A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis
A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost guided by biocatalytic retrosynthesis
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DOI：
10.21203/rs.3.rs-257517/v1
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发表时间：
2021-03
期刊：
影响因子：
8.4
通讯作者：
Kejie Zhu;Meifen Jiang;Baijun Ye;Guo‐Tai Zhang;Weijian Li;Pei Tang;Zedu Huang;Fen‐er Chen
中科院分区：
文献类型：
--
作者：
Kejie Zhu;Meifen Jiang;Baijun Ye;Guo‐Tai Zhang;Weijian Li;Pei Tang;Zedu Huang;Fen‐er Chen
由于前列腺素（PG）有价值的医学应用和独特的化学结构，开发有效的立体选择性合成前列腺素（PG）至关重要。我们在此报告了在生物催化逆合成指导下，从容易获得的含二氯双环酮 6a 中统一合成 PG 氯前列醇、比马前列素、PGF2α、氟前列醇和曲伏前列素，分 11-12 个步骤，总产率为 3.8-8.4%。首次组合使用前所未有的拜耳-维利格单加氧酶 (BVMO) 催化的 6a (99% ee) 立体选择性氧化和酮还原酶 (KRED) 催化的烯酮 12 (87:13 至 99:1 dr) 的非对映选择性还原，以在温和条件下设定关键的立体化学构型。另一个关键转化是铜(ii)催化的二醇10的仲醇的区域选择性对苯基苯甲酰化(9.3:1rr)。这项研究不仅为PGs的高度立体选择性合成提供了一条替代途径，而且展示了生物催化在复杂分子构建中的有用性和巨大潜力。
Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11–12 steps with 3.8–8.4% overall yields. An unprecedented Baeyer–Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.