Simple synthetic transformations of highly enantio-enriched 4-alkyl-2,5,7-cyclooctatrienols into functionalized bicyclo[4.2.0]octa-2,4- dienes and 2,6-cyclooctadienones

Article abstract of DOI:10.1002/ejoc.200400355

4-Alkyl-2,5,7-cyclooctatrienols with high enantiomeric purities (93-96% ee), obtained by an improved copper-phosphoramidite-catalyzed addition of dialkylzinc reagents to cyclooctatetraene monoepoxide, have been subjected to simple and practical manipulati

Full text of DOI:10.1002/ejoc.200400355

FULL PAPER
Simple Synthetic Transformations of Highly Enantio-Enriched
4-Alkyl-2,5,7-cyclooctatrienols into Functionalized Bicyclo[4.2.0]octa-2,4-dienes
and 2,6-Cyclooctadienones
Mauro Pineschi,*[a] Federica Del Moro,[a] Paolo Crotti,[a] and Franco Macchia[a]
Keywords: Asymmetric catalysis / Copper / Electrocyclic reactions / Sigmatropic rearrangement / Zinc
4-Alkyl-2,5,7-cyclooctatrienols with high enantiomeric puri-
ties (93−96% ee), obtained by an improved copper-phos-
phoramidite-catalyzed addition of dialkylzinc reagents to
cyclooctatetraene monoepoxide, have been subjected to
simple and practical manipulations. Simple esterification re-
actions are able to deliver new functionalized isomeric 8-al-
kyl-7-acyloxybicyclo[4.2.0]octa-2,4-dienes through a domino
sequence of rearrangement reactions, in good yields. More-
over, new 4-alkyl-substituted-2,6-cyclooctadienones with
high optical purity can be efficiently obtained from gram-
scale reactions by simple thermal treatment.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
tuted 2,6-cyclooctadienones has not been reported to date.
We report here some novel and practical syntheses of
various new, non-racemic, chiral functionalized isomeric 8-
alkyl-7-acyloxybicyclo[4.2.0]octa-2,4-dienes and new 4-
alkyl-substituted 2,6-cyclooctadienones by simple trans-
formations of alkylcyclooctatrienols of high enantiomeric
purity.
The bicyclo[4.2.0]octane moiety is a structural feature
that is present in many naturally occurring molecules;[1,2]
bicyclo[4.2.0]octa-2,4-dienes, in particular, have been
known for a long time.[3,4] The conversion of cyclooctatetra-
enes into cycloocta-1,3,5-trienes, and subsequently to bi-
cyclo[4.2.0]octa-2,4-dienes, is an interesting stereospecific
series of electrocyclic reactions.[5,6] However, compounds
containing the bicyclo[4.2.0]octa-2,4-diene framework, in-
cluding natural products, are chiral but are usually found in
a racemic form. For example, endiandric acids are natural
polycyclic molecules that contain this framework. However,
despite the presence of eight asymmetric centers, they occur
in nature in a racemic form, and are formed from an achiral
precursor by a series of non-enzymatic electrocycliza-
tions.[7]
The development of simple and efficient routes to func-
tionalized enantio-enriched medium-sized carbocycles is a
worthy endeavor due to the presence of such systems in
many biologically active and structurally interesting natural
products.[8] There are a few reports on the synthesis of non-
racemic cyclooctadienones — these methods are based on
the use of a chiral-pool approach.[9] In particular, substi-
tuted 2,6-cyclooctadienones have been obtained only by the
reaction of cyclobutenones with dienyllithiums.[10] To the
best of our knowledge, the asymmetric synthesis of substi-
Results and Discussion
We have recently reported that 1,3,5,7-cyclooctatetraene
(COT) monoepoxide (1), despite its non-planar tub form,
can be successfully alkylated with appropriate organoc-
opper reagents, such as cyanocuprates, without the occur-
rence of any ring-contraction isomerization.[11] The enanti-
oselective desymmetrization reaction of compound 1 was
based on the use of dialkylzinc reagents and a chiral copper
complex containing the phosphoramidite (R,S,S)-2 devel-
oped by Feringa et al. (Scheme 1).[12]
The dihedral angle of about 60° present between the π-
orbital of the double bond and the σ-bond connecting the
leaving group (the allylic oxirane bond) represents the larg-
est deviation from coplanarity in any allylic substitution re-
action.[13] From a synthetic point of view, the possibility to
access previously unobtainable 4-alkyl-2,5,7-cyclooctatrien-
ols of type 4 allowed us to study their reactivity for the first
time.[14] We report here an improved preparation of 4-alkyl-
2,5,7-cyclooctatrienols of type 4 in the presence of the phos-
phoramidite ligand (R,R,R)-3.[15] With this catalyst the en-
antioselective desymmetrization reaction of 1 can be per-
formed on a gram scale with higher yields and enantio-
[a]
Dipartimento di Chimica Bioorganica
e
Biofarmacia,
`
Universita di Pisa,
Via Bonanno 33, 56126 Pisa, Italy
Fax: ϩ 39 050-221-9660
E-mail: pineschi@farm.unipi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200400355
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Functionalized Bicyclo[4.2.0]octa-2,4-dienes and 2,6-Cyclooctadienones
FULL PAPER
Table 1. Results of the esterification reaction of compounds 4aϪc
in accordance with protocols A (R1COCl/Py) and B (R1COOH/
DCC)
Entry Substrate Reaction
R1
Products
(ratio)[b]
Yields
(%)[c]
protocol[a]
1
2
3
4
5
6
7
8
4a
4b
4b
4b
4c
4b
4c
4b
A
A
A
B
B
B
B
B
p-NO2-C6H4
p-Br-C6H4
p-NO2-C6H4
5a/6a (78:22)
5d/6d (82:18)
5b/6b (75:25)
36
42
46
83
80
90
88
65
p-NO2P-C6H4 5b/6b (74:26)
p-NO2-C6H4
CH3(CH2)3
CH3(CH2)3
5c/6c (74:26)
5e/6e (86:14)
5f/6f (86:14)
CH3(CHϭCH)2 5g/6g (83:17)
[a]
All reactions were carried out in accordance with the reaction
protocols A and B described in the Exp. Sect. In all cases substrate
[b]
1
conversions were Ͼ98%.
