Practical optical resolution of dl-muscone using tartaric acid derivatives as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2005.03.119

A simple and practical synthesis of (R)-(-)-muscone was achieved by optical resolution of dl-muscone using tartaric acid derivatives. The acetalization of dl-muscone with N,N′-dibenzyl-l-tartaramide in the presence of Sc(OTf)₃ and methyl orthoformate furnished a diastereomeric mixture of acetals, which were readily separated by simple recrystallization. Diastereomerically pure acetal was hydrolyzed to give optically pure muscone and recovered N,N′-dibenzyl-l-tartaramide.

Full text of DOI:10.1016/j.tetlet.2005.03.119

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3457–3460
Practical optical resolution of dl-muscone using tartaric
acid derivatives as a chiral auxiliary
*
Kunihiko Takabe, Masataka Sugiura, Yuya Asumi, Nobuyuki Mase,
Hidemi Yoda and Hiroyasu Shimizu
Department of Molecular Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu 432-8561, Japan
Received 7 February 2005; revised 15 March 2005; accepted 18 March 2005
Available online 6 April 2005
Abstract—A simple and practical synthesis of (R)-(ꢀ)-muscone was achieved by optical resolution of dl-muscone using tartaric acid
0
derivatives. The acetalization of dl-muscone with N,N -dibenzyl-L-tartaramide in the presence of Sc(OTf)
furnished a diastereomeric mixture of acetals, which were readily separated by simple recrystallization. Diastereomerically pure
3
and methyl orthoformate
0
acetal was hydrolyzed to give optically pure muscone and recovered N,N -dibenzyl-L-tartaramide.
2005 Elsevier Ltd. All rights reserved.
ꢀ
(
R)-(ꢀ)-Muscone ((R)-1) is the most important classical
O
source of musk odors for perfumes. Muscone is ex-
tracted from musk pods, which are the secretion from
a gland of the endangered musk deer. Following
O
O
R
R
O
O
RuzickaÕs structural elucidation of natural muscone as
(
R)-1
1
rac-1
+
+
(R)-3-methylcyclopentadecanone in 1926, muscone has
been synthesized by various synthetic approaches in
recovered 2
2
3
racemic form as well as enantiomerically pure form.
O
OH
Although synthetic muscone 1 is commercially available
in its racemic form, the enantiomerically pure synthesis
of muscone is not practical. Therefore, a practical and
simple process for the isolation of optically pure (R)-
muscone is needed. This study focuses on the optical reso-
lution of racemic muscone (rac-1), as the enantiomers
are extremely difficult to separate by chiral chromato-
graphy due to the lack of steric and electrical difference
R
R
(R)-3
OH
2
O
Scheme 1. Optical resolution of dl-muscone (1).
acetal is easily introduced by treating the carbonyl com-
pound with 1,2-diol in the presence of a catalytic
amount of acid. Conversely, acetals are easily removed
by hydrolysis. We chose tartaric acid derivatives 2 as a
chiral auxiliaries because both enantiomers are commer-
cially available, and they are inexpensive, safe, and
stable compounds. First we examined acetalization
of racemic muscone 1 with dialkyl L-tartrate 4 in
4
between S and R isomers. To the best of our knowl-
edge, the optical resolution of racemic muscone 1 using
5
chiral auxiliaries has not been reported. As detailed
in this letter, we investigated the optical resolution of
racemic muscone 1 using tartaric acid derivatives 2 as
a chiral auxiliaries to afford optically pure muscone
(
R)-1 (Scheme 1).
the presence of scandium trifluoromethanesulfonate
6
One of the most useful chiral auxiliaries used to func-
tionalize a carbonyl group is the cyclic acetal. The cyclic
(
Sc(OTf) ). The results are shown in Table 1. Dimethyl
3
L-tartrate (4a) and diethyl L-tartrate (4b) afforded the
corresponding cyclic acetals 5a, 5b in good yield, but
these acetals did not crystallize (entries 1 and 2). Crystal-
linity was remarkably changed by using dibenzyl L-tar-
trate (4c) (entry 3). Acetal 5c was obtained in 47%
yield with 23% de, which formed a colorless solid after
Keywords: (R)-(ꢀ)-Muscone; Optical resolution; Chiral auxiliary.
