.0 Hz, 3 H, H, 6-H), 3.21 (dddd, J = 1.3, 3.3, 11.0, 13.0 Hz, 1 H, 2-H), 3.34
7-Me), 1.60 (dd, J = 11.1, 14.4 Hz, 1 H, 6-H), 1.75 (dd, J = (dd, J = 13.0, 15.3 Hz, 1 H, 1-H), 3.55 (dd, J = 3.3, 15.3 Hz, 1
10.8, 13.9 Hz, 1 H, 12-H), 1.84 (sept, J = 6.9 Hz, 1 H, CHMe2), H, 1-H), 4.03 (dd, J = 1.3, 11.6 Hz, 1 H, 7-H), 6.93–6.96,
1.95 (dd, J = 0.9, 14.4 Hz, 1 H, 6-H), 2.70–2.77 (m, 1 H, 7-H), 7.00–7.05, 7.08–7.13, 7.18–7.22, 7.27–7.32 (5 m, 1 H, 1 H, 2
3.10–3.15 (m, 1 H, 2-H), 3.21 (dd, J = 12.8, 14.8 Hz, 1 H, 1-H), H, 3 H, 2 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 16.7,
3.32 (dd, J = 2.9, 14.8 Hz, 1 H, 1-H), 6.99–7.01, 7.14–7.17, 17.5 (2 q, CHMe2), 30.6 (d, C-7), 34.9 (t, C-12), 39.0 (t, C-1),
7.27–7.36 (3 m, 1 H, 1 H, 2 H, Ar) ppm. 13C NMR (CDCl3, 39.1 (d, CHMe2), 40.7 (d, C-2), 41.5 (t, C-6), 90.8 (s, C-5),
125 MHz): δ = 16.6, 17.4 (2 q, CHMe2), 22.9 (q, 7-Me), 29.6 126.5, 126.7, 128.0, 128.3, 128.5, 128.6, 130.3, 136.4, 145.2,
(d, C-7), 30.5 (t, C-12), 34.6 (t, C-1), 38.5 (d, CHMe2), 38.9 (d, 145.8 (7 d, 3 s, Ar), 181.5 (s, C-3) ppm. IR (KBr):
C-2), 45.3 (t, C-6), 91.2 (s, C-5), 125.4, 126.6, 127.9, 130.3, 3085–2840 (=C-H, C-H), 1760 (C=O) cm–1. MS (EI, 70 eV):
136.7, 146.6 (4 d, 2 s, Ar), 181.7 (s, C-3) ppm. IR (KBr): m/z (%) = 320 (75) [M]+, 309 (15), 277 (92), 179 (49), 91 (92),
=
=
3075–2850 (=C-H, C-H), 1765 (C=O) cm–1. MS (EI = 70 eV): 43 (100). HRMS (80 eV) calcd for C22H24O2: [M]+ =
m/z (%) = 258 (46) [M]+, 215 (72), 187 (41), 173 (50), 145 320.17764; found: 320.17735.
(69), 117 (37), 91 (28), 71 (32), 43 (100). C17H22O2 (258.4):
calcd: C 79.03, H 8.58; found: C 79.09, H 8.41.
(2RS,5SR,7SR)-5-Isopropyl-7-phenyl-1,5,6,7-tetrahydro-2,5-
methano-4-benzoxonin-3(2H)-one (17b): 1H NMR (CDCl3,
500 MHz): δ = 0.93, 1.01 (2 d, J = 6.9 Hz, 2 × 3 H, CHMe2),
SmI2-induced reaction of 14
General procedure B: Compound 14 (0.276 g, 0.87 mmol), 1.86 (sept, J = 6.9 Hz, 1 H, CHMe2), 2.34 (dd, J = 2.5, 14.5 Hz,
SmI2 (1.92 mmol), HMPA (2.75 mL, 15.7 mmol) and t-BuOH 1 H, 6-H), 2.38 (dd, J = 9.5, 13.8 Hz, 1 H, 12-H), 2.44 (dd, J =
(0.129 g, 1.74 mmol). The crude product was purified by 12.4, 14.5 Hz, 1 H, 6-H), 2.48 (dd, J = 1.0, 13.8 Hz, 1 H, 12-H),
column chromatography (silica gel, ethyl acetate/hexane 1:9) to 3.29 (dddd, J = 1.0, 4.9, 9.5, 14.3 Hz, 1 H, 2-H), 3.30–3.36 (m,
furnish 15 (0.103 g, 58%) as a colourless oil.
2 H, 1-H), 4.40 (dd, J = 2.5, 12.4 Hz, 1 H, 7-H), 6.79–6.82,
7.04–7.07, 7.09–7.12, 7.23–7.29, 7.32–7.36 (5 m, 1 H, 2 H, 1
Methyl 3-(2-isopropenylphenyl)propanoate (15): H, 3 H, 2 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 16.8,
1H NMR (CDCl3, 500 MHz): δ = 2.07 [br s, 3 H, =C(Ar)Me], 17.3 (2 q, CHMe2), 37.0 (t, C-12), 37.9 (t, C-1), 39.5 (t, C-6),
2.60 (t, J = 8.2 Hz, 2 H, 2-H), 2.98 (t, J = 8.2 Hz, 2 H, 3-H), 40.3 (d, CHMe2), 42.5 (d, C-2), 42.8 (d, C-7), 90.6 (s, C-5),
3.69 (s, 3 H, CO2Me), 4.87 (br. s, 1 H, =CH2), 5.22 (br. s, 1 H, 126.2, 126.6, 128.0, 128.3, 128.3, 128.6, 132.0, 135.6, 144.3,
=CH2), 7.10–7.20 (m, 4 H, Ar) ppm. 13C NMR (CDCl3, 100 145.3 (7 d, 3 s, Ar), 176.2 (s, C-3) ppm. IR (KBr):
=
1239

Beilstein J. Org. Chem. 2010, 6, 1229–1245.