Determined from the H NMR spec-
Scheme 1. Copper-phosphoramidite-catalyzed enantioselective de-
symmetrization of COT monoepoxides with dialkylzincs
[c]
trum of the crude reaction mixture.
Isolated yields of the dia-
stereoisomeric mixture after chromatographic purification on SiO2.
selectivities (ee у 93%) than in our previous report
(Scheme 1).[11]
this way, compounds 4aϪc were cleanly transformed into
The trans-4-alkyl-2,5,7-cyclooctatrienols 4aϪc obtained the corresponding trans-8-alkyl-7-acyloxybicyclo[4.2.0]-
by our procedure can be purified by chromatography on octa-2,4-dienes (1S,6R,7R,8S)-5aϪg and (1R,6S,7R,8S)-
SiO2, albeit with partial decomposition, and it is possible 6aϪg, with higher yields and a more simple workup pro-
to store them for several days at ϩ5 °C. Whenever a simple cedure (entries 4Ϫ8, Table 1). Compounds of type 5aϪg,
derivatization of these compounds with a common acylat- bearing the alkyl group on the same side as the hydrogen
ing agent (for example R1COCl/Py) was attempted, the cor- on the bridgeheads, always constituted the major reaction
responding eight-membered esters of type A were never ob- product (74Ϫ86% of the crude mixture) after the esterifi-
tained (Scheme 2). For example, when ethylcyclooctatrienol cation reaction and workup procedures. It should be noted
[(1R,4R)-4b] was treated with p-nitrobenzoyl chloride in an- that related racemic cis- and trans-8-methyl-7-acetoxybicy-
hydrous pyridine in the presence of a catalytic amount of clo[4.2.0]octa-2,4-dienes (R ϭ R1 ϭ Me) have been ob-
4-(dimethylamino)pyridine (DMAP; protocol A), a clean tained to date only by electrochemical oxidation of COT in
rearrangement reaction occurred to give 8-ethyl-7-(p-nitro- acetic acid containing the acetate ion (3% yield).[16] Our
benzoyloxy)bicyclo[4.2.0]octa-2,4-dienes 5b and 6b (46% new approach provides a general entry to non-racemic
combined yield after chromatography) as a 75:25 mixture trans-7-acyloxy-8-alkylbicyclo[4.2.0]octa-2,4-dienes, albeit
of isomers (Scheme 2 and entry 3, Table 1).
as a mixture of diastereoisomers. It is likely that the mix-
Moderate yields were also obtained with the methyl-sub- tures of bicyclic compounds 5 and 6 are obtained under
stituted cyclooctatrienol 4a (entry 1) and by using protocol thermodynamic control, as each isomerically pure bi-
A with p-bromobenzoyl chloride and compound 4b (entry cyclo[4.2.0] compound 5aϪg or 6aϪg, when allowed to
2). The esterification reactions can be more conveniently stand for several hours in a solvent, undergoes an equili-
performed with RCOOH/dicyclohexyl carbodiimide bration reaction affording approximately the product ratio
(DCC)/DMAP in CH2Cl2 at room temp. (protocol B). In indicated in Table 1.
Scheme 2. Synthesis of functionalized 8-alkyl-7-acyloxybicyclo[4.2.0]octa-2,4-dienes by esterification reactions
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M. Pineschi, F. Del Moro, P. Crotti, F. Macchia
FULL PAPER
As a consequence of this rapid equilibration process, the
NMR spectroscopic data for the pure isomeric compounds
had to be recorded rapidly in order to minimize the corre-
sponding isomerization reactions.[17] The relative stereo-
chemistry of bicyclo[4.2.0] compounds 5aϪg or 6aϪg was
unambiguously demonstrated by the NOEs observed in
ROESY experiments. For example, after chromatographic
separation of the mixture by preparative TLC, compounds
5a and 6b were rapidly subjected to ROESY experiments
and it was found that the alkyl group on C8 and the oxygen-
ated group on C7 were invariably in a trans relationship in
both isomers. In the most abundant isomer 5b, there is a
strong NOE between H1/H6 and the methylene protons of
the ethyl substituent in C8 (Figure 1). The absence of a cor-
responding NOE between H1/H6 and the methylene protons
of the ethyl substituent in C8 suggests that these hydrogens
are not on the same face in the minor isomer 6b. In this
isomer a strong NOE effect between H1/H6 and H8 across
the cyclobutane ring is observed, indicating that all these
hydrogens are on the convex face. The absolute R configu-
ration of C(8) of compounds 4aϪc, which is maintained in
the rearranged bicyclic compounds 5 and 6 (vide infra), has
been previously demonstrated by catalytic hydrogenation of
the three double bonds to the corresponding saturated en-
antiomerically enriched 4-alkylcyclooctanols.[11]
Scheme 3. Proposed mechanism for the formation of functionalized
bicyclo[4.2.0]octa-2,4-dienes
7aϪc were obtained with high yields. It is known that 2,4-
cyclooctadien-1-ol thermally rearranges into cycloocta-3-
en-1-one by a 1,5-hydrogen shift.[21] Furthermore, the for-
mation of racemic 4-tert-butylcycloocta-2,6-diene-1-one by
the reaction of tBuLi with COT monoepoxide and sub-
sequent distillation has been described, albeit without the
isolation of the intermediate 4-tert-butyl-2,5,7-cyclooctatri-
ene-1-ol.[22] In our hands the rearrangement of isolated
crude 4-alkyl-2,5,7-cyclooctatriene-1-ols to new 4-alkyl-2,6-
cyclooctadien-1-ones 7aϪc has been easily and thoroughly
accomplished by means of a simple pre-treatment of the
crude mixture containing cyclooctatrienes 4aϪc with re-
