A three-carbon (n+1+2) ring expansion method for the synthesis of macrocyclic enones. Application to muscone synthesis

Article abstract of DOI:10.1016/j.tet.2008.03.109

The three-carbon ring expansion methodology commences with the preparation of a cyclic allene (C9, C11, C13), readily available from the corresponding cycloalkene via dibromocarbene addition and subsequent treatment with methyllithium. Dichloroketene addition to the cyclic allene regioselectively provides the [2+2] cycloadduct, which is reductively dechlorinated with zinc in methanol. The resulting cyclobutanone is then catalytically hydrogenated; cyclobutanone ring opening is affected with trimethylsilyl iodide; immediate dehydroiodination of the resulting β-iodocycloalkanone with diazabicycloundecane (DBU) provides the corresponding macrocyclic enone. The 15-membered enone was converted to d,l-muscone with (CH₃)₂CuLi.

Full text of DOI:10.1016/j.tet.2008.03.109

Tetrahedron 64 (2008) 5497–5501
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A three-carbon (nþ1þ2) ring expansion method for the synthesis of macrocyclic
enones. Application to muscone synthesis
*
Ihsan Erden , Weiguo Cao, Mary Price, Michael Colton
San Francisco State University, Department of Chemistry and Biochemistry, 1600 Holloway Avenue, San Francisco, CA 94132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2008
Received in revised form 28 March 2008
Accepted 31 March 2008
Available online 8 April 2008
The three-carbon ring expansion methodology commences with the preparation of a cyclic allene (C9,
C11, C13), readily available from the corresponding cycloalkene via dibromocarbene addition and sub-
sequent treatment with methyllithium. Dichloroketene addition to the cyclic allene regioselectively
provides the [2þ2] cycloadduct, which is reductively dechlorinated with zinc in methanol. The resulting
cyclobutanone is then catalytically hydrogenated; cyclobutanone ring opening is affected with trimethyl-
silyl iodide; immediate dehydroiodination of the resulting
cycloundecane (DBU) provides the corresponding macrocyclic enone. The 15-membered enone was
converted to d,l-muscone with (CH3)2CuLi.
b-iodocycloalkanone with diazabi-
This paper is dedicated to Professor
Waldemar Adam on the occasion of his
75th birthday
Ó 2008 Elsevier Ltd. All rights reserved.
O
O
1. Introduction
Cl
Cl
Macrocyclic ring synthesis has become increasingly important
due to the abundance of large rings in various naturally occurring
systems.1 Muscone and its 3-demethyl analog exaltone (cyclo-
pentadecanone) are prominent members of the class of macrocyclic
musk odorants2 and have been popular targets for demonstrating
individually developed synthetic methodologies.3 In the course of
our studies on dichloroketene cycloadditions,4a–d we have com-
bined a number of well-known reactions into a straightforward and
practical three-carbon ring expansion methodology5 starting from
the readily available cycloalkenes and featuring dichloroketene
additions to cyclic allenes.
Zn
H+
DCK
1
2
3
Pd/H2
O
O
O
1. TMSiI
2. DBU
Me2CuLi
This paper describes the applicability of this methodology to the
synthesis of 11-, 13-, and 15-membered cyclic enones, as well
the naturally occurring muscone, the odorous principle of musk.6
The muscone synthesis commences with the commercially avail-
able cyclododecene. The ring expansion sequence utilizes consec-
utive one- and two-carbon ring homologations (Scheme 1).7
6
5
4
Scheme 1.
at room temperature;10,11 agitation of the mixture was provided by
an ultrasound bath.12 The 1H NMR spectrum of the cycloadduct
showed a 7.5:1 mixture of two stereoisomers (total yield 83% after
chromatography on silica gel). The major product turned out to be
the expected (E)-isomer, whereas the minor isomer was (Z),
according to its characteristic 1H NMR spectrum. Although their
separation was not necessary for the subsequent synthetic protocol,
analytical samples of both isomers were obtained by careful
column chromatography (the (Z)-isomer eluted faster than the
(E)-isomer) on silica gel and characterized by spectroscopy. The
reductive dechlorination of the cycloadduct with simultaneous
hydrogenolysis of the double bond with H2/Pd/C in ethyl acetate
solution in a single step was attempted next. Presumably due to
catalyst poisoning by HCl, only partial reduction could be realized
2. Results and discussion
Cyclotrideca-1,2-diene (1), obtained in high yield from cyclo-
dodecene via the dibromocarbene adduct and subsequent treat-
ment with methyllithium,8 was reacted with a slight excess of
dichloroketene (DCK),9 generated in situ from trichloroacetyl
chloride and activated zinc in the presence of POCl3 in diethylether
* Corresponding author. Tel.: þ1 415 338 1627; fax: þ1 415 338 2384.