*
Corresponding author. Tel./fax: +81 53 478 1148; e-mail: tcktaka@
ipc.shizuoka.ac.jp
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.119

3458
K. Takabe et al. / Tetrahedron Letters 46 (2005) 3457–3460
a
Table 1. Acetalization of racemic muscone (rac-1) with chiral dialkyl L-tartrate 4
O
O
O
RO
OR
O
OH
catalyst
additive
O
O
OR
+
RO
solvent
OH
O
4
rac-1
5
b
c
Entry
Diol
R
Catalyst
Additive
Solvent
Temp
ꢁC)
Time
(h)
Yield
(%)
de
(%)
Product
Crystallinity
(
1
2
3
4
5
6
7
8
9
4a
4b
4c
4c
4c
4c
4c
4c
4c
4d
4e
4f
Me
Et
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
HC(OMe)
HC(OMe)
HC(OMe)
HC(OMe)
HC(OMe)
HC(OMe)
HC(OMe)
—
3
3
3
3
3
3
3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Benzene
Benzene
MeCN
MeCN
MeCN
MeCN
rt
7
21
26
48
26
26
26
37
61
26
26
2
75
82
47
64
92
64
30
24
23
57
34
29
16
7
8
5a
5b
5c
5c
5c
5c
5c
5c
5c
5d
5e
5f
X
X
O
O
D
O
O
O
O
X
X
X
X
3
3
3
3
rt
PhCH
PhCH
PhCH
PhCH
PhCH
PhCH
2
2
2
2
2
2
2
–
–
–
–
–
–
–
0
23
11
2
0
rt
d
McSc(OTf)
3
rt
32
26
39
32
14
21
—
—
Yb(OTf)
3
0
p-TsOH
e
CSA
Reflux
Reflux
PhCH
—
i
4-Pr C
10
11
12
13
6
H
4
CH
CH
CH
CH
2
–
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
HC(OMe)
HC(OMe)
HC(OMe)
HC(OMe)
3
3
3
3
0
t
4-Bu C
6
H
4
2
–
3
3
3
0
2-MeOC
4-NO
6
H
4
2
–
rt
rt
4g
2
C
6
H
4
2
–
4
5g
a
b
c
Reactions were carried out using dialkyl L-tartrate (2 equiv), acid catalyst (5 mol %) and additive (2 equiv).
Isolated yield.
Determined by chiral HPLC analysis using CHIRALCEL OD.
d
e
mcSc(OTf)
3
= microencapsulated scandium trifluoromethanesulfonate.
CSA = (1S)-(+)-10-camphorsulfonic acid.
usual workup. We found that acetal 5c with over 10% de
was readily recrystallized to separate the diastereomers
dard conditions to give the enantiomerically pure natu-
ral muscone (R)-1 in quantitative yield. Unfortunately,
hydrolysis of dibenzyl L-tartrate (4c) also occurred,
resulting in contamination with a small amount of
inseparable dibenzyl ether (6).
(
entries 3–5, vide infra). Microencapsulated Sc(OTf)3
and ytterbium trifluoromethanesulfonate (Yb(OTf)3)
also catalyzed the acetalization (entries 6 and 7). On
the other hand, a Brønsted acid catalyst such as p-tolu-
enesulfonic acid (p-TsOH) and (1S)-(+)-10-camphor-
sulfonic acid (CSA) gave the acetal 5c in low yield
along with dibenzyl ether (6), because hydrolysis of di-
benzyl L-tartrate (4c) occurred during the actalyzation
A stable chiral auxiliary was needed that could be recov-
ered intact and afford muscone in high optical purity.
Therefore, we examined acetalization of rac-1 using
0
7
N,N -dibenzyl-L-tartaramide 7 (Table 2). Acetalization
in the presence of Sc(OTf) proceeded smoothly to give
(
entries 8 and 9). Substituents on the benzene ring, such
3
as 4-isopropyl, 4-tert-butyl, 2-methoxy, and 4-nitro
groups, did not show good results; oily products 5d–g
were obtained (entries 10–13).
the acetal 8 in excellent yield after 2 h stirring under
8
,9
reflux (entry 1). The acetal 8 with even 3% de was
easily recrystallized. Microencapsulated Sc(OTf) and
3
Yb(OTf) catalyzed the reaction in good yield (entries
3
Several recrystallizations of the acetal 5c (11% de) from
hexane afforded diastereomerically pure acetal (R)-5c in
2 and 3). p-TsOH acid and CSA also gave the acetal 8
0
in good yield without hydrolysis of N,N -dibenzyl-L-tar-
taramide 7 (entries 4 and 5).
7
2
% yield based on the racemic muscone rac-1 (Scheme
). Deacetalization of (R)-5c was performed under stan-
The first recrystallization of the acetal 8 (3% de) from
methanol furnished diastereomerically pure acetal (R)-
8 in 15% yield, and the second recrystallization also gave
O
O
(
R)-8 in 10% yield. The total yield of product based on
BnO
OBn
O
O
the racemic muscone (rac-1) was 25% (Scheme 3). Purity
of (R)-1 as well as recovery of the chiral auxiliary was
dramatically changed in the case of N,N -dibenzyl-L-tar-
taramide (7) compared to that of dibenzyl L-tartrate (4c)
(
R)-1 (>95%)
+
5
c
a
b
0
(
11% de)
Bn2O (6)
(
Scheme 2 vs 3). Deacetalization of (R)-8 gave the enan-
tiomerically pure natural muscone (R)-1 in 93% yield
(
R)-5c
(
7% yield based on rac-1, >98% de)
1
0
without loss of optical purity. No formation of dibenz-
0
Scheme 2. Reagents and conditions: (a) 3 times recrystallization from
hexane; (b) p-TsOH, 1,4-dioxane/H
O = 4/1, 80 ꢁC, 4 h.