fluxing toluene for 1 h followed by vacuum distillation
(Scheme 4). For example, with this procedure it was pos-
sible to obtain enantiomerically enriched (4R)-7b (94% ee,
85% distilled yield) from a gram-scale reaction. Similar re-
sults were obtained with simple thermal treatment of com-
pound 4a to give 7a (93% ee, 70% distilled yield) and 4c to
give 7c (96% ee, 73% distilled yield; Scheme 4). Considering
Figure 1. Determination of relative stereochemistry by the NOEs
observed in ROESY experiments
It is likely that the esterification of alcohols 4aϪc is the
first step of a sequence of reactions which, starting from A,
has as the first step a [3,3]-sigmatropic rearrangement[18]
with full involvement of the carbonyl oxygen to a presumed
1-acyloxy-2-alkyl-3,5,7-cyclooctatriene, which exists as an
equilibrating mixture of conformers
B
and BЈ
(Scheme 3).[19] Each conformer can undergo a disrotatory
6π-electron electrocyclization to give a mixture of bi-
cyclo[4.2.0]octa-2,4-dienes
(1S,6R,7R,8S)-5aϪg
and
(1R,6S,7R,8S)-6aϪg. A back-opening of 5aϪg and 6aϪg
to the corresponding cyclooctatetraenes B and BЈ can then
occur to give the final thermodynamic product distri-
bution.[20]
During our study we found that the obtained trans-4-
alkyl-2,5,7-cyclooctatrienols 4aϪc are not stable to thermal
treatment. When purification of compounds 4aϪc was at-
tempted by distillation rather than by standard chromato-
graphic purification, most of the substance isomerized and
Scheme 4. Synthesis of enantio-enriched 4-alkyl-2,6-cyclooc-
the corresponding new 4-alkyl-2,6-cyclooctadien-1-ones tadienones by thermally induced 1,5-sigmatropic shifts
4616
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Functionalized Bicyclo[4.2.0]octa-2,4-dienes and 2,6-Cyclooctadienones
FULL PAPER
vent flow and detection at 225 nm. For other general information,
see references 11 and 15.
that the enantiomers of compounds 7aϪc are very easily
separated by HPLC on a chiral stationary phase (Daicel
Chiralcel OB-H), this procedure provides a fast and reliable
method for the determination of optical purities of com-
pounds 4aϪc.[23] 4-Alkyl-2,6-cyclooctadienones with a high
optical purity are interesting new building blocks because
the presence of two different double bonds allows for
further manipulations.
Reference racemic compounds 4aϪc were prepared by CuCN-pro-
moted addition of Grignard reagents to COT monoepoxide 1[11] as
follows. A stirred suspension of CuCN (1.504 g, 16.78 mmol) in
anhydrous THF (35 mL) was slowly added to RMgX (13.98 mmol)
at Ϫ18 °C. After 20 min, a solution of freshly distilled 1 (560 mg,
4.66 mmol) in THF (3 mL) was added and the resulting solution
was allowed to warm to 0 °C. The mixture was quenched (1Ϫ3 h)
at 0 °C with a saturated aqueous NH4Cl solution (reaction followed
by TLC) and the aqueous layer was extracted with Et2O. Evapo-
ration of the dried (MgSO4) organic phase afforded a crude
product which was directly used in the next step. BuMgCl: 99%
crude yield; EtMgBr: 99% crude yield; MeMgBr: 95% crude yield.
For spectroscopic data of compounds 4aϪc, see reference 11.
Conclusions
In conclusion, the present work reports an improved
preparation of enantiomerically enriched 4-alkyl-2,5,7-
cyclooctatrienols by a copper phosphoramidite-catalyzed
addition of Me2Zn, Et2Zn and Bu2Zn to COT monoepox-
ide 1, as well as some simple synthetic transformations of
this almost unexplored class of compounds. Simple esterifi-
cation reactions afforded a mixture of new functionalized
isomeric bicyclo[4.2.0]octa-2,4-dienes through a novel dom-
ino sequence of a [3,3]-sigmatropic shift and a 6π electron
disrotatory electrocyclization. Moreover, the exploitation of
Highly Enantioselective Synthesis of Compounds 4aϪc by Copper/
(R,R,R)-3-catalyzed Addition of R2Zn to 1. General Procedure: A
solution of Cu(OTf)2 (54 mg, 0.15 mmol) and chiral ligand
(R,R,R)-3 (161 mg, 0.3 mmmol) in anhydrous toluene (6 mL) was
stirred at room temp. for 40 min. The colorless solution was cooled
to Ϫ78 °C followed by subsequent addition of a solution of 1
(1.20 g, 10.0 mmol) in toluene (2 mL). After 5 min, R2Zn (15.0
a thermally induced [1,5]-sigmatropic shift is able to give a mmol, 1.5 equiv.) was added and the stirred reaction mixture was
allowed to warm slowly to 0 °C. After complete conversion, the
mixture was quenched (3Ϫ6 h) at 0 °C with saturated aqueous
NH4Cl solution (5 mL). Extraction with Et2O (2 ϫ 35 mL) and
evaporation of the dried (MgSO4) organic phase afforded a crude
product containing cyclooctatrienols 4aϪc and chiral ligand 3
which was directly used in the next step. Et2Zn: 91% crude yield
(93% ee); Me2Zn: 81% crude yield (94% ee); Bu2Zn: 95% crude
yield (96% ee).
Attempted purification of compounds 4aϪc by distillation gave
substantial conversion into the corresponding 4-alkyl-2,6-cyclooc-
tadienones 7aϪc (vide infra). Compounds 4aϪc can be obtained
with high purity, albeit with partial decomposition, by flash chro-
matography (SiO2, 85:15 hexanes/EtOAc ϩ 1% NEt3). For spectro-
scopic data of compounds 4aϪc see reference 11.
practical and flexible access to new 4-alkyl-2,6-cyclooc-
tadienones with high optical purity (93Ϫ96% ee).
