Ring closing metathesis directed synthesis of (R)-(-)-muscone from (+)- citronellal

Article abstract of DOI:10.1016/S0040-4020(00)00333-1

A concise and simple synthesis of the valuable perfumery ingredient (R)- (-)-muscone 1 has been achieved through ring closing olefin metathesis (RCM) aided macrocyclization protocol as the key step. Commercially available starting material (R)-(+)-citronellal 3 has been employed as a building unit in preparing the acyclic diolefinic substrate 16, which in turn was exposed to bis(tricyclohexylphosphine)benzylideneruthenium dichloride catalyst 2 to afford the cyclic RCM reaction product 17 in 78% yield. Catalytic hydrogenation of 17 furnished enantiomerically pure (R)-(-)-muscone 1. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00333-1

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4397±4403
Ring Closing Metathesis Directed Synthesis of (R)-(±)-Muscone
from (+)-Citronellal
b
b
b
Vijayendra P. Kamat,a Hisahiro Hagiwara,b, Tomoko Katsumi, Takashi Hoshi, Toshio Suzuki
*
and Masayoshi Andoa
aFaculty of Engineering, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
bGraduate School of Science and Technology, Niigata University, 8050, 2-nocho, Ikarashi, Niigata 950-2181, Japan
Received 13 March 2000; accepted 12 April 2000
AbstractÐA concise and simple synthesis of the valuable perfumery ingredient (R)-(2)-muscone 1 has been achieved through ring closing
ole®n metathesis (RCM) aided macrocyclization protocol as the key step. Commercially available starting material (R)-(1)-citronellal 3 has
been employed as a building unit in preparing the acyclic diole®nic substrate 16, which in turn was exposed to bis(tricyclohexyl-
phosphine)benzylideneruthenium dichloride catalyst 2 to afford the cyclic RCM reaction product 17 in 78% yield. Catalytic hydrogenation
of 17 furnished enantiomerically pure (R)-(2)-muscone 1. q 2000 Elsevier Science Ltd. All rights reserved.
(R)-(2)-Muscone (3-methylcyclopentadecan-1-one) 1 is the
main odorous principle of musk pod obtained from the male
musk deer Moschus moschiferus.1 Its absolute con®guration
was established by an asymmetric synthesis2 via the
electrolytic method using monomethyl ester of tri-
decanedioic acid and b-methylglutaric acid and further
con®rmed by ORD studies.3 Owing to its rare occurrence
in nature, and its exotic odor, several approaches have been
made towards the synthesis of muscone. Being a macro-
cyclic ketone, muscone in racemic form has been synthe-
sized earlier4 by several routes involving a variety of
conventional procedures such as acyloin condensation,
fragmentation reaction of tosyl hydrazones derived from
a,b-epoxy ketones, one carbon homologation and ring
enlargement protocols. Similarly, a number of reports on
the synthesis of (R)-muscone 1 have appeared in literature
from time to time.5 Some of the recent syntheses reported
for (R)-muscone 1 were based on key reactions like free
radical macrocyclization,6 diastereoselective conjugate
addition to a cyclic ester followed by Dieckmann condensa-
tion reaction7 and asymmetrically catalyzed macrocycliza-
tion of an v-alkynal in combination with a hydroxyl group
directed cyclopropanation of the resulting cyclic allyl
alcohol.8 Though these syntheses have successfully
addressed the problem of enantioselectivity, most of them,
however, employed the laboriously prepared and not so
easily available chiral catalytic systems in order to transfer
enantioselectively either the methyl group or a cyclopropyl
moiety on a pre-formed functionalized cyclic substrate
which in turn was prepared via the multistep synthetic
sequence. In order to overcome these limitations, we visua-
lized a simple approach for (R)-muscone 1 starting from an
acyclic chiral substrate which could be easily accessible in
good yield through readily available starting material and
then utilizing ring closing ole®n metathesis as the key reac-
tion to effect macrocyclization. Recourse to the molybde-
num alkylidene catalyst developed by Schrock9e gave the
same result (Fig. 1).
In recent years, the ole®n metathesis has advanced in a
widely applicable synthetic method9 with the development
of stable transition metal based catalysts and more particu-
larly, the ring closing ole®n metathesis (RCM) guided
synthetic protocol continues to yield spectacular success
during the natural product synthesis.10 Among various
catalysts available, the ruthenium and the molybdenum
alkylidenes are the most frequently used initiators for ole®n
metathesis.11
In principle, muscone 1 could be obtained by RCM reaction
involving a suitable diole®nic substrate. In this paper, we
Keywords: catalysis; cyclic ketones; cycloalkanes; metathesis; ruthenium
and compounds.
* Corresponding author. Tel./fax: 181-25-262-7368;
e-mail: hagiwara@gs.niigata-u.ac.jp
Figure 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00333-1

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V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
Scheme 1. Reagents and conditions: (a) 10-bromodec-1-ene, Mg, Et2O, 16 h; (b) Jones reagent, CH3COCH3, 10 min; (c) 5 mol% of 2, 21 h, 458C.
describe in detail12 the realization of this assumption in
practice which leads us to a simple and concise synthesis
of (R)-muscone 1 in good chemical and optical yields.
Although, muscone 1 in optically active form has been
synthesized by different routes, none of them employed an
RCM protocol for effecting macrocyclization leading to the
natural product 1.