3065–2875 (=C-H, C-H), 1755 (C=O) cm–1. MS (EI, 70 eV): SmI2-induced cyclization of 21
m/z (%) = 320 (100) [M]+, 277 (97), 179 (45), 91 (91), 43 (59). General procedure B: Compound 21 (0.270 g, 0.99 mmol),
C22H24O2 (320.4): calcd: C 82.46, H 7.55; found: C 81.83, H SmI2 (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and
7.59.
t-BuOH (0.148 g, 2.00 mmol). The crude product was purified
by column chromatography (silica gel, ethyl acetate/hexane
1:9), then HPLC (iso-propanol/hexane 2:98) to furnish 22
SmI2-induced cyclization of 18
General procedure A: Compound 18 (0.200 g, 0.77 mmol), (0.152 g, 56%) and 23 (0.012 g, 6%) as colourless oils.
SmI2 (1.70 mmol), HMPA (2.43 mL, 13.8 mmol) and t-BuOH
(0.114 g, 1.54 mmol). The crude product was purified by Methyl (6RS,8SR,9SR)-8-ethyl-8-hydroxy-9-methyl-
column chromatography (silica gel, ethyl acetate/hexane 1:9) to 5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carboxylate
furnish 19 (0.108 g, 54%) and 20 (0.040 g, 20%) as colourless (22): Compound 22 shows temperature-dependent NMR
oils.
spectra. At rt several signals appear broad; however, for
measurements at 40 °C, the signals are more clearly seen.
Methyl (6RS,8SR,9SR)-8-hydroxy-8,9-dimethyl-5,6,7,8,9,10- 1H NMR (CDCl3, 500 MHz, 40 °C): δ = 0.87 (t, J = 7.2 Hz, 3
hexahydro-benzo[8]annulene-6-carboxylate (19): Com- H, 8-CH2Me), 0.92 (d, J = 6.9 Hz, 3 H, 9-Me), 1.39, 1.50 (2 qd,
pound 19 shows temperature-dependent NMR spectra. J = 7.2, 14.4 Hz, 2 × 1 H, 8-CH2Me), 1.56–1.70 (m, 2 H, 7-H),
At rt several signals appear broad; however, for 1.97–2.03 (m, 1 H, 9-H), 2.55 (dd, J = 8.5, 13.6 Hz, 1 H, 10-H),
measurements at 55 °C, signals are more clearly seen. 2.97–3.02 (m, 1 H, 6-H), 3.05–3.13 (m, 2 H, 5-H, 10-H), 3.27
1H NMR (CDCl3, 500 MHz, 55 °C): δ = 0.97 (d, J = 7.0 Hz, 3 (dd, J = 4.0, 13.7 Hz, 1 H, 5-H), 3.72 (s, 3 H, CO2Me),
H, 9-Me), 1.17 (s, 3 H, 8-Me), 1.62 (dd, J = 2.8, 14.8 Hz, 1 H, 7.08–7.11, 7.14–7.18 (2 m, 1 H, 3 H, Ar) ppm, the OH group
7-H), 1.77 (dd, J = 12.0, 14.8 Hz, 1 H, 7-H), 1.94–2.01 (m, 1 H, could not be assigned unambiguously. 13C NMR (CDCl3,
9-H), 2.54 (dd, J = 9.1, 14.0 Hz, 1 H, 10-H), 2.96–3.08 (m, 3 H, 125 MHz, 40 °C): δ = 7.1 (q, 8-CH2Me), 16.0 (q, 9-Me), 33.4 (t,
5-H, 6-H, 10-H), 3.22 (dd, J = 5.0, 13.8 Hz, 1 H, 5-H), 3.70 (s, C-7), 35.3 (t, C-5), 36.6 (t, 8-CH2Me), 36.8 (t, C-10), 43.0 (d,
3 H, CO2Me), 7.07–7.15 (m, 4 H, Ar) ppm, the signal for the C-6), 44.2 (d, C-9), 75.7 (s, C-8), 126.7, 126.9, 130.6, 130.7,
OH group could not be assigned unambiguously. 13C NMR 138.3, 139.7 (4 d, 2 s, Ar), 51.6, 176.4 (q, s, CO2Me) ppm. IR
(CDCl3, 125 MHz, 55 °C): δ = 17.0 (q, 9-Me), 32.0 (q, 8-Me), (neat): = 3535 (br, O-H), 3060–2860 (=C-H, C-H), 1720
35.1 (t, C-5), 35.8 (t, C-7), 37.4 (t, C-10), 43.0 (d, C-6), 47.0 (d, (C=O) cm–1. HRMS (ESI) calcd for C17H24O3: [M+Na]+ =
C-9), 74.8 (s, C-8), 126.8, 127.0, 130.6, 130.7, 138.1, 139.7 (4 299.1618; found: 299.1614.
d, 2 s, Ar), 51.7, 176.3 (q, s, CO2Me) ppm. IR (neat): = 3510
(br, O-H), 3100–2850 (=C-H, C-H), 1720 (C=O) cm−1. Methyl 3-{2-[(1E)-propen-1-yl]phenyl}propanoate
C16H22O3 (262.3): calcd: C 73.25, H 8.45; found: C 73.43, H (23): 1H NMR (CDCl3, 400 MHz): δ = 1.90 (dd, J = 1.6, 6.6
8.30.