E-mail address: ierden@sfsu.edu (I. Erden).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.109

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I. Erden et al. / Tetrahedron 64 (2008) 5497–5501
Table 1
Macrocyclic enones from cyclic allenes
Entry
Cyclic allene
DCK-adduct
Cyclobutanonea
Macrocyclic enone
O
O
Cl
Cl
O
1
90%
82%
78%
86%
72%
75%
1
4
2
5
O
O
O
Cl
Cl
2
7
8
9
10
O
O
O
Cl
Cl
3
77%
83%
67%
11
14
13
12
a
Overall yields of compounds 4, 9, and 13 for the two-step reductive dechlorination–catalytic hydrogenation sequence.
under these conditions leading to the corresponding
a
-chloro-
On an interesting note, the DCK–cylonona-1,2-diene adduct
13
cyclobutanone (two isomers). In an attempt to circumvent this
problem the catalytic reduction was repeated in the presence of
triethylamine; however, this variation proved unsatisfactory in
terms of the isolated yield on the fully reduced cyclobutanone (35%)
as well as problems separating 4 from undesired side products. The
remaining chlorine atom was, therefore, reduced with zinc in acetic
acid at 90 ꢀC in an overall yield of 78% in the two-step reduction
sequence. This reduction protocol was abandoned in favor of
a much more efficient route described below.
1222 was subjected to reaction with NaOMe in methanol. It was
known that
a,
a-dihalocyclobutanones undergo ring cleavage to
g,g
-dihalocarboxylic acids with base, however, cis-fused a,a
,-
dichlorocyclobutanones undergo quantitative ring contraction into
bifunctional cyclopropanes.23 On the other hand, Harding et al.
found that the cis-fused a,a-dichlorocyclobutanone to cyclohexene
gave, upon treatment with NaOMe in a ‘Cine’ substitution to give
the methoxychlorocyclobutanones.24 The question was, what role
the
a,b-unsaturation at the cyclobutanone ring of the bicyclic
The chlorine atoms in 2 were selectively reduced with zinc in
framework would play during the base attack.
methanol, saturated with NH4Cl14 to give the
a
,b
-unsaturated
Upon treatment of 12 with sodium methoxide at room tem-
perature, the solution immediately turned red. After stirring at
room temperature and monitoring the progress of the reaction by
TLC, the reaction was stopped, and after work-up and column
chromatography on silica gel, two fractions were isolated in a ratio
of 5:1, to which the structures 15 and 16 were assigned, re-
spectively, based on spectroscopic data. Compound 16 clearly stems
from a double Cine substitution, whereas compound 15 is a sec-
ondary product derived from 16 via base-catalyzed double bond
isomerization. A few cases of similar double-Cine substitutions in
DCK-adducts onto ordinary alkenes have previously been observed
(Scheme 2).25–29
cyclobutanone 3; catalytic hydrogenation of 3 in ethyl acetate over
Pd/C again delivered a mixture of both isomers of 4 (75% cis, 25%
trans) in 78% overall yield, starting from 2. The bicyclo[11.2.0]-
pentadecan-13-one (4) thus obtained gave a satisfactory elemental
analysis for the C15H26O composition. Upon treatment of this
mixture with KOH in methanol at room temperature, complete
conversion of the cis isomer to the trans isomer took place. The trans
stereochemistry in 4 was inferred from the coupling constants15,16
between the cyclobutanone ring hydrogens, obtained from selective
decoupling experiments. Moreover, inspection of Dreiding models
of the two isomers suggests that the trans isomer is indeed the less
strained, thus thermodynamically more stable isomer. The prefer-
O
O
O
ence for the trans stereochemistry has also been observed in
a,a-
dimethylcyclobutanones fused to nine-membered rings.17,18
NaOMe
MeOH
+
Cl
OMe
OMe
OMe
OMe
The cyclobutanone cleavage in 4 was realized with trimethylsilyl
iodide in CCl4 in the presence of metallic mercury according to
Miller and McKean’s method.19 The resulting 3-iodocyclopentade-
canone20 was treated without further purification with an
equimolar amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
CH2Cl2 solution at room temperature to furnish (E)-2-cyclo-
pentadecen-1-one 521 (76% from 4). Finally, treatment of 5 with
lithium dimethylcuprate in diethylether at ꢁ25 ꢀC gave an 85%
yield of d,l-muscone (6). We have successfully applied the
three-carbon ring expansion methodology described above to
the synthesis of two other macrocyclic enones, (E)-2-cyclo-
undecen-1-one (14) and (E)-2-cyclotridecen-1-one (10), re-
spectively (Table 1).
Cl
65%
:
13%
12
15
16
Scheme 2.
3. Conclusion
In summary, we have developed a convenient and general
three-carbon ring expansion methodology starting with readily
available cycloalkenes. After a well-documented one-carbon ex-
pansion to the corresponding cyclic allene, regisoselective
dichloroketene addition, followed by reduction of the chlorine

I. Erden et al. / Tetrahedron 64 (2008) 5497–5501
5499
atoms and double bond, the ring opening with TMSI/Hg, and im-
mediate dehydroiodination completes the sequence. In the case of
the 15-membered system, the enone was converted to d,l-muscone
by reaction with Me2CuLi.
funnel was placed a solution of 0.01 mol of cyclic 1,2-diene in 50 mL
dry ether, and 1.71 g of zinc dust was added. The suspension was
partially submerged in a Branson B-321 ultrasonic cleaner (50/
60 Hz, 117 V) filled 95% with water in a place that produced maxi-
mum agitation. To this suspension, 3.05 g (0.017 mol) of freshly
distilled trichloroacetyl chloride in 25 mL dry ether was added
dropwise within 30 min while sonication continued. Ice was added
occasionally to the water bath to maintain the bath temperature
between 15 and 20 ꢀC. After the completion of the reaction (ca.