Among the catalysts, we opted for bis(tricyclohexyl-
phosphine)benzylidene ruthenium dichloride 2 as the
initiator for the ring closing metathesis after considering
its commercial availability, excellent functional group
tolerance and the reported retention of catalytic activity
even under reaction conditions which did not include
rigorous exclusion of moisture and oxygen.9 Accordingly,
the diole®nic substrate 6 was exposed to ruthenium
The required acyclic diole®nic RCM substrate was prepared
from the commercially available chiral starting material
(R)-(1)-citronellal 3 (Scheme 1). For this purpose, dec-9-
en-1-ol was converted into the corresponding bromide by
treatment with carbon tetrabromide in the presence of
triphenylphosphine using acetonitrile as a solvent. The
Grignard reagent prepared from this bromide was reacted
with 3 to give the alcohol 4. Some quantity of a by-product
identi®ed as isopulegol 513 was also isolated during the
Grignard reaction. The formation of this by-product can
be rationalized on the basis of a carbonyl ene-cyclization
of highly reactive citronellal under the experimental con-
ditions employed for the Grignard reaction. Repeated
attempts to suppress the formation of this by-product
yielded no success. The alcohol 4 was then subjected to
Jones oxidation to yield the keto compound 6. Having the
desired diole®nic substrate 6 in hand, we then turned our
attention towards the selection of a suitable RCM catalyst.
alkylidene 2 under the RCM reaction conditions.
However, compound 6 failed to undergo ring closing
metathesis and instead provided the corresponding acyclic
dimer 7, formed as a product of intermolecular metathesis
reaction. This result further con®rms the earlier reported
observation that the RCM process is sensitive to steric
hindrance close to the double bond to be metathesized in
the substrate.11
Based on the foregoing result, it was evident that, to induce
a productive RCM reaction using ruthenium alkylidene 2, it
is essential to convert the trisubstituted double bond existing
in substrate 6 to a terminal ole®nic moiety. This was
achieved as shown in Scheme 2. When 4 was directly
subjected to ozonolysis-Wittig reaction protocol, we were
unable to isolate any appreciable quantity of the correspond-
ing ole®nic compound 10. Hence, the alcohol 4 was
converted to its TBDMS ether 8 and was then subjected to
Scheme 2. Reagents and conditions: (a) TBDMSCI, imidazole, DMF, 21 h; (b) O3, CH2Cl2, 2788C, Me2S, 2788C then rt, 12 h; (c) Ph3PMeBr, n-BuLi, THF,
2788 then rt, 4 h; (d) TBAF, THF, 24 h.

V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
4399
Scheme 3. Reagents and conditions: (a) TBDMSCI, imidazole, DMF, 10 h; (b) O3, CH2Cl2, 2788C, Me2S, 2788C then rt; 12 h; (c) Ph3PMeBr, n-BuLi, THF,
2788C then rt, 3 h; (d) TBAF, THF, 1 h; (e) OsO4, dioxane, NaIO4, H2O, 36 h; (f) Ph3PMeBr, n-BuLi, THF, 2788C then rt, 4 h; (g) SO3´pyridine, CH2Cl2,
DMSO, NEt3, 1.5 h; (h) 10-bromodec-1-ene, Mg, Et2O, 4 h.
ozonolysis at 2788C followed by Wittig ole®nation of the
resulting dialdehyde to furnish the diole®nic TBDMS ether
9. Deprotection of the TBDMS group in 9 was achieved
with TBAF to provide the alcohol 10. Alternatively, 10
was also prepared directly by the Grignard reaction on alde-
hyde 15, which in turn was made available by repeating the
above set of reactions on (R)-citronellol 11 (Scheme 3). This
approach also helped us to prevent the formation of
undesired by-product 5 arising from 3 under the Grignard
reaction conditions as observed earlier.
Alternatively, the hydroxyl group protection and deprotec-
tion sequence leading to 14 could be avoided by resorting to
osmium tetroxide-periodate oxidation (Scheme 3). Thus,
(1)-citronellol 11 was treated with a catalytic amount of
osmium tetroxide in dioxane, followed by cleavage of the
resulting diol with sodium periodate in one pot operation
and Wittig ole®nation of the derived aldehyde directly gave
14 in 67% combined yield. The ole®nic alcohol 14 was then
converted to aldehyde 15 by oxidation with sulfurtrioxide
pyridine complex in dimethyl sulfoxide and triethylamine.
Without further puri®cation, the aldehyde 15 was treated
with Grignard reagent prepared from 10-bromodec-1-ene
as before to yield the alcohol 10 in 66% yield (over two
steps) without any contamination of the by-product.
Attempts of further improvement in the yield of 10 gave
no success apparently due to the labile and volatile nature
of aldehyde 15. Surprisingly, all our efforts to use the
previously prepared alcohol 4 or its TBDMS ether 8 as a
substrate for osmium tetroxide-periodate oxidation and
subsequent Wittig reaction ended up in very poor yields
of the corresponding terminal ole®ns 10 and 9, respectively.
Thus, when (1)-citronellol 11 prepared by sodium boro-
hydride reduction of 3 was subjected to ozonolysis, the
reaction provided only trace quantities of the desired alde-
hyde and hence the hydroxyl group in 11 was protected in
the form of its TBDMS ether 12. The isopropenyl double
bond present in 12 was then cleaved smoothly by ozonolysis
followed by the Wittig ole®nation of the derived aldehyde to
afford the ole®n 13 in good yield. Deprotection of the
TBDMS group in 13 was achieved by treatment with
TBAF to provide alcohol 14.
Scheme 4. Reagents and conditions: (a) Jones reagent, CH3COCH3, 5 min; (b) 5 mol% of 2, CH2Cl2, 21 h, 458C; (c) H2, 10% Pd-C, MeOH, 3 h.

