A practical synthesis of (E)-2-cyclopentadecen-1-one: an important precursor of macrocyclic muscone

Article abstract of DOI:10.1016/j.tetlet.2007.11.065

A practical synthesis of (E)-2-cyclopentadecen-1-one (E)-2 which is an important precursor of macrocyclic muscone (1) was investigated. Olefination of 2-mesyloxycyclopentadecanone (7c) with strong acid such as sulfuric acid or trifluoromethanesulfonic acid afforded the desired (E)-2 in high yield with extremely high stereoselectivity, which was treated with methylmagnesium cuprate to furnish the dl-muscone in good yield.

Full text of DOI:10.1016/j.tetlet.2007.11.065

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Tetrahedron Letters 49 (2008) 548–551
A practical synthesis of (E)-2-cyclopentadecen-1-one:
an important precursor of macrocyclic muscone
Yusuke Hisanaga, Yuya Asumi, Masaki Takahashi, Yasuhiro Shimizu,
Nobuyuki Mase, Hidemi Yoda and Kunihiko Takabe*
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 18 September 2007; revised 9 November 2007; accepted 13 November 2007
Available online 17 November 2007
Abstract—A practical synthesis of (E)-2-cyclopentadecen-1-one (E)-2 which is an important precursor of macrocyclic muscone (1)
was investigated. Olefination of 2-mesyloxycyclopentadecanone (7c) with strong acid such as sulfuric acid or trifluoromethanesul-
fonic acid afforded the desired (E)-2 in high yield with extremely high stereoselectivity, which was treated with methylmagnesium
cuprate to furnish the dl-muscone in good yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Muscone (1) is the primary contributor to the odor of
natural musk. Natural muscone is obtained from musk
pods, which are the secretion from a gland of the
endangered musk deer. Naturally occurring muscone is
composed of the (R)-(À)-enantiomer,1,2 therefore, an
efficient asymmetric synthesis of (R)-(À)-muscone is
desirable.2 Asymmetric conjugate addition of metal
methyl reagents to (E)-2-cyclopentadecen-1-one (2) is a
promising approach to enantiomerically pure muscone.
In the early 1990s, Tanaka and co-workers developed
the stoichiometric conjugate addition of chiral methyl-
cuprate to 2 to give (R)-1 with 100% optical purity.3
Recently, several groups demonstrated catalytic asym-
metric synthesis of (R)-1 with moderate to high enantio-
selectivity.4 To achieve the high enantioselectivity the
configurationally fixed (E)-2 is crucial, however, the
preparation of (E)-2 occasionally requires meticulous
handling in commonly employed procedures such as
halogen-, S-, Se, and Pd-based transformations.5 On
the other hand, Nicolaou and co-workers reported a
direct one-step synthesis of (E)-2 from cyclopentadeca-
none using o-iodoxybenzoic acid, however, a small
amount of undesired dienone was also obtained.6
densation, is another important precursor for the syn-
thesis of (E)-2. For example, thermal dehydration of 6
in the presence of silica–alumina catalyst afforded (E)-
2.7 Recently, Tanabe and co-workers reported that 2-
mesyloxy- or 2-tosyloxycyclopentadecanone (7b or 7c)
with ammonium sulfonate in the presence of base was
transformed to (E)-2.8 Although these are simple mani-
pulations, high temperature (140–220 ꢁC) is essential to
complete the reaction; in addition, the inseparable 3-
cyclopentadecen-1-one (8) is also formed. Therefore,
the preparation of (E)-2 is still difficult to achieve in a
truly efficient synthetic method. Herein, we report a
straightforward and stereoselective synthesis of (E)-2
O
O
rac-1
2
O
It is known that 2-hydroxycyclopentadecanone (6),
which is readily prepared from diester 5 by acyloin con-
LG
( )11
HO2C
CO2H
4
Keywords: Elimination; Muscone; Macrocycles.
3
*
Corresponding author. Tel./fax: +81 53 478 1148; e-mail: tcktaka@
ipc.shizuoka.ac.jp
Scheme 1. Synthesis of muscone (1).
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.065