60 min), it was quenched with wet ether (10 mL) and the reaction
mixture suction-filtered through Celite. The filtrate was washed
successively with water (2ꢂ20 mL), saturated aqueous bicarbonate
(5ꢂ20 mL), and brine solution (2ꢂ20 mL). After drying the ether
solution over Na2SO4, the solvent was evaporated in vacuo, and the
product isolated by column chromatography on silica gel, eluting
with pet. ether/CH2Cl2 (90:10).
4. Experimental
4.1. General
1H NMR spectra were obtained with a GE-Nicolet QE-Plus
300 MHz and Bruker Avance DRX 300 MHz spectrometers, using
CDCl3 as solvent and TMS as internal standard, unless otherwise
specified. IR spectra were obtained with a Nicolet 20DBX FT-IR
instrument. Non-deuterated solvents were dried and distilled be-
fore use. The cyclic allenes 1, 7, and 11 can readily be synthesized
from the corresponding cycloalkenes by the two-step protocol
according to Moore and Ward, as well as Skattebol’s method by
dibromocarbene addition followed by treatment of the adduct with
methyllithium at ꢁ20 ꢀC. All three cyclic allenes used in this study
were previously reported in literature.30 For the dibromocarbene
additions, we used the Makosza method employing a two-phase
system using a phase-transfer catalyst.31 Full details for the two-
step protocol are described below.
4.3.1. (E)-11,11-Dichlorobicyclo[7.2.0]undec-8-en-10-one (12)
Yield 77%; mp 62–64 ꢀC (from pet. ether). Though this com-
pound had been described by Brady et al., its 1H NMR was recorded
on a lower resolution instrument. Below, high resolution NMR
spectra of 12 and its IR data are described: 1H NMR (300 MHz,
CDCl3)
2.2–2.5 (m, 3H), 2.1 (m, 1H), 1.7 (m, 2H), 1.3–1.6 (m, 6H); 13C NMR
(CDCl3, TMS, 75 MHz) 187.0, 146.2, 141.7, 88.5, 58.8, 31.0, 29.3,
26.5, 25.9, 25.7, 22.6 ppm; FTIR (KBr): 2930, 2860, 1772.5, 1660,
1457, 911, 747 cmꢁ1
d
6.73 (ddd, J¼2.8, 6.9, 9.6 Hz, 1H), 3.43 (dm, J¼12.0 Hz, 1H),
d
4.2. General procedure for the synthesis of allenes
.
(a) Dibromocarbene additions. To an ice-cold solution of
20 mmol of cycloalkene, bromoform (15 g, 60 mmol), 145 mg of
benzyltriethylammonium chloride (TEBA), and 1 mL of ethanol was
added dropwise a 50% aqueous KOH solution (from 10 g KOH), with
efficient mechanical stirring (Hershberg-stirrer). After stirring the
brown mixture for 12 h, 100 mL of H2O was added, and the product
extracted with n-hexane (5ꢂ30 mL). The combined organic extracts
were washed with 30 mL of brine, dried over anhydrous Na2SO4,
and the solvent rotaevaporated. The residue was purified by
Kugelrohr distillation. Yields: 9,9-dibromobicyclo[6.1.0]nonane
(90%), 11,11-dibromo[8.1.0]undecane (76%), and 13,13-dibromobi-
cyclo[10.1.0]tridecane (84%).
(b) Treatment of the diboromocarbene adducts with MeLi. To
a solution of 20 mmol of the diboromocarbene adduct in 40 mL of
anhydrous ether was added dropwise 27 mL of MeLi (38 mmol,
1.4 M) at ꢁ78 ꢀC under a dry nitrogen atmosphere. After stirring
for15 min, the solution was allowed to warm to room temperature
(22 ꢀC). Water (40 mL) was added dropwise, and the ether layer
was separated, washed once with saturated NaHCO3 solution, twice
with brine (each 20 mL), and dried over anhydrous Na2SO4. The
solvent was rotoevaporated and the product isolated by Kugelrohr
distillation.