4400
V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
When 10 was subjected to Jones oxidation, it provided the
desired RCM substrate 16 in high yield (Scheme 4). As
anticipated, when 16 was exposed to ruthenium alkylidene
catalyst 2 in re¯uxing dichloromethane, it smoothly under-
went ring closing ole®n metathesis to yield the desired
cyclic product 17 in 78% yield as a mixture of E/Z isomers
along with a small quantity of cyclic dimeric compound 18
formed as a result of intermolecular metathesis. Finally,
catalytic hydrogenation of 17 over palladium carbon
provided pure (R)-(2)-muscone 1 which was identical in
all respects with an authentic sample.
was removed from the combined organic part to leave a
pale yellow oil, puri®ed by column chromatography on
silica gel using n-hexane as eluent followed by distilla-
tion in a Kugelrohr short-path apparatus to give 10-
bromodec-1-ene (4.42 g, 100%) as a colorless oil; nmax
/
cm21 3088, 2930, 1641, 1545, 912 and 744; dH
(200 MHz) 1.23±1.47 (10H, m), 1.86 (2H, m), 2.02 (2H,
m), 2.09 (4H, m), 3.41 (2H, t, Jˆ6.9 Hz, CH2Br), 4.89±
5.05 (2H, m, CH2vCHCH2) and 5.81 (1H, ddt, Jˆ16.9,
10.6, 6.7 Hz, CH2CHvCH2).
(6R)-2,6-Dimethyl-2,17-octadecadien-8-ol 4. A slurry of
magnesium powder (121 mg, 5.0 mmol) in diethyl ether
(1.3 cm3) was stirred with a trace quantity of iodine until
the solution became colorless. 10-Bromodec-1-ene
(1.095 g, 5.0 mmol) in diethyl ether (1 cm3) was then
added dropwise to the slurry. The reaction for the formation
of Grignard reagent was initiated by adding a small crystal
of iodine and the reaction mixture was re¯uxed for 5 min.
After the exothermic reaction had started, it was stirred at
room temperature for 30 min and then diluted with diethyl
ether (5 cm3). A solution of (R)-citronellal 3 (771 mg,
5.0 mmol) in diethyl ether (1.3 cm3) was added slowly to
the Grignard reagent at 08C and then the reaction mixture
was stirred at room temperature for 16 h. The reaction
mixture was quenched with aqueous ammonium chloride
and extracted with diethyl ether. Evaporation of solvent
followed by puri®cation of the product by MPLC provided
alcohol 4 (926 mg, 63%) as an inseparable diastereomeric
mixture (ratio 1:1); nmax/cm21 3648, 3008, 2964, 1644,
1461, 1450, 1379 and 907; dH (200 MHz) 0.91 and 0.92
(total 3H, ratioˆ1:1, d, Jˆ6.5 Hz, CH3CH), 1.1±1.5 (19H,
m), 1.6 and 1.68 (3H each, s, ole®nic methyl), 1.88±2.12
(4H, m), 2.32 (1H, br s, hydroxy), 3.7 (1H, m, CHOH),
4.89±5.16 (23H, m, CH2CHvCH2), 5.1 (1H, m,
CH2CHvCMe2) and 5.81 (1H, ddt, Jˆ17 Hz, 10.2 and
6.6, CH2CHvCH2); m/z (EI) 294 (M1, 0.2%), 276
(M12H2O, 0.6), 109 (48), 95 (43), 82 (100), 69 (79) and
67 (38).
Thus, a new simple synthesis of the rare and classical
perfumery compound (R)-(2)-muscone 1 has been achieved
starting from readily available synthons by employing ring
closing ole®n metathesis. The key macrocyclization step
involving the acyclic substrate in the present synthesis
proceeds under mild reaction condition with moderate
catalyst load and in good yield.
Experimental
IR spectra were recorded on a Shimadzu FT/IR-4200 spec-
trophotometer for solutions in carbon tetrachloride unless
1
otherwise indicated. H NMR (200 MHz) and 13C NMR
(50 MHz) spectra were obtained for solutions in deuterio-
chloroform on a Varian Gemini 200H instrument with tetra-
methylsilane as internal standard. Mass spectra were run on
a JEOL HX-110 spectrometer of the Instrumental Analysis
Center for Chemistry, Tohoku University or a JEOL
GCmate, Niigata University. Speci®c rotations, [a]D were
determined on a Horiba SEPA-200 polarimeter for solutions
in chloroform and are given in 1021 deg cm2 g21. Medium
pressure liquid chromatographies (MPLC) were carried out
on a JASCO PRC-50 instrument with a pre-packed silica gel
column. Microanalyses were carried out in the micro-
analytical laboratory of the Instrumental Analysis Center
for Chemistry, Tohoku University. Reactions were run
under an atmosphere of nitrogen. Tetrahydrofuran and
diethyl ether were distilled over sodium benzophenone
ketyl and dichloromethane was distilled over calcium
hydride and stored under nitrogen atmosphere. Anhydrous
sodium sulfate (Na2SO4) was used for drying the organic
extracts. The work-up procedure involved dilution of the
reaction mixture with water or saturated aqueous sodium
hydrogen carbonate or ammonium chloride solution
followed by extraction with diethyl ether (n-hexane or
ethyl acetate or dichloromethane), washing of the combined
organic extract with water, brine, drying (Na2SO4) and
evaporation of the solvent at aspirator pressure. (R)-(1)-
Citronellal used in this work was procured from Tokyo
Kasei Kogyo Co., Ltd.
The above reaction also gave the by-product 5 (285 mg,
37% based on 3); nmax/cm21 3588, 3008, 2953, 2926,
1644, 1460, 1375, 1282 and 901; dH (200 MHz) 0.94 (3H,
d, Jˆ6.5 Hz, CH3H), 1.18±1.68 (6H, m), 1.71 (3H, s,
ole®nic methyl), 1.78±2.11 (3H, m), 3.46 (1H, td, Jˆ10
and 4.3 Hz, CHOH) and 4.84±4.92 (2H, m, CH2vCMe);
dC (50 MHz) 19.16, 22.21, 29.60, 31.41, 34.29, 42.61,
54.09, 70.29, 112.81 and 146.57.