Experimental Section
General Remarks: All reactions were conducted in flame-dried
glassware with magnetic stirring under an atmosphere of argon.
Toluene, diethyl ether and THF were distilled from sodium/benzo-
phenone ketyl and stored under argon. The following compounds
are commercially available and were used without purification:
1,3,5,7-cyclooctatetraene (COT), MCPBA (70%), Me2Zn (2.0 
solution in toluene), Et2Zn (1.1  solution in toluene), Bu2Zn (1.0
 solution in heptane), EtMgBr (3.0  solution in Et2O), MeMgBr
(3.0  in Et2O), BuMgCl (2.0  in Et2O), Cu(OTf)2, CuCN, penta-
noic acid and sorbic acid. p-Nitrobenzoyl chloride and p-bromo-
benzoyl chloride were recrystallized before use. The COT monoe-
poxide 1 was prepared by monoepoxidation of COT in accordance
with a previously described procedure.[24]
Reactions were monitored by thin-layer chromatography (TLC)
with Alugram SIL G/UV254 silica-gel sheets with detection by
0.5% phosphomolybdic acid solution in 95% EtOH or ethanolic p-
anisaldehyde containing acetic acid and H2SO4. Silica gel 60
(230Ϫ400 mesh) was used for flash chromatography. Solvents for
extraction and chromatography were of HPLC grade.
General Procedure for Protocol A: A solution of optically active
cyclooctatrienols 4aϪc (1.33 mmol) in anhydrous pyridine (4.0 mL)
was treated at 0 °C in the presence of dimethylaminopyridine
(DMAP; 10 mg) and R1COCl (2.66 mmol, 2.0 equiv.). After 18 h
at room temp., the reaction was quenched with H2O and extracted
with Et2O. Evaporation of the washed organic solution (saturated
aqueous CuSO4, brine) afforded a crude reaction mixture that was
filtered through SiO2 (using hexanes containing 4% of EtOAc as
the eluent).
General Procedure for Protocol B:[25] A solution of optically active
cyclooctatrienols 4aϪc (1.12 mmol) in CH2Cl2 (10 mL) was treated
with R1COOH (1.34 mmol, 1.2 equiv.), stirred for 5 min, and then
dicyclohexylcarbodiimide (DCC; 278 mg, 1.34 mmol) and DMAP
(16 mg, 0.13 mmol) were added. After 18 h at room temp. the reac-
tion mixture was filtered and the filtrate was evaporated. The resi-
due was taken up in CH2Cl2 and again filtered. The CH2Cl2 solu-
tion was washed (0.5  HCl and saturated aqueous NaHCO3 solu-
tion) and concentrated followed by filtration through a short SiO2
column eluting with CH2Cl2.
1H NMR spectra were recorded at 200 MHz in CDCl3 solution
unless otherwise specified. Chemical shifts are reported in ppm
downfield from tetramethylsilane with the solvent resonance as the
internal standard (deuteriochloroform: δ ϭ 7.26 ppm). 13C NMR
spectra were recorded at 50 MHz with complete proton decoupling.
Chemical shifts are reported in ppm downfield from tetramethylsil-
ane with the solvent resonance as the internal standard (deuterio-
chloroform: δ ϭ 77.7 ppm). The relative stereochemistry of bicyclic
compounds 5aϪg and 6aϪg was established from ROESY spectra,
which were recorded at 600 MHz with a mixing time of 0.6 s. The
spectral width used was the minimum required in both dimensions.
The pulse delay was maintained at 6 s; 200 increments of 4 scans
and 2 K data points each were collected.
Reaction of 4a with p-Nitrobenzoyl Chloride (Protocol A): Following
the general procedure a solution of optically active ethylcycloocta-
trienol 4a (250 mg, 1.86 mmol) in anhydrous pyridine (5.0 mL) in
the presence of dimethylaminopyridine was treated at 0 °C with
p-nitrobenzoyl chloride (640 mg, 3.72 mmol). The usual workup
Analytical high-performance liquid chromatography (HPLC) was
performed on a Daicel Chiralcel OB-H column with a 0.5 mL sol-
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M. Pineschi, F. Del Moro, P. Crotti, F. Macchia
FULL PAPER
afforded a crude reaction mixture that was purified by flash chro-
matography eluting with hexanes containing 5% of Et2O to give
190 mg (36% yield) of an approximate 8:2 mixture of 5a and 6a,
respectively. Further chromatographic purification on semiprepar-
2.66Ϫ3.03 (m, 3 H), 1.47Ϫ1.71 (m, 2 H), 1.13Ϫ1.37 (m, 4 H), 0.87
(t, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR (50 MHz, C6D6: δ ϭ 163.5,
130.5, 128.3, 127.8, 125.7, 125.0, 124.8, 123.4, 123.1, 82.3, 52.6,
39.5, 30.8, 30.3, 28.4, 23.0, 14.2 ppm. C19H21NO4: calcd. C 69.71,
ative TLC (hexanes containing 5% of Et2O) gave, as the first eluting N 4.28, H 6.47; found C 69.80, N 4.25, H 6.41.
fraction 15 mg of pure (1R,6S,7R,8S)-8-methyl-7-(p-nitroben-
zoyloxy)bicyclo[4.2.0]octa-2,4-diene (6a) as a solid. M.p. 68Ϫ69 °C.