yl ether (6) was observed with N,N -dibenzyl-L-tartar-
amide (7) being recovered in 83% yield. The isolation
2

K. Takabe et al. / Tetrahedron Letters 46 (2005) 3457–3460
3459
0
a
Table 2. Acetalization of racemic muscone (rac-1) with chiral N,N -dibenzyl-L-tartaramide 7
O
O
rac-1
+
BnHN
NHBn
catalyst
HC(OMe)3
O
O
O
OH
NHBn
MeCN
reflux
BnHN
OH
O
7
8
b
Yield (%)
c
De (%)
Entry
Catalyst
Time (h)
Crystallinity
1
2
3
4
5
Sc(OTf)
mcSc(OTf)
3
2
24
17
5
94
71
50
49
70
3
4
O
O
O
O
O
d
3
Yb(OTf)
p-TsOH
3
0.4
3
e
CSA
8
13
a
b
c
0
Reactions were carried out using N,N -dibenzyl-L-tartaramide (0.9 equiv), acid catalyst (5 mol %) and HC(OMe)
3
(1 equiv).
Isolated yield.
Determined by chiral HPLC analysis using CHIRALPAK AD.
d
e
3
mcSc(OTf) = microencapsulated scandium trifluoromethanesulfonate.
CSA = (1S)-(+)-10-camphorsulfonic acid.
O
O
3. Recent studies for the syntheis of chiral (R)-muscone. (a)
Scafato, P.; Labano, S.; Cunsolo, G.; Rosini, C. Tetrahe-
dron: Asymmetry 2003, 14(24), 3873–3877; (b) Fraser, P.
K.; Woodward, S. Chem. Eur. J. 2003, 9(3), 776–783; (c)
Yamamoto, T.; Ogura, M.; Kanisawa, T. Tetrahedron
2002, 58(45), 9209–9212; (d) Tanabe, Y.; Matsumoto, N.;
Higashi, T.; Misaki, T.; Itoh, T.; Yamamoto, M.; Mitarai,
K.; Nishii, Y. Tetrahedron 2002, 58(41), 8269–8280; (e)
Fujimoto, S.; Yoshikawa, K.; Itoh, M.; Kitahara, T.
Biosci. Biotechnol. Biochem. 2002, 66(6), 1389–1392; (f)
Choi, Y. H.; Choi, J. Y.; Yang, H. Y.; Kim, Y. H.
Tetrahedron: Asymmetry 2002, 13(8), 801–804; (g) Louie,
J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
BnHN
NHBn
O
(
O
(
R)-1
8
a
(93%, >98% ee)
+
b
(
3% de)
7
(83%)
R)-8
(
25% yield yield based on rac-1, >98% de)
Scheme 3. Reagents and conditions: (a) recrystallized twice from
MeOH; (b) p-TsOH, 1,4-dioxane/H
O = 8/1, 80 ꢁC, 3 h.
2
2
001, 123(45), 11312–11313; (h) Kamat, V. P.; Hagiwara,
H.; Katsumi, T.; Hoshi, T.; Suzuki, T.; Ando, M.
Tetrahedron 2000, 56(26), 4397–4403, see also references
cited therein.
of (S)-(+)-muscone was achieved in 19% yield based on
racemic muscone by the same procedure as above using
N,N -dibenzyl-D-tartaramide.
0
4. Yuki, H.; Okamoto, Y.; Okamoto, I. J. Am. Chem. Soc.
1
980, 102(20), 6356–6358.
In summary, tartaric acid derivatives, especially the
0
5. Previously, we reported that enzymatic resolution of
racemic muscone derivatives such as alcohol and oxime
was investigated. Chiral (R)-muscone with 99% ee was
obtained via lipase AK-catalyzed acetylation of the
corresponding hydroxy derivative. Takabe, K.; Aoyama,
T.; Kawanishi, Y.; Yamada, T.; Yoda, H. In 39th TEAC;
Chemical Society of Japan: Utsunomiya, 1995; Vol. 1III-
N,N -dibenzyl-L-tartaramide derivative, have proven to
be good chiral auxiliaries for optical resolution of a
racemic muscone. This method provides a practical
access to optically pure (R)-muscone, which is one of
the most important fragrance compounds.