(6R)-2,6-Dimethyloctadeca-2,17-octadien-8-one 6. To a
stirred solution of alcohol 4 (120 mg, 0.407 mmol) in
acetone (3 cm3) was added Jones reagent dropwise at ice
bath temperature until a slight orange color persisted.
After 10 min, the reaction mixture was quenched by the
addition of isopropyl alcohol and the product was extracted
with ethyl acetate (2£10 cm3). Evaporation of the combined
extracts followed by puri®cation of the residue using MPLC
provided ketone 6 (96 mg, 81%) (Found: C, 81.9; H, 12.2.
C20H36O requires C, 82.1; H, 12.4%); nmax/cm21 3008,
2928, 1713, 1644, 1379, 916 and 746; dH (200 MHz) 0.88
(3H, d, Jˆ6.6 Hz, CH3 CH), 1.10±1.45 (12H, m), 1.45±1.57
(3H, m), 1.59 and 1.68 (3H each, s, ole®nic methyl), 1.85±
2.10 (4H, m), 2.20 (1H, dd, Jˆ15.5 and 7.9 Hz), 2.36 (2H, t,
10-Bromodec-1-ene. Carbon tetrabromide (10.62 g,
32 mmol) was added to a solution of dec-9-en-1-ol
(3.15 g, 20 mmol) and triphenylphosphine (8.39 g, 32
mmol) in acetonitrile (30 cm3) at 08C. The reaction mixture
was stirred at room temperature for 22 h, and the acetonitrile
was evaporated under reduced pressure. n-Hexane (20 cm3)
was added to the residue and the precipitated triphenylpho-
sphine oxide was ®ltered off. The ®ltered residue was
washed twice with n-hexane (2£10 cm3) and the n-hexane

V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
4401
Jˆ7 Hz), 2.38 (1H, dd, Jˆ15.5 and 7.8 Hz), 4.95 (2H, m,
CH2CHvCH2), 5.1 (1H, m, CH2CHvCMe2) and 5.81 (1H,
ddt, Jˆ17, 10.2 and 6.6 Hz, CH2CHvCH2).
for 1 h and then at room temperature for 3 h. The reaction
was quenched by the addition of aqueous ammonium
chloride and extracted with ethyl acetate. Evaporation of
the solvent followed by puri®cation of the product by
MPLC gave 9 (62 mg, 73%) as a diastereomeric mixture
(Found: C, 75.85; H, 12.4. C24H48OSi requires C, 75.7; H,
12.7%); nmax/cm21 3008, 2955, 1645, 1255, 1070 and 837;
dH (200 MHz) 0.04 (6H, s, 2£OSiCH3), 0.88 (12H, br s,
CH3CH and 3£SiCCH3), 1.05±1.5 (19H, m), 1.9±2.1 (4H,
m, allylic), 3.7 (1H, m, CHOSi), 4.9±5.5 (4H, m,
2£CH2CHvCH2) and 5.8 (2H, ddt, Jˆ17, 10.2 and
6.6 Hz, 2£CH2CHvCH2).
Acyclic dimer 7. To a solution of keto-diole®n 6 (33 mg,
0.11 mmol) in dry degassed dichloromethane (25 cm3) was
added via cannula, a solution of ruthenium alkylidene 2
(6 mg, 0.007 mmol) predissolved in CH2Cl2 (6 cm3). The
resulting purple colored solution was heated to 458C for
21 h and concentrated under reduced pressure to afford an
oily brown residue. Puri®cation by MPLC [eluent:
n-hexane±ethylacetate (5:1)] afforded the dimer 7 (26 mg,
83%) as a diastereomeric mixture (Found: C, 81.8; H, 11.9.
C38H68O2 requires C, 81.9; H, 12.3%); nmax/cm21 2928,
2856, 1715, 1461, 1410, 1377 and 966; dH (200 MHz)
0.89 (6H, d, Jˆ6.5 Hz, 2£CH3CH), 1.10±1.40 (32H, brs),
1.60 and 1.68 (6H each, s, 2£2 ole®nic methyls), 1.85±2.10
(6H, m), 2.18 (2H, dd, Jˆ15.5 and 7.9 Hz), 2.37 (4H, t,
Jˆ6.7 Hz), 2.40 (2H, dd, Jˆ15.6 and 7.8 Hz), 5.00±5.15
(2H, brt, Jˆ8.8 Hz, 2£CH2CHvCMe2) and 5.30±5.42
(2H, m, ole®nic).
(5R)-5-Methylpentadeca-1,16-diene-7-ol 10. To a stirred
solution of 9 (366 mg, 0.961 mmol) in THF (3.5 cm3) was
added tetrabutylammonium ¯uoride (1.0 mol dm23 in tetra-
hydrofuran; 2.87 cm3, 2.87 mmol) at room temperature and
stirring was continued for 24 h. Reaction was quenched by
the addition of aqueous ammonium chloride. The product
was extracted with ethyl acetate and puri®ed by MPLC to
give 10 (248 mg, 97%) as an oily liquid.
(R)-11-tert-Butyldimethylsiloxy-13,17-dimethyloctadeca-
1,16-diene 8. A mixture of alcohol 4 (544 mg, 1.85 mmol),
imidazole (377 mg, 5.53 mmol) and tert-butyldimethyl-
silylchloride (833 mg, 5.53 mmol) in N,N-dimethylforma-
mide (2 cm3) was stirred at room temperature for 21 h.
The reaction mixture was quenched with aqueous ammo-
nium chloride and extracted with ethyl acetate (2£10 cm3).
