Benzannulated cyclooctanol derivatives by samarium diiodide induced intramolecular carbonyl-alkene coupling - Scope, limitations, stereoselectivity

Article abstract of DOI:10.1002/ejoc.200600360

A series of γ-oxo esters 27-34 was prepared from methyl 2-silyloxycyclopropanecarboxylates 1-9 as key building blocks in a flexible modular synthesis. Their samarium diiodide promoted cyclization to benzannulated cyclooctanol derivatives was systematicall

Full text of DOI:10.1002/ejoc.200600360

FULL PAPER
DOI: 10.1002/ejoc.200600360
Benzannulated Cyclooctanol Derivatives by Samarium Diiodide Induced
Intramolecular Carbonyl–Alkene Coupling – Scope, Limitations,
Stereoselectivity
Hans-Ulrich Reißig,*[a] Faiz Ahmed Khan,[b][‡] Regina Czerwonka,[b]
Chimmanamada U. Dinesh,[b] Aarif L. Shaikh,[a] and Reinhold Zimmer[a]
Keywords: Samarium diiodide / Styrene derivatives / Ketones / Electron transfer / Cyclooctanes / Medium-sized rings
A series of γ-oxo esters 27–34 was prepared from methyl 2-
silyloxycyclopropanecarboxylates 1–9 as key building blocks
dergo the samarium diiodide promoted ring-closure process.
An explanation for this intriguing behaviour is presented, to-
in a flexible modular synthesis. Their samarium diiodide pro- gether with an explanation for the cis/trans selectivity. Tricy-
moted cyclization to benzannulated cyclooctanol derivatives
was systematically investigated. Samarium ketyl compounds
derived from aldehydes 27 and 28 mainly provided tricyclic
γ-lactones 38 and 39 as a result of a cis-selective ring-closure
process, whilst the related ketones 29–31 underwent trans-
selective reductive cyclization to furnish the expected
benzannulated cyclooctanol derivatives 43–45 in moderate to
excellent yields. With cyclohexanones 33 and 34 an interest-
ing stereochemical matched/mismatched situation was ob-
served. Whereas diastereomers 33a and 34a smoothly af-
forded tricyclic products 47 and 48 in good yields, compound
33b with apparently mismatched configuration did not un-
clic γ-lactone 38 could be smoothly deprotonated at one
bridgehead and the generated lithium enolate was trapped
with suitable alkyl halides. Remarkably, a clean α-hydroxyl-
ation of 38 and 39 by direct employment of molecular oxygen
was possible, providing high yields of the corresponding ter-
tiary alcohols 54 and 55. These results demonstrate that the
cyclization products prepared can easily be converted into
higher functionalized benzannulated cyclooctane deriva-
tives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
ple model compounds that 8-endo-trig cyclizations of sa-
marium ketyl compounds to produce cyclooctanol deriva-
tives in fair yields are possible. One example is depicted in
Scheme 1. Because of the occurrence of the bicyclo[6.4.0]-
undecane core in taxol we were interested in synthesizing
this unit[7] by a samarium ketyl promoted cyclization of sty-
rene-type precursors, which would be expected to gain ad-
ditional driving force by benzylic stabilization of the inter-
mediates involved during the 8-endo-trig reaction. We have
already reported our preliminary results[8] and now wish to
present full details showing the scope and limitations of the
method, as well as some intriguing stereochemical features.
Introduction
The development of new synthetic methods for the ster-
eoselective creation of eight-membered rings has received
considerable attention during the last two decades,[1] this
search certainly having been motivated by the occurrence
of functionalized cyclooctane moieties in structurally inter-
esting natural products, some of them of particular impor-
tance due to their biologically activity (e.g., taxol and re-
lated compounds).[2] In general, the formation of eight-
membered rings is not very favourable because of the con-
straints generated during their construction.[3] Despite these
obstacles, however, surprisingly efficient and flexible meth-
ods have been found.[4] One of the newer reaction modes
for the construction of eight-membered rings is the cycliza-
tion of samarium ketyl compounds to olefins;[5] pioneering
investigations by Molander et al.[6] demonstrated with sim-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Institut für Organische Chemie, Technische Universität
Dresden,
01069 Dresden, Germany
[‡] Present address: Department of Chemistry, Indian Institute of
Technology, Kanpur 208016, India
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 1.
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H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L. Shaikh, R. Zimmer
FULL PAPER
Results
Syntheses of precursors 28, 30 and 31 were accomplished
by an inverted sequence in which cyclopropane derivatives
14, 16 and 17 were first ring-opened to give oxo esters 35,
36 and 37, which were then converted into the required sty-
Precursor Synthesis
The model substrates for cyclization studies were pre-
pared by a reliable modular approach employing methyl 2-
silyloxycyclopropanecarboxylates 1–5 and 8–9 as precursors
(Scheme 2).[9] Their deprotonation with LDA and subse-
quent treatment with 1-iodo-2-(iodomethyl)benzene deriva-
tives 10, 11 or 12 provided the benzyl-substituted cyclopro-
panes 13–19 in moderate to excellent yields. Subsequent
Stille coupling with tributylvinylstannane under standard
conditions[10] furnished styrene derivatives 20, 21, 24 and
25, and ensuing fluoride-induced ring cleavage afforded the
desired cyclization precursors 27–34 in excellent yields (for
substituents and individual yields see Table 1). Styrene de-
rivatives 22 and 23 were prepared by a shortened reaction
sequence by direct alkylation of methyl cyclopropanecar-
boxylates 6 and 7 with 2-vinylbenzyl iodide (26).
rene derivatives with reasonable overall efficacy by Stille
coupling (Scheme 3). In summary, the preparation of the
required starting materials by our flexible route via donor/
acceptor-substituted cyclopropanes[11] was easy to achieve
and smoothly allowed generation of different substitution
patterns.
Scheme 3.
Cyclization Experiments
Cyclization reactions were generally performed in THF
as solvent with 2.2 equiv. of samarium diiodide (generated
from samarium metal with 1,2-diiodoethane) in the pres-
ence of 18 equiv. of HMPA and 2 equiv. of tert-butyl
alcohol. The use of the very strong donor ligand HMPA
is required to increase the reduction ability of samarium
diiodide[12] – without this additive samarium ketyl forma-
tion and couplings are generally not efficient. A search
aimed at substitution of this carcinogenic reagent by suit-
Scheme 2. (For R, R1-R6 see Table 1.).
Table 1. Substitution patterns of compounds 1–9, 13–19, 20–25 and 27–34 (Schemes 2 and 3).
Entry Starting material
R
R1
R2
R3
Alkylating agent
R4
R5
R6
Products
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
Me
Me
tBu
Me
tBu
tBu
Me
tBu
Me
H
H
Me
iPr
tBu
Ph
–(CH2)4–
–(CH2)4–
–(CH2)4–
Me
Me
H
H
H
Me
Me
H
H
H
H
H
H
H
10
11
10
10
10
26
26
10
12
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
13 92%[a] 20 86% 27 98%
14 78%[a]
–
28 55%[b]
15 87%[c] 21 76% 29 97%
16 53%
17 52%[c]
–
–
–
30 98%[b]
31 88%[b]
H
22 65% 32 99%
23 57% 33 97%[d]
24 72% 33 90%[d]
25 94% 34 91%
–
18 84%
OMe OMe 19 88%
[a] Mixture of trans and cis isomers (ca. 75:25). [b] Compound was prepared by an alternative route (see Scheme 3). [c] Result taken from
ref.[7] [d] Mixture of 2 diastereomers (1:1).
