title: One-pot synthesis of (-)-oseltamivir and mechanistic insights into the organocatalyzed Michael reaction.
abstract: The one-pot sequential synthesis of (-)-oseltamivir has been achieved without evaporation or solvent exchange in 36% yield over seven reactions. The key step was the asymmetric Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO2 H as an acid additive, were key to produce the first Michael adduct in both excellent yield and excellent diastereo- and enantioselectivity. Investigation into the effect of acid demonstrated that an acid additive accelerates not only the E-Z isomerization of the enamines derived from pentan-3-yloxyacetaldehyde with diphenylprolinol silyl ether, but also ring opening of the cyclobutane intermediate and the addition reaction of the enamine to (Z)-N-2-nitroethenylacetamide. The transition-state model for the Michael reaction of pentan-3-yloxyacetaldehyde with (Z)-N-2-nitroethenylacetamide was proposed by consideration of the absolute configuration of the major and minor isomers of the Michael product with the results of the Michael reaction of pentan-3-yloxyacetaldehyde with phenylmaleimide and naphthoquinone.
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza Aoba, Aoba-ku, Sendai 980-8578 (Japan), Fax: (+81) 22-795-6566; Previous address (before 30thJune 2012), Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan).
authors.forename: Takasuke
authors.initials: T
authors.lastname: Mukaiyama
authors.forename: Hayato
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshino
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Hayashi
mesh_terms: D002384:Catalysis; D015394:Molecular Structure; D053139:Oseltamivir / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D053139:Oseltamivir
keywords: Michael addition; Tamiflu; asymmetric synthesis; one-pot reaction; organocatalysis