Puri®cation of the residue after removal of solvent was
carried out using silica gel column chromatography to
give the silylether 8 (660 mg, 87%) (Found: C, 76.4; H,
12.8. C26H52OSi requires C, 76.4; H, 12.8%); nmax/cm21
3008, 2955, 1645, 1545, 1462, 1380, 1255, 1070 and 910;
dH (200 MHz) 0.03 (6H, s, 2£OSiCH3), 0.88 (12H, br s,
CH3CH and 3£SiCCH3), 1.2±1.55 (19H, m), 1.6 and 1.68
(3H each, s, ole®nic methyl), 1.9±2.1 (4H, m, allylic), 3.69
(1H, m, CHOSi), 4.89±5.16 (2H, m, CH2CHvCH2), 5.1
(1H, m, CH2CHvCMe2) and 5.81 (1H, ddt, Jˆ17, 10.2
and 6.6 Hz, CH2CHvCH2).
Alternatively, the Grignard reagent was prepared as in the
previous experiment from magnesium powder (43 mg,
1.76 mmol) and 10-bromodec-1-ene (383 mg, 1.75 mmol)
in diethyl ether (3.5 cm3). A solution of the aldehyde 15
(57 mg, 0.46 mmol) in diethyl ether (2 cm3) was then
added at ice bath temperature with stirring. Thereafter, the
reaction mixture was stirred at room temperature for 4 h and
then quenched by the addition of aqueous ammonium
chloride solution. Extraction with diethyl ether, evaporation
of the solvent and puri®cation of the product by MPLC
furnished alcohol 10 (80 mg, 66%) (Found: C, 81.4; H,
12.9. C18H34O requires C, 81.1; H, 12.9%); nmax/cm21
,
3648, 3008, 2857, 1641, 1462, 1379, 995 and 912; dH
(200 MHz) 0.91 and 0.92 (total 3H, ratioˆ1:1, d,
Jˆ6.5 Hz, CH3CH), 1.1±1.5 (19H, m), 1.98±2.2 (4H, m,
allylic), 2.35 (1H, br s, hydroxy), 3.7 (1H, m, W1/2 16.6,
CHOH), 4.8±5.1 (4H, m, 2£CH2CHvCH2) and 5.81 (2H,
ddt, Jˆ17, 10.2 and 6.6 Hz, 2£CH2CHvCH2).
(5R)-7-tert-Butyldimethylsiloxy-5-methylheptadeca-1,16-
diene 9. Ozone (10% in oxygen) was bubbled through a
stirred solution of ole®n 8 (91 mg, 0.223 mmol) in dichloro-
methane (10 cm3) at 2788C for 15 min. Dimethyl sul®de
(0.1 cm3) was added to the resulting pale blue solution
and the reaction mixture was stirred at room temperature
overnight. After removal of the solvent, the residue was
passed through a short silica gel column with a pad of
Na2SO4 on the top and eluted with a mixture of n-hexane±
ethyl acetate (1:1). Evaporation of the solvent provided the
corresponding dienal of silyl derivative 8, an oily liquid
which was subjected directly to the next reaction without
further puri®cation.
(R)-(1)-Citronellol 11. To a stirred suspension of sodium
borohydride (1.642 g, 43.4 mmol) in methanol (25 cm3)
maintained at 08C was added a solution of (R)-(1)-citronel-
lal 3 (6.12 g, 7.2 cm3, 39.7 mmol) in methanol (3 cm3) and
the reaction mixture was stirred for 5 h. The reaction was
quenched by careful addition of water followed by extrac-
tion with ether. Evaporation of the solvent left behind an oil
which was puri®ed by distillation using Kugelrhor apparatus
to give 11 (5.63 g, 91%); nmax/cm21 3638, 2964, 2856,
1452, 1379, 1057, 910 and 801; dH (200 MHz) 0.91 (3H,
d, Jˆ6.5 Hz, CH3CH), 1.09±1.51 (6H, m), 1.61 and 1.69
(3H each, s, ole®nic methyl), 1.93±2.05 (2H, m, allylic),
3.69 (2H, m, CH2OH) and 5.10 (1H, t, Jˆ7.1 Hz, ole®nic).
Spectral data were identical with authentic sample.
To a slurry of methyl(triphenyl)phosphonium bromide
(223 mg, 0.624 mmol) in tetrahydrofuran (3 cm3) at 08C
was added dropwise, a solution of n-BuLi (1.6 mol dm3 in
n-hexane; 0.37 cm3, 0.595 mmol) and the resulting orange
brown solution was stirred for 30 min. Then, the above
dialdehyde (64 mg, 0.166 mmol) dissolved in tetrahydro-
furan (1.5 cm3) was added in the Wittig reagent at 2788C
with stirring. The stirring was continued at this temperature
(R)-2,6-Dimethyl-8-tert-butyldimethylsiloxyoct-2-ene 12.
To a stirred mixture of TBDMS chloride (181 mg,
1.66 mmol) and imidazole (170 mg, 2.49 mmol) in N,N-
dimethylformamide (0.3 cm3) was added 11 (156 mg,
1 mmol) at ice bath temperature and then the reaction
mixture was stirred at room temperature for 10 h. The reac-
tion mixture was diluted with water and extracted with ethyl

4402
V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
acetate. Removal of the solvent left behind an oily liquid
which was puri®ed by silica gel column chromatography
using n-hexane as the eluent to give TBDMS ether 12
(270 mg, 99%); nmax/cm21 2959, 2858, 1471, 1255, 1095
and 839; dH (200 MHz) 0.05 (6H, s, 2£OSiCH3), 0.87±0.91
(12H, m, CH3CH and 3£SiCCH3), 1.00±1.44 (5H, m), 1.61
and 1.69 (3H each, s, ole®nic methyl), 1.91±2.04 (2H, m,
allylic), 3.64 (2H, td, Jˆ6.7 and 2.5 Hz, CH2OSi) and 5.11
(1H, t, Jˆ6.4 Hz, ole®nic).
