Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core
Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core
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DOI：
10.1021/acs.joc.1c00326
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发表时间：
2021-04-15
影响因子：
3.6
通讯作者：
Berkowitz，David B.
中科院分区：
文献类型：
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作者：
Tiwari，Virendra K.;Powell，Douglas R.;Berkowitz，David B.
抗病毒药物(−)-奥司他韦（达菲）的正式合成已经完成，从茴香酸开始，通过溶解金属或电化学桦木还原。正确的绝对立体化学是通过酶催化羰基还原得到的外消旋α，β-不饱和酮有效地设定的。对一个广泛的酮还原酶（KRED）文库进行筛选，发现了几个在每个对映底物的新中心以近乎完美的表面选择性传递所需烯丙醇的酶，这表明该酶也能够完全克服底物中固有的非对映异构体偏倚。转化完成，葡萄糖作为末端氢化物供体（葡萄糖脱氢酶）。对于每一种非对映异构仲醇，O/ n的相互转化可以通过合成[3,3]-异位烯丙基酰亚胺重排或直接的立体反相N-Mitsunobu化学有效地实现。这两种立体化学结果在晶体学上都得到了证实。然后，α，β-不饱和通过α-苯基硒化/氧化/热解顺序引入，得到目标(S)- n -酰基保护的5-氨基-1,3-环己二烯羧酸盐，这是Corey （N-Boc）和Trost （N-phthalamido）分别率先开发的奥司他韦的关键高级中间体。
A formal synthesis of the antiviral drug (−)-oseltamivir (Tamiflu) has been accomplished starting fromm-anisic acid via a dissolving metal or electrochemical Birch reduction. The correct absolute stereochemistry is efficiently set through enzyme-catalyzed carbonyl reduction on the resultant racemic α,β-unsaturated ketone. A screen of a broad ketoreductase (KRED) library identified several that deliver the desired allylic alcohol with nearly perfect facial selectivity at the new center for each antipodal substrate, indicating that the enzyme also is able to completely override inherent diastereomeric bias in the substrate. Conversion is complete, withd-glucose serving as the terminal hydride donor (glucose dehydrogenase). For each resulting diastereomeric secondary alcohol, O/N-interconversion is then efficiently effected either by synfacial [3,3]-sigmatropic allylic imidate rearrangement or by direct, stereoinverting N-Mitsunobu chemistry. Both stereochemical outcomes have been confirmed crystallographically. The α,β-unsaturation is then introduced via an α-phenylselenylation/oxidation/pyrolysis sequence to yield the targeted (S)-N-acyl-protected 5-amino-1,3-cyclohexadiene carboxylates, key advanced intermediates for oseltamivir pioneered by Corey (N-Boc) and Trost (N-phthalamido), respectively.