Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588, United States.
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.
J Org Chem. 2021 May 7;86(9):6494-6503. doi: 10.1021/acs.joc.1c00326. Epub 2021 Apr 15.
A formal synthesis of the antiviral drug (-)-oseltamivir (Tamiflu) has been accomplished starting from -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, with d-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 ()--acyl-protected 5-amino-1,3-cyclohexadiene carboxylates, key advanced intermediates for oseltamivir pioneered by Corey (-Boc) and Trost (-phthalamido), respectively.
抗病毒药物（-）-奥司他韦（达菲）的全合成已从 - 茴香酸开始，通过溶解金属或电化学伯奇还原来完成。通过对所得的外消旋 α，β-不饱和酮进行酶催化羰基还原，有效地设定了正确的绝对立体化学。对广泛的酮还原酶（KRED）文库进行筛选，发现了几种可以提供所需烯丙醇的酶，每种对映体底物的新中心都具有几乎完美的面选择性，这表明该酶还能够完全克服底物中固有的非对映体偏置。转化率完全，以 d-葡萄糖作为末端氢供体（葡萄糖脱氢酶）。对于每个得到的非对映立体化学仲醇，然后通过顺式[3,3]-西格玛重排或直接、立体反转的 N-Mitsunobu 化学有效地进行 O/N-互变。这两种立体化学结果都通过晶体学得到了证实。然后通过α-硒化/氧化/热解序列引入α，β-不饱和，得到目标（）-酰基保护的 5-氨基-1,3-环己二烯羧酸酯，这是 Corey（-Boc）和 Trost（-phthalamido）分别为奥司他韦开创的关键高级中间体。
