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).
Chemistry. 2013 Dec 23;19(52):17789-800. doi: 10.1002/chem.201302371. Epub 2013 Nov 18.
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.
（-）-奥司他韦的一锅法连续合成，在 7 步反应中无需蒸发或溶剂交换，收率为 36%。关键步骤是用（Z）-N-2-硝基亚乙烯基乙酰胺对戊烷-3-氧基乙醛进行不对称迈克尔加成反应，由二苯丙醇硅醚催化。使用大体积的 O-硅基取代的二苯丙醇硅醚催化剂、氯苯作为溶剂以及 HCO2 H 作为酸添加剂，是在优异的产率和非对映选择性和对映选择性下生成第一个迈克尔加成产物的关键。对酸的影响的研究表明，酸添加剂不仅加速了由戊烷-3-氧基乙醛与二苯丙醇硅醚衍生的烯胺的 E-Z 异构化，而且还加速了环丁烷中间体的开环以及烯胺与（Z）-N-2-硝基亚乙烯基乙酰胺的加成反应。通过考虑与苯马来酰亚胺和萘醌的迈克尔反应的结果，对戊烷-3-氧基乙醛与（Z）-N-2-硝基亚乙烯基乙酰胺的迈克尔反应的过渡态模型进行了推测。