Hz, 3 H, =CHMe), 2.57 (t, J = 8.2 Hz, 2 H, 2-H), 2.99 (t, J =
8.2 Hz, 2 H, 3-H), 3.69 (s, 3 H, CO2Me), 6.12 (qd, J = 6.6, 15.5
Methyl (2SR,4RS,4aSR)-4-hydroxy-4-methyl-8-[(1E)- Hz, 1 H, =CHMe), 6.62 (qd, J = 1.6, 15.5 Hz, 1 H, =CHAr),
propen-1-yl]-1,2,3,4,4a,7-hexahydro-naphthalene-2-carbox- 7.10–7.21, 7.39–7.42 (2 m, 3 H, 1 H, Ar) ppm. 13C NMR
ylate (20): 1H NMR (CDCl3, 500 MHz): δ = 1.02 (s, 3 H, (CDCl3, 100 MHz): δ = 19.0 (q, =CHMe), 28.6 (t, C-3), 35.2 (t,
4-Me), 1.79 (dd, J = 1.5, 6.6 Hz, 3 H, =CHMe), 1.87-1.91 (m, 2 C-2), 126.2, 126.8, 127.2, 128.1, 128.2, 129.3, 136.9, 137.2 (6
H, 1-H, 3-H), 2.07 (dd, J = 3.8, 12.5 Hz, 1 H, 3-H), 2.37 (tt, J = d, 2 s, ArCH=CH), 51.8, 173.6 (q, s, CO2Me) ppm. IR (neat):
3.8, 12.9 Hz, 1 H, 2-H), 2.70–2.84 (m, 3 H, 1-H, 7-H), 3.21 (dd, = 3065–2850 (=C-H, C-H), 1735 (C=O), 1600 (C=C) cm–1.
J = 1.6, 3.8 Hz, 1 H, 4a-H), 3.72 (s, 3 H, CO2Me), 5.64 (qd, J = HRMS (ESI) calcd for C13H16O2: [M+Na]+ = 227.1043,
6.6, 15.6 Hz, 1 H, =CHMe), 5.84–5.87, 5.89–5.92 (2 m, 2 × 1 [M+K]+ = 243.0782; found: 227.1018, 243.0936.
H, 5-H, 6-H), 6.53 (qd, J = 1.5, 15.6 Hz, 1 H, CH=CHMe) ppm,
the signal for the OH group could not be assigned unambigu- SmI2-induced cyclization of 24
ously. 13C NMR (CDCl3, 125 MHz): δ = 18.9 (q, =CHMe), General procedure A: Compound 24 (0.300 g, 1.04 mmol),
22.0 (q, 4-Me), 27.5 (t, C-1), 31.2 (t, C-7), 41.0 (d, C-2), 44.0 (t, SmI2 (2.30 mmol), HMPA (3.30 mL, 18.8 mmol) and t-BuOH
C-3), 50.2 (d, C-4a), 74.6 (s, C-4), 123.2, 124.8, 125.8, 126.6, (0.156 g, 2.10 mmol). The crude product was purified by
128.2, 129.3 (4 d, 2 s, =CH, =Cq), 52.0, 175.2 (q, s, CO2Me) column chromatography (silica gel, ethyl acetate/hexane 1:9) to
ppm. Due to instability of the sample and storage before the MS furnish 25 (0.188 g, 63%) as colourless crystals (mp 89–90 °C).
analysis was accomplished, only the rearomatized product could
be detected. HRMS (ESI) calcd for C16H20O3: [M+Na]+ = Methyl (6RS,8RS,9SR)-8-hydroxy-8-isopropyl-9-methyl-
283.1305; found: 283.1295.
5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carboxylate
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
(25): Compound 25 shows temperature-dependent spectra. At rt Mixture of 27 + 28: 13C NMR (CDCl3, 175 MHz, 40 °C): δ =
most signals appear very broad; however, for measurements at 17.3, 18.9, 20.1, 20.7, 21.2, 24.4, 25.2, 26.6, 27.4, 27.6, 30.5,
65 °C, the signals are clearly seen; 1H NMR (d6-DMSO, 32.0, 37.3, 40.2, 41.5, 43.0, 44.2, 45.2, 45.3, 51.2, 51.5, 51.9,
500 MHz, 65 °C): δ = 0.78 (d, J = 7.0 Hz, 3 H, 9-Me), 0.85, 75.4 (s, C-4b, 28), 75.9 (s, C-12a, 27), 123.0, 124.7, 126.0,
0.86 (2 d, J = 6.7 Hz, 2 × 3 H, CHMe2), 1.14 (dd, J = 12.7, 14.9 126.2, 128.0, 129.2 (4 d, 2 s, C-1, C-3, C-4, C-10a, CH=CHMe,
Hz, 1 H, 7-H), 1.40 (dd, J = 2.7, 14.9 Hz, 1 H, 7-H), 1.49 (sept, 28), 125.8, 126.7, 129.5, 132.6, 136.0, 140.4 (4 d, 2 s, Ar, 27),
J = 6.7 Hz, 1 H, CHMe2), 2.01–2.07 (m, 1 H, 9-H), 2.33 (dd, J 175.5 (s, C=O, 28), 176.6 (s, C=O, 27) ppm, no unambiguous
= 5.9, 13.8 Hz, 1 H, 10-H), 2.92 (dd, J = 2.4, 13.4 Hz, 1 H, assignment of signals was possible. IR (neat): = 3510 (br,
5-H), 2.99 (dddd, J = 2.4, 2.7, 6.6, 12.7 Hz, 1 H, 6-H), 3.33 (dd, OH), 3060–2860 (=C-H, C-H), 1720 (br, C=O), 1600 (C=C)
J = 2.0, 13.8 Hz, 1 H, 10-H), 3.44 (dd, J = 6.6, 13.4 Hz, 1 H, cm–1. HRMS (ESI) calcd for C19H26O3: [M+Na]+ = 325.1774;
5-H), 3.61 (s, 3 H, CO2Me), 6.89–6.91, 7.06–7.12 (2 m, 1 H, 3 found: 325.1798.
