ORGANIC
LETTERS
2003
Vol. 5, No. 13
2287-2290
Asymmetric Total Synthesis of
Pseurotin A
,†
Yujiro Hayashi,* Mitsuru Shoji,† Shinpei Yamaguchi,† Takasuke Mukaiyama,†
Junichiro Yamaguchi,† Hideaki Kakeya,‡ and Hiroyuki Osada‡
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and Antibiotics Laboratory,
DiscoVery Research Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received April 11, 2003
ABSTRACT
The asymmetric total syntheses of pseurotin A and 8-O-demethylpseurotin A have been accomplished. Key reactions are a NaH-promoted
intramolecular cyclization of an alkynylamide to form a γ-lactam, an aldol reaction of a benzylidene-substituted ketone, and the late-stage
introduction of the benzoyl group by a selective oxidation of a benzylidene moiety with dimethyldioxirane (DMD).
The pseurotins are a small family of secondary microbial
metabolites isolated from a culture broth of Pseudeurotium
oValis (strain S2269/F) in 1976 by P. Bloch and C. Tamm
et al.1 Pseurotin A was reported to inhibit chitin synthase
by Sterner et al. in 19932 and also found to induce cell
differentiation of PC12 cells by Komagata et al. in 1995.3
Structurally, it contains a novel, highly substituted, and
oxygenated 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skel-
eton with five chiral centers (Figure 1). The structure of
pseurotin A, including its absolute stereochemistry, has been
unambiguously determined by a single-crystal X-ray analysis
of its 12,13-dibromo derivative.4 Recently, azaspirene, pos-
sessing the same core structure, has been isolated from the
fungus Neosartorya sp. by Kakeya and Osada et al. and
found to inhibit the endothelial migration induced by vascular
endothelial growth factor.5 Because of the unprecedented,
densely functionalized core structure of the pseurotins and
azaspirene, their total synthesis poses a significant challenge,
and several synthetic endeavors aimed at the total synthesis
of pseurotin A have been reported.6 We have completed the
first total synthesis of a member of this class of compounds,
that of azaspirene, in which a Sharpless asymmetric dihy-
droxylation, a MgBr2-mediated, highly diastereoselective
Mukaiyama aldol reaction, and a NaH-mediated, intramo-
lecular addition of an amide to an alkyne are employed as
key steps.7 Just recently, Tadano et al. have orally presented
syntheses of pseurotin A and of 8-O-demethylpseurotin A2
from D-glucose.8 At the same time, as described in this paper,
our group has also accomplished total syntheses of both
pseurotin A and 8-O-demethylpseurotin A from the key
intermediate in our synthesis of azaspirene.
† Tokyo University of Science.
‡ RIKEN.
(1) (a) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H. P.
HelV. Chim. Acta, 1976, 59, 133. (b) Bloch, P.; Tamm, C. HelV. Chim.
Acta, 1981, 64, 304. (c) Breitenstein, W.; Chexal, K. K.; Mohr, P.; Tamm,
C. HelV. Chim. Acta, 1981, 64, 379.
(5) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada,
H. Org. Lett. 2002, 4, 2845.
(6) (a) Dolder, M.; Shao, X.; Tamm, C. HelV. Chim. Acta, 1990, 73, 63.
(b) Shao, X.; Dolder, M.; Tamm, C. HelV. Chim. Acta, 1990, 73, 483. (c)
Su, Z.; Tamm, C. HelV. Chim. Acta, 1995, 78, 1278. (d) Su, Z.; Tamm, C.
Tetrahedron 1995, 51, 11177. (e) Aoki, S.; Ohi, T.; Shimizu, K.; Shiraki,
R.; Takao, K.; Tadano, K. Heterocycles 2002, 58, 57.
(7) Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yamaguchi, S.;
Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya, H.; Osada, H. J. Am. Chem.
Soc. 2002, 124, 12078.
(2) Wenke, J.; Anke, H.; Sterner, O. Biosci. Biotech. Biochem. 1993,
57, 961.
(3) Komagata, D.; Fujita, S.; Yamashita, N.; Saito, S.; Morino, T. J.
Antibiot. 1996, 49, 958.
(4) Weber, H. P.; Petcher, T. J.; Bloch, P.; Tamm, C. HelV. Chim. Acta,
1976, 59, 137.
10.1021/ol034630s CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/30/2003