The second eluting fraction gave pure (1S,6R,7R,8S)-8-butyl-7-(p-
nitrobenzoyloxy)bicyclo[4.2.0]octa-2,4-diene (5c; 29 mg), as a light-
1H NMR (200 MHz, CDCl3): δ ϭ 8.08Ϫ8.41 (m, 4 H), 5.66Ϫ5.71 yellow oil. 1H NMR (200 MHz, C6D6): δ ϭ 7.61Ϫ7.85 (m, 4 H),
(m, 3 H), 5.56Ϫ5.68 (m, 1 H), 5.04 (t, J ϭ 6.6 Hz, 1 H), 2.84Ϫ3.28 5.77Ϫ5.90 (m, 1 H), 5.45Ϫ5.70 (m, 3 H), 5.08 (t, J ϭ 7.7 Hz, 1 H),
(m, 3 H), 1.27 (d, J ϭ 6.3 Hz, 3 H) ppm. 13C NMR (50 MHz, 3.43Ϫ3.57 (m, 1 H), 3.04 (quint, J ϭ 7.8 Hz, 1 H), 2.00 (ddd, 1 H,
CDCl3): δ ϭ 164.7, 131.4, 126.6, 125.1 (2C), 124.9 (2C), 124.2,
123.6, 84.0, 47.8, 39.5, 31.6, 13.9 ppm. C16H15NO4: calcd. C 67.36,
N 4.91, H 5.30; found C 67.57, N 4.66, H 5.40.
J ϭ 9.6, 9.4, 5.5 Hz), 1.05Ϫ1.56 (m, 6 H), 0.85 (t, J ϭ 6.5 Hz, 3
H) ppm. 13C NMR (50 MHz, C6D6): δ ϭ 163.7, 135.3, 130.6, 128.8,
127.8, 126.6, 125.2, 123.5, 122.1, 81.1, 52.3, 38.7, 33.5, 33.0, 30.0,
22.9, 14.1 ppm. C19H21NO4: calcd. C 69.71, N 4.28, H 6.47; found
C 69.88, N 4.35, H 6.31.
The second eluting fraction gave pure (1S,6R,7R,8S)-8-methyl-7-
(p-nitrobenzoyloxy)bicyclo[4.2.0]octa-2,4-diene (5a) as
a solid.
1
M.p. 76Ϫ77 °C. H NMR (200 MHz, CDCl3): δ ϭ 8.08Ϫ8.28 (m,
4 H), 5.86Ϫ6.01 (m, 1 H), 5.66Ϫ5.78 (m, 2 H), 5.49 (dd, J ϭ 4.1,
10.1 Hz, 1 H), 5.16 (t, J ϭ 7.8 Hz 1 H), 3.61Ϫ3.76 (m, 1 H),
3.01Ϫ3.11 (m, 1 H), 2.31Ϫ2.41 (m, 1 H), 1.22 (d, J ϭ 6.85 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 165.0, 136.2, 131.5,
126.5, 125.6, 124.2 (2C), 123.8, 122.7, 82.9, 47.5, 39.0, 34.5, 18.5
ppm. C16H15NO4: calcd. C 67.36, N 4.91, H 5.30; found C 67.77,
N 4.86, H 5.35.
Reaction of 4b with p-Bromobenzoyl Chloride (Protocol A): Follow-
ing the general procedure, a solution of ethylcyclooctatrienol 4b
(150 mg, 0.84 mmol) in anhydrous pyridine (4.0 mL) in the pres-
ence DMAP (10 mg) was treated at 0 °C with p-bromobenzoyl
chloride (369 mg, 1.68 mmol). The usual workup afforded a crude
reaction mixture (340 mg) that was purified by flash chromatogra-
phy eluting with hexanes containing 5% of Et2O to give 116 mg
(42% yield) of an approximate 8:2 mixture of 5d and 6d, respec-
tively. Further chromatographic purification by semipreparative
TLC gave, as the first eluting fraction, 10 mg of pure
Reaction of 4b with p-Nitrobenzoic Acid (Protocol B): Following the
general procedure a solution of optically active cyclooctatrienol 4b
(150 mg, 1.0 mmol) in CH2Cl2 (10 mL) was treated with DCC (1R,6S,7R,8S)-8-ethyl-7-(p-bromobenzoyloxy)bicyclo[4.2.0]octa-
(249 mg, 1.2 mmol), p-nitrobenzoic acid (201 mg, 1.2 mmol) and 2,4-diene (6d) as an oil. 1H NMR (200 MHz, CDCl3): δ ϭ
DMAP (15 mg, 0.12 mmol). After 18 h at room temp., usual
workup and chromatographic purification afforded 247 mg (83%
yield) of an approximate 7:3 mixture of 5b/6b. A 100-mg sample
was further purified by semipreparative TLC eluting with 5% Et2O
7.79Ϫ7.92 (m, 2 H), 7.44Ϫ7.56 (m, 2 H), 5.79Ϫ5.90 (m, 1 H),
5.69Ϫ5.78 (m, 2 H), 5.51Ϫ5.64 (m, 1 H), 4.99 (t, J ϭ 7.6 Hz, 1
H), 3.06Ϫ3.21 (m, 1 H), 2.87Ϫ2.95 (m, 1 H), 2.79Ϫ2.86 (m, 1 H),
1.53Ϫ1.72 (m, 2 H), 0.85 (t, J ϭ 7.4 Hz, 3 H) ppm. 13C NMR
in hexanes to afford, as the first eluting fraction, pure (50 MHz, CDCl3): δ ϭ 166.8, 132.5, 131.9, 129.9, 128.7, 126.3,
(1R,6S,7R,8S)-8-ethyl-7-(p-nitrobenzoyloxy)bicyclo[4.2.0]octa-2,4-
diene (6b; 7 mg) as a solid. M.p 73Ϫ75 °C. H NMR (200 MHz,
CDCl3): δ ϭ 8.17Ϫ8.31 (m, 4 H), 5.74Ϫ5.94 (m, 4 H), 5.10 (t, J ϭ
125.5, 125.0, 122.4, 82.1, 54.7, 43.4, 31.0, 26.2, 13.0 ppm.
C17H17BrO2: calcd. C 60.91, H 5.71; found C 61.30, H 5.40.
