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首页> 外文期刊>Chemistry: A European journal >One-Pot Synthesis of (-)-Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction
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One-Pot Synthesis of (-)-Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

机译：一锅合成（-）-奥司他韦和机理的见解对有机催化迈克尔反应。

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摘要

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-nitroeth-enylacetamide, catalyzed by a diphenylprolinol silyl ether. The use of a bulky O-silyl-substituted diphenylprolinol catalyst, chlorobenzene as a solvent, and HCO_2H 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.
机译：（-）-oseltamivir的一锅顺序合成无需七个步骤即可进行蒸发或溶剂交换，收率36％。关键步骤是戊二-3-戊氧基乙醛与（Z）-N-2-硝基乙炔基乙酰胺的不对称迈克尔反应，该反应由二苯基脯氨醇甲硅烷基醚催化。使用大体积的O-甲硅烷基取代的二苯基脯氨醇催化剂，氯苯作为溶剂和HCO_2H作为酸添加剂，对于以优异的收率，优异的非对映和对映选择性同时生产第一个迈克尔加成物至关重要。对酸作用的研究表明，酸添加剂不仅可以促进戊三-3-基氧基乙醛与二苯基脯氨醇甲硅烷基醚的烯胺的E-Z异构化，而且还可以促进环丁烷中间体的开环以及烯胺加成反应。 （Z）-N-2-硝基乙烯基乙酰胺。考虑到迈克尔产物主要和次要异构体的绝对构型以及迈克尔反应的结果，提出了戊烷-3-基氧基乙醛与（Z）-N-2-硝基乙烯基乙酰胺的迈克尔反应的过渡态模型戊-3-基氧基乙醛与苯基马来酰亚胺和萘醌的混合物

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