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C. D. Donner / Tetrahedron Letters 48 (2007) 8888–8890
Final conversion of 13 to the natural product 1 required
epimerization at C1 and a series of oxidations. Firstly,
the naphthol was oxidized to quinone 14 using a 2-step
process involving aromatic bromination using N-bro-
mosuccinimide followed by oxidation of the resultant
p-bromonaphthol with ceric ammonium nitrate
(CAN). Demethylation of 14 with aluminium chloride9
proceeded efficiently (94%) and selectively to give 15.
In contrast, the use of boron tribromide led to partial
epimerization at C1, along with demethylation, to give
a mixture of cis/trans-pyrans 15 and 18. The primary
alcohol in cis-pyran 15 was converted to a carboxylic
acid using a conventional 2-step procedure involving,
firstly, use of TEMPO/PhI(OAc)2 to form the intermedi-
ate aldehyde followed by further oxidation with NaClO2
to give the required acid 16. Cyclization of carboxylic
acids such as 16 to their corresponding c-lactones has
been reported to proceed efficiently under mild condi-
tions in the presence of atmospheric oxygen via an inter-
mediate quinone-methide.16,17 However, this method
was found to form, along with the desired c-lactone
17, product 19 resulting from further oxidation. Treat-
ment of the crude mixture (ꢂ1:1) of 17 and 19 with
BF3 Æ Et2O/Et3SiH delivered 5-epi-kalafungin 17 as the
exclusive product in 65% yield over the two steps.
acknowledged. Professor Carl Schiesser, The University
of Melbourne, is acknowledged for generous support of
this work.
References and notes
1. Thomson, R. H. In Naturally Occurring Quinones III:
Recent Advances, 3rd ed.; Chapman and Hall, 1987;
Thomson, R. H. In Naturally Occurring Quinones IV:
Recent Advances, 4th ed.; Blackie Academic and Profes-
sional, 1997.
2. Brimble, M. A.; Duncalf, L. J.; Nairn, M. R. Nat. Prod.
Rep. 1999, 16, 267–281.
3. Moore, H. W. Science 1977, 197, 527–531.
4. Halliwell, B.; Gutteridge, M. C. In Free Radicals in
Biology and Medicine, 3rd ed.; Oxford University Press,
1999; pp 564–572.
5. Bergy, M. E. J. Antibiot. 1968, 21, 454–457.
6. Hoeksema, H.; Krueger, W. C. J. Antibiot. 1976, 29, 704–
709.
7. Duchamp, D. J. American Crystallographic Association
Summer Meeting, 1968, paper 82.
8. Omura, S.; Tanaka, H.; Okada, Y.; Marumo, H. J. Chem.
Soc., Chem. Commun. 1976, 320–321.
9. Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.;
Kinoshita, M. Bull. Chem. Soc. Jpn. 1985, 58, 1699–1706.
10. Fernandes, R. A.; Bruckner, R. Synlett 2005, 1281–1285.
¨
Finally, inversion of the C5 configuration was effected
by exposure of 17 to concentrated sulfuric acid.10,16 This
resulted in almost complete epimerization to the ther-
modynamically favoured 5,3a-trans-pyran 1 (93:7 mix-
ture of 1:17). Importantly, the spectroscopic data18 for
synthetic 1 prepared in this way from (S)-aspartic acid
5 was in good agreement with that reported for (+)-kala-
fungin 1.9
11. For a comprehensive review, see: Brimble, M. A.; Nairn,
M. R.; Prabaharan, H. Tetrahedron 2000, 56, 1937–1992.
12. Volkmann, R. A.; Kelbaugh, P. R.; Nason, D. M.; Jasys,
V. J. J. Org. Chem. 1992, 57, 4352–4361.
13. Mori, K.; Ikunaka, M. Tetrahedron 1984, 40, 3471–3479.
14. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–
394.
15. (a) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem.
Soc., Chem. Commun. 1986, 1568–1569; (b) Kraus, G. A.;
Molina, M. T.; Walling, J. A. J. Org. Chem. 1987, 52,
1273–1276.
16. Li, T.; Ellison, R. H. J. Am. Chem. Soc. 1978, 100, 6263–
6265.
In conclusion, this work constitutes a novel, stereoselec-
tive synthesis of (+)-kalafungin 1. Additionally, the late-
stage introduction of the C5 alkyl group should allow a
variety of other substituents to be incorporated conve-
niently at this position by appropriate selection of Grig-
nard reagent. This idea is currently being explored and
should provide access to other members of this pyrano-
naphthoquinone family, including 2 and 3.
17. (a) Hoffmann, B.; Schonebaum, A.; Lackner, H. Liebigs
Ann. Chem. 1993, 333–342; (b) Masquelin, T.; Hengartner,
U.; Streith, J. Synthesis 1995, 780–786.
18. Selected spectroscopic data for synthetic 1: 1H NMR
(500 MHz, CDCl3) d 1.57 (3H, d, J 6.8 Hz), 2.71 (1H, d, J
17.7 Hz), 2.97 (1H, dd, J 17.7 and 5.2 Hz), 4.69 (1H, dd, J
5.2 and 3.0 Hz), 5.09 (1H, q, J 6.8 Hz), 5.26 (1H, d,
J 3.0 Hz), 7.31 (1H, dd, J 8.3 and 1.5 Hz), 7.67 (1H, dd, J
8.3 and 7.6 Hz), 7.71 (1H, dd, J 7.6 and 1.5 Hz), 11.84
(1H, s); 13C NMR (125 MHz, CDCl3) d 18.6, 36.9, 66.2,
66.4, 68.6, 114.8, 119.8, 124.9, 131.5, 135.1, 137.2, 149.7,
161.9, 173.9, 181.5, 188.0.
Acknowledgements
Financial support from the Australian Research Council
through the Centres of Excellence program is gratefully