The second eluting fractions afforded 50 mg of pure (1S,6R,7R,8S)-
1
7.3 Hz, 1 H), 3.22Ϫ3.27 (m, 1 H), 2.86Ϫ3.10 (m, 2 H), 1.63Ϫ1.78 8-ethyl-7-(p-bromobenzoyloxy)bicyclo[4.2.0]octa-2,4-diene
(5d),
also as an oil. H NMR (200 MHz, CDCl3): δ ϭ 7.79Ϫ7.90 (m, 2
δ ϭ 163.4, 130.1, 128.8, 127.5, 125.2, 124.6, 124.4, 123.0, 122.8, H), 7.47Ϫ7.56 (m, 2 H), 5.77Ϫ5.89 (m, 1 H), 5.61Ϫ5.69 (m, 2 H),
1
(m, 2 H), 0.93 (t, J ϭ 7.4 Hz, 3 H) ppm. 13C NMR (50 MHz, C6D6:
81.9, 54.0, 39.0, 30.3, 21.4, 11.9 ppm. C17H17NO4: calcd. C 68.21,
N 4.68, H 8.98; found C 68.65, N 4.58, H 8.91.
5.40 (dd, J ϭ 9.9, 3.8 Hz, 1 H), 5.10 (t, J ϭ 7.8 Hz, 1 H), 3.47Ϫ3.62
(m, 1 H), 2.79Ϫ2.99 (m, 1 H), 2.31 (ddd, J ϭ 9.7, 4.9, 1.9 Hz, 1
H), 1.35Ϫ1.65 (m, 2 H), 0.84 (t, J ϭ 7.4 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 166.3, 132.5, 131.9, 129.8, 128.8, 127.2,
125.4, 124.2, 122.5, 80.8, 54.4, 39.0, 33.1, 27.2, 12.7 ppm.
The second eluting fraction gave pure (1S,6R,7R,8S)-8-ethyl-7-(p-
nitrobenzoyloxy)bicyclo[4.2.0]octa-2,4-diene (5b; 35 mg), as a light-
1
yellow oil. H NMR (200 MHz, CDCl3): δ ϭ 8.17Ϫ8.32 (m, 4 H),
5.89Ϫ5.93 (m, 1 H), 5.71Ϫ5.74 (m, 2 H), 5.46 (dd, J ϭ 9.8, 3.7 Hz, C17H17BrO2: calcd. C 60.91, H 5.71; found C 61.12, H 5.33.
1 H), 5.21 (t, J ϭ 7.3 Hz, 1 H), 3.61Ϫ3.64 (m, 1 H), 2.90Ϫ3.03 (m,
(1S,6R,7R,8S)-8-Ethyl-7-(pentanoyloxy)bicyclo[4.2.0]octa-2,4-diene
(5e) and (1R,6S,7R,8S)-8-Ethyl-7-(pentanoyloxy)bicyclo[4.2.0]octa-
2,4-diene (6e): Following the general procedure (Protocol B), a
solution of cyclooctatrienol 4b (100 mg, 0.56 mmol) in CH2Cl2
(6 mL) was treated with DCC (162.3 mg, 0.80 mmol), pentanoic
acid (0.087 mL, 0.80 mmol) and DMAP (10.0 mg, 0.08 mmol).
After 18 h at room temp. usual workup and chromatographic puri-
fication afforded 118 mg (90% yield) of an approximate 85:15 in-
1 H), 2.30Ϫ2.40 (m, 1 H), 1.40Ϫ1.86 (m, 2 H), 0.92 (t, J ϭ 7.4 Hz
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 170.7, 136.2, 131.5
(2C), 127.2, 125.6, 124.2, 123.7, 122.5, 81.2, 54.3, 38.9, 33.1, 27.1,
12.6 ppm. C17H17NO4: calcd. C 68.21, N 4.68, H 8.98; found C
68.87, N 4.60, H 8.95.
Reaction of 4c with p-Nitrobenzoic Acid (Protocol B): Following the
general procedure, a solution of optically active cyclooctatrienol
4c (450 mg, 2.7 mmol) in CH2Cl2 (27 mL) was treated with DCC separable mixture of 5e and 6e.
(672.3 mg, 3.24 mmol), p-nitrobenzoic acid (543 mg, 3.24 mmol)
5e: 1H NMR (200 MHz, CDCl3): δ ϭ 5.78Ϫ5.93 (m, 1 H),
and DMAP (41 mg, 0.32 mmol). After 18 h at room temp., usual 5.60Ϫ5.75 (m, 2 H), 5.40 (dd, J ϭ 9.7, 3.7 Hz, 1 H), 4.92 (t, J ϭ
workup and chromatographic purification afforded 706 mg (80%
yield) of a mixture of 5c/6c. A 110-mg sample was further purified
by semipreparative TLC eluting with 5% Et2O in hexanes to give,
as the first eluting fraction, pure (1R,6S,7R,8S)-8-butyl-7-(p-nitro-
benzoyloxy)bicyclo[4.2.0]octa-2,4-diene (6c; 8 mg) as a solid. M.p.
7.8 Hz, 1 H), 3.41Ϫ3.56 (m, 1 H), 2.67Ϫ2.88 (m, 1 H), 2.20Ϫ2.48
(m, 3 H), 1.23Ϫ1.71 (m, 6 H), 0.78Ϫ0.96 (m, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 174.4, 127.1, 125.2, 124.4, 122.4, 80.0, 54.2,
38.8, 35.7, 34.6, 33.0, 27.8, 27.2, 23.0, 14.4 ppm.
