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.