Y. Hisanaga et al. / Tetrahedron Letters 49 (2008) 548–551
549
O
O
OH
OR
a
c
b
( )11
( )11
CO2Me
HO2C
CO2H
MeO2C
4
5 (99%)
6 (85%)
7
a: R = Ac (89%)
b: R = Ts (65%)
c: R = Ms (81%)
Scheme 2. Reagents and conditions: (a) p-TsOH, MeOH, reflux, 17 h; (b) Na, Me3SiCl, toluene, 100 ꢁC, 7 h, then p-TsOHÆH2O; (c) Ac2O, pyridine,
rt, 24 h for 7a. TsCl, pyridine, rt, 24 h for 7b. MsCl, pyridine, CH2Cl2, rt, 24 h for 7c.
Table 1. Acid promoted elimination of acyloin derivativesa
Table 3. Solvent screening in acid promoted elimination of 2-mesyl-
oxycyclopentadecanone (7c)a
Entry Substrate LG
Time Conversion (E)-2 yieldb
Entry Solvent Time (h) Conversion (%) (E)-2 yieldb (%)
(h)
(%)
(%)
1
2
3
4
6
–OH
4
9
9
1
97
77
90
98
0
1
47
90
1
2
3
4
5
6c
Ether
DMSO
DMF
Hexane
CH2Cl2
CH2Cl2
9
9
9
1
3
2
23
13
22
98
97
99
9
9
18
90
93
97
7a
7b
7c
–OAc
–OTs
–OMs
a Conditions: acyloin derivative (0.1 mmol) and sulfuric acid
(0.4 mmol) in hexane (0.5 mL) at 25 ꢁC with vigorous stirring.
b Isolated yield.
a Conditions: mesylate 7c (0.1 mmol) and sulfuric acid (0.4 mmol) in
hexane (0.5 mL) at 25 ꢁC with vigorous stirring.
b Isolated yield.
c The reaction was carried out using mesylate 7c (3.0 g, 9.4 mmol) and
CF3SO3H (16 mmol) in CH2Cl2 (14 mL) at rt.
using acid promoted elimination of 2-mesyloxycyclo-
pentadecanone (7c) (Scheme 1).
Acyloin derivatives 7 were prepared in 3 steps from
readily available pentadecanedioic acid (4) as shown in
Scheme 2. Fischer esterification of 4 with methanol gave
diester 5 in quantitative yield. The acyloin condensation
of 5 furnished acyloin 6 in high yield. Generally, to
decrease the formation of intermolecular cyclized product,
macrocyclization is performed in a highly diluted solu-
tion. In comparison, the acyloin condensation carried
out in the presence of trimethylsilyl chloride gives acy-
loin 6 in 85% yield in toluene (0.53 M solution).9
Acetylation, mesylation, and tosylation of acyloin 6 by
standard reaction conditions furnished the acyloin
derivatives 7 in good yields.
Table 2. Acid promoted elimination of 2-mesyloxycyclopentadeca-
none (7c)a
Sulfuric acid promoted elimination reactions of acyloin
derivatives are compared in Table 1.10 This elimination
reaction depends on the leaving-group ability. Poor
leaving-groups such as hydroxy and acetoxy groups
did not give the desired enone 2 but an unidentified solid
Entry Acid
Time (h) Conversion (%) (E)-2 yieldb (%)
1
2
3
4
5
6
7
8
9c
AlCl3
9
9
9
9
9
9
1
0.3
0.3
85
98
41
83
88
83
98
99
99
5
7
3
Sc(OTf)3
CH3COOH
CF3COOH
CH3SO3H
p-TsOH
H2SO4
CF3SO3H
CF3SO3H
5
20
63
90
94
93
a Conditions: mesylate 7c (0.1 mmol) and acid (0.4 mmol) in hexane
(0.5 mL) at 25 ꢁC with vigorous stirring.
b Isolated yield.
Scheme 3. Reagents and conditions: (a) mixture of ketones (0.1 mmol)
and sulfuric acid (0.4 mmol) in hexane (0.5 mL) at 25 ꢁC for 1 h with
vigorous stirring.
c CF3SO3H (0.1 mmol) was used.