phenyl)phosphonium bromide (1.368 g, 3.83 mmol) in
tetrahydrofuran (12 cm3) and n-BuLi (1.6 mol dm23 in
n-hexane; 2.2 cm3, 3.56 mmol). The aldehyde (102 mg,
0.785 mmol) obtained in the above reaction was added to
the Wittig reagent as a solution in THF (2 cm3) at 2788C
with stirring. The reaction mixture was allowed to warm to
room temperature over a period of 4 h and then quenched
with saturated solution of ammonium chloride. Extraction
with ethyl acetate followed by puri®cation of the product by
MPLC gave 14 (88 mg, 87%); nmax/cm21 3638, 3008, 2961,
1641, 1240, 1051 and 910; dH (200 MHz) 0.91 (3H, d,
Jˆ6.5 Hz, CH3CH), 1.14±1.72 (6H, m), 1.95±2.20 (2H,
m, allylic), 3.69 (2H, td, Jˆ6.7 and 2.5 Hz, CH2OH), 4.8±
5.1 (4H, m, 2£CH2CHvCH2) and 5.81 (2H, ddt, Jˆ17.1,
10.2 and 6.7 Hz, 2£CH2CHvCH2); m/z (EI) 110
(M12H2O, 31%), 95 (87), 86 (31), 72 (79), 68 (100), 62
(75) and 55 (91); HR MS m/z 128.1196 M1, C8H16O
requires 128.1201.
(R)-5-Methyl-7-tert-butyldimethylsiloxyoct-1-ene 13. The
TBDMS ether 12 (250 mg, 0.925 mmol) in dichloro-
methane (10 cm3) was subjected to ozonolysis and
worked-up as in the previous experiment to give the corre-
sponding aldehyde which was used as such for the next
reaction. To the Wittig reagent prepared from methyl tri-
phenylphosphonium bromide (635 mg, 1.75 mmol) in tetra-
hydrofuran and n-BuLi (1.6 mol dm23 in n-hexane;
1.06 cm3, 1.70 mmol), was added a solution of the above
prepared aldehyde (220 mg, 0.91 mmol) in tetrahydrofuran
(1.5 cm3) at 2788C with stirring. The yellow colored reac-
tion mixture was stirred further for 1 h and then continued
stirring at room temperature for another 2 h. The reaction
mixture was diluted with aqueous ammonium chloride and
extracted with ethyl acetate. Removal of the solvent
followed by puri®cation of the product by MPLC using
only n-hexane as the solvent provided the ole®n 13
(210 mg, 94%) (Found: C, 69.1; H, 12.4. C14H30 OSi
requires C, 69.4; H, 12.5%); nmax/cm21 3008, 2957, 1644,
1462, 1256, 1096 and 908; dH (200 MHz) 0.05 (6H, s,
2£OSiCH3), 0.86±0.89 (12H, m, CH3CH and 3£SiCCH3),
1.18±1.47 (5H, m), 1.982.14 (2H, m, allylic), 3.63 (2H, td,
Jˆ6 and 2.5 Hz, CH2OSi), 4.89±5.05 (2H, m,
CH2vCHCH2) and 5.81 (1H, ddt, Jˆ17.1, 10.3 and
6.7 Hz, CH2CHvCH2).
(R)-3-Methylhept-6-enal 15. To a stirred mixture of
alcohol 14 (95 mg, 0.738 mmol) in dichloromethane
(5 cm3) containing dimethyl sulfoxide (3.15 cm3,
44.4 mmol) and triethylamine (1.31 cm3, 9.4 mmol) was
added a solution of sulfur trioxide pyridine complex
(772 mg, 4.85 mmol) in dichloromethane (3 cm3) at 08C.
The reaction mixture was stirred for 1.5 h by gradually rais-
ing the temperature to 258C and then diluted with n-pentane
(20 cm3) followed by successive washing of the organic
phase with water, 1 M aqueous hydrochloric acid, aqueous
sodium hydrogencarbonate and brine. Careful removal of
the solvent followed by puri®cation of the product by
passing it through a small silica gel column with a layer
of anhydrous sodium sulfate on the top provided the labile
aldehyde 15 (79 mg, 85%) which was used immediately for
the next reaction; nmax/cm21 2959, 2928, 2856, 2736, 1730,
1644, 1462, 1379, 1263 and 909; dH (200 MHz) 0.98 (3H, d,
Jˆ6.6 Hz, CH3CH), 1.22±1.50 (3H, m), 2.0±2.2 (2H, m,
allylic), 2.25±2.5 (2H, m, CH2CHO), 4.92±5.08 (2H, m,
CH2CHvCH2), 5.80 (1H, ddt, Jˆ17, 10.2 and 6.7 Hz,
CH2CHvCH2) and 9.75 (1H, t, Jˆ2.3 Hz, CHO).
(R)-3-Methylhept-6-en-1-ol 14. The TBDMS ether 13
(200 mg, 0.83 mmol) in tetrahydrofuran (2 cm3) was stirred
with tetrabutylammonium ¯uoride (1 mol l3 in tetrahydro-
furan; 2.47 cm3, 2.47 mmol) at room temperature for 1 h.
The reaction mixture was diluted with water and extracted
with diethyl ether. Careful removal of the solvent followed by
puri®cation by MPLC provided 14 (103 mg, 98%) as an oil.
(R)-5-Methylheptadeca-1,16-diene-7-one
16.
