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迈向阿尔皮尼定的全合成:对异喹啉三酮CE环系合成子的迈克尔加成反应

Toward the Total Synthesis of Alpkinidine: Michael Addition to Isoquinolinetrione CE Ring-System Synthons.

作者信息

Buccini Marco, Dhoro Francis, Tham Louisa, Skelton Brian W, Williams Craig M, Piggott Matthew J

机构信息

Chemistry, School of Molecular Sciences, University of Western Australia, Perth 6009, Australia.

School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.

出版信息

ACS Omega. 2022 Jun 1;7(23):19093-19105. doi: 10.1021/acsomega.2c02117. eCollection 2022 Jun 14.

Abstract

Strategies toward the total synthesis of the marine pyrroloacridine alkaloid alpkinidine have been explored, focusing on linking quinonoid CE ring-system synthons with the A ring, followed by condensation to form the B and D rings. The key Michael addition of the ester enolate derived from ethyl -nitrophenylacetate to 2-methylisoquinoline-1,5,8(2)-trione proceeded with the wrong regiochemistry. This issue was addressed by incorporating the D-ring nitrogen at an earlier stage, affording advanced intermediates possessing the complete carbon skeleton of alpkinidine. However, attempts to close the D and B rings were unsuccessful. The novel isoquinolinetriones reported here, and the general strategy of connecting CE- and A-ring synthons through Michael additions, may be useful in the synthesis of other pyrrolo- and pyridoacridines, in particular the anticancer lead neoamphimedine and analogues.

摘要

人们探索了海洋吡咯并吖啶生物碱阿尔平尼定的全合成策略,重点是将醌型CE环系合成子与A环连接,然后缩合形成B环和D环。由乙基 -硝基苯乙酸酯衍生的酯烯醇盐与2-甲基异喹啉-1,5,8(2)-三酮进行的关键迈克尔加成反应,其区域化学是错误的。通过在较早阶段引入D环氮解决了这个问题,得到了具有阿尔平尼定完整碳骨架的高级中间体。然而,闭合