5302
T. Sasaki et al. / Tetrahedron Letters 42 (2001) 5299–5303
conditions led to the formation of the adduct in 54%
yield, which was converted to carboxylic acid 13 via a
two-step sequence in 76% overall yield.
Tanaka, T.; Hirama, M.; Imajo, S.; Ishiguro, M.;
Yoshida, K.-i.; Otani, T. Tetrahedron Lett. 1996, 38,
4997.
5. Xu, Y.-j.; Zhen, X.; Zhen, Y.-s.; Goldberg, I. H. Bio-
chemistry 1997, 36, 14975 and references cited therein.
6. (a) Iida, K.-i.; Hirama, M. J. Am. Chem. Soc. 1995, 117,
8875; (b) Hirama, M. Pure Appl. Chem. 1997, 69, 525.
7. (a) Hirama, M.; Akiyama, K.; Tanaka, T.; Noda, T.;
Iida, K.-i.; Sato, I.; Hanaishi, R.; Otani, T.; Leet, J. E. J.
Am. Chem. Soc. 2000, 122, 720; (b) Tanaka, T.; Fukuda-
Ishisaka, S.; Hirama, M.; Otani, T. J. Mol. Biol. 2001,
309, 267.
8. For recent synthetic studies on nine-membered enediyne
antibiotics, see: (a) Myers, A. G.; Liang, J.; Hammond,
M.; Harrington, P. M.; Wu, Y.; Kuo, E, Y. J. Am. Chem.
Soc. 1998, 120, 5319; (b) Myers, A. G.; Goldberg, S. D.
Angew. Chem., Int. Ed. 2000, 39, 2732; (c) Magnus, P.;
Carter, R.; Davies, M.; Elliott, J.; Pitterna, T. Tetra-
hedron 1996, 52, 6283; (d) Caddick, S.; Delisser, V. M.;
Doyle, V. E.; Khan, S.; Avent, A. G.; Vile, S. Tetra-
hedron 1999, 55, 2737; (e) Tanaka, H.; Yamada, H.;
Matsuda, A.; Takahashi, T. Synlett 1997, 381 and refer-
ences cited therein.
9. (a) Iida, K.-i.; Hirama, M. J. Am. Chem. Soc. 1994, 116,
10310; (b) Sato, I.; Toyama, K.; Kikuchi, T.; Hirama, M.
Synlett 1998, 1308.
10. Sato, I.; Kikuchi, T.; Hirama, M. Chem. Lett. 1999, 511.
11. Sato, I.; Akahori, Y.; Sasaki, T.; Kikuchi, T.; Hirama,
M. Chem. Lett. 1999, 867.
12. Although other cyclization strategies, such as intramolec-
ular Sonogashira coupling or intramolecular epoxide
opening reaction, were pursued, we could not improve
the yield above 25%. These results will be discussed in a
full account.
As expected, the Corey–Nicolaou macrolactonization
of 13 did give a better yield than that of 10. Thioester
14 was prepared in 98% yield by the action of 2,2%-
dipyridyl disulfide and PPh3. By heating 14 to reflux in
toluene, the macrolactone was isolated in 57% yield as
an inseparable 1:1.1 mixture of atropisomers 15a and
15b, respectively. These isomers were separated by SiO2
chromatography after TBS ether deprotection. Com-
pounds 16a and 16b were then separately converted to
their methoxymethyl ethers (17a, 17b), whose
stereostructures were determined unambiguously by
NOESY experiments (Fig. 2).19
To investigate the thermodynamic behavior of each
atropisomer, 17a and 17b were separately heated to
160°C in deuterated 1,2-dichlorobenzene for 12 h (Fig.
2).20 However, no isomerization was observed under
these conditions and the substrates slowly decomposed.
Thus, the problem of controlling the atropisomer
remains to be solved.
Lastly, it was necessary to liberate the C5 hydroxy
group for further synthetic manipulation. After exten-
sive experimentation, selective removal of the acetonide
group was achieved by treating 17a with trifluoro-
methanesulfonic acid in trifluoroethanol at 0°C.21 In
this way, triol 18a was generated in 73% yield and
anticipated to be a key intermediate for the total syn-
thesis of the C-1027 chromophore.
13. Kawata, S.; Hirama, M. Tetrahedron Lett. 1998, 39,
8707.
14. Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976,
49.
15. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
16. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96,
5614.
In conclusion, we have developed an efficient strategy
for the construction of macrolactones by screening both
the reaction conditions and the substrates. The ace-
tonide group proved to be the superior protective group
for efficient cyclization of this system. Further studies
for the total synthesis of C-1027 chromophore, includ-
ing that of the formation of the nine-membered ring,
are currently underway in this laboratory.
17. Hikota, M.; Tone, H.; Horita, K.; Yonemitsu, O. J. Org.
Chem. 1990, 55, 7.
18. We applied a similar protective group strategy for the
intramolecular Sonogashira coupling in a synthetic study
of kedarcidin chromophore, see: Yoshimura, F.; Kawata,
S.; Hirama, M. Tetrahedron Lett. 1999, 40, 8281.
19. Physical data for 17a and 17b. 17a: IR (film) 3468, 3283,
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