H, Ar) ppm, the signal for the OH group could not be assigned
unambiguously. 13C NMR (d6-DMSO, 125 MHz, 65 °C): δ = SmI2-induced cyclization of 26b
13.3 (q, 9-Me), 15.7, 16.2 (2 q, CHMe2), 28.0 (t, C-7), 33.2 (t, General procedure A: Compound 26b (0.300 g, 1.00 mmol),
C-5), 34.9 (t, C-10), 36.0 (d, CHMe2), 39.9 (d, C-9), 40.9 (d, SmI2 (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and
C-6), 74.8 (s, C-8), 125.2, 125.7, 129.5, 130.8, 137.4, 139.3 (4 t-BuOH (0.148 g, 2.00 mmol). The crude product was purified
d, 2 s, Ar), 50.8, 175.1 (q, s, CO2Me) ppm. IR (KBr): = 3490 by column chromatography (silica gel, ethyl acetate/hexane 1:9)
(br, O-H), 3000–2840 (=C-H, C-H), 1715 (C=O) cm–1. MS (EI to furnish 29 (0.025 g, 9%) as colourless crystals (mp
= 70 eV): m/z (%) = 290 (24) [M]+, 247 (74), 215 (90), 187 119–121 °C), 23 (0.082 g, 27%) and 26b (0.120 g, 40%) as
(100), 157 (54), 117 (54), 71 (21), 43 (80). C18H26O3 (290.4): colourless oils.
calcd: C 74.45, H 9.02; found: C 74.51, H 8.74.
(4aRS,5RS,12RS,12aSR)-5-Methyl-1,3,4,5,6,11,12,12a-
SmI2-induced cyclization of 26a
octahydro-2H-4a,12-(epoxymethano)dibenzo[a,e][8]-
General procedure A: Compound 26a (0.300 g, 1.00 mmol), annulen-13-one (29): 1H NMR (CDCl3, 500 MHz): δ = 0.90
SmI2 (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and (d, J = 7.1 Hz, 3 H, 5-Me), 1.25–1.31, 1.39–1.48, 1.52–1.60,
t-BuOH (0.148 g, 2.00 mmol). The crude product was purified 1.65–1.81 (4 m, 1 H, 2 × 2 H, 3 H, 1-H, 2-H, 3-H, 4-H),
by column chromatography (silica gel, ethyl acetate/hexane 1.97–2.12 (m, 1 H, 12a-H), 2.19 (dqd, J = 2.0, 7.1, 7.2 Hz, 1 H,
1:9), then HPLC (ethyl acetate/hexane 15:85) to furnish 27 and 12a-H), 2.57 (dd, J = 7.2, 14.6 Hz, 1 H, 6-H), 2.79 (br. d, J ≈
28 (0.054 g, 18%) as an inseparable mixture (27:28 = 5:3 by in- 14.6 Hz, 1 H, 6-H), 2.82 (ddd, J = 1.0, 5.2, 9.6 Hz, 1 H, 12-H),
tegration of NMR signals) and 26a (0.125 g, 42%) as colour- AB part of ABX system (δA = 3.24, δB = 3.27, JAB = 15.2 Hz,
less oils.
JAX = 9.6 Hz, JBX = 5.2 Hz, 2 H, 11-H), 7.05–7.07, 7.14–7.21
(2 m, 1 H, 3 H, Ar) ppm. 13C NMR (CDCl3, 100 MHz): δ =
Methyl (4aSR,5RS,12SR,12aRS)-12a-hydroxy-12-methyl- 15.4 (q, 5-Me), 16.4, 16.5 (2 t, C-2, C-3), 28.6, 28.8 (2 t, C-1,
1,2,3,4,4a,5,6,11,12,-12a-decahydro-dibenzo[a,e][8]annu- C-4), 35.0 (t, C-6), 35.8 (t, C-11), 42.0 (d, C-5), 47.4 (d, C-12),
lene-5-carboxylate (27): 1H NMR (CDCl3, 700 MHz): 91.3 (s, C-4a), 126.7, 126.9, 131.3, 132.1, 137.7, 142.6 (4 d, 2 s,
δ = 0.80–2.03 (m, 10 H, 1-H, 2-H, 3-H, 4-H, 4a-H, OH), 1.04 Ar) ppm, the signal for C-13 is not clearly visible. Signals for
(d, J = 6.6 Hz, 3 H, 12-Me), 2.56–2.62 (m, 1 H, 12-H), 2.70 C-2, C-3, C-5, C-6, C-11, C-12, 5-Me, and three of the aromatic
(dd, J = 11.3, 16.8 Hz, 1 H, 11-H), 2.82 (dd, J = 2.2, 15.0 Hz, 1 carbon atoms are broad. IR (KBr): = 3045–2870 (=C-H,
H, 6-H), 2.97 (dd, J = 3.8, 16.8 Hz, 1 H, 11-H), 3.00 (ddd, J = C-H), 1745 (C=O) cm–1. HRMS (ESI) calcd for C18H22O2:
2.2, 7.3, 9.6 Hz, 1 H, 5-H), 3.61 (dd, J = 7.3, 15.0 Hz, 1 H, [M+H]+ = 271.1693, [M+Na]+ = 293.1512; found: 271.1692,
6-H), 3.63 (s, 3 H, CO2Me), 7.03–7.07, 7.10–7.15 (2 m, 2 × 2 293.1509.