4.3.2. (E)-13,13-Dichlorobicyclo[9.2.0]tridec-10-en-12-one (8)
Yield 82%; 1H NMR (CDCl3, TMS):
6.8 (m, 1H), 3.5 (m, 1H), 2.1–
2.5 (m, 4H), 1.3–1.7 (m, 8H) ppm; FTIR (film): 2928, 2859, 1774,
1658, 1455, 1442, 910, 751 cmꢁ1. Anal. Calcd for C13H18Cl2O: C,
59.78; H, 6.95; Cl, 27.15. Found: C, 59.76; H, 6.94; Cl, 26.96.
d
4.3.3. (E)-15,15-Dichlorobicyclo[11.2.0]pentadec-12-en-14-one (2a)
Yield 79%; 1H NMR (300 MHz, CDCl3)
d
6.8 (ddd, J¼2.9, 6.1,
10.3 Hz,1H), 3.57 (m,1H), 2.22 (m, 2H),1.97 (m,1H),1.8 (m,1H),1.2–
1.7 (m, 16H); 13C NMR (75 MHz, CDCl3)
186.3, 143.5, 142.4, 87.7,
d
55.9, 29.9, 27.9, 26.4, 26.1, 25.9, 25.83, 25.81, 24.6, 24.5, 24.2 ppm;
FTIR (film): 2932, 2860, 1774, 1655, 1463, and 1446 cmꢁ1. Anal.
Calcd for C15H22Cl2O: C, 62.29; H, 7.67; Cl, 24.51. Found: C, 62.26; H,
7.66; Cl, 24.46.
4.3.4. (Z)-15,15-Dichlorobicyclo[11.2.0]pentadec-12-en-14-one (2b)
Yield 11%; 1H NMR (300 MHz, CDCl3)
d
6.35 (ddd, J¼2.1, 5.1,
11.6 Hz), 3.15 (m, 1H), 3.0 (m, 1H), 2.1 (m, 2H), 1.95 (m, 1H), 1.2–1.75
(m, 16H); 13C NMR (75 MHz, CDCl3)
188.0, 146.5, 143.5, 86.8, 55.8,
d
31.0, 30.5, 27.1, 26.8, 26.2, 25.3, 25.1, 24.8, 23.7, 23.0 ppm. Anal.
Calcd for C15H2H22Cl2O: C, 62.29; H, 7.67; Cl, 24.51. Found: C, 62.28;
H, 7.64; Cl, 24.58.
4.2.1. 1,2-Cyclononadiene (11, 72%)
1H NMR (300 MHz, CDCl3)
(m, 8H) ppm.
d 5.26 (m, 2H), 2.20 (m, 4H), 1.2–1.9
4.4. Reductive dechlorination of allene–DCK cycloadducts
4.2.2. 1,2-Cycloundecadiene (7, 68%)
To a solution of 0.1 mol of the DCK–allene cycloadduct in
100 mL of methanol (previously saturated with NH4Cl) 2 g of zinc
dust was added, and the mixture was stirred at room temperature
overnight. The solid was removed by suction filtration, the filter
cake washed with 50 mL of ether. To the filtrate, another 150 mL of
ether was added, and the solution transferred to a separatory
funnel and extracted sequentially with each 200 mL of water,
200 mL of brine, and 100 mL of saturated aqueous NaHCO3 solu-
tion, respectively. The ethereal solution was then dried over
MgSO4, and the solvent rotaevaporated to give a yellowish oil that
was purified by flash chromatography (20% EtOAc/pet. ether) on
silica gel.
1H NMR (300 MHz, CDCl3)
(m, 12H) ppm.
d 5.25 (m, 1H),1.8–2.2 (m, 4H), 1.2–1.8
4.2.3. 1,2-Cyclotridecatriene (1, 82%)
1H NMR (300 MHz, CDCl3)
5.13 (m, 2H), 2.1 (m, 4H), 1.0–1.7 (m,
16H) ppm.
d
4.3. Dichloroketene additions
In a 250 mL two-necked flask equipped with a reflux condenser
carrying a drying tube and a 50 mL pressure-equalizing dropping

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I. Erden et al. / Tetrahedron 64 (2008) 5497–5501
4.4.1. (E)-Bicyclo[7.2.0]undec-8-en-10-one
1778, 1459, 1445, 1160 cmꢁ1. A cis–trans mixture of this compound
has previously been reported by an alternate route, see Ref. 32.
1H NMR (300 MHz, CDCl3):
d
6.3 (m, 1H), 3.1 (dd, J¼9.0, 17.1 Hz,
1H), 2.95 (m, 1H), 2.48 (dd, 4.8, 17.1 Hz, 1H), 2.3 (m, 1H), 2.0 (m, 1H),
1.3–1.7 (m, 10H); 13C NMR (75 MHz, CDCl3):
199.6, 153.4, 130.3,
d
4.6.3. trans-Bicyclo[11.2.0]pentadecan-14-one (4)
51.6, 37.1, 33.25, 29.8, 28.9, 27.2, 26.2, 22.9 ppm; FTIR (neat): 2923,
2861, 1750, 1669, 1450, 1120.4, 1049 cmꢁ1. Anal. Calcd for C11H16O:
C, 80.44; H, 9.82. Found: C, 80.48; H, 9.86.
1H NMR (300 MHz, CDCl3)
d
3.05 (ddd, J¼2.8, 8.7, 17.6 Hz, 1H),
2.85 (m, 1H), 2.6 (ddd, J¼3.3, 7.2, 17.6 Hz, 1H), 2.0 (m, 1H), 1.8 (m,
2H), 1.1–1.7 (m, 20H); 13C NMR (75 MHz, CDCl3)
65.3, 50.3, 36.5,
d
31.3, 28.2, 27.2, 26.1, 25.8, 25.7, 25.5, 25.4, 25.1, 23.9 ppm; FTIR
4.4.2. (E)-Bicyclo[9.2.0]tridec-10-en-12-one
(film): 2930, 2861, 1779, 1462, 1450, 1150 cmꢁ1. Anal. Calcd for
C15H26O: C, 81.02; H, 11.79. Found: C, 81.06; H, 11.77.
