A highly efficient total synthesis of (R)-(+)-muscopyridine by intramolecular [4+2] cycloaddition of bisketene

Article abstract of DOI:10.1016/j.tetlet.2007.12.112

A highly efficient total synthesis of (R)-(+)-muscopyridine 1 has been accomplished in 12 steps with 40% overall yield. A highlight of the synthesis is the intramolecular [4+2] cycloaddition of bisketene to afford a bridged pyrone and ring transformation

Full text of DOI:10.1016/j.tetlet.2007.12.112

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Tetrahedron Letters 49 (2008) 1510–1513
A highly efficient total synthesis of (R)-(+)-muscopyridine
by intramolecular [4+2] cycloaddition of bisketene
Kie Suwa *, Yasuko Morie, Yumiko Suzuki, Kiyoshi Ikeda, Masayuki Sato *
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi 422-8526, Japan
Received 30 November 2007; revised 17 December 2007; accepted 20 December 2007
Available online 25 December 2007
Abstract
A highly efficient total synthesis of (R)-(+)-muscopyridine 1 has been accomplished in 12 steps with 40% overall yield. A highlight of
the synthesis is the intramolecular [4+2] cycloaddition of bisketene to afford a bridged pyrone and ring transformation of the pyrone to
afford pyridine derivatives.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Intramolecular cycloaddition; Bisketene; Ring transformation; Muscopyridine
The design and synthesis of cyclophanes, macrocycles
containing aromatic or heteroaromatic groups, is a fasci-
nating branch of organic chemistry.1,2 Recently, we have
developed a convenient method for synthesizing cyclo-
phanes by the intramolecular [4+2] cycloaddition of
bis(acylketene), which is generated from bis(4,6-dioxo-
1,3-dioxane) in refluxing chlorobenzene.3 Furthermore,
we reported the efficient and unique synthetic method of
meta-pyridinophanes using this ketene cycloaddition metho-
dology (Scheme 1).4
The meta-pyridinophane derivative (R)-(+)-muscopyr-
idine 1 is one of the odoriferous constituents of natural
musk obtained from the male musk deer Moschus mos-
chiferus (Fig. 1). Its empirical formula was determined by
O
O
OH
O
O
O
O
O
O
O
O
O
O
4+2
O
O
O
(CH2)n
Me
Me
Me
Me
O
O
PhCl
reflux
(CH2)n
(CH2)n
O
O
EtOH
or
conc. HCl
RNH2
O
N
R
(CH2)n
(CH2)n
Scheme 1. Ketene cycloaddition methodology for synthesizing cyclophanes.
*
Corresponding authors. Tel.: +81 54 264 5750; fax: +81 54 264 5755 (K.S.); tel./fax: +81 54 264 5754 (M.S.).
E-mail addresses: d5201@u-shizuoka-ken.ac.jp (K. Suwa), msato@mail.u-shizuoka-ken.ac.jp (M. Sato).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.112

K. Suwa et al. / Tetrahedron Letters 49 (2008) 1510–1513
1511
N
Me
Fig. 1. (R)-(+)-muscopyridine 1.
Ruzicka and Prelog5 in 1946. Despite its rather simple
structure, 1 is a fascinating and repeated target for a total
synthesis.6–8 In this study, we report an application of the
ketene cycloaddition methodology to the highly efficient
synthesis of compound 1.
We envisaged the application of the ketene methodology
to the synthesis of muscopyridine 1, as illustrated in
Scheme 2. The pyridine ring of 1 would be accessible by
the ring transformation of para-cyclophane 5, which we
plan to obtain from bis(4,6-dioxo-1,3-dioxane) 4 through
an intramolecular cycloaddition of bis(acylketene).3 4 can
be derived from the chiral dicarboxylic acid 3, which can
be obtained from benzyl (R)-citronellate 2. Compound 2
is readily synthesized from the commercially available
(R)-(+)-citronellic acid.9,10
afforded aldehyde 8. The Wittig reaction of 8 with phos-
phonium salt 1011 provided the olefinic acid 9 in 76% yield,
which was hydrogenated to afford 3 in 99% yield.
para-Cyclophanes 5a,b were prepared from 3 in three
steps.3 Intermediate 4, obtained by condensation of dicar-
boxylic acid dichloride derived from 3 with two molecules
of Meldrum’s acid, was heated in refluxing chlorobenzene
to generate bisketene 10, which in situ underwent intra-
molecular cycloaddition to afford 5a,b in 96% yield as a
1:1 mixture of isomers (Scheme 4).
It has been reported that dehydroacetic acid is trans-
formed into 2,6-dimethyl-4-pyrone on heating with concd
HCl,12,13 and the pyrone ring is converted into a pyridine
ring by heating with ammonia.12,14 We have applied this
ring transformation to the synthesis of meta-pyridinophane
from para-cyclophane.4 It was anticipated that both the iso-
mers of para-cyclophanes 5a,b would be transformed into
4-pyrone 11. Therefore, 5a,b were subjected to the transfor-
mation as a mixture. On heating with concd HCl, 5a,b were
transformed into 11 in 89% yield. A solution of 11 in
The synthesis of 3 was commenced with the epoxidation
of the olefinic benzyl ester 2 with m-CPBA to provide epox-
ide 6 in 98% yield as a mixture of diastereomers (Scheme 3).
The ring opening reaction of 6 to yield diol 7, followed by
the oxidative cleavage of 7 with NaIO4, quantitatively
HO
O
O
O
O
O
O
O
Me
(CH2)8
O
O
O
O
N
Me
O
O
Me
Me
Me
Me
Me
4
5
1
Me
Me
Me
CO2Bn
CO2H
Me
HO2C(CH2)8
2
3
Scheme 2. Retrosynthesis of muscopyridine.
Me
Me
O
Me
Me
Me
Me
Me
HO
c
b
a
d
CO2Bn
Me
CO2Bn
CO2Bn
Me
Me
OH
2
6
7
Me
Me
e
CO2H
CO2Bn
CO2Bn
HO2C(CH2)8
HO2C
OHC
8
9
3
Scheme 3. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 °C, 1 h then rt, 10 h, 98%; (b) H2SO4, Et2O/H2O, quant.; (c) NaIO4, Et2O/H2O, rt, 1 h,
quant.; (d) BrPPh3(CH2)5CO2H (10), t-BuOK, THF, 0 °C, 1 h then rt, 30 h, 76%; (e) H2, Pd(OH)2, AcOEt, rt, 12 h, 99%.