Jones
reagent was added to a stirred solution of alcohol 10
(160 mg, 0.60 mmol) in acetone (3.5 cm3) at ice bath
temperature until a slight orange color persisted. After
5 min, the excess reagent was destroyed by the addition of
isopropyl alcohol and the reaction mixture was diluted with
water. The aqueous phase was extracted with ethyl acetate
followed by evaporation of solvent and puri®cation of the
product by MPLC gave the diole®nic ketone 16 (154 mg,
97%) (Found: C, 81.6; H, 12.2. C18H32O requires C, 81.7; H,
12.2%); [a]Dˆ12.94. (c 0.9 in MeOH); nmax/cm21 3079,
2928, 1715, 1641, 1462, 1367, 993 and 912; dH (200 MHz)
0.89 (3H, d, Jˆ6.5 Hz, CH3CH), 1.2±1.45 (12H, brs), 1.5±
1.8 (3H, m), 1.9±2.1 (4H, m, allylic), 2.18 (1H, dd, Jˆ14.2
and 5.5 Hz), 2.34±2.50 (3H, m), 4.88±5.05 (4H, m,
2£CH2vCHCH2) and 5.695.92 (2H, m, 2£CH2CHvCH2);
dC (50 MHz) 19.69, 23.76, 28.71, 28.87, 29.04, 29.21,
29.28, 29.34, 31.21, 33.76, 36.03, 43.36, 50.14, 114.09,
114.40, 138.64, 139.14 and 211.15.
Alternatively, a solution of osmium tetroxide (8 mg,
0.03 mmol) in water (1 cm3) was added to a vigorously
stirred solution of (1)-citronellol 11 (159 mg, 1.02 mmol)
in 1,4-dioxane (4 cm3). After stirring for 15 min at room
temperature, a solution of sodium periodate (642 mg,
3.0 mmol) in water (3 cm3) was added. After being stirred
for 36 h at room temperature, the reaction mixture was
®ltered through a pad of celite and the ®ltrate was poured
into saturated solution of ammonium chloride. The aqueous
layer was extracted with chloroform and the solvent was
removed. The product was puri®ed rapidly, by silica gel
column chromatography to give the oily aldehyde
(102 mg, 77%); nmax/cm21 3605, 2955, 2928, 2874, 2736,
1741, 1459, 1373 and 1049; dH (200 MHz) 0.94 (3H, d, Jˆ
6.2 Hz, CH3CH), 1.21±1.82 (6H, m), 2.48 (2H, m, CH2CHO),
3.71 (2H, m, CH2OH) and 9.79 (1H, t, Jˆ 1.7 Hz, CHO)
which was used immediately for the next reaction.
(R)-3-Methylcyclopentadec-6-en-1-one 17. To a solution
of 16 (30 mg, 0.114 mmol) in dry degassed dichloro-
The Wittig reagent was prepared as usual from methyl(tri-

V. P. Kamat et al. / Tetrahedron 56 (2000) 4397±4403
4403
methane (25 cm3) was added via syringe, a solution of
ruthenium alkylidene catalyst 2 (5 mg, 0.006 mmol) pre-
dissolved in dichloromethane (6 cm3). The resulting purple
solution was heated to 458C for 21 h and then concentrated
under reduced pressure to afford an oily brown residue.
Puri®cation by MPLC [pre-packed silica gel column
2£50 cm, eluent:ethylacetate-n-hexane(1:9)] provided 17
(20.9 mg, 78%); nmax/cm21 3056, 2858, 1705, 1462, 1378,
1265 and 908; dH (500 MHz) 0.91 and 0.94 (total 3H,
ratioˆ3:1, d, Jˆ6.5 Hz, CHCH3), 1.2±1.6 (11H, m), 1.8±
2.6 (12H, m), and 5.32 (2H, m, ole®nic); dC (50 MHz)
20.89, 22.62, 24.70, 26.11, 26.74, 26.79, 27.10, 27.17,
27.95, 29.39, 36.58, 41.43, 50.43, 129.68, 130.33 and
211.90; m/z (EI) 236 (M1, 21%), 221 (5), 125 (8), 109
(19), 95 (33), 81 (54), 55 (87) and 41 (100).
3. Djerassi, C.; Krankoner, G. W. J. Am. Chem. Soc. 1959, 81,
237.
4. For some earlier racemic synthesis see: (a) Nair, M. S. R.;
Mathur, H. H.; Bhattacharyya, S. C. J. Chem. Soc. 1964, 4154.
(b) Ohloff, G.; Becker, J.; Schulte-Elte, K. H. Helv. Chim. Acta
1967, 50, 705. (c) Eschenmoser, A.; Felix, O.; Ohloff, G. Helv.
Chim. Acta 1967, 50, 708. (d) Yoshii, E.; Kimoto, S. Chem. Pharm.
Bull. 1969, 17, 629. (e) Nozaki, H.; Yamamoto, Y.; Mori, T. Can.
J. Chem. 1969, 47, 1107. (f) Mookherjee, B. D.; Patel, R. R.; Ledig,
W. O. J. Org. Chem. 1971, 36, 4124. (g) Backer, R.; Cookson,
R. C.; Winston, J. R. J. Chem. Soc., Chem. Commun. 1974, 515.
(h) Hiyama, T.; Mishima, T.; Kitatani, K.; Nozaki, H. Tetrahedron
Lett. 1974, 3297. (i) Stork, G.; Macdonald, T. L. J. Am. Chem. Soc.
1975, 97, 1264. (j) Takahashi, T.; Machida, K.; Kido, Y.;
Nagashima, K.; Ebata, S.; Doi, T. Chem. Lett. 1997, 1291 and
the references cited therein.