1H NMR (300 MHz, CDCl3):
d
6.25 (ddd, J¼2.47, 3.48, 12 Hz, 1H),
3.15 (m, 1H), 3.0 (dd, J¼8.9, 16.9 Hz, 1H), 2.56 (dd, 4.72, J¼16.9 Hz,
1H), 2.35 (m, 1H), 2.1 (m, 1H), 1.2–1.7 (m, 14H); 13C NMR (CDCl3,
4.7. General procedure for the synthesis of the cyclic enones
TMS, 75 MHz):
d 199.3, 151.4, 131.7, 49.1, 35.1, 32.4, 26.9, 26.7, 26.1,
26.0, 24.5, 23.6 ppm; FTIR (neat): 2925, 2860, 1751, 1656, 1469,
1445, 1122 cmꢁ1. Anal. Calcd for C13H20O: C, 81.20; H, 10.48. Found:
C, 81.24; H, 10.45.
Cyclobutanone (1 mmol) was dissolved in 2 mL of CCl4 and
150 mg of Hg was added. The mixture was kept under an argon
atmosphere while freshly distilled TMSiI (0.6 g, 3 mmol) was
added, and the mixture stirred for 2 h. The mixture was then
diluted with 25 mL of ether, and washed with 5% Na2SO3, followed
by 5 mL of NaHCO3, dried, and the solvent rotaevaporated. The
4.4.3. (E)-Bicyclo[11.2.0]pentadec-12-ene-14-one (3)
Mp 39–40 ꢀC; 1H NMR (300 MHz, CDCl3):
d
6.25 (ddd, J¼2.5, 5.4,
9.4 Hz, 1H), 3.2 (m, 1H), 3.0 (dd, J¼9.4, 17.4 Hz, 1H), 2.7 (dd, J¼5.4,
b-iodocycloalkanone was dissolved in 10 mL of dry CH2Cl2 and
17.4 Hz, 1H), 2.15 (m, 2H), 1.9 (m, 1H), 1.2–1.7 (m, 16H); 13C NMR
1 mmol of DBU was added dropwise at 0 ꢀC. The solution was
stirred for 30 min at room temperature, then 10 mL of H2O was
added, the organic layer washed successively with 5% HCl and
NaHCO3, the solution dried over MgSO4, the filtrate rotaevaporated,
and the residue purified by column chromatography on silica gel
(15% EtOAc/hexane) to give the macrocyclic enone. During the
TMSI-promoted ring opening reaction of 9, a small aliquot was
(75 MHz, CDCl3):
d 199.2, 150.8, 132.1, 48.6, 33.8, 31.3, 26.8, 26.7,
26.5, 26.0, 24.7, 24.6, 24.4, 23.0 ppm; FTIR: 2927, 2856, 1749,
1663 cmꢁ1. Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C,
81.73; H, 10.94.
4.5. General procedure for the catalytic hydrogenations of the
isolated and analyzed by 1H NMR spectrum. The
tridecanone derivative was clearly discernible in the spectrum due
to the characteristic 3ꢀ
-hydrogen at 4.3 ppm (m, 1H), and the
b-iodocyclo-
a
,b-unsaturated cyclobutanones
b
A solution of 0.1 mol of unsaturated compound obtained by
a
-CH2 group exhibiting an AB system at 2.7 (dd, J¼9.2, 17.2 Hz,
reductive dechlorination of the DCK-adduct was dissolved in 25 mL
of ethyl acetate, and hydrogenated over 0.1 g of Pd/C. The progress
of hydrogen uptake was monitored by means of a burette. After
filtration of the catalyst, the solvent was rotaevaporated to give the
fully saturated bicyclic cyclobutanone as a mixture of cis–trans
isomers. Though for the TMSI-promoted cyclobutanone ring
opening it was not necessary to isomerize the cis–trans mixtures to
the more stable trans isomers, small amounts were subjected to
base-catalyzed isomerization for characterization purposes.
1H) and 2.15 (dd, J¼7.0, 17.2 Hz, 1H).
4.7.1. (E)-Cycloundec-2-enone (14)
Yield 67%; 1H NMR
d
6.8 (dt, J¼7.8, 16.5 Hz, 1H), 6.15 (dt, J¼1.2,
16.5 Hz), 2.6 (t, J¼6.6 Hz, 2H), 2.25 (m, 2H), 1.66 (m, 4H), 1.3 (m,
12H); 13C NMR (75 MHz, CDCl3)
205.5, 149.1, 134.3, 37.3, 33.9, 28.1,
d
26.4, 26.1, 23.9, 23.0, 22.4 ppm; FTIR (film): 2931, 2859, 1690, 1668,
1165, 1463, 1445, 1212, 985 cmꢁ1; see Ref. 33.