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Benzannulated Cyclooctanol Derivatives
FULL PAPER
able alternatives has not so far provided a general solu- of the formation of eight-membered rings.[3] The assign-
tion.[13]
ment of the trans diastereomers is in part based on observed
Treatment of styryl-substituted aldehydes 27 and 28 un- coupling constants in the 1H NMR spectra, but also on the
der these standard conditions provided tricyclic compounds fact that these compounds did not form the corresponding
38[14] and 39 in approximately 50% yields. Obviously, the γ-lactones (even under treatment with catalytic amounts of
ketyl–olefin coupling to form the eight-membered ring was acid).
followed by an intramolecular attack of the samarium alk-
oxide on the cis-positioned methoxycarbonyl group to form
the γ-lactone ring (Scheme 4). This treatment of 27 also fur-
nished the diastereomeric cyclization product 40, which
cannot form a γ-lactone ring, as a by-product. In addition,
fragmentation product 41 and compound 42 were isolated
in varying yields. Reductive cleavages of C–C bonds of 1,4-
dicarbonyl compounds are known in the literature[15] and
apparently also occur to some extent with the precursor
compounds employed in this study, which may be the
reason for the moderate mass balances of several cyclization
experiments, although fragmentation products such as 41
were not always actually isolated. γ-Methoxy-substituted γ-
lactone 42 is probably the result of a Lewis acid catalysed
rearrangement of starting material 27.[16] The acting Lewis
acid can either be samarium diiodide or one of the gener-
Scheme 5.
ated samarium(III) compounds. When the cyclization of 27
was attempted with samarium diiodide in the presence of
nickel diiodide,[17] compound 42 was isolated in as much as
87% yield.
Phenyl ketone 32, in contrast, did not undergo cycliza-
tion to the expected cyclooctanol derivative under the stan-
dard conditions employed, with starting material mainly be-
ing recovered instead (Scheme 5). Since the ketyl compound
of 32 should actually be formed more easily we have to
assume that its higher stability, and thus the lower driving
force for cyclization, prevent the formation of a product.
This and a similar result with a compound bearing an iso-
propenyl group instead of the phenyl substituent support
our opinion that the ketyl formation and the cyclization
step are equilibrium reactions (see discussion below and
Scheme 8).[19]
The two diastereomers of cyclohexanone derivatives 33
and 34 were easily separated by chromatography. Interest-
ingly, only the unlike diastereomers[20] underwent smooth
samarium diiodide promoted cyclization, whilst oxo ester
33a, with the matching unlike configuration, furnished a
moderate yield of the desired tricyclic product 47
(Scheme 6). The configuration of 47 was confirmed by an
Scheme 4.
Whereas aldehydes 27 and 28 furnished tricyclic γ-lac-
tones 38 and 39 as major or exclusive products as a result
of cis-selective cyclization,[18] the stereochemical outcome
was different when alkyl ketones 29–31 were used as precur-
sors in the samarium ketyl–alkene cyclization process.
Methyl ketone 29 furnished the benzannulated cyclooctanol
derivative 43 as the major component (Scheme 5), but the
tricyclic product 46 originating from the diastereomeric cy-
clization intermediate was also isolated in 10% yield. With
bulkier carbonyl substituents such as isopropyl (precursor
30) or tert-butyl (precursor 31) the samarium ketyl cycliza-
tion was highly trans-selective[18] and only products 44 and
45 were found. The conversion of isopropyl ketone 30 into
compound 44 was remarkably efficient – the yield of 84%
was excellent considering the generally unfavourable nature Scheme 6.
Eur. J. Org. Chem. 2006, 4419–4428
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H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L. Shaikh, R. Zimmer
FULL PAPER
X-ray analysis, which also revealed a boat conformation of
the central eight-membered ring (Figure 1).[21] As a by-
product a small amount of compound 49 was isolated, ap-
parently formed by simple reduction of the carbonyl group
with subsequent lactonization. The mismatched like dia-
stereomer 33b was essentially inert to samarium diiodide
and starting material was mainly recovered. We also iso-
lated 41 in 15% yield (see Scheme 4), which is again the
result of the reductive fragmentation of 1,4-dicarbonyl com-
pounds discussed above. Dimethoxy-substituted precursor
34a with the matching unlike configuration cyclized very
smoothly under standard conditions and provided the ex-
pected product 48 in 71% yield (99% yield when recovered
34a is taken into account).
Scheme 7.
Discussion
The mechanism of the 8-endo-trig cyclizations of styrene
derivatives as described above is straightforward in light of
related reactions.[5,6] Formation of samarium ketyl 56 is fol-
lowed by its attack at the terminal carbon atom of the sty-
rene unit to provide a benzyl radical 57, which accepts an
electron from the second equivalent of samarium diiodide
to generate the benzylic samarium species 58. Protonation
by tert-butyl alcohol (and during aqueous workup) provides
the isolated benzannulated cyclooctanol derivative
(Scheme 8). We assume that the first two steps of this se-
quence are reversible, a hypothesis supported by the recov-
ery of starting material when the cyclization is unfavourable
(e.g., substrate 32). Although we have no real proof for this
suggestion, the stabilities of the two intermediates 56 and
57 should be fairly similar and so an equilibrium can rea-
sonably be assumed. Even the formation of samarium spe-
Figure 1. Benzocyclooctanol derivative 47 (only selected hydrogen
atoms are depicted).
Subsequent Reactions
Tricyclic compounds 38 and 39 each bear a geminal di- cies 58 from radical 57 may be reversible according to litera-
methyl moiety, as present in the taxol structure, and hence ture precedence,[25] although we regard this as less likely in
served as model substrates for functionalization at the our system.
bridgehead position. Deprotonation of 38 with LDA and
The reactivity of cyclohexanone derivatives 33 and 34
treatment with electrophiles such as methyl iodide and allyl demonstrates that conformative prerequisites must be ful-
bromide in the presence of HMPA furnished the alkylation filled to allow a successful formation of eight-membered
products 50 and 51 in very good yields (Scheme 7). Less rings. The matching configuration of 33a and the resulting
reactive alkylating agents could also be used, but the yields samarium ketyl may prefer a conformation with a pseudo-
of substitution products were disappointingly low.[22] Dur- equatorially positioned methoxycarbonyl group, in which
ing these experiments we unexpectedly discovered that α- the proximity of the carbonyl group and the ethenyl group
hydroxylation of lactones 38 and 39 occurred in the pres- easily allows cyclization (A in Scheme 9). In contrast, the
ence of traces of oxygen. This observation proved to be ex- energetically most favourable conformation of mismatching
ploitable, with this synthetically valuable hydroxylation pro- diastereomer 33b should arrange the carbonyl group and
cess being performed intentionally[23] by generating the lith- the accepting styrene unit into a transoid relationship, es-
ium enolates of 38 and 39 and subsequent treatment with sentially preventing cyclization (B in Scheme 9). For the
dry oxygen. The resulting hydroperoxides 52 and 53 were proposed transition structures we have sketched out some
smoothly converted into the desired α-hydroxy-γ-lactones boat-like arrangements with respect to the forming eight-
54 and 55 by reduction with sodium iodide. These experi- membered ring, which reflects the preferred conformation
ments demonstrate that substitution and functionalization of product 47 as established by the X-ray analysis (see Fig-
at the bridgehead positions in compounds such as 38 are ure 1).[21] This may also be valid in the transition structure
easily performed with reactive electrophiles although the in- leading to this compound. A similar dependence on the rel-
termediate enolates formally break Bredt’s rule.[24]
ative configuration of the cyclohexanone precursors has
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Benzannulated Cyclooctanol Derivatives
FULL PAPER
Scheme 10.