1512
K. Suwa et al. / Tetrahedron Letters 49 (2008) 1510–1513
O
O
O
O
Me
O
O
O
O
Me
c
O
(CH2)8
O
a, b
CO2H
Me
Me
Me
Me
HO2C(CH2)8
3
4
O
O
OH
O
O
O
4+2
R2
O
O
Me
O
O
O
O
Me
R1
5a: R1 = H, R2 = Me
5b: R1 = Me, R2 = H
(5a:5b = 1:1)
10
10
Scheme 4. Reagents and conditions: (a) SOCl2, reflux, 30 min; (b) Meldrum’s acid, DMAP, CH2Cl2, 0 °C, 2 h then rt, 1 h; (c) PhCl, reflux, 20 h (three
steps, 84%).
Cl
N
O
O
O
OH
O
O
O
b
a
d
c
R2
N
H
N
Me
Me
Me
Me
R1
5a: R1 = H, R2 = Me
5b: R1 = Me, R2 = H
11
12
13
1
Scheme 5. Reagents and conditions: (a) concd HCl, reflux, 12 h, 89%; (b) NH3, EtOH, sealed tube, 140 °C, 3 d, 87%; (c) POCl3, reflux, 1 h, 93%; (d)
H2/Pd–C, AcONa, rt, 12 h, 89%.
2. Vo¨gtle, F. Cyclophane Chemistry; Wiley & Sons: New York, 1993.
3. Sato, M.; Uehara, F.; Sato, K.; Yamaguchi, M.; Kabuto, C. J. Am.
ethanol saturated with ammonia at 0 °C was heated in a
stainless sealed tube at 140 °C for 3 days to afford pyridine
Chem. Soc. 1999, 121, 8270–8276.
12 in 87% yield. The chlorination of 12 afforded chloropyri-
4. Sato, M.; Oda, T.; Iwamoto, K.-I.; Murakami, E. Tetrahedron 2003,
dine 13 in 93% yield. The subsequent hydrogenation of 13
59, 2651–2655.
afforded the target muscopyridine 1 in 89% yield (Scheme
5). Since the starting (R)-citronellic acid is 98% ee and inter-
mediate dicarboxylic acid 3 was purified by recrystalliza-
tion, this compound would be >98% ee. The synthetic
muscopyridine15 exhibited properties identical to those
reported previously.5,6a,7b The total number of steps leading
to 1 was 12 with 40% overall yield, while the synthesis by
5. Schinz, H.; Ruzicka, L.; Geyer, U.; Prelog, V. Helv. Chim. Acta 1946,
29, 1524–1528.
6. Syntheses of rac-1 (a) Biemann, K.; Buchi, G.; Walker, B. H. J. Am.
¨
Chem. Soc. 1957, 79, 5558–5564; (b) Tamao, K.; Kodama, S.;
Nakatsuka, T.; Kiso, Y.; Kumada, M. J. Am. Chem. Soc. 1975, 97,
4405–4406; (c) Sakane, S.; Matsumura, Y.; Yamamura, Y.; Ishida,
Y.; Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 672–
674; (d) Saimoto, H.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1980,
21, 3897–3898; (e) Ohloff, G. Riechstoffe und Geruchssinn: Die
Molekulare Welt der Du¨fte; Springer: Berlin, 1990; (f) Hadj-Abo,
F.; Hesse, M. Helv. Chim. Acta 1992, 75, 1834–1839.
Hagiwara7b and Furstner7c resulted in overall yields of 7%
¨
and 19% in 12 and 11 steps, respectively.
In summary, our research involves an efficient synthetic
route to (R)-(+)-muscopyridine from the readily available
benzyl (R)-citronellate 2. Our synthesis has been completed
in 12 steps with 40% overall yield, which is the best yield
ever reported in syntheses of (R)-(+)-muscopyridine. The
present synthesis demonstrates that this ketene cycloaddi-
tion methodology followed by ring transformations is effi-
cient and practical for constructing 2,6-bridged pyridines.
7. Syntheses of (R)-(+)-1 (a) Utimoto, K.; Kato, S.; Tanaka, M.;
Hoshino, Y.; Fujikura, S.; Nozaki, H. Heterocycles 1982, 18, 149–152;
(b) Hagiwara, H.; Katsumi, T.; Kamat, V. P.; Hoshi, T.; Suzuki, T.;
Ando, M. J. Org. Chem. 2000, 65, 7231–7234; (c) Fu¨rstner, A.;
Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308–311.
´
8. Syntheses of muscopyridine isomers (a) Georgi, U. K.; Retey, J.
Chem. Commun. 1971, 32–33; (b) Balaban, A. T.; Gavat, M.;
Nenitzescu, C. D. Tetrahedron 1962, 18, 1079–1081; (c) Dubs, P.;
Stussi, R. J. Chem. Soc., Chem. Commun. 1976, 1021.
¨
9. Yang, D.; Yang, M.; Zhu, N.-Y. Org. Lett. 2003, 5, 3749–3752.
10. Synthesis of 2: A mixture of (R)-citronellic acid (4.93 g, 29.0 mmol),
potassium carbonate (8.00 g, 58.0 mmol) and benzyl bromide
(4.50 ml, 37.7 mmol) in acetone (100 ml) was stirred for 12 h at room
temperature. The mixture was quenched with water and extracted
with ethyl acetate. The organic layer was washed with water and
brine, dried over anhydrous MgSO4, and concentrated. The residue
References and notes
1. Breitenbach, J.; Boosfeld, J.; Vo¨gtle, F. In Comprehensive Supra-
molecular Chemistry; Vo¨gtle, F., Ed.; Pergamon: New York, 1996;
Vol. 2, p 29.