1
1, pp 177–178; Lately, Matsumura et al. reported
enzymatic resolution of racemic muscone derivatives in a
similar way to ours. See, Matsumura, Y.; Fukawa, H.;
Terao, Y. Chem. Pharm. Bull. 1998, 46(9), 1484–1485.
6. Ishihara, K.; Karumi, Y.; Kubota, M.; Yamamoto, H.
Synlett 1996 (9), 839–841.
References and notes
1
2
. Ruzicka, L. Helv. Chim. Acta 1926, 9, 715–729.
. Recent studies for the syntheis of racemic muscone. (a)
Ruedi, G.; Hansen, H.-J. Tetrahedron Lett. 2004, 45(26),
143–5145; (b) Nagel, M.; Hansen, H.-J.; Frater, G.
Synlett 2002 (2), 280–284; (c) Nicolaou, K. C.; Pastor, J.;
Winssinger, N.; Murphy, F. J. Am. Chem. Soc. 1998,
20(20), 5132–5133; (d) Takahashi, T.; Machida, K.;
Kido, Y.; Nagashima, K.; Ebata, S.; Doi, T. Chem. Lett.
997 (12), 1291–1292; (e) Fujita, Y.; Fukuzumi, S.; Otera,
J. Tetrahedron Lett. 1997, 38(12), 2121–2124; (f) Taka-
hashi, T.; Yamada, H.; Haino, T.; Kido, Y.; Fukazawa, Y.
Tetrahedron Lett. 1992, 33(49), 7561–7564; (g) Dowd, P.;
Choi, S.-C. Tetrahedron Lett. 1991, 32(5), 565–568, see
also references cited therein.
0
7. N,N -Dibenzyl-L-tartaramide 7 was the most effective
chiral auxiliary, while other substituted tartaramide deriva-
5
0
0
tives, such as N,N -dipyrrolidinyl- and N,N -di-(4-meth-
oxyphenyl)methyl-L-tartaramide, gave an inseparable
diastereomeric mixture.
1
8. Typical procedure: To a solution of racemic muscone rac-1
0
1
(1.0 mmol) and N,N -dialkyl-L-tartaramide 7 (0.9 mmol) in
MeCN (2.0 mL) were added trimethyl orthoformate
(1.0 mmol) and Sc(OTf) (0.05 mmol) at indicated temper-
3
ature. The reaction mixture was stirred for the indicated
time, then cooled to room temperature. After evaporation
of MeCN, the solid was filtered and washed with ether

3
460
K. Takabe et al. / Tetrahedron Letters 46 (2005) 3457–3460
10 mL). The filtrate was concentrated to give a crude oil, Ph), 4.60 (d, J = 6.9 Hz, 1H, –CHOC–), 4.67 (d,
2 · –CH
(
2
which was purified by column chromatography (silica gel,
hexane/ethyl acetate as an eluent) to give a mixture of
diastereomers 8 in excellent yield. These diastereomers
were separated by recrystallization from MeOH to give
J = 6.9 Hz, 1H, –CHOC–), 7.10–7.44 (m, 12H, 2 · –Ph,
13
–NH); C NMR (75 MHz, CDCl ) d 169.73, 169.67,
3
137.72, 137.66, 128.83, 127.81, 127.70, 116.87, 77.63,
77.14, 43.72, 43.31, 43.23, 35.85, 35.71, 27.59, 26.98,
26.87, 26.52, 26.45, 26.40, 26.17, 26.02, 25.89, 24.74, 22.23,
20.60; IR (KBr) 3363.6, 2927.7, 2856.4, 1685.7, 1672.2,
1649.0, 1525.6, 1456.2, 1109.0, 698.2; MS (EI) m/z 548
(M , 0.4), 379 (2), 310 (6), 176 (36), 106 (33), 91 (100);
Anal. Calcd for C H N O : C, 74.42; H, 8.82; N, 5.10.
Found: C, 74.36; H, 9.13; N, 4.91.
(
R)-8 as a colorless solid with >99% de determined by
chiral HPLC using CHIRALPAK AD. The acetal 8 would
be used for the enantiopurity determination of muscone 1,
as the acetalization of 1 quantitatively proceeded.
+
1
8
9
. Acetal (R)-8: R = 0.37 (hexane/AcOEt = 70/30); ½aꢁ
f
D
34 48
2
4
1
ꢀ
9.71 (c 0.780, CHCl
3
); mp 136–137 ꢁC; H NMR
),
.97–1.47 (m, 23H), 1.47–1.90 (m, 4H), 4.37–4.59 (m, 4H,
2
5
25
(
0
CDCl
3
, 300 MHz) d 0.87 (d, J = 6.5 Hz, 3H, –CH
3
10. (R)-1: ½aꢁ ꢀ12.3 (c 1.0, MeOH), lit. ½aꢁD ꢀ12.3 (c 1.2,
D
MeOH). See Ref. 3c.