Conclusions
In this report we have been able to demonstrate that a
series of styryl-substituted oxo esters can be cyclized with
samarium diiodide to provide benzannulated cyclooctanol
derivatives in moderate to good yields. These results nicely
supplement our investigations of alkynyl-substituted com-
pounds that provided the corresponding cyclooctenols
fused to a benzene ring.[27] Furthermore, certain stereo-
chemical features were discovered and interpreted by transi-
tion structure models taking into account the preferred
conformations of the precursors and the samarium ketyl
compounds derived from them. Particularly interesting re-
sults have been obtained with the pair of diastereomers con-
taining the cyclohexanone moiety. The products are suitable
for further synthetic manipulations providing higher substi-
tuted benzannulated cyclooctane derivatives. With tricyclic
γ-lactones 38 and 39 as starting materials we were able to
easily perform enolate chemistry at the bridgehead carbon
atoms, introducing new alkyl substituents or a hydroxy
group. Future investigations will deal with the role of ad-
ditional substituents at the alkenyl moiety of the precursor
molecules, which may not only steer the regioselectivity
(formation of seven-membered vs. eight-membered rings)
but also the diastereoselectivity.[28]
Scheme 8.
been observed during the samarium ketyl triggered cycliza-
tions of related benzyl-substituted oxo esters to afford de-
aromatized hexahydronaphthalene derivatives.[26]
Scheme 9.
The cis/trans selectivity observed with respect to the
methoxycarbonyl substituent and the generated hydroxy
group can be interpreted in terms of a similar model. If the
group R at the carbonyl carbon atom is small (hydrogen
or methyl) the bulky samarium(III)oxy substituent can still
occupy the preferred pseudoequatorial position in an eight-
membered transition structure (C in Scheme 10) to afford a
cis product. As R becomes bulkier, this group prefers the
Experimental Section
General: All reactions were performed under argon in flame-dried
flasks, and the components were added by syringe. All solvents
were dried by standard methods. Thin layer chromatography (TLC)
was carried out on commercial Polygram Sil G/UV254 or Polygram
Alox N/UV254 (Macherey & Nagel). Column chromatography was
performed with 70–230 mesh silica gel (Merck) or neutral alumin-
pseudoequatorial position and the samarium(III)oxy group ium oxide (activity grade III; Fluka or Merck). Unless stated other-
wise, 1H NMR and 13C NMR spectra were determined with Bruker
AC 200, AC 300, DRX 500 or Jeol Eclipse 500 instruments in
is forced into a pseudoaxial position (D in Scheme 10). This
arrangement would deliver products with trans-positioned
CDCl3 solution. The chemical shifts are related to TMS or to the
functional groups. Unfortunately, we were unable to pre-
CDCl3 signal (δH = 7.26 ppm; δC = 77.0 ppm). IR spectra were
pare the aldehyde analogous to 27 but without a geminal
measured with a Nicolet 205 FT-IR spectrometer and gas-phase
dimethyl system, which would allow a more unambiguous
IR spectra were measured with an HP5965B FT-IRD spectrometer
comparison of results. Nevertheless, the sequence of dia-
stereoselectivities observed during cyclizations of 27, 29, 30
(Hewlett–Packard). Melting points are uncorrected. Boiling points
of compounds obtained in small-scale experiments refer to the tem-
and 31, showing high cis selectivity with 27 and exclusive
trans product formation with 31, is consistent with the sug-
gested transition structure model.
perature in a Büchi Kugelrohrofen. MS 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
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H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L. Shaikh, R. Zimmer
FULL PAPER
= 80 eV, 3 kV) instruments. The GC-MS data were recorded with
a Hewlett–Packard HP 5890 (series II) and a HP 5972 MS-selective
detector. Operating conditions were as follows: start temperature
70 °C, programmed to 310 °C at 10 °Cmin–1. Compounds 10, 11
and 26 were prepared according to known or analogous pro-
cedures.[29] Preparation of starting materials and intermediates 12–
31 is described in the Supporting Information.
145 (100), 91 (36), 42 (31). HRMS (80 eV): calcd. for C16H22O3
262.1569, found 262.1590.
Methyl 3-(2-Vinylphenyl)propanoate (41): 1H NMR (CDCl3,
200 MHz): δ = 7.51–7.45, 7.26–7.10 (2×m, 1 H, 3 H, Ar), 6.98,
5.66, 5.33 (ABX system, JAX = 17.3 Hz, JBX = 11 Hz, JAB = 1.5 Hz,
1 H each, CH=CH2), 3.68 (s, 3 H, CO2Me), 3.06–2.98, 2.61–2.53
(2×m, 2 H each, 2-H, 3-H) ppm. 13C NMR (CDCl3, 50.3 MHz):
δ = 173.2, 51.6 (s, q, CO2Me), 137.7, 136.5, 129.3, 127.9, 126.8,
126.0 (2×s, 4 ×d, Ar), 134.1, 116.1 (d, t, CH=CH2), 35.1, 28.4
SmI2-Induced Intramolecular Cyclization. General Procedure 1: Sa-
marium metal (2.4 equiv.) was placed under a flow of argon in a
flame-dried, two-necked round-bottomed flask containing a mag-
netic stirring bar and a septum inlet. The flask and the Sm were
flame-dried. THF (12 mL/mmol of 1,2-diiodoethane) was added to
the metal, followed by the addition of 1,2-diiodoethane (2.2 equiv.).
The mixture was stirred at room temperature for 1 h. HMPA
(18 equiv.) was added to this solution of SmI2 (2.2 equiv.), and ar-
gon was bubbled through the solution for 10 min. A solution of
the styrene derivative (1 equiv.) and tBuOH (2 equiv.) in THF
(40 mL/mmol of substrate) was added over 1.5 h. The mixture was
stirred at room temperature for 16 h. The mixture was 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 layers were washed with water and brine (10 mL/mmol of
substrate) and dried (Na2SO4).
(2×t, C-2, C-3) ppm. IR (neat): ν = 3100–2850 (=C–H, C–H), 1740
˜
(C=O) cm–1. C12H14O2 (190.2): calcd. C 75.76, H 7.42; found C
75.53, H 7.57.