4.7.2. (E)-Cyclotridec-2-one (10)
4.6. General procedure for the base-catalyzed isomerization
of the cis–trans mixtures to the trans isomers
Yield 75%; 1H NMR (300 MHz, CDCl3)
d
6.8 (dt, J¼7.5, 15.3 Hz,
1H), 6.15 (dt, J¼1.2, 15.3 Hz, 1H), 2.45 (m, 2H), 2.2 (m, 2H), 1.67 (m,
2H),1.53 (m, 2H) 1.2–1.3 (m,12H); 13C NMR (75 MHz, CDCl3)
204.1,
d
Bicyclic cyclobutanone (0.01 mol) dissolved in 5 mL of methanol
was added dropwise to a solution of 0.5 g of KOH in 10 mL of
methanol at 0 ꢀC. The solution was stirred at room temperature for
30 min, then 50 mL water and 20 mL of ether were added, the
layers separated, the aqueous layer extracted with two 20 mL
portions of ether, the combined ether extracts dried over MgSO4,
and the solvent rotaevaporated. The residue was purified by pre-
parative TLC, eluting with 15% EtOAc/hexane.
149.3, 132.8, 39.2, 33.4, 27.4, 27.3, 26.9, 26.7, 26.6, 26.1, 25.9,
25.8 ppm; FTIR (film): 2972, 2924, 2865, 1689, 1659, 1622, 1464,
1442, 1387, 1350, 1119, 912.6, 740 cmꢁ1; see Ref. 34.
4.7.3. (E)-Cyclopentadec-2-one (5)
Yield 73%. All spectral data were identical to those reported in
literature, see Refs. 3 and 35.
4.7.4. d,l-Muscone (6)
4.6.1. trans-Bicyclo[7.2.0]undecan-10-one (13)
Dried CuI (2.8 g, 14.7 mmol) was placed in a 50 mL two-necked
round-bottomed flask, equipped with a magnetic stir bar and
a rubber septum. Dry ether (25 mL) was added to the flask and the
mixture was cooled to ca. ꢁ25 ꢀC under an argon atmosphere. To
the stirred suspension was added MeLi (23 mL of a 1.18 M ethereal
solution, 26.7 mmol) with stirring. The mixture was stirred for
30 min, a solution of enone 5 (1 g, 45 mmol) in 10 mL of ether was
added over a period of 25 min. The mixture was stirred for 1 h at
ꢁ25 ꢀC, and 25 mL of H2O and 3 N HCl were added. The mixture
was extracted with 3ꢂ25 mL of ether, the combined extracts were
washed with NaHCO3 solution, then Na2SO3 solution, and finally
with brine. After drying over MgSO4, the solvent was rotaevapo-
rated. The resulting yellowish oil was purified by column
1H NMR (300 MHz, CDCl3)
d
3.0 (ddd, J¼2.1, 8.1,16.8 Hz,1H), 2.95
(m, 1H), 2.65 (ddd, J¼2.1, 9.3,16.8 Hz,1H), 2.15 (m,1H), 2.08 (m, 1H),
1.85 (m, 1H), 1.25–1.7 (m, 12H); 13C NMR (75 Hz, CDCl3)
199.6,
d
68.5, 52.6, 37.4, 35.3, 28.4, 27.9, 26.7, 26.6, 26.0 ppm; FTIR (film):
2919, 2860, 1784, 1476, 1448, 1136 cmꢁ1. This compound has pre-
viously been prepared by Ghosez et al.18
4.6.2. trans-Bicyclo[9.2.0]tridecan-12-one (9)
1H NMR (300 MHz, CDCl3)
d
3.1 (ddd, J¼2.6, 8.8, 17.5 Hz, 1H), 2.9
(m, 1H), 2.65 (ddd, J¼2.8, 7.2, 17.5 Hz, 1H), 2.18 (m, 1H), 1.9 (2H), 1.2–
1.65 (m, 16H); 13C NMR (75 MHz, CDCl3)
212, 66.2, 51.4, 35.3, 32.5,
27.1, 26.6, 26.2, 25.9, 25.7, 24.9, 22.9 ppm; FTIR (film): 2929, 2859,
d

I. Erden et al. / Tetrahedron 64 (2008) 5497–5501
5501
Takabe, K. Tetrahedron Lett. 2008, 49, 548; (c) Scafato, P.; Larocca, A.; Rosini, C.
Tetrahedron: Asymmetry 2006, 17, 2511.
4. (a) Erden, I.; Sorensen, E. M. Tetrahedron Lett. 1983, 23, 2731; (b) Erden, A. I.; de
Meijere, A. Tetrahedron Lett. 1983, 24, 3811; (c) Erden, I. Tetrahedron Lett. 1984,
25, 1535; (d) Erden, I. Tetrahedron Lett. 1985, 26, 5635.
chromatography on silica gel, eluting with 15% EtOAc/pet. ether to
give 1.1 g of d,l-muscone (85%), identical in all respects to an au-
thentic sample.
