ORGANIC
LETTERS
2002
Vol. 4, No. 17
2877-2880
Studies Aimed at the Total Synthesis of
Azadirachtin. A Modeled Connection of
C-8 and C-14 in Azadirachtin
Takehiro Fukuzaki, Satoshi Kobayashi, Takamasa Hibi, Yohei Ikuma,
,†
Jun Ishihara,* Naoki Kanoh, and Akio Murai*
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
Received May 30, 2002
ABSTRACT
Studies on the connection between the right and left segments of azadirachtin are described. The Ireland−Claisen rearrangement of Li-enolate
of the modeled ester with dichlorodimethylsilane in toluene afforded the desired limonoid framework stereoselectively in good yield.
Azadirachtin (1) is a C-seco limonoid, isolated as an insect
antifeedant from the seeds of Azadirachta indica A. Juss.1,2
Its highly functionalized structure as well as biological
activities urged us toward the total synthesis of this com-
pound, which has not yet been reported.3 In particular, the
connection of the right and left segments remains unsolved
due to the seriously hindered positions at C-8 and C-14. Our
synthetic strategy involves coupling the right and left
segments using Ireland-Claisen rearrangement,4 as shown
in Scheme 1. We have already reported the syntheses of the
Decalin portion 25,6 as the left segment and the tricyclic
dihydrofuran moiety 37 as the right segment. Claisen
rearrangement is widely used as a key step in the syntheses
of natural products, especially for the construction of a
quaternary center, due to its high selectivity and ease of
reaction.8 Recently, Ley showed the utility of Claisen
rearrangement of allyl vinyl ether in the formation between
† Current address: 6-14-4 Asabu-cho, Kita-ku, Sapporo 001-0045, Japan.
(1) (a) Culver, J. N.; Dawson, W. O. Mol. Plant-Microbe. Interact.
1991, 4, 458. (b) Van den Ackerveken, G. F. J. M.; Van Kan, J. A. L.;
Dewit, P. J. G. M. M. Plant J. 1992, 2, 359. (c) Broughton, H. B.; Ley, S.
V.; Slawin, A. M. Z.; Williams, D. J.; Morgan, E. D. J. Chem. Soc., Chem.
Commun. 1986, 46. (d) Kraus, W.; Bokel, M.; Klenk, A.; Po¨hnl, H.
Tetrahedron Lett. 1985, 26, 6435.
(2) For comprehensive reviews on azadirachtin, see: (a) Mordue (Luntz),
A. J.; Blackwell, A. J. Insect Physiol. 1993, 39, 903. (b) Govindachari, T.
R.; Gopalakrishnan, G. J. Indian Chem. Soc. 1998, 75, 655.
(3) (a) Ley, S. V.; Denholm, A. A.; Wood, A. Nat. Prod. Rep. 1993,
109, and references therein. (b) Nishikimi, Y.; Iimori, T.; Sodeoka, M.;
Shibasaki, M. J. Org. Chem. 1989, 54, 3354. (c) Henry, K. J., Jr.; Fraser-
Reid, B. J. Org. Chem. 1994, 59, 5128. (d) Watanabe, H.; Watanabe, T.;
Mori, K. Tetrahedron 1996, 52, 13939. (e) Watanabe, H.; Watanabe, T.;
Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 37, 4429, 2103-2106. (f)
Nicolaou, K. C.; Follmann, M.; Roecker, A. J.; Hunt, K. W. Angew. Chem.,
Int. Ed. 2002, 41, 2103. (g) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.;
Baati R. Angew. Chem., Int. Ed. 2002, 41, 2107.
(4) (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897.
(b) Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976,
98, 2868. (c) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III. J. Org. Chem.
1991, 56, 650.
(5) (a) Kanoh, N.; Ishihara, J.; Murai, A. Synlett 1995, 895. (b) Kanoh,
N.; Ishihara, J.; Murai, A. Synlett 1997, 737. (c) Kanoh, N.; Ishihara, J.;
Yamamoto, Y.; Murai, A. Synthesis 2000, 13, 1878.
(6) (a) Ishihara, J.; Yamamoto, Y.; Kanoh, N.; Murai, A. Tetrahedron
Lett. 1999, 40, 4387. (b) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A.
Synthesis 2000, 13, 1894.
(7) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, 1907.
(8) (a) Ireland, R. E. Aldrichmica Acta 1988, 21, 59. (b) Gilbert, J. C.;
Kelly, T. A. Tetrahedron Lett. 1989, 32, 4193. (c) Gilbert, J. C.; Selliah,
R. D. J. Org. Chem. 1993, 58, 6255. (d) Chai, Y.; Hong S.-p.; Lindsay H.
A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905.
10.1021/ol026260y CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/31/2002