5-Methoxy-4,4-dimethyl-3-(2-vinylbenzyl)dihydrofuran-2(3H)-one
(42): Mixture of diastereomers = 75:25. 1H NMR (CDCl3,
200 MHz): major diastereomer: δ = 7.49–7.45, 7.30–7.18 (2×m, 1
H, 3 H, Ar), 6.99, 5.64, 5.35 (ABX system, JAX = 17.3 Hz, JBX
=
10.9 Hz, JAB = 1.5 Hz, 1 H each, CH=CH2), 4.75 (s, 1 H, 5-H),
3.43 (s, 3 H, OMe), 3.22 (dd, J = 5.6, 14.1 Hz, 1 H, CH2Ar), 2.91
(dd, J = 5.6, 8.5 Hz, 1 H, 3-H), 2.73 (dd, J = 8.5, 14.1 Hz, 1 H,
CH2Ar), 1.09, 0.81 (2×s, 3 H each, 3-Me) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 177.9 (s, C-2), 136.7, 136.2, 134.4, 130.5, 127.0,
126.3 (2×s, 4 ×d, Ar), 127.6, 116.4 (d, t, CH=CH2), 109.7 (d, C-
5), 56.6 (q, OMe), 47.8 (d, C-3), 43.6 (s, C-4), 28.1 (t, CH2Ar),
21.4, 20.5 (2×q, 4-Me) ppm. Additional signals for the minor dia-
stereomer: δ = 4.87 (s, 1 H, 5-H), 3.56 (s, 3 H, OMe), 3.28 (dd, J
= 9.1, 14.0 Hz, 1 H, CH2Ar), 1.03, 0.89 (2×s, 3 H each, 3-Me)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 175.6 (s, C-2), 136.65,
136.0, 134.5, 130.5, 126.95, 126.4 (2×s, 4 ×d, Ar), 127.7, 116.3 (d,
t, CH=CH2), 110.3 (d, C-5), 58.3 (q, OMe), 51.5 (d, C-3), 43.7 (s,
SmI2-Induced Intramolecular Cyclization of 27. a) The reaction was
performed as described in General Procedure 1, with 27 (0.600 g,
2.29 mmol), SmI2 (7.51 mmol), HMPA (10.7 mL, 60.9 mmol) and
tBuOH (0.339 g, 4.58 mmol). The crude product was purified by
column chromatography (alumina, ethyl acetate/hexane 10%) to
furnish 41 (0.008 g, 2%), 42 (0.069 g, 11%, mixture of two dia-
stereomers = 3:1), 38 (0.252 g, 48%) and finally 40 (0.063 g, 11%).
b) In the presence of NiI2.[17] The reaction was performed as de-
scribed in General Procedure 1, with 27 (0.403 g, 1.55 mmol), SmI2
(3.75 mmol), NiI2 (5 mg, 0.016 mmol) and tBuOH (0.251 g,
3.39 mmol). The crude product was purified by column chromatog-
raphy (alumina, ethyl acetate/hexane 10%) to furnish 42 (0.351 g,
87%, mixture of two diastereomers = 75:25).
C-4), 29.1 (t, CH Ar), 23.9, 15.7 (2×q, 4-Me) ppm. IR (neat): ν =
˜
2
3100–2850 (=C–H, C–H), 1810 (C=O) cm–1. MS (EI = 70 eV): m/z
(%) = 260 (6) [M]+, 229 (6), 129 (59), 115 (27), 99 (17), 86 (100),
71 (13). HRMS (80 eV): calcd. for C16H20O3 260.1412, found
260.1409.
SmI2-Induced Intramolecular Cyclization of 28: The reaction was
performed as described in General Procedure 1, with 28 (0.060 g,
0.206 mmol), SmI2 (0.495 mmol), HMPA (0.65 mL, 3.71 mmol)
and tBuOH (0.040 g, 0.540 mmol). The crude product was purified
by column chromatography (alumina, ethyl acetate/hexane 10%) to
furnish 39 (0.029 g, 54%) as a colourless solid, m.p. 128–132 °C.
14,14-Dimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3(8),4,6-trien-13-
1
one (38): Colourless crystals, m.p. 115–116 °C. H NMR (CDCl3,
500 MHz): δ = 7.25–7.08 (m, 4 H, Ar), 4.27 (t, J = 3.5 Hz, 1 H,
11-H), 3.21 (dd, J = 2.1, 14.8 Hz, 1 H, 2-H), 3.09 (dd, J = 9.5,
14.8 Hz, 1 H, 2-H), 2.98 (dt, J = 3.4, 13.5 Hz, 1 H, 9-H), 2.68–2.60
(m, 2 H, 1-H, 9-H), 2.34–2.22 (m, 1 H, 10-H), 2.02 (qd, J Ϸ 3.8,
15.2 Hz, 1 H, 10-H), 1.31, 1.20 (brs, s, 3 H each, Me) ppm. 13C
NMR (CDCl3, 126.9 MHz): δ = 177.3 (s, C-13), 139.9, 136.6, 132.1,
129.4, 127.7, 126.5 (2×s, 4 ×d, Ar), 88.6 (d, C-11), 52.1 (d, C-1),
41.8 (s, C-14), 33.1, 31.2, 29.8 (3×t, C-2, C-9, C-10), 33.3, 18.0
7-Methoxy-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3(8),
1
4,6-trien-13-one (39): H NMR (CDCl3, 500 MHz): δ = 7.09 (t, J
= 8.1 Hz, 1 H, Ar), 6.75 (d, J = 8.1 Hz, 2 H, Ar), 4.26 (t, J =
3.3 Hz, 1 H, 11-H), 3.79 (s, 3 H, OMe), 3.19 (dd, J = 1.8, 14.7 Hz,
1 H, 2-H), 3.11–2.97, 2.75–2.67 (2×m, 2 H, 1 H, 1-H, 2-H, 9-H),
2.63 (brdd, J Ϸ 2, 10 Hz, 1 H, 9-H), 2.32–2.23 (m, 1 H, 10-H),
1.89 (dq, J = 3.9, 15.4 Hz, 1 H, 10-H), 1.33, 1.18 (brs, s, 3 H each,
Me) ppm. 13C NMR (CDCl3, 126.9 MHz): δ = 157.0 (s, C-13),
138.3, 132.0, 128.0, 126.7, 124.2, 109.3 (3×s, 3 ×d, Ar), 89.0 (d, C-
11), 55.4 (q, OMe), 52.3 (d, C-1), 41.8 (s, C-14), 33.4, 31.4, 30.9
(2×q, Me) ppm. IR (neat): ν = 3100–2850 (=C–H, C–H), 1765
˜
(C=O) cm–1. MS (EI = 70 eV): m/z (%) = 230 (84) [M]+, 186 (52),
169 (27), 143 (42), 129 (45), 115 (51), 105 (41), 91 (26), 83 (100),
77 (14), 41 (19). C15H18O2 (230.3): calcd. C 78.23, H 7.88; found
C 78.62, H 8.27.
(3×t, C-2, C-9, C-10), 33.4, 18.0 (2×q, Me) ppm. IR (neat): ν =
˜
3065–2850 (=C–H, C–H), 1775 (C=O) ppm. MS (EI = 80 eV): m/z
(%) = 260 (100) [M]+, 216 (35), 199 (22), 173 (18), 159 (15), 147
(11), 135 (14), 115 (12), 91 (8), 83 (31). HRMS (80 eV): calcd. for
C16H20O3 260.1412; found 260.1429.