6e: 1H NMR (200 MHz, CDCl3): δ ϭ 5.63Ϫ5.95 (m, 3 H), 5.56
71Ϫ72 °C. 1H NMR (200 MHz, C6D6: δ ϭ 7.64Ϫ7.80 (m, 4 H), (dd, J ϭ 9.9, 3.8 Hz, 1 H), 4.82 (t, J ϭ 7.5 Hz, 1 H) 3.03Ϫ3.18 (m,
5.75Ϫ5.96 (m, 3 H), 5.42Ϫ5.53 (m, 1 H), 5.21 (t, J ϭ 7.3 Hz, 1 H), 1 H), 2.67Ϫ2.88 (m, 2 H), 2.18Ϫ2.48 (m, 3 H), 1.23Ϫ1.72 (m, 6
4618
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4614Ϫ4620

Functionalized Bicyclo[4.2.0]octa-2,4-dienes and 2,6-Cyclooctadienones
FULL PAPER
H), 0.80Ϫ0.95 (m, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 2.40Ϫ2.53 (m, 1 H), 1.85Ϫ2.04 (m, 1 H), 1.03Ϫ1.56 (m, 2 H), 0.78
170.3, 126.3, 125.6, 124.9, 122.7, 81.1, 54.7, 39.6, 34.7, 30.9, 27.0, (t, J ϭ 7.4 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 201.8,
22.7, 22.2, 14.9, 12.6 ppm.
148.6, 131.7, 130.7, 121.4, 44.7, 39.7, 34.6, 30.6, 13.0 ppm. MS (EI,
70 eV): m/z (%)ϭ 150 (6) [Mϩ], 106 (15), 96 (59), 67 (12), 53 (28),
39 (28). C10H14O: calcd. C 79.96, H 9.39; found C 78.86, H 8.98.
The enantiomeric excess (94%) was determined by chiral HPLC
(OB-H) (hexanes/2-propanol: 99:1): tR ϭ 14.1 (major); tR ϭ 16.8
(minor).
(1S,6R,7R,8S)-8-Butyl-7-(pentanoyloxy)bicyclo[4.2.0]octa-2,4-diene
(5f) and (1R,6S,7R,8S)-8-Butyl-7-(pentanoyloxy)bicyclo[4.2.0]octa-
2,4-diene (6f): Following the general procedure (Protocol B), a solu-
tion of compound 4c (200 mg, 1.12 mmol) in CH2Cl2 (10 mL) was
treated with DCC (278 mg, 1.34 mmol), pentanoic acid (0.145 mL,
1.34 mmol) and DMAP (16 mg, 0.13 mmol). After 18 h at room
temp. the reaction mixture was filtered and the filtrate evaporated.
The residue was taken up in CH2Cl2 and again filtered. The CH2Cl2
solution was washed (0.5  HCl and saturated aqueous NaHCO3
solution) and concentrated. Filtration through a short SiO2 column
eluting with CH2Cl2 afforded 230 mg (88% yield) of an inseparable
86:14 mixture of compounds 5f and 6f, respectively.
(4R)-4-Methyl-2,6-cyclooctadiene-1-one (7a): A solution of com-
pound 4a (1.0 g, 7.3 mmol) in toluene (3 mL) was heated at reflux
for 1 h. Evaporation of the solvent followed by a short-path distil-
lation (115 °C, 4 Torr) afforded pure 7a (0.694 g, 70% yield) as a
light-yellow liquid. [α]2D0 ϭ ϩ298.4 (c ϭ 0.5, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 6.04 (dd, J ϭ 7.3, 5.5 Hz, 1 H), 5.82Ϫ5.89
(m, 1 H), 5.46Ϫ5.56 (m, 2 H), 3.64Ϫ3.75 (m, 1 H), 3.28Ϫ3.43 (m,
1 H), 2.86Ϫ2.98 (m, 1 H), 2.33Ϫ2.45 (m, 1 H), 1.93Ϫ2.03 (m, 1
H), 1.1 (d, J ϭ 6.6 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3):
δ ϭ 202.2, 149.7, 131.9, 130.1, 121.5, 44.8, 36.9, 32.8, 23.2 ppm.
MS (EI, 70 eV): m/z (%)ϭ 136 (10) [Mϩ], 82 (100), 81 (41), 92 (12),
54 (54), 39 (62). C9H12O: calcd. C 79.36, H 8.89; found C 78.96,
H 8.96. The enantiomeric excess (93%) was determined by chiral
HPLC (OB-H) (hexanes/2-propanol: 99:1): tR ϭ 16.2 (major); tR ϭ
24.7 (minor).
5f: 1H NMR (200 MHz, CDCl3): δ ϭ 5.83Ϫ5.96 (m, 1 H),
5.65Ϫ5.72 (m, 2 H), 5.40 (dd, J ϭ 9.7, 3.8 Hz, 1 H), 4.93 (t, J ϭ
7.7 Hz, 1 H), 3.43Ϫ3.56 (m, 1 H), 2.72Ϫ2.96 (m, 1 H), 2.20Ϫ2.51
(m, 3 H), 1.13Ϫ1.73 (m, 10 H), 0.80Ϫ0.98 (m, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 174.2, 126.8, 125.0, 124.3, 122.3, 80.2, 52.3,
38.8, 35.5, 34.4, 34.0, 33.2, 27.7, 26.8, 22.9, 22.6, 14.2 ppm.
6f: 1H NMR (200 MHz, CDCl3): δ ϭ 5.65Ϫ5.96 (m, 3 H), 5.53Ϫ5-
63 (m, 1 H), 4.83 (t, J ϭ 7.0 Hz, 1 H), 3.02Ϫ3.18 (m, 1 H),
2.72Ϫ2.96 (m, 2 H), 2.20Ϫ2.37 (m, 2 H), 1.20Ϫ1.73 (m, 10 H),
0.81Ϫ0.97 (m, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 170.1,
126.3, 125.5, 124.8, 122.8, 81.1, 52.8, 39.7, 38.8, 34.7, 33.9, 31.3,
31.0, 30.4, 23.2, 19.7, 14.6 ppm.