K. Suwa et al. / Tetrahedron Letters 49 (2008) 1510–1513
1513
was purified by silica gel column chromatography to afford 2 (7.54 g,
quant.) as a colorless oil.
11. Maryanoff, B. E.; Duhl-Emswiler, B. A. Tetrahedron Lett. 1981, 22,
4185–4188.
12. Barton, D.; Ollis, D. W. In Comprehensive Organic Chemistry;
Staunton, J., Ed.; Pergamon: New York, 1979; Vol. 4, p 629.
13. (a) Arndt, F. Organic Synthesis. In Allen, C. F. H., Ed.; Wiley: New
York, 1940; p 26; (b) King, L. C.; Ozog, F. J.; Moffat, J. J. Am. Chem.
Soc. 1951, 73, 300–302; (c) Marcus, E.; Stephen, F. J.; Chan, K. J. J.
Heterocycl. Chem. 1969, 6, 13–22.
14. (a) Iguchi, S.; Inoue, A.; Kurahashi, C. Chem. Pharm. Bull. 1962, 11,
385–390; (b) Iguchi, S.; Inoue, A. Chem. Pharm. Bull. 1962, 11, 390–
395.
23
23
15. Analytical data of 1: ½aꢀD +13.1 (c 0.50, CHCl3), lit.,5 ½aꢀD +17.4
25
23
(c 1.92, CHCl3), lit.,6a ½aꢀD +13.3 (c 0.90, CHCl3), lit.,7b ½aꢀD +12.5 (c
1.80, CHCl3), 1H NMR (500 MHz, CDCl3) d: 1.06 (d, 3H,
J = 6.8 Hz), 0.86–1.34 (m, 13H), 1.79–1.83 (m, 2H), 2.02–2.07 (m,
1H), 2.54 (dd, 1H, J = 13.0, 10.1 Hz), 2.82–2.89 (m, 2H), 6.96 (dd,
2H, J = 7.5, 2.0 Hz), 7.50 (t, 1H, J = 7.5 Hz).