Methyl trans-8-Hydroxy-7,7-dimethyl-5,6,7,8,9,10-hexahydrobenzo-
cyclooctene-6-carboxylate (40): 1H NMR (CDCl3, 200 MHz): δ =
7.19–7.07 (m, 4 H, Ar), 3.69 (s, 3 H, CO2Me), 3.41, 3.02–2.58 (mc,
m, 1 H, 3 H, 5-H, 6-H, 8-H), 1.79–1.22 (m, 5 H, 9-H, 10-H, OH),
0.92, 0.89 (2×s, 6 H, 2 ×Me) ppm. 13C NMR (CDCl3, 50.3 MHz):
δ = 173.5, 51.6 (s, q, CO2Me), 140.2, 138.2, 129.3, 128.9, 126.6,
126.2 (2×s, 4 ×d, Ar), 76.7 (d, C-8), 40.5 (s, C-7), 35.6, 33.7, 27.8
SmI2-Induced Intramolecular Cyclization of 29: The reaction was
performed as described in General Procedure 1, with 29 (0.204 g,
0.830 mmol), SmI2 (1.84 mmol), HMPA (2.65 g, 14.8 mmol) and
(3×t, C-5, C-9, C-10), 35.3 (d, C-6), 18.8, 13.6 (2×q, 2×Me) ppm. tBuOH (0.120 g, 1.64 mmol). The crude product was purified by
IR (neat): ν = 3500 (O–H), 3100–2880 (=C–H, C–H), 1735 (C=O) column chromatography (alumina, ethyl acetate/hexane 10%) to
cm–1. MS (EI = 70 eV): m/z (%) = 262 (2) [M]+, 216 (10), 198 (20), furnish 46 (17 mg, 10%), followed by 43 (64 mg, 31%).
˜
4424
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4419–4428

Benzannulated Cyclooctanol Derivatives
FULL PAPER
Methyl trans-8-Hydroxy-8-methyl-5,6,7,8,9,10-hexahydrobenzocy- (2×s, 4 ×d, Ar), 76.6 (s, C-8), 42.8 (d, C-6), 40.1, 24.6 (s, q, tBu),
clooctene-6-carboxylate (43): 1H NMR (CDCl3, 200 MHz): δ = 39.2, 35.3, 33.0, 28.9 (4×t, 4×CH ) ppm. IR (KBr): ν = 3500 (br.,
˜
2
7.18–7.03 (m, 4 H, Ar), 3.71 (s, 3 H, CO2Me), 3.30–2.29 (m, 4 H, O–H), 3060–2860 (=C–H, C–H), 1715 (C=O) cm–1. C18H26O3
5-H, 6-H, 10-H), 2.71 (ddd, J = 3.6, 8.9, 14.1 Hz, 1 H, 10-H), 2.01–
1.54 (m, 5 H, 7-H, 9-H, OH), 1.21 (s, 3 H, Me) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 176.1, 51.7 (s, q, CO2Me), 141.6, 137.2,
130.0, 129.3, 127.1, 126.7 (2×s, 4 ×d, Ar), 71.9 (s, C-8), 46.3, 38.6,
34.1, 29.3 (4×t, C-5, C-7, C-9, C-10), 42.7 (d, C-6), 34.6 (q, Me)
(290.4): calcd. C 74.45, H 9.02; found C 74.17, H 9.42.
SmI2-Induced Intramolecular Cyclization of 33a: The reaction was
performed as described in General Procedure 1, with 33a (0.220 g,
0.760 mmol), SmI2 (1.66 mmol), HMPA (2.42 g, 13.6 mmol) and
tBuOH (0.115 g, 1.55 mmol). The crude product was purified by
column chromatography (silica gel, ethyl acetate/hexane 10%) to
furnish 49 (12 mg, 6%, mixture of 2 diastereomers = 1:1), followed
by 47 (0.110 g, 50%) as colourless crystals (m.p. 80–81 °C).
ppm. IR (neat): ν = 3490 (O–H), 3100–2850 (=C–H, C–H), 1730
˜
(C=O) cm–1. MS (EI = 70 eV): m/z (%) = 248 (3) [M]+, 230 (10)
[M+ –H2O], 215 (8), 197 (17), 170 (32), 154 (23), 144 (100), 129
(26), 115 (42), 91 (29), 42 (28). C15H20O3 (248.3): calcd. C 72.55,
H 8.12; found C 72.39, H 7.91.
Methyl (4aSR,5SR,12aRS)-12a-Hydroxy-1,2,3,4,4a,5,6,11,12,12a-
decahydrodibenzo[a,e][8]annulene-5-carboxylate (47): 1H NMR
(CDCl3, 500 MHz): δ = 7.18–7.10, 6.97–6.96 (2×m, 3 H, 1 H, Ar),
3.75 (dd, J = 6.6, 14.9 Hz, 1 H, 6-H), 3.65 (s, 3 H, CO2Me), 3.18
(ddd, J = 3.5, 6.4, 17.3 Hz, 1 H, 11-H), 2.99 (ddd, J = 2.8, 6.6,
10.5 Hz, 1 H, 5-H), 2.91 (ddd, J = 3.6, 12.6, 17.3 Hz, 1 H, 11-H),
2.80 (dd, J = 2.8, 14.9 Hz, 1 H, 6-H), 2.57 (ddd, J = 3.5, 12.6,
15.0 Hz, 1 H, 12-H), 1.80 (ddd, J = 3.6, 6.4, 15.0 Hz, 1 H, 12-H),
1.72–1.60, 1.59–1.47, 1.39–1.25, 1.19–1.07 (4×m, 3 H, 3 H, 2 H, 1
H, CH, CH2) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 175.8, 51.0
(s, q, CO2Me), 139.6, 135.5, 132.3, 129.7, 126.6, 125.5 (2×s, 4 ×d,
Ar), 74.0 (s, C-12a), 48.1 (d, C-5), 42.5 (t, C-12), 41.1 (d, C-4a),
39.9 (t, C-1), 35.7 (t, C-6), 30.8 (t, C-11), 27.1, 24.9, 21.0 (3×t,
11-Methyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3(8),4,6-trien-13-one
1
(46): H NMR (CDCl3, 200 MHz): δ = 7.25–7.12, 7.04 (m, d, J =
8 Hz, 3 H, 1 H, Ar), 3.30–3.16 (m, 3 H, 1-H, 2-H), 2.81–2.48, 2.32–
2.09, 2.03–1.52 (3×m, 2 H, 1 H, 3 H, 9-H, 10-H, 14-H), 1.40 (s, 3
H, Me) ppm. 13C NMR (CDCl3, 50.3 MHz) shows temperature-
dependent spectrum at room temp.; all signals except δ = 136.6 (s),
129.8 (d), 127.7 (d), 126.8 (d), 86.3 (s) appear as very broad signals;
measurement in [D6]DMSO as solvent at 80 °C showed all the sig-
nals clearly: δ = 178.4 (s, C-13), 141.1, 136.5, 130.5, 129.3, 127.0,
125.9 (2×s, 4 ×d, Ar), 85.5 (s, C-11), 41.7, 35.2, 34.7, 28.2 (4×t,
4×CH ), 29.3 (d, C-1) ppm. IR (gas-phase): ν = 3100–2850 (=C–
˜
2
H, C–H), 1795 (C=O) cm–1. MS (EI = 70 eV): m/z (%) = 216 (100)
[M]+, 159 (82), 129 (62), 115 (53), 115 (53), 104 (37), 91 (27), 43
(39). C14H16O2 (216.3): calcd. C 77.75, H 7.46; found C 77.68, H
7.31.