H, Ar) ppm.
SmI2-induced cyclization of 30
Methyl (4aS,4bR,8aR,9S)-4b-hydroxy-1-[(1E)-prop-1-en-1- General procedure B: Compound 30 (0.288 g, 1.00 mmol),
yl]-2,4a,4b,5,6,7,8,8a,-9,10-decahydro-phenanthrene-9-car- SmI2 (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and
boxylate (28): 1H NMR (CDCl3, 700 MHz): δ = 0.80–2.03 (m, t-BuOH (0.148 g, 2.00 mmol). The crude product was purified
15 H, 2-H, 5-H, 6-H, 7-H, 8-H, 8a-H, 9-H, 10-H, OH), 1.81 (dd, by column chromatography (silica gel, ethyl acetate/hexane 1:9)
J = 1.2, 6.5 Hz, 3 H, =CHMe), 3.14 (dd, J = 3.8, 13.3 Hz, 1 H, to furnish 31 (0.022 g, 8%) as colourless crystals (mp
4a-H), 3.72 (s, 3 H, CO2Me), 5.66 (qd, J = 6.5, 15.4 Hz, 1 H, 81–83 °C), 32 (0.064 g, 31%) and 30 (0.092 g, 32%) as colour-
=CHMe), 5.83–5.85, 5.90–5.93 (2 m, 2 × 1 H, 3-H, 4-H), 6.53 less oils.
(br. d, J = 15.4 Hz, 1 H, 1-CH=) ppm.
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
Methyl (6RS,8RS,9RS)-8-hydroxy-8-isopropyl-9-methyl- J = 6.7 Hz, 2 × 3 H, CHMe2), 1.12 (s, 1 H, OH), 1.28–1.33 (m,
5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carboxylate 1 H, 9-H), 1.60–1.68, 1.87–1.91 (2 m, 2 × 1 H, 7-H), 2.06 (sept,
(31): Compound 31 shows temperature-dependent spectra. At rt J = 6.7 Hz, 1 H, CHMe2), 2.68 (dd, J = 6.9, 13.9 Hz, 1 H,
most signals appear very broad; for measurements at 55 °C, the 10-H), 2.94–2.99 (m, 1 H, 6-H), 3.07 (dd, J = 4.1, 13.9 Hz, 1 H,
signals are clearly seen. 1H NMR (CDCl3, 500 MHz, 55 °C): δ 10-H), 3.18–3.21 (m, 1 H, 5-H), 3.41 (dd, J = 5.6, 13.7 Hz, 1 H,
= 0.89, 0.90 (2 d, J = 6.8 Hz, 2 × 3 H, CHMe2), 0.94 (d, J = 7.0 5-H), 3.71 (s, 3 H, CO2Me), 7.04–7.07, 7.11–7.15, 7.26–7.30 (3
Hz, 3 H, 9-Me), 1.49–1.65 (m, 1 H, 7-H), 1.62 (sept, J = 6.8 Hz, m, 1 H, 2 H, 1 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz, 51
1 H, CHMe2), 1.71–1.82 (m, 1 H, 7-H), 2.04–2.11 (m, 1 H, °C): δ = 3.8, 6.6 (2 t, C-2', C-3'), 11.7 (d, C-1'), 17.1, 17.3 (2 q,
9-H), 2.57 (dd, J = 8.4, 13.2 Hz, 1 H, 10-H), 2.87–2.97 (m, 1 H, CHMe2), 34.8, 35.2, 35.9 (d, 2 t, CHMe2, C-5, C-10), 41.9 (d,
6-H), 3.07 (dd, J = 5.9, 13.7 Hz, 1 H, 5-H), 3.03–3.14 (m, 1 H, C-6), 51.4 (d, C-9), 77.7 (s, C-8), 126.2, 126.5, 130.3, 131.0,
10-H), 3.24–3.35 (m, 1 H, 5-H), 3.72 (s, 3 H, CO2Me), 138.1, 140.2 (4 d, 2 s, Ar), 51.8, 176.5 (q, s, CO2Me) ppm, the
7.07–7.09, 7.13–7.18 (2 m, 1 H, 3 H, Ar) ppm, the signal for the signal for C-7 is not clearly visible, the signals for C-5, C-8,
OH group could not be assigned unambiguously. 13C NMR C-9, C-10, C-1', C-2', C-3', CHMe2, Ar (2 d, 2 s) are broad. IR
(CDCl3, 125 MHz, 55 °C): δ = 15.4 (q, 9-Me), 16.3, 16.5 (2 q, (KBr): = 3490 (br, O-H), 3080–2875 (=C-H, C-H), 1715
CHMe2), 36.7 (d, CHMe2), 42.8 (d, C-9), 65.9 (s, C-8), 126.7, (C=O) cm–1. C20H28O3 (316.4): calcd: C 75.91, H 8.92; found:
127.0, 130.7, 130.8, 138.6, 139.9 (4 d, 2 s, Ar), 51.7, 176.5 (q, C 76.09, H 8.88.
s, CO2Me) ppm. The signals for C-5, C-6 and C-7 are not
clearly visible, the signals for C-9 and 9-Me are broad. IR Methyl 3-{2-[(E)-2-cyclopropylvinyl]phenyl}propanoate
(KBr): = 3490 (br, O-H), 3060–2850 (=C-H, C-H), 1710 (35): 1H NMR (CDCl3, 500 MHz): δ = 0.82–0.91 (m, 4 H, 2'-H,
(C=O) cm–1. HRMS (ESI) calcd for C18H26O3: [M+Na]+ = 3'-H), 1.61 (ttd, J = 4.5, 8.5, 8.9 Hz, 1 H, 1'-H), 2.59 (t, J =
313.1774; found: 313.1773.