5. A three-carbon ring expansion methodology via cyclopentenone annulation to
cyclododeacanone has been applied to muscone synthesis: Tsuji, J.; Yamada, T.;
Shimizu, I. J. Org. Chem. 1980, 45, 5209.
4.8. Reaction of 12 with NaOMe
6. See: The Merck Index, 13th Edition; for a review, see: Ohloff, G. Fortschr. Chem.
Forsch. 1969, 12, 185.
(E)-11,11-Dichlorobicyclo[7.2.0]undec-8-en-10-one (1 g, 4.3 mmol)
was dissolved in 20 mL of MeOH. This solution was added dropwise
to a NaOMe solution (preformed from 0.2 g, 8.3 mmol of Na and
20 mL of MeOH) at 0 ꢀC. Upon addition, the color of solution
immediately turned red. The mixture was stirred at 0 ꢀC for
30 min, then heated to 50 ꢀC for 1 h. It was poured onto 100 mL
of ice-water, acidified with 10% HCl, extracted with 3ꢂ50 mL of
ether. The combined ether extracts were dried over MgSO4, the
solvent rotaevaporated, and the yellowish waxy material was
purified by column chromatography on silica gel (15% EtOAc/
pet. ether) to give two products.
7. Other ring expansion methodology based on dichloroketene cycloadditions
have been reported: (a) one-carbon ring expansion: Greene, A. G.; Depres, J.-P.
J. Am. Chem. Soc. 1979, 101, 4003; Greene, A. E.; Luche, M.-J.; Serra, A. A. J. Org.
Chem. 1985, 50, 3957; (b) two-carbon expansion: Depres, J.-P.; Navarro, B.;
Greene, A. E. Tetrahedron 1989, 45, 2989; (c) free-radical five- and six-carbon
ring expansions: Zhang, W.; Collins, M. R.; Mahmood, K.; Dowd, P. Tetrahedron
Lett. 1995, 36, 2729 and references cited therein.
8. (a) von Doering, W. E.; La Flamme, P. M. Tetrahedron 1958, 2, 75; (b) Moore,
W. R.; Ward, H. R. J. Org. Chem. 1962, 27, 4179; (c) Skattebol, L. Acta Chem. Scand.
1963, 17, 1683; (d) Gutsche, C. D.; Redmore, D. Carbocyclic Ring Expansion
Reactions; Academic: New York, NY, 1968; Krow, G. R. Tetrahedron 1987, 43, 3
and references cited therein.
9. (a) Tidwell, T. T. Ketenes; Wiley-Interscience: New York, NY, 1995; (b) Lee-Ruff,
E. Advances in Strain in Organic Chemistry; Halton, B., Ed.; JAI: London, 1991;
Vol. I, pp 167–213; (c) Namylso, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103,
1485; (d) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
10. Bak, D. A.; Brady, W. T. J. Org. Chem. 1979, 44, 107.
11. Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43, 2879.
4.8.1. (E)-11,11-Dimethoxybicyclo[7.2.0]undec-8-en-10-one (16)
Yield 13%; 1H NMR (300 MHz, CDCl3)
d
6.6 (ddd, J¼2.9, 7.4,
9.6 Hz, 1H), 3.5 (s, 3H), 3.3 (s, 3H), 3.0 (m, 1H), 2.35 (m, 2H), 2.0 (m,
2H), 1.4–1.7 (m, 8H); 13C NMR (75 MHz, CDCl3)
194.0, 147.8, 138.3,
d
12. Mehta, G.; Rao, H. S. P. Synth. Commun. 1985, 15, 991.
13. A 2:1 mixture of two epimers, as indicated by the characteristic doublets of
121.9, 52.9, 51.6, 51.2, 30.4, 29.6, 26.7, 26.5, 26.4, 22.5 ppm. Anal.
Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C, 75.60; H, 9.95.
doublets at
d 4.95 and 5.00 ppm for the respective CHCl hydrogens.
14. Pinder, A. R. Synthesis 1980, 425 and references cited therein.
15. (a) Jeffs, P. W.; Molina, G.; Cass, M. W.; Cortese, N. A. J. Org. Chem. 1982, 47, 3871;
(b) Rosini, G.; Ballini, R. Tetrahedron 1983, 39, 1085.
16. Braillon, B.; Salaun, J.; Gore, J.; Conia, J. M. Bull. Soc. Chim. Fr. 1964, 1981.
17. (a) Bertrand, M.; Gras, J.-L.; Gore, J. Tetrahedron Lett. 1972, 1189; (b) Bertrand,
M.; Maurin, R.; Gras, J.-L.; Gil, G. Tetrahedron 1975, 31, 849; (c) Bertrand, M.;
Gras, J.-L.; Gore, J. Tetrahedron 1975, 31, 857.