3×CH ) ppm. IR (KBr): ν = 3510 (br., O–H), 3060–2860 (=C–H,
˜
2
C–H), 1730 (C=O) cm–1. MS (EI = 70 eV): m/z (%) = 270 (84)
[M+ –18], 238 (50), 209 (44), 196 (100), 129 (81), 117 (65), 104 (45),
91 (47), 55 (26), 41 (23). C18H24O3 (288.4): calcd. C 74.97, H 8.39;
found C 74.97, H 8.65.
SmI2-Induced Intramolecular Cyclization of 30: The reaction was
performed as described in General Procedure 1, with 30 (0.210 g,
0.780 mmol), SmI2 (1.73 mmol), HMPA (2.53 g, 14.2 mmol) and
tBuOH (0.120 g, 1.64 mmol). The crude product was purified by
column chromatography (silica gel, ethyl acetate/hexane 10%) to
furnish 44 as a colourless oil (0.180 g, 84%).
3-(2-Vinylbenzyl)hexahydro-1-benzofuran-2(3H)-one (49): Mixture
of two diastereomers (1:1). 1H NMR (CDCl3, 200 MHz): δ = 7.49–
7.45, 7.25–7.04 (2×m, 1 H, 3 H, Ar), 6.97, 5.60, 5.29 (ABX system:
JAX = 17.3 Hz, JBX = 10.9 Hz, JAB = 1.4 Hz, 1 H each, CH=CH2),
4.55 (dd, J = 6.3, 10.6 Hz, 1 H, 4-H), 3.75–3.58, 3.46–3.12, 2.69–
2.45, 2.30–1.05 (4 ×m, 12 H, 2 ×CH, 5× CH2) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 174.0, 164.0, 141.4, 137.7, 137.0 (5×s,
C=O, Ar), 135.4, 134.7, 130.2, 129.6, 129.5, 127.8, 127.0, 126.5,
122.2 (2×s, 7 ×d, Ar, =CH), 116.1, 101.5 (2×t, =CH2), 80.1, 49.7,
42.0 (3×d, CH), 39.4, 38.2, 34.3, 33.3, 28.0, 27.4, 27.1, 26.2, 26.0,
Methyl trans-8-Hydroxy-8-isopropyl-5,6,7,8,9,10-hexahydrobenzo-
cyclooctene-6-carboxylate (44): 1H NMR (CDCl3, 200 MHz): δ =
7.22–7.11, 7.10–7.02 (2×m, 3 H, 1 H, Ar), 3.70 (s, 3 H, CO2Me),
3.29 (dd, J = 5.5, 13.7 Hz, 1 H, 5-H), 3.08 (dd, J = 5.2, 13.7 Hz, 1
H, 5-H), 3.05–2.92 (m, 2 H, 10-H), 2.77–2.66 (m, 1 H, 6-H), 1.86–
1.73 (m, 4 H, 7-H, 9-H, OH), 1.55 (sept, J = 6.8 Hz, 1 H, CHMe2),
1.39 (dd, J = 12.3, 14.7 Hz, 1 H, 7-H), 0.86, 0.85 (2×d, J = 6.8 Hz,
3 H each, Me) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 176.3, 51.5
(s, q, CO2Me), 142.1, 137.3, 130.1, 129.2, 127.0, 126.5 (2×s, 4 ×d,
Ar), 75.0 (s, C-8), 42.6, 42.1 (2×d, C-6, CHMe2), 40.7, 34.5 (2×t,
C-5, C-10), 34.5, 28.7 (2×t, C-7, C-9), 17.0, 16.5 (2×q, CHMe2)
23.3, 22.8, 22.6 (12×t, CH ) ppm. IR (neat): ν = 3100–2850 (=C–
˜
2
H, C–H), 1795 (C=O) cm–1. MS (EI = 70 eV): m/z (%) = 256 (82)
[M]+, 238 (38), 183 (28), 159 (100), 129 (74), 117 (72), 104 (43), 91
(38), 41 (25).
Methyl 12a-Hydroxy-8,9-dimethoxy-1,2,3,4,4a,5,6,11,12,12a-deca-
hydrodibenzo[a,e][8]annulene-5-carboxylate (48): The reaction was
performed as described in General Procedure 1, with 34a (35 mg,
0.100 mmol), SmI2 (0.220 mmol), HMPA (0.330 g, 1.81 mmol) and
tBuOH (15 mg, 0.200 mmol). The crude product was purified by
flash chromatography (silica gel, ethyl acetate/hexane 15%) to fur-
nish 48 (25 mg, 71%) as a colourless oil and starting material 34a
ppm. IR (neat): ν = 3520 (br., O–H), 3060–2880 (=C–H, C–H),
˜
1730 (C=O) cm–1. C17H24O3 (276.4): calcd. C 73.88, H 8.75; found
C 73.02, H 8.63.
SmI2-Induced Intramolecular Cyclization of 31: The reaction was
performed as described in General Procedure 1, with 31 (0.190 g,
0.660 mmol), SmI2 (1.45 mmol), HMPA (2.12 g, 11.9 mmol) and
tBuOH (0.097 g, 1.32 mmol). The crude product was purified by
flash chromatography (silica gel, ethyl acetate/hexane 7%) to fur-
nish 45 (75 mg, 39%) as colourless crystals (m.p. 86–88 °C).
1
(10 mg, 28%). H NMR (CDCl3, 300 MHz): δ = 6.59, 6.45 (2×s,
1 H each, Ar), 3.84, 3.82 (2×s, 3 H each, ArOMe), 3.63 (s, 3 H,
CO2Me), 3.10 (ddd, J = 3.5, 6.4, 17.2 Hz, 1 H, 5-H), 2.95–2.77 (m,
2 H, 11-H), 2.71 (dd, J = 2.9, 15.1 Hz, 1 H, 6-H), 2.53 (td, J = 3.5,
Methyl trans-8-tert-Butyl-8-hydroxy-5,6,7,8,9,10-hexahydrobenzo- 15.1 Hz, 1 H, 6-H), 1.81–1.09 (m, 12 H, 4a-H, 11-H, OH, CH,
cyclooctene-6-carboxylate (45): 1H NMR (CDCl3, 300 MHz): δ = CH2) ppm. 13C NMR (CDCl3, 75.5 MHz): δ = 176.0, 51.2 (s, q,
7.20–7.11, 7.08–7.05 (2×m, 3 H, 1 H, Ar), 3.71 (s, 3 H, CO2Me), CO2Me), 147.4, 146.5, 131.5, 127.5, 115.5, 112.9 (4×s, 2 ×d, Ar),
3.22 (dd, J = 4.8, 13.8 Hz, 1 H, 5-H), 3.08 (dd, J = 6.7, 13.8 Hz, 1 74.1 (s, C-12a), 55.8, 55.7 (2×q, ArOMe), 48.4 (d, C-5), 42.3 (t,
H, 5-H), 2.95–2.74 (m, 3 H, 6-H, 10-H), 2.12 (dd, J = 2.5, 15.0 Hz, CH2), 41.2 (d, C-4a), 39.9 (t, CH2), 35.4 (t, C-12), 30.6, 27.2, 24.9,
1 H, 7-H), 1.91–1.86 (m, 2 H, 9-H), 1.41 (dd, J = 12.1, 15.0 Hz, 1 21.0 (4×t, 4×CH ) ppm. IR (neat): ν = 3525 (br., O–H), 2995–
˜
2
H, 7-H), 0.87 (s, 9 H, tBu) ppm. 13C NMR (CDCl3, 75.5 MHz): δ
2835 (=C–H, C–H), 1730 (C=O) cm–1. C20H28O5 (348.4): calcd. C
= 176.6, 51.7 (s, q, CO2Me), 141.9, 137.8, 130.1, 129.1, 127.2, 126.7
68.94, H 8.10; found C 68.71, H 8.42.