550
Y. Hisanaga et al. / Tetrahedron Letters 49 (2008) 548–551
Scheme 4. Proposed reaction mechanism.
(entries 1 and 2). Sulfonate leaving groups in general
were best for acid promoted elimination, but in parti-
cular, the mesylate was the best performing leaving group.
The reaction of 2-mesyloxycyclopentadecanone (7c)
took place in the presence of sulfuric acid at room tem-
perature in a short reaction time and 90% yield (entry 4).
Interestingly, the desired (E)-enone 2 was exclusively
formed, confirmed by a single peak in capillary GC
analysis. Neither (Z)-enone 2 nor 3-cyclopentadecen-1-
one (8) was observed.
enol intermediate 9, which undergoes intramolecular
nucleophilic substitution. Cyclopropyl cationic inter-
mediate 10 was transformed to the cation intermediate
11 with C–C bond fission. b-Elimination and tautomeri-
zation finally furnishes the desired enone (E)-2.
In summary, we have developed a practical synthesis of
(E)-2-cyclopentadecen-1-one (2) from readily available
pentadecanedioic acid (4). The strong acid promoted
elimination reactions of acyloin derivatives demonstrate
excellent stereoselectivity to give (E)-2 which is an
important precursor of macrocyclic muscone. No
formation of undesired isomers was observed. Further
studies focusing on the use of the acid promoted elimi-
nation reactions of acyloin derivatives are currently
under investigation and will be reported in due course.
2-Mesyloxycyclopentadecanone (7c) was chosen for the
further study of acid promoted elimination reactions
with various acids (Table 2). Lewis acids and weak
Brønsted acids were ineffective elimination reagents
(entries 1–4), whereas sulfonic acids improved the reac-
tivity as well as yield (entries 5–9). Trifluoromethane-
sulfonic acid was the best acid of those tested in the
elimination reaction, giving (E)-enone 2 stereoselec-
tively in a very short reaction time and 94% yield (entries
8 and 9).
Acknowledgments
We would like to thank Mr. N. Okui, Kawaguchi Chem-
ical Co., Ltd, for a helpful suggestion. We gratefully
acknowledge Dr. D. D. Steiner for a scientific discussion.
Solvent screening studies were performed as shown in
Table 3. Polar solvents such as DMF and DMSO
resulted in low yields (entries 1–3). Whereas, dichloro-
methane and hexane gave high yields (entries 4 and
5).11 These reaction conditions were readily scaled. To
study a multi-gram-scale synthesis, trifluoromethanesul-
fonic acid (1.7 equiv) was added to a solution of mesy-
late 7c (3.0 g, 9.4 mmol) in CH2Cl2 (14 mL) at room
temperature. The reaction mixture was stirred for 2 h.
Usual workup and purification to afford enone (E)-2
(2.0 g, 97%, entry 6). Reacting (E)-2 with a methyl Grig-
nard reagent in the presence of cuprous iodide in THF
produced a racemic mixture of muscone (rac-1) in 76%
yield. Since optical resolution of rac-1 using tartaric acid
derivatives was recently achieved,12 this simple and
practical synthesis of rac-1 from dicarboxylic acid 4
makes an immediate contribution to fragrance
chemistry.
References and notes
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Thermal dehydration of 6 or ammonium sulfonates pro-
moted elimination of 7c results in the formation of
enone (E)-2 and ketone 8 as noted above. Although
these compounds are inseparable by column chromato-
graphy, we found that sulfuric acid promoted isomeriza-
tion of 8 into (E)-2 proceeded with high stereoselectivity
(Scheme 3). This result suggests that even if the unde-
sired ketone 8 is formed during acid promoted elimina-
tion reaction, it must be converted to (E)-2. Therefore,
no formation of 8 was observed.
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The proposed mechanism for the elimination reaction is
shown in Scheme 4.13 Mesylate 7c is protonated to form

Y. Hisanaga et al. / Tetrahedron Letters 49 (2008) 548–551
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(E)-56345-01-8, (Z)-56345-02-9, 32247-08-8; Rf = 0.63
1
(hexane–AcOEt = 80:20); H NMR (CDCl3, 300 MHz) d
1.16–1.31 (m, 16H, 8 · –CH2–), 1.47–1.60 (m, 2H, –CH2–
CH2–CH@CH–), 1.60–1.76 (m, 2H, –CH2–CH2–C@O),
2.20–2.33 (m, 2H, –CH2–CH@CH–), 2.50 (t, J = 6.4 Hz,
2H, –CH2–C@O ), 6.19 (d,J = 15.4 Hz, 1H, –CH@CH–
C@O), 6.82 (td, J = 7.4, 15.4 Hz, 1H, –CH@CH–C@O);
13C NMR (CDCl3, 75 MHz) d = 25.07 (CH2), 25.16
(CH2), 25.82 (CH2), 26.01 (CH2), 26.30 (CH2), 26.47
(CH2), 26.49 (CH2), 26.69 (CH2), 26.76 (CH2), 31.45
(CH2), 39.89 (CH2), 115.90 (CH2), 130.70 (CH), 148.07
(CH), 201.86 (O@C); GC tR = 23.24 min (CBP1-M25-025,
N2 = 0.6 kg/cm2, H2 = 0.5 kg/cm2, air = 0.5 kg/cm2, INJ.
200 ꢁC, DET.T. 250 ꢁC, COL (initial temp; 170 ꢁC, initial
time; 10 min, PROG rate; 0.5 ꢁC/min, final temp; 180 ꢁC,
final time; 10 min)).
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use of the same synthetic procedure (Table 3, entry 5); (E)-
cycloicos-2-enone (y. 98%), (E)-cyclohexadec-2-enone (y.
98%), (E)-cyclotridec-2-enone (y. 66%), and (E)-cyclodo-
dec-2-enone (y. 38%). Elimination reactions of less than
10-membered ring mesylates did not proceed, probably
due to a highly labile cyclopropyl cationic intermediate.
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mechanism of ammonium sulfonates promoted elimina-
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reaction is considered to proceed through the cyclopropyl
cationic intermediates, that is, via the 1,3-elimination
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¨
10. Typical procedure: To a solution of 2-mesyloxycyclopen-
tadecanone (7c) (0.1 mmol) in hexane (0.5 mL) were added
sulfuric acid (0.4 mmol) and/or trifluoromethanesulfonic
acid (0.1 mmol) at 25 ꢁC. The reaction mixture was stirred
for the indicated time, and quenched with saturated
NaHCO3 aq (1.0 mL). Aqueous layer was separated and
extracted with ethyl acetate (3 · 1 mL). The combined
organic extracts were washed with water (5 mL) and brine