4.8.2. (Z)-11,11-Dimethoxybicyclo[7.2.0]undec-7-en-10-one (15)
Yield 65%; 1H NMR (300 MHz, CDCl3)
d
5.73 (dd, J¼6.8, 10.5 Hz,
1H), 5.56 (ddt, J¼1.7, 6.2, 10.5 Hz, 1H), 3.85 (dd, J¼6.8, 10.8 Hz, 1H),
3.4 (s, 3H), 3.3 (s, 3H), 2.2 (m, 2H), 2.1 (m, 2H), 1.85 (5, 1H), 1.2–1.7
(m, 6H); 13C NMR (75 MHz, CDCl3)
d 204.7, 133.1, 125.3, 58.5, 53.5,
18. Marko, I.; Ronsmans, B.; Hesbain-Frisque, A.-M.; Dumas, S.; Ghosez, L. J. Am.
Chem. Soc. 1985, 107, 2192.
50.4, 46.7, 27.5, 27.1, 26.6, 26.0, 21.8 ppm; FTIR (film): 3012, 2931,
2861, 2834, 1785, 1445, 1256, 1210, 1125, 1078, 1044, 997, 909, 797,
727 cmꢁ1. Anal. Calcd for C14H22O2: C, 75.63; H, 9.97. Found: C,
75.65; H, 9.96.
19. Miller, R. D.; McKean, D. R. Tetrahedron Lett. 1980, 2639.
20. 1H NMR (CCl4, 60 MHz):
20H).
d 4.5 (m, 1H), 3.05 (m, 2H), 2.0–2.8 (m, 4H), 1.4 (m,
21. Mookherjee, B. D.; Patel, R. R.; Ledig, W. O. J. Org. Chem. 1971, 36, 4124.
22. Compound 12 has previously been prepared by Brady et al. by dichloroketene
addition, generated from dichloroacetyl chloride with triethylamine, to 1,2-
cyclononadiene: Brady, W. T.; Stockton, J. D.; Patel, A. D. J. Org. Chem. 1974,
39, 236.
23. Conia, J. M.; Robson, M. J. Angew. Chem., Int. Ed. Engl. 1975, 14, 473 and refer-
ences cited therein.
24. Harding, K. E.; Trotter, J. W.; May, L. M. J. Org. Chem. 1977, 42, 2715.
25. Cagnon, J. R.; Marchand-Brynaert, J.; Ghosez, L. J. Braz. Chem. Soc. 1996, 7, 371.
26. (a) Paryzek, Z.; Blaszczyk. Liebigs Ann. 1993, 615; (b) Paryzek, Z.; Blaszczyk.
Liebigs Ann. 1995, 341.
Acknowledgements
This work was supported by funds from the National Science
Foundation (CHE-9729001), the National Institutes of Health,
MBRS-SCORE Program-NIGMS (Grant No. GM52588), and in part
from a grant (P20 MD) from the Research Infrastructure in Minority
Institutions Program, NCMHD, NIH.
27. Hassner, A.; Naidorf-Meir, S.; Frimer, A. A. J. Org. Chem. 1996, 61, 4051.
28. Chun, K. H.; Yoon, T.; Shin, Y. E. N.; Jo, C.; Jo, Y.-J.; Yun, H.; Oh, J. Bull. Korean
Chem. Soc. 2005, 26, 1104.
29. Donskaya, N. A.; Bessmertnykh, A. G.; Drobysh, V. A.; Shabarov, Y. S. Zh. Org.
Khim. 1987, 23, 751.
References and notes
30. (a) Brown, J.; Pawar, D. M.; Noe, E. A. J. Org. Chem. 2003, 68, 3420; (b) Nozaki,
H.; Aratani, T.; Toraya, T.; Noyori, R. Tetrahedron 1971, 27, 905; (c) Shea, K.; Kim,
J.-S. J. Am. Chem. Soc. 1992, 114, 3044.
31. Makosza, M. Pure Appl. Chem. 1975, 43, 439.
32. Abad, A.; Agullo, C.; Arno, M.; Seoane, E. Tetrahedron 1986, 42, 2429.
33. Friedrich, E.; Lutz, W. Chem. Ber. 1980, 113, 1245.
34. (a) Ruedi, G.; Hansen, H.-J. Helv. Chim. Acta 2004, 87, 1628; (b) Ruedi, G.; Oberli,
M. A.; Nagel, M.; Hansen, H.-J. Org. Lett. 2004, 6, 3179.
35. Tsuji, J.; Yamada, T.; Shimizu, I. J. Org. Chem. 1980, 45, 5211.
1. (a) Weinheimer, A. J.; Chang, C. W. J.; Matson, J. A. Fortschr. Chem. Org. Naturst.
1979, 36, 285; (b) Hanson, J. R. Nat. Prod. Rep. 1984, 1, 171; (c) Macrolide Anti-
biotics; Omura, S., Ed.; Academic: New York, NY, 1984; (d) Sorm, F. Fortschr.
Chem. Org. Naturst. 1961, 19, 1.
2. Mookherjee, B. D.; Wilson, R. A. Fragrance Chemistry; Theimer, E. T., Ed.; Aca-
demic: New York, NY, 1982; p 433.
3. For recent syntheses, see: (a) Ruedi, G.; Hansen, H.-J. Tetrahedron Lett. 2004, 45,
5143; (b) Hisanaga, Y.; Asumi, Y.; Takahashi, M.; Shimizu, Y.; Mase, N.; Yoda, H.;