Eur. J. Org. Chem. 2006, 4419–4428
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4425

H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L. Shaikh, R. Zimmer
FULL PAPER
Deprotonation of Lactones 38 and 39 and Treatment with Electro-
philes. General Procedure 2: A mixture of lactone derivative and
HMPA in THF was added at –78 °C to a solution of 2 equiv. of
LDA (generated in situ from diisopropylamine and n-butyllithium
in THF at –78 °C, 20 min). The mixture was stirred for 2 h and
then 10 equiv. of the electrophile in THF was added. The mixture
was stirred overnight (12–16 h), allowed to warm slowly to 10 °C
during this period and quenched with satd. aqueous NH4Cl solu-
tion. The two phases were separated and the aqueous phase was
repeatedly extracted with diethyl ether. The combined organic
phases were washed with water and brine and dried (Na2SO4). Af-
ter removal of the solvent, the crude product was purified by col-
umn chromatography (alumina, ethyl acetate/hexane 10–30%).
of the solvent furnished product 52 (0.412 g, 97%), which was then
treated with NaI (0.500 g, 3.33 mmol) in THF (10 mL) and stirred
overnight. After the usual workup, purification by column
chromatography (alumina, ethyl acetate/hexane 30 %) provided
compound 54 as a colourless oil (0.328 g, 82%).
14,14-Dimethyl-1-perhydroxy-12-oxatricyclo[9.2.1.03,8]tetradeca-
1
3(8),4,6-trien-13-one (52): Colourless crystals, m.p. 127–128 °C. H
NMR (CDCl3, 200 MHz): δ = 10.25 (s, 1 H, OOH), 7.20–7.09 (m,
4 H, Ar), 4.29 (t, J = 4 Hz, 1 H, 11-H), 3.86, 3.51 (2×d, J =
14.5 Hz, 1 H each, 2-H), 3.13 (dt, J = 5, 14 Hz, 1 H, 9-H), 2.73–
2.60 (m, 1 H, 9-H), 2.43–2.03 (m, 2 H, 10-H), 1.48, 1.24 (2×s, 3 H
each, Me) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 176.1 (s, C-
13), 139.8, 134.4, 132.2, 129.1, 128.2, 127.1 (2×s, 4 ×d, Ar), 88.7
(d, C-11), 87.6 (s, C-1), 46.0 (s, C-14), 33.3, 32.3, 30.0 (3×t, C-2,
1,14,14-Trimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3(8),4,6-trien-
13-one (50): The reaction was performed as described in General
Procedure 2. LDA (0.610 mmol), 38 (70 mg, 0.300 mmol), methyl io-
dide (433 mg, 3.05 mmol), HMPA (218 mg, 1.22 mmol) in THF
(4 mL) were used. The crude product was purified by column
chromatography (alumina, ethyl acetate/hexane 10%) to give 50 as
colourless crystals (73 mg, 99%), m.p. 123–125 °C. 1H NMR (CDCl3,
200 MHz): δ = 7.19–7.05 (m, 4 H, Ar), 4.23 (t, J = 3.5 Hz, 1 H, 11-
H), 3.43 (d, J = 14.3 Hz, 1 H, 2-H), 3.06 (dt, J = 4.8, 13.7 Hz, 1 H,
9-H), 2.71–2.60 (m, 1 H, 9-H), 2.57 (d, J = 14.3 Hz, 1 H, 2-H), 2.37–
2.17 (m, 1 H, 10-H), 2.06 (qd, J = 4.8, 15.7 Hz, 1 H, 10-H), 1.40,
1.33, 1.11 (3×s, 3 H each, Me) ppm. 13C NMR (CDCl3, 50.3 MHz):
δ = 178.5 (s, C-13), 139.7, 136.7, 132.3, 128.7, 127.8, 126.5 (2×s,
4×d, Ar), 87.9 (d, C-11), 52.1 (s, C-1), 44.2 (s, C-14), 41.3, 32.8, 30.4
(3×t, C-2, C-9, C-10), 31.2, 20.9, 17.4 (3×q, 3×Me) ppm. IR (KBr):
C-10, C-9), 27.2, 17.1 (2×q, Me) ppm. IR (KBr) ν = 3515–3330
˜
(O–H), 3060–2935 (=C–H, C–H), 1750 (C=O) cm–1. HRMS
(80 eV): calcd. for C15H18O4 [M]+ 262.1205, found 262.1204.
1-Hydroxy-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3,5,7-
1
trien-13-one (54): H NMR (CDCl3, 200 MHz): δ = 7.20–7.11 (m,
4 H, Ar), 4.31 (t, J = 3.5 Hz, 1 H, 11-H), 3.79 (d, J = 14.5 Hz, 1
H, 2-H), 3.07 (dt, J = 4.9, 14.1 Hz, 1 H, 9-H), 2.87 (d, J = 14.5 Hz,
1 H, 2-H), 2.68 (dt, J = 5.8, 14.1 Hz, 1 H, 9-H), 2.39–2.20 (m, 1
H, 10-H), 2.10 (qd, J = 4.4, 15.5 Hz, 1 H, 10-H), 1.47, 1.19 (2×s,
3 H each, Me) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 177.3 (s,
C-13), 139.6, 134.6, 132.4, 128.9, 128.1, 126.9 (2×s, 4 ×d, Ar), 87.6
(d, C-11), 81.1 (s, C-1), 44.9 (s, C-14), 43.1, 32.2, 30.1 (3×t, C-2,
C-10, C-9), 28.5, 16.9 (2×q, Me) ppm. IR (KBr): ν = 3450 (O–
˜
H), 3100–2850 (=C–H, C–H), 1755 (C=O) cm–1. C15H18O3 (246.3):
ν = 3100–2850 (=C–H, C–H), 1755 (C=O) cm–1. C H O (244.3):
˜
16 20
2
calcd. C 73.15, H 7.37; found C 73.15, H 7.93.
calcd. C 78.65, H 8.25; found C 78.42, H 8.70.
