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 hayashi@ci.kagu.tus.ac.jp 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 1993 2 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 MgBr 2 -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 A 2 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. (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. (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. ORGANIC LETTERS 2003 Vol. 5, No. 13 2287-2290 10.1021/ol034630s CCC: $25.00 © 2003 American Chemical Society Published on Web 05/30/2003