A Synthesis of Tamiflu by Using a Barium-Catalyzed Asymmetric Diels-Alder-Type Reaction
A Synthesis of Tamiflu by Using a Barium-Catalyzed Asymmetric Diels-Alder-Type Reaction
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DOI：
10.1002/anie.200804777
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Shibasaki, Masakatsu
中科院分区：
文献类型：
--
作者：
Yamatsugu, Kenzo;Yin, Liang;Shibasaki, Masakatsu
流感病毒对世界公共卫生构成严重威胁。目前用于治疗流感患者的两种药物是Tamiflu（1;（N）-磷酸奥司他韦）[1]和Relenza（扎那米韦）[2]，这两种药物都能抑制病毒神经氨酸酶。目前，达菲是由罗氏公司生产和供应的，使用（S）-莽草酸作为起始原料。[3]然而，生产具有一致纯度的（N）-莽草酸需要大量时间并且成本高。此外，依赖单一的合成路线来供应如此重要的药物是不明智的。因此，迫切需要从容易获得的起始材料开始开发达菲的替代实用合成。[4，5]我们在此报道了达菲的新合成，其特征在于由钡/F2-FujiCAPO络合物催化的新型不对称Diels-Alder型反应。C3的3-戊氧基应在后期通过在Mitsunobu条件下由β-醇2产生的N-乙酰基氮丙啶[4a]的开环反应引入。在我们以前的报告中，[4 b，d，e]我们利用氰化物基团作为C1处酯基的前体，然而，它的引入和转化为乙氧羰基仅得到中等产率的所需产物。因此，我们寻求
Influenza viruses pose a serious threat to world public health. Two of the drugs currently used to treat influenza patients are Tamiflu (1;(À)-oseltamivir phosphate)[1] and Relenza (zanamivir),[2] both of which inhibit viral neuraminidase. Currently, Tamiflu is produced and supplied by Roche using (À)-shikimic acid as the starting material.[3] The production of (À)-shikimic acid with consistent purity, however, requires a lot of time and is costly. In addition, the dependence on a single synthetic route for the supply of such an important drug is unwise. Therefore there is an urgent demand for the development of alternative practical syntheses of Tamiflu, starting from easily available starting materials.[4, 5] We report herein a new synthesis of Tamiflu which features a novel asymmetric Diels–Alder-type reaction catalyzed by a barium/F2-FujiCAPO complex.Our retrosynthetic analysis is shown in Scheme 1. The 3-pentyloxy group at C3 should be introduced at a late stage by a ring-opening reaction of an N-acetyl aziridine [4a] produced from β-alcohol 2 under Mitsunobu conditions. In our previous reports,[4b, d, e] we utilized a cyanide group as a precursor for the ester group at C1, however, its introduction and conversion into an ethoxycarbonyl group afforded only moderate yields of the desired product. Therefore, we sought