8.2 Hz, 2 H, 2-H), 3.02 (t, J = 8.2 Hz, 2 H, 3-H), 3.70 (s, 3 H,
CO2Me), 5.60 (dd, J = 8.9, 15.5 Hz, 1 H, 1'-CH=), 6.69 (d, J =
Methyl 3-{2-[(1Z)-propen-1-yl]phenyl}propanoate (32): 15.5 Hz, 1 H, =CHAr), 7.12–7.18, 7.36–7.39 (2 m, 3 H, 1 H,
1H NMR (CDCl3, 250 MHz): δ = 1.72 (dd, J = 1.6, 7.0 Hz, 3 H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 7.5 (t, C-2', C-3'),
=CHMe), 2.54 (t, J = 8.2 Hz, 2 H, 2-H), 2.92 (t, J = 8.2 Hz, 2 H, 15.0 (d, C-1'), 28.6 (t, C-2), 35.2 (t, C-3), 124.4 (d, =CHAr),
3-H), 3.66 (s, 3 H, CO2Me), 5.85 (qd, J = 7.0, 11.5 Hz, 1 H, 137.2 (d, 1'-CH=), 125.8, 126.8, 126.9, 129.3, 136.6, 137.0 (4 d,
=CHMe), 6.52 (qd, J = 1.6, 11.5 Hz, 1 H, =CHAr), 7.18 (br. s, 4 2 s, Ar), 51.8, 173.6 (q, s, CO2Me) ppm. HRMS (ESI) calcd for
H, Ar) ppm. 13C NMR (CDCl3, 125 MHz): δ = 14.4 (q, C15H18O2: [M+Na]+ = 253.1199; found: 253.1201.
=CHMe), 28.8 (t, C-3), 34.8 (t, C-2), 126.1, 127.1, 127.8, 128.4,
129.0, 129.8, 136.4, 138.7 (6 d, 2 s, ArCH=CH), 51.7, 173.6 (q, SmI2-induced cyclization of 36
s, CO2Me) ppm. IR (neat): = 3065–2870 (=C-H, C-H), 1735 General procedure B: Compound 36 (0.200 g, 0.57 mmol),
(C=O) cm–1. MS (EI, 70 eV): m/z (%) = 204 (56) [M]+, 144 SmI2 (1.26 mmol), HMPA (1.80 mL, 10.3 mmol) and
(36), 129 (100), 115 (88), 91 (51), 77 (19), 18 (70); HRMS t-BuOH (0.085 g, 1.15 mmol). The crude product was purified
(80 eV) calcd for C13H16O2: [M]+ = 204.11504; found: by column chromatography (silica gel, ethyl acetate/hexane
204.11464.
1:9) to furnish 37 (0.094 g, 47%) as colourless
crystals (mp 135–137 °C) and 36 (0.040 g, 20%) as a colour-
less oil.
SmI2-induced cyclization of 33
General procedure B: Compound 33 (0.314 g, 1.00 mmol),
SmI2 (2.20 mmol), HMPA (3.16 mL, 18.0 mmol) and Methyl (6RS,8RS,9RS)-8-hydroxy-8-isopropyl-9-phenyl-
t-BuOH (0.148 g, 2.00 mmol). The crude product was purified 5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carboxylate
by column chromatography (silica gel, ethyl acetate/hexane 1:9) (37): 1H NMR (CDCl3, 500 MHz): δ = 1.07 (br. s, 1 H, OH),
to furnish 34 (0.075 g, 24%) as colourless crystals 1.10, 1.17 (2 d, J = 6.8 Hz, 2 × 3 H, CHMe2), 2.06 (dd, J =
(mp 131–133 °C) and 35 (0.109 g, 47%) as a colourless oil. 12.4, 14.2 Hz, 1 H, 7-H), 2.07 (sept, J = 6.8 Hz, 1 H, CHMe2),
2.40–2.44 (m, 1 H, 7-H), 2.81 (dddd, J = 1.8, 2.6, 12.3, 12.4 Hz,
Methyl (6RS,8RS,9RS)-9-cyclopropyl-8-hydroxy-8-iso- 1 H, 6-H), 2.91 (dd, J = 3.0, 13.1 Hz, 1 H, 10-H), 3.02 (dd, J =
propyl-5,6,7,8,9,10-hexahydro-benzo[8]annulene-6-carbox- 1.8, 14.8 Hz, 1 H, 5-H), 3.08 (dd, J = 11.9, 13.1 Hz, 1 H, 10-H),
ylate (34): Compound 35 shows temperature-dependent 3.21 (dd, J = 3.0, 11.9 Hz, 1 H, 9-H), 3.44 (dd, J = 12.3, 14.8
spectra. At rt most signals appear very broad; however, for Hz, 1 H, 5-H), 3.74 (s, 3 H, CO2Me), 6.52–6.54, 6.75–6.77,
measurements at 51 °C, the signals are clearly seen. 6.85–6.88, 7.04–7.14 (4 m, 1 H, 2 H, 1 H, 5 H, Ar) ppm.
