8686
I. O. Roberts et al. / Tetrahedron Letters 45 (2004) 8685–8686
resulted in a 92% de. Chromatography after each fol-
lowing step improved the de further. Reduction of 8a
to the trans-alcohol 7a, then bromination, formation
of the nitrile 9a and hydrolysis gave [(1S,2R)-2-hexyl-
cycloprop-1-yl]-acetic acid (10a).
tively. Cepaciamide, a derivative of the acid 14,14 the
corresponding hydroxy acid chain of plakoside A,15
and a derivative of acid 15 from the slime mould
Pyhysarum polycephalum,16 all have an S,R-configura-
tion of fatty acid and alkyl chains, respectively (Scheme
3). A number of other natural cis-cyclopropane fatty
acids are of unknown absolute stereochemistry.17
Cascarillic acid was obtained from cascarilla oil,9 by
base extraction followed by chromatography; the spect-
roscopic properties of the extracted material were in
agreement with those already published.1b The 1H
NMR spectra reported and obtained in this work for
natural cascarillic acid show the presence of a small
amount of what appears to be a cis-disubstituted cyclo-
propane. The corresponding methyl ester showed one
major peak on GCMS, together with a minor compo-
nent (ca. 5%) at a slightly longer retention time show-
ing an essentially identical MS to that of the major
isomer. The spectroscopic properties of 10a synthe-
sised above (1H, 13C NMR, IR, MS) and the GCMS
References and notes
1. (a) Motl, O.; Amin, M.; Sedmera, P. Phytochemistry 1972,
11, 407; (b) Wilson, S. R.; Prodan, K. A. Tetrahedron Lett.
1976, 47, 4231; (c) Hiyama, T.; Yamamoto, H.; Nishio,
K.; Kitatani, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1979,
52, 3632–3637.
2. Coxon, G. D.; Al Dulayymi, J. R.; Baird, M. S.; Knobl,
S.; Roberts, E.; Minnikin, D. E. Tetrahedron: Asymmetry
2003, 14, 1211–1222.
3. Stuart, L. J.; Buist, P. H. Tetrahedron: Asymmetry 2004,
15, 401–403.
4. Sitachitta, N.; Gerwick, W. H. J. Nat. Prod. 1998, 61, 681–
684; He, R.; Deng, M.-Z. Org. Lett. 2002, 4, 2759–2762.
5. Al Dulayymi, J. R.; Baird, M. S.; Jones, K. Tetrahedron
2004, 60, 341–345.
were identical to those of the naturally obtained mate-
20
D
rial. Furthermore, the ½aꢁ values for the natural and
synthetic samples were ꢀ8.9 and ꢀ10.9, respectively,
20
while synthetic methyl cascarillate was found to have
an ½aꢁ of ꢀ9.8, which compares favourably with the lit-
D
erature value of ꢀ10.5.1 Taking into account the slightly
lower purity of the natural sample of free acid than the
synthetic sample, the above results represent proof that
the two molecules are of identical stereochemistry.
6. See, for example, Watanabe, M.; Aoyagi, Y.; Mitome, H.;
Fujita, T.; Naoki, H.; Ridell, M.; Minnikin, D. E.
Microbiology 2002, 148, 1881; Watanbe, M.; Aoyagi, Y.;
Ridell, M.; Minnikin, D. E. Microbiology 2001, 147, 1825.
20
7. This showed ½aꢁD ꢀ21.3, c = 1.87 in CHCl3; lit. ꢀ18.9.2
8. Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron 1991, 47,
1215–1230.
cis-Cascarillic acid (10) was obtained in three steps from
[(1S,2R)-2-hexylcyclopropyl]methanol 7, bromination,
formation of the nitrile and hydrolysis to the acid. Its
1H NMR spectrum, GC retention time and MS were
identical to those of the minor component in the natural
sample.
9. We thank Lionel Hitchen (Essential Oils) Ltd for supply-
ing a sample of the natural oil.
10. Nagle, D. G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31,
2995–2998; Nagle, D. G.; Gerwick, W. H. J. Org. Chem.
1994, 59, 7227–7237; Miyaoka, H.; Shigemoto, T.;
Yamada, Y. Tetrahedron Lett. 1996, 37, 7407–7408; Baba,
Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.;
Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81–88.
11. Critcher, D. J.; Connolly, S.; Wills, M. J. Chem. Soc.,
Chem. Commun. 1995, 139–140; Critcher, D. J.; Connolly,
S.; Wills, M. Tetrahedron Lett. 1995, 3763–3766; Critcher,
D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997, 62,
6638–6657.
The stereochemistry of natural cascarillic acid matches
that of grenadamide (4) (though the Cahn–Prelog–
Ingold descriptors are different). The absolute stereo-
chemistries of the cyclopropane reported for the acid
and alkyl derived side chains of halicholactones such
as 11,11 and solande-lactones such as 12,12 are also the
same.
12. Seo, Y.; Cho, K. I.; Rho, J.-R.; Shin, J. Tetrahedron 1996,
52, 10583–10596.
13. (a) Buist, P. H.; Pon, R. A. J. Org. Chem. 1990, 55, 6240–
6241; (b) Coxon, G. D.; Knobl, S.; Roberts, E.; Baird, M.
S.; Al Dulayymi, J. R.; Besra, G. S.; Brennan, P. J.;
Minnikin, D. E. Tetrahedron Lett. 1999, 40, 6689–6692.
14. Jiao, Y.; Yoshihara, T.; Ishikuri, S.; Uchino, H.; Ichihara,
A. Tetrahedron Lett. 1996, 37, 1039–1042.
Other natural derivatives such as costanolactone E (13)
are reported to have the opposite absolute stereochemis-
tries of the two chains.10 The related cis-cyclopropane
fatty acids, lactobacillic acid2,13 and dihydrosterculic
acid3 are reported to be 11R,12S, and 9S,10R, respec-
15. Mori, K.; Tashiro, T.; Akasaka, K.; Ohrui, H.; Fat-
torusso, E. Tetrahedron Lett. 2002, 43, 3719–3722.
16. Kobayashi, S.; Tokunoh, R.; Shibasaki, M.; Shinigawa,
R.; Murakami-Murofushi, K. Tetrahedron Lett. 1993, 34,
4047–4050; Liliom, K.; Bittman, R.; Swords, B.; Tibor, G.
Mol. Pharmacol. 1996, 50, 616–623.
17. See, for example, Jie, L. K. J. Chem. Soc., Chem. Commun.
1977, 78; Grondin, I.; Smadja, J.; Farines, M.; Soulier, J.
Ol. Corps Gras Lipides 1997, 4, 459–463; Fenical, W.;
Howard, S. L.; Paul, V. J.; Stallard, M. O.; Sun, H. H.
Pure Appl. Chem. 1979, 51, 1865–1874; Shin, B. A.; Kim,
Y. R.; Lee, I.-S.; Sung, C. K.; Hong, J.; Sim, C. J.; Im, K.
S.; Jung, J. H. J. Nat. Prod. 1999, 62, 1554–1557.
OH
OH
O
R
R
OH
S
R
R
O
CH3(CH2)4
H
12
14
(CH2)4CH3
O
O
11 OH
O
H
R
HO
R
CO2H
OH
CH3(CH2)5
S
O
H
13
OH
(CH2)4CH3
O
CH3(CH2)5
(CH2)7
OH
15
Scheme 3.