The fractions also provided the cyclic dimer 18 (5 mg, 18%)
as a solid (Found: C, 81.2; H, 12.1. C32H56O2 requires C,
81.3; H, 11.95%); nmax/cm21 2928, 2854, 1713, 1462, 1410,
1370 and 970; dH (200 MHz) 0.89 (6 H, d, Jˆ6.2 Hz,
2£CH3CH), 1.17±1.43 (24H, brs), 1.47±1.65 (6H, m),
1.9±2.1 (8H, m, 2£CH2COCH2), 2.15 (2H, dd, Jˆ14.2
and 5.5 Hz, allylic), 2.3±1.47 (6H, m, allylic) and 5.33±
5.40 (4 H, m, ole®nic).
5. For some earlier synthesis of (R)-(2)-muscone see: (a)
Mamdapur, V. R.; Pal, P. P.; Chakravarti, K. K.; Nayak, U. G.;
Bhattacharyya, S. C. Tetrahedron 1964, 20, 2601. (b) Branca, Q.;
Fishli, A. Helv. Chim. Acta 1977, 60, 925. (c) Abad, A.; Arno, M.;
Pardo, A.; Pedro, J. R.; Seoane, E. Chem. Ind. 1985, 29. (d) Nelson,
K. A.; Mash, E. A. J. Org.Chem. 1986, 51, 2721. (e) Nozawa, H.;
Nohira, H. J. Org. Chem. 1987, 52, 1630. (f) Xie, Z.-F.; Suemune,
H.; Sakai, K. J. Chem. Soc., Chem. Commun. 1988, 1638. (g) Xie,
Z.-F.; Sakai, K. J. Org. Chem. 1990, 55, 820. (h) Tanaka, K.;
Ushino, H.; Kawabata, Y.; Suzuki, H. J. Chem. Soc., Perkin
Trans. 1 1991, 1445. (i) Dowd, P.; Choi, S. C. Tetrahedron
1992, 48, 4773. (j) Tanaka, K.; Matsui, J.; Somemiya, K. Synlett.
1994, 351. (k) Xie, B. H.; Lu, S. J.; Fu, H. X.; Gao, L. Chin. Chem.
Lett. 1997, 8, 477. (l) Alexakis, A; Benhaim, C; Fournioux, X; van
der Heuvel, A.; Leveque, J.-M.; March, S.; Rosset, S. Synlett 1999,
1811.
(R)-3-Methylcyclopentadecan-1-one or muscone 1. 5%
Palladium on charcoal (5 mg) was added to a stirred solution
of 17 (20 mg, 0.08 mmol) in methanol (3 cm3) and stirred
under hydrogen atmosphere at room temperature for 3 h.
The catalyst was ®ltered off and the residue was washed
twice with ethanol. The combined washings and the ®ltrate
was concentrated to provide an oily product, puri®ed by
MPLC [eluent: ethylacetate±n-hexane (1:9)] to give
muscone 1 (20 mg, 98%); [a]Dˆ212.6 (c 0.9 in MeOH)
(lit.5h 212.5 in MeOH); nmax/cm21 2930, 1713, 1533, 1460
and 1371; dH (200 MHz) 0.94 (3H, d, Jˆ6.7 Hz, CH3CH),
1.1±1.5 (20H, brs, CH2), 1.5±1.8 (3H, m, CH2CH2CO and
CH3CH), 2.18 (1H, dd, Jˆ14.8 and 5.2 Hz, COCHHCH)
and 2.35±2.50 (3H, m, CH2COCHH).
6. Porter, N. A.; Lacher, B.; Chang, V. H.-T.; Magnin, D. R. J. Am.
Chem. Soc. 1989, 111, 8309.
7. Ogawa, T.; Fang, C.-L.; Suemune, H.; Sakai, K. J. Chem. Soc.,
Chem. Commun. 1988, 1638.
8. Oppolzer, W.; Radinov, W. J. Am. Chem. Soc. 1993, 115, 1593.
9. (a) Grubbs, R. H.; Miller, J. S.; Fu, G. C. Acc. Chem. Res. 1995,
28, 466. (b) Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. Engl.
1997, 36, 2036. (c) Furstner, A. Top. Catal. 1997, 4, 285.
(d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(e) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
DiMare, M.; O'Regan, J. Am. Chem. Soc. 1990, 112, 3875.
10. (a) Xu, Z.; Johannes, C. W.; Salman, S. S.; Hoveyda, A. H.
J. Am. Chem. Soc. 1996, 118, 10 926. (b) Meng, D.; Su, D. S.;
Balog, A.; Bertinato, P.; Sorensen, E. J.; Denishefsky, S. J.; Zheng,
Y.; Chou, T.; Le, L.; Horwitz, S. B. J. Am. Chem. Soc. 1997, 119,
2733. (c) Meng, D.; Bertinato, D.; Balog, A.; Su, D.; Kamenecka,
T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119,
10 073. (d) Furstner, A.; Muller, Th. J. Org. Chem. 1998, 63, 424.
11. Kirkland, T.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
12. Preliminary communication: Kamat, V. P.; Hagiwara, H.;
Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 1998, 2253.
13. Nakatani, Y.; Kawashima, K. Synthesis 1978, 147.
Acknowledgements
We thank Soda Aromatics Co. Ltd., for the generous supply
of racemic muscone. Thanks are also due to Mr T. Sato and
Mrs H. Ando of the microanalytical laboratory of the Instru-
mental Analysis Center for Chemistry, Tohoku University,
for the mass spectral measurements and for the elemental
analyses.
References
1. (a) Walbaum, H. J. J. Prakt. Chem. 1906, 73, 488. (b) Ruzicka,
L. Helv. Chim. Acta 1926, 9, 715, 1008.
2. Stallberg-Stenhagen, S. Arkiv Kemi 1951, 3, 517.