1H NMR (CDCl3, 500 MHz, 51 °C): δ = 0.27–0.32, 0.47–0.57, 13C NMR (CDCl3, 125 MHz): δ = 17.5, 17.7 (2 q, CHMe2),
0.62–0.69 (3 m, 1 H, 3 H, 1 H, 1'-H, 2'-H, 3'-H), 0.90, 0.98 (2 d, 35.2 (t, C-10), 35.3 (d, CHMe2), 38.3 (t, C-5), 38.5 (t, C-7),
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Beilstein J. Org. Chem. 2010, 6, 1229–1245.
40.5 (d, C-6), 57.8 (d, C-9), 74.2 (s, C-8), 125.9, 126.5, 127.5, 2 H, 1 H, 1-H, 2-H, 3-H, 4-H), 2.54 (dd, J = 6.6, 11.4 Hz, 1 H,
128.1, 128.9, 130.9, 134.4, 137.6, 139.4, 140.5 (7 d, 3 s, Ar), 11a-H), 2.65 (dd, J = 11.3, 12.8 Hz, 1 H, PhCH2), 2.71 (dd, J =
52.1, 176.8 (q, s, CO2Me) ppm. IR (KBr): = 3485 (br, O-H), 2.6, 6.6 Hz, 1 H, 11-H), 2.94 (dd, J = 2.4, 12.8 Hz, 1 H,
3100–2845 (=C-H, C-H), 1710 (C=O) cm–1. MS (EI = 70 eV): PhCH2), 3.02 (dd, J = 2.4, 11.3 Hz, 1 H, 5-H), 3.23–3.31 (m, 2
m/z (%) = 352 (41) [M]+, 309 (15), 267 (22), 157 (70), 91 H, 10-H), 6.29–6.31, 6.71–6.74, 6.81–6.85, 7.04–7.07,
(100), 71 (40), 43 (95). C23H28O3 (352.5): calcd C 78.38, H 7.11–7.15 (5 m, 1 H, 2 H, 2 × 1 H, 4 H, Ar) ppm. 13C NMR
8.01; found: C 78.05, H 8.04.
(CDCl3, 125 MHz): δ = 21.5 (t, C-3), 23.6 (t, C-2), 29.9 (t,
C-1), 33.7 (t, C-4), 36.6 (t, C-10), 39.6 (t, PhCH2), 43.5 (d,
C-11a), 49.5 (d, C-5), 62.4 (d, C-11), 86.0 (s, C-4a), 126.3,
SmI2-induced cyclization of 38a
General procedure A: Compound 38a (0.170 g, 0.47 mmol), 126.5, 127.1, 128.2, 129.2, 131.2, 133.3, 135.5, 137.6, 139.6 (7
SmI2 (1.04 mmol), HMPA (1.48 mL, 8.43 mmol) and t-BuOH d, 3 s, Ar), 178.2 (s, C-12) ppm. IR (neat): = 3060–2855 (=C-
(0.070 g, 0.94 mmol). The crude product was purified by H, C-H), 1760 (C=O) cm–1. C23H24O2 (332.4): calcd: C 83.10,
column chromatography (silica gel, ethyl acetate/hexane 1:9), H 7.28; found: C 82.64, H 7.08.
then HPLC (ethyl acetate/hexane 15:85) to furnish 39 (0.074 g,
44%) as colourless crystals (mp 114–115 °C).
SmI2-induced cyclization of 41
General procedure A: Compound 41 (0.223 g, 0.81 mmol),
Methyl (4aSR,5SR,11RS,11aSR)-5-benzyl-4a-hydroxy- SmI2 (1.80 mmol), HMPA (2.56 mL, 14.6 mmol) and t-BuOH
2,3,4,4a,5,10,11,11a-octahydro-1H-dibenzo[a,d][7]annulene- (0.120 g, 1.62 mmol). The crude product was purified by
11-carboxylate (39): 1H NMR (CDCl3, 500 MHz): δ = 1.10 (s, column chromatography (silica gel, ethyl acetate/hexane 1:9),
1 H, OH), 1.24–1.36, 1.42–1.51, 1.59–1.64, 1.66–1.75, then HPLC (ethyl acetate/hexane 1:5) to furnish 42 (0.031 g,
2.01–2.08 (5 m, 2 H, 2 × 1 H, 3 H, 1 H, 1-H, 2-H, 3-H, 4-H), 14%) and 43 (0.014 g, 7%) as colourless oils.