(4R)-4-Butyl-2,6-cyclooctadiene-1-one (7c): A solution of com-
pound 4c (0.90 g, 5.5 mmol) in toluene (3 mL) was heated at reflux
for 1 h. Evaporation of the solvent followed by a short-path distil-
lation (130 °C, 4 Torr) afforded pure 7c (0.657 g, 73% yield) as a
light-yellow liquid. [α]2D0 ϭ ϩ231.0 (c ϭ 1.2, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 6.07 (dd, J ϭ 12.2, 7.2 Hz, 1 H), 5.94 (d,
J ϭ 12.2 Hz, 1 H), 5.43Ϫ5.66 (m, 2 H), 3.68Ϫ3.84 (m, 1 H),
3.12Ϫ3.31 (m, 1 H), 2.87Ϫ3.02 (m, 1 H), 2.36Ϫ2.53 (m, 1 H),
1.83Ϫ2.05 (m, 1 H), 1.19Ϫ1.52 (m, 6 H), 0.80Ϫ0.95 (m, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 202.3, 149.3, 132.0, 130.9, 121.6,
45.1, 38.4, 37.9, 35.3, 30.3, 23.3, 14.7 ppm. MS (EI, 70 eV): m/z
(%)ϭ 178 (5) [Mϩ], 150 (18), 124 (41), 53 (47), 39 (37). C12H18O:
calcd. C 80.84, H 10.18; found C 79.96, H 9.98. The enantiomeric
excess (96%) was determined by chiral HPLC (OB-H) (hexanes/2-
propanol: 97:3): tR ϭ 11.2 (major); tR ϭ 12.6 (minor).
(1S,6R,7R,8S,2ЈE,4ЈZ)-8-Ethyl-7-(hexa-2Ј,4Ј-dienoyloxy)bicyclo-
[4.2.0]octa-2,4-diene (5g) and (1R,6S,7R,8S,2ЈE,4ЈZ)-8-Ethyl-7-
(hexa-2Ј,4Ј-dienoyloxy)bicyclo[4.2.0]octa-2,4-diene (6g): Following
the general procedure (Protocol B), a solution of optically active
cyclooctatrienol 4b (250 mg, 1.67 mmol) in CH2Cl2 (15 mL) was
treated with DCC (413.5 mg, 2.0 mmol), 2,4-hexadienoic acid
(224 mg, 2.0 mmol) and DMAP (25 mg, 0.20 mmol). After 18 h at
room temp. usual workup and chromatographic purification af-
forded 275 mg (65% yield) of an approximate 80:20 inseparable
mixture of 5g and 6g.
5g: 1H NMR (200 MHz, CDCl3): δ ϭ 7.03Ϫ7.32 (m, 2 H),
6.04Ϫ6.23 (m, 2 H), 5.55Ϫ5.89 (m, 3 H), 5.36 (dd, J ϭ 9.8, 3.8 Hz,
1 H), 4.93 (t, J ϭ 7.7 Hz, 1 H), 3.38Ϫ3.52 (m, 1 H), 2.66Ϫ2.86 (m,
1 H), 2.14Ϫ2.29 (m, 1 H), 1.77 (d, J ϭ 5.2 Hz, 3 H), 1.30Ϫ1.64
(m, 2 H), 0.78 (t, J ϭ 7.4 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 167.7, 146.0, 140.2, 130.4, 127.1, 125.1, 124.6, 122.4,
119.3, 80.0, 54.2, 39.0, 33.0, 27.2, 19.4, 12.7 ppm.
Acknowledgments
This work was supported by M.I.U.R. (PRIN 2002) and by the
University of Pisa.
6g: 1H NMR (200 MHz, CDCl3): δ ϭ 7.20Ϫ7.33 (m, 2 H),
5.95Ϫ6.22 (m, 2 H), 5.58Ϫ5.86 (m, 3 H), 5.51 (dd, J ϭ 9.5, 3.6 Hz,
1 H), 4.83 (t, J ϭ 7.2 Hz, 1 H), 2.98Ϫ3.13 (m, 1 H), 2.65Ϫ2.87 (m,
2 H), 1.78 (d, J ϭ 5.2 Hz, 3 H), 1.30Ϫ1.64 (m, 2 H), 0.80 (t, J ϭ
7.3 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 167.2, 145.8,
126.3, 126.0, 125.7, 124.2, 123.1, 122.8, 119.5, 81.1, 54.8, 43.5, 39.6,
30.9, 22.2, 12.9 ppm.
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(4R)-4-Ethyl-2,6-cyclooctadiene-1-one (7b): A solution of com-
pound 4b (1.0 g, 6.66 mmol) in toluene (3 mL) was heated at reflux
for 1 h. Evaporation of the solvent followed by a short-path distil-
lation (120 °C, 4 Torr) afforded pure 7b (0.850 g, 85% yield) as a
colorless liquid that became yellow on standing. [α]2D0 ϭ ϩ262.5
(c ϭ 1.8, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 6.03Ϫ6.17 (m,
1 H), 5.95 (d, J ϭ 12.3, 7.3 Hz, 1 H), 5.44Ϫ5.66 (m, 2 H),
3.72Ϫ3.86 (m, 1 H), 3.09Ϫ3.20 (m, 1 H), 2.91Ϫ3.01 (m, 1 H),
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[8]
[9]
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Eur. J. Org. Chem. 2004, 4614Ϫ4620
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4619

M. Pineschi, F. Del Moro, P. Crotti, F. Macchia
FULL PAPER
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The same non-isolable intermediate of type BЈ could be ob-
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3,5,7-cyclooctatriene, see: I. D. Gridnev, A. Meller, J. Org.
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A valence tautomerism between compounds of type 5 and con-
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on a catalytic hydrogenation of the three double bonds, fol-
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and or HPLC analysis proceeding with incomplete baseline
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For the only example we are aware of describing the obtain-
[14]
[20]
ment of a 4-alkyl-2,5,7-cyclooctatrienol, albeit as a dia-
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[21]
[22]
[15]
For the application of this ligand to the regiodivergent kinetic
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Unfortunately, all the attempted analysis of the enantiopurity
[17]
of bicyclic compounds 5aϪg and 6aϪg by HPLC on a chiral
stationary phase were unsuccessful. Also, polarimetric meas-
urements were found not to be reproducible, probably due the
rapid equilibration reaction of these compounds.
[24]
[25]
4620
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4614Ϫ4620