1-Hydroxy-7-methoxy-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]te-
tradeca-3,5,7-trien-13-one (55): LDA (0.514 mmol), 39 (0.067 g,
0.257 mmol) and HMPA (0.184 g, 1.03 mmol) in THF (3 mL),
analogously to the preparation of 54, gave hydroperoxide 53 as a
pale yellow oil (0.071 g, 94%). Subsequent treatment of 53 with
NaI (0.077 g, 0.514 mmol) in THF (2 mL) overnight and purifica-
tion by column chromatography (alumina, ethyl acetate/hexane
30 %) gave 55 (0.052 g, 71 %) as colourless crystals (m.p. 189–
192 °C).
1-Allyl-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-3(8),4,6-
trien-13-one (51): The reaction was performed as described in Ge-
neral Procedure 2. LDA (0.610 mmol), 38 (70 mg, 0.300 mmol), al-
lyl bromide (370 mg, 3.06 mmol), HMPA (218 mg, 1.22 mmol) and
THF (4 mL) were used. The crude product was purified by column
chromatography (alumina, ethyl acetate/hexane 10 %) to give 51
1
(65 mg, 79%) as a colourless oil. H NMR (CDCl3, 500 MHz): δ
= 7.18–7.11 (m, 3 H, Ar), 7.07 (d, J = 7.4 Hz, 1 H, Ar), 6.14–6.06
(m, 1 H, 2Ј-H), 5.29–5.23 (m, 2 H, 3Ј-H), 4.15 (t, J = 3.4 Hz, 1 H,
11-H), 3.38 (d, J = 14.4 Hz, 1 H, 2-H), 3.03 (dt, J = 4.4, 14.2 Hz,
1 H, 1Ј-H), 2.84 (d, J = 14.4 Hz, 1 H, 2-H), 2.70 (dd, J = 6, 14.7 Hz,
1 H, 9-H), 2.64 (dt, J = 4.6, 14.2 Hz, 1 H, 1Ј-H), 2.50 (dd, J = 8.5,
14.7 Hz, 1 H, 9-H), 2.27–2.19 (m, 1 H, 10-H), 2.05 (dq, J = 3.8,
15.8 Hz, 1 H, 10-H), 1.43, 1.21 (brs, s, 3 H each, Me) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 177.8 (s, C-13), 139.9, 136.7, 132.2,
128.7, 127.7, 126.5 (2×s, 4 ×d, Ar), 133.1, 118.9 (d, t, C-2Ј, C-3Ј),
87.8 (d, C-11), 53.7 (s, C-1), 44.8 (s, C-14), 40.5, 38.0, 32.6, 30.4
(4×t, C-2, C-10, C-9, C-1Ј), 30.1, 18.7 (2×q, Me) ppm. IR (neat):
7-Methoxy-14,14-dimethyl-1-perhydroxy-12-oxatricyclo[9.2.1.03,8]-
tetradeca-3,5,7-trien-13-one (53): 1H NMR (CDCl3, 250 MHz): δ =
10.28 (s, 1-H, OOH), 7.10 (t, J Ϸ 8 Hz, 1 H, Ar), 6.80, 6.77 (2×d,
J Ϸ 8 Hz, 1 H each, Ar), 4.26 (t, J = 3.3 Hz, 1 H, 11-H), 3.78, 3.43
(2×d, J = 14.6 Hz, 1 H each, 2-H), 3.74 (s, 3 H, OMe), 3.20–3.08
(m, 1 H, 9-H), 2.65 (dd, J = 3.6, 13.7 Hz, 1 H, 9-H), 2.32–2.15,
2.00–1.87 (2×m, 1 H each, 10-H), 1.41, 1.17 (brs, s, 3 H each, Me)
ppm.
1-Hydroxy-7-methoxy-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]-
tetradeca-3,5,7-trien-13-one (55): 1H NMR (CDCl3, 500 MHz): δ =
7.07 (t, J = 8 Hz, 1 H, Ar), 6.76, 6.74 (2×d, J = 8 Hz, 1 H each,
Ar), 4.27 (t, J = 3.3 Hz, 1 H, 11-H), 3.78 (s, 3 H, OMe), 3.75 (d, J
= 14.7 Hz, 1 H, 2-H), 3.20–3.06 (m, 1 H, 9-H), 2.85 (d, J = 14.7 Hz,
1 H, 2-H), 2.75–2.67, 2.38–2.20, 1.55–1.43 (3×m, 1 H each, 9-H,
10-H), 1.23, 1.16 (brs, s, 3 H each, Me) ppm. 13C NMR (CDCl3,
126.9 MHz): δ = 177.4 (s, C-13), 156.6, 136.1, 127.8, 127.0, 124.5,
109.6 (3×s, 3 ×d, Ar), 88.0 (d, C-11), 81.3 (s, C-1), 55.5 (q, OMe),
45.0 (s, C-14), 43.3, 30.1, 28.5 (3×t, C-2, C-9, C-10), 21.7, 16.9
ν = 3100–2850 (=C–H, C–H), 1760 (C=O), 1640 (C=C) cm–1
.
˜
C18H22O2 (270.4): calcd. C 79.96, H 8.20; found C 79.74, H 8.29.
1-Hydroxy-14,14-dimethyl-12-oxatricyclo[9.2.1.03,8]tetradeca-
3(8),4,6-trien-13-one (54): A mixture of lactone 38 (0.374 g,
1.62 mmol) and HMPA (1.16 g, 6.52 mmol) in THF (10 mL) was
added at –78 °C to a solution of LDA (3.24 mmol, generated in
situ from diisopropylamine and n-butyllithium, in 10 mL of THF
at –78 °C, 20 min). The mixture was stirred for 2 h and then dry
oxygen gas was bubbled through the mixture (1 h), which was
stirred overnight and allowed to warm slowly to 10 °C during this
period. The mixture was quenched with satd. aqueous NH4Cl solu-
tion, the phases were separated, and the aqueous phase was repeat-
edly extracted with diethyl ether. The combined organic phases
were washed with water and brine and dried (Na2SO4). Removal
(2×q, Me) ppm. IR (KBr): ν = 3420 (O–H), 3005–2835 (=C–H,
˜
C–H), 1760 (C=O) cm–1. MS (EI = 80 eV): m/z (%) = 276 (100)
[M]+, 179 (39), 161 (25), 160 (29), 159 (15), 135 (63), 134 (68), 104
(19), 28 (11). HRMS (80 eV): calcd. for C16H20O4 [M]+ 276.1362,
found: 276.1336.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4419–4428

Benzannulated Cyclooctanol Derivatives
FULL PAPER
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Supporting Information (see footnote on the first page of this arti-
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Acknowledgments
Financial support by the Volkswagen-Stiftung, the Deutsche For-
schungsgemeinschaft, the Fonds der Chemischen Industrie and the
Schering AG is gratefully appreciated. F. K. and C. U. D. thank the
Alexander-von-Humboldt-Stiftung for a fellowship and A. L. S.
thanks the DAAD for a fellowship. We thank Dr. Margit Gruner
(TU Dresden) for her help in structural assignments by NMR spec-
troscopy and Lasse Köhler (FU Berlin) for his help in experimental
work.
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Eur. J. Org. Chem. 2006, 4419–4428
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4427

H.-U. Reißig, F. A. Khan, R. Czerwonka, C. U. Dinesh, A. L. Shaikh, R. Zimmer
FULL PAPER
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Received: April 25, 2006
Published Online: August 3, 2006
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Eur. J. Org. Chem. 2006, 4419–4428