2.24 (ddd, J = 3.7, 11.2, 11.4 Hz, 1 H, 11a-H), 2.56 (ddd, J =
1.6, 11.2, 12.2 Hz, 1 H, 11-H), 2.75 (dd, J = 1.6, 15.0 Hz, 1 H, Methyl (2SR,4RS,4aSR)-4-hydroxy-4-methyl-8-(2-methyl-
10-H), 2.81 (dd, J = 3.3, 11.2 Hz, 1 H, 5-H), AB part of ABX propen-1-yl)-1,2,3,4,4a,7-hexahydro-naphthalene-2-carbox-
system (δA = 3.11, δB = 3.19, JAB = 13.3 Hz, JAX = 3.3 Hz, JBX ylate (42): 1H NMR (CDCl3, 500 MHz): δ = 1.08 (s, 3 H,
= 11.2 Hz, 2 H, PhCH2), 3.57 (dd, J = 12.2, 15.0 Hz, 1 H, 4-Me), 1.54, 1.74 (2 s, 2 × 3 H, =CMe2), 1.75–1.82 (m, 2 H,
10-H), 3.73 (s, 3 H, CO2Me), 6.54–6.56, 6.81–6.83, 6.87–6.91, 1-H, 3-H), 2.04 (ddd, J = 1.8, 3.8, 12.5 Hz, 1 H, 3-H), 2.38 (tt, J
7.05–7.12 (4 m, 1 H, 2 H, 1 H, 5 H, Ar) ppm, the signal for the = 3.8, 12.9 Hz, 1 H, 2-H), 2.50–2.62 (m, 2 H, 7-H), 2.71–2.77
OH group could not be assigned unambiguously. 13C NMR (m, 2 H, 1-H, 4a-H), 3.67 (s, 3 H, CO2Me), 5.50 (br. s, 1 H,
(CDCl3, 125 MHz): δ = 21.9 (t, C-3), 25.8 (t, C-2), 28.5 (t, CH=CMe2), 5.82–5.88 (m, 2 H, 5-H, 6-H) ppm, the signal for
C-1), 35.7 (t, PhCH2), 38.6 (t, C-10), 39.7 (t, C-4), 44.7 (d, the OH group could not be assigned unambiguously. 13C NMR
C-11a), 47.8 (d, C-11), 64.9 (d, C-5), 72.7 (s, C-4a), 125.9, (CDCl3, 125 MHz): δ = 19.5, 25.3 (2 q, =CMe2), 22.3
126.7, 127.5, 128.1, 128.9, 130.6, 133.7, 138.1, 138.6, 141.0 (7 (q, 4-Me), 31.5 (t, C-7), 32.6 (t, C-1), 40.5 (d, C-2), 44.0 (t,
d, 3 s, Ar), 51.7, 176.6 (q, s, CO2Me) ppm. IR (KBr): = 3430 C-3), 49.3 (d, C-4a), 74.2 (s, C-4), 123.7, 124.7, 125.9, 127.5,
(br, O-H), 3055–2845 (=C-H, C-H), 1705 (C=O) cm–1. MS (EI 128.8, 134.2 (3 d, 3 s, =CH, =Cq), 51.9, 175.5 (q, s, CO2Me)
= 70 eV): m/z (%) = 364 (4) [M]+, 267 (39), 169 (39), 115 (23), ppm.
91 (100), 41 (10). HRMS (80 eV) calcd for C24H28O3: [M]+ =
364.2039; found: 364.2034.
(1SR,4SR,9aSR)-1-Methyl-6-(2-methylpropen-1-yl)-4,5,7,9a-
tetrahydro-1,4-methano-2-benzoxepin-3(1H)-one (43):
1H NMR (CDCl3, 500 MHz): δ = 1.51, 1.76 (2 s, 2 × 3 H,
SmI2-induced cyclization of 38b
General procedure A: Compound 38b (0.145 g, 0.40 mmol), =CMe2), 1.54 (s, 3 H, 4-Me), AB part of ABX system (δA =
SmI2 (0.88 mmol), HMPA (1.27 mL, 7.23 mmol) and t-BuOH 1.86, δB = 1.91, JAB = 11.5 Hz, JAX = 4.7 Hz, JBX too small to
(0.059 g, 0.80 mmol). The crude product was purified by see signal splitting, 2 H, 10-H), 2.22–2.27 (m, 1 H, 5-H),
column chromatography (silica gel, ethyl acetate/hexane 1:9) to 2.52–2.67 (m, 3 H, 5-H, 7-H), 2.84–2.90 (m, 1 H, 4-H),
furnish 40 (0.084 g, 63%) as colourless crystals (mp 3.16–3.20 (m, 1 H, 9a-H), 5.49 (br. s, 1 H, CH=CMe2),
193–195 °C).
5.74–5.78, 5.84–5.88 (2 m, 2 × 1 H, 8-H, 9-H) ppm, the signal
for the OH group could not be assigned unambiguously.
(4aRS,5RS,11RS,11aRS)-5-Benzyl-1,2,3,4,5,10,11,11a- 13C NMR (CDCl3, 125 MHz): δ = 19.7, 25.4 (2 q, =CMe2),
octahydro-4a,11-(epoxy-methano)-dibenzo[a,d][7]annulen- 23.7 (q, 1-Me), 30.1 (t, C-5), 31.6 (t, C-7), 37.1, 37.9 (2 d, C-4,
12-one (40): 1H NMR (CDCl3, 500 MHz): δ = 1.11–1.29, C-9a), 45.3 (t, C-10), 88.7 (s, C-1), 123.9, 124.2, 124.4, 126.8,
1.47–1.56, 1.71–1.75, 1.95–2.03, 2.19–2.23 (5 m, 2 H, 1 H, 2 × 131.9, 136.1 (3 d, 3 s, =CH, =Cq), 180.9 (s, C-3) ppm.
1243

Beilstein J. Org. Chem. 2010, 6, 1229–1245.
19.Molander, G. A. Acc. Chem. Res. 1998, 31, 603–609.
Supporting Information
doi:10.1021/ar960101v
20.Berndt, M.; Gross, S.; Hölemann, A.; Reissig, H.-U. Synlett 2004,
422–438. doi:10.1055/s-2004-815429
Supporting Information File 1
Experimental procedures and characterization data of
synthesized compounds.
21.Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis using
Samarium Diiodide; Royal Society of Chemistry: Cambridge, U.K.,
2009.
Supporting Information File 1 contains all experimental
procedures for the syntheses of the starting materials 2, 4,
5, 7, 11, 14, 16, 18, 21, 24, 26, 30, 33, 36, 38, and 41 and
their analytical data.
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Acknowledgments
Generous support of this work by the Deutsche Forschungsge-
meinschaft, the Fonds der Chemischen Industrie and the Bayer
Schering Pharma AG is most gratefully acknowledged. We also
thank Dr. R. Zimmer and Dr. C. Beemelmanns for their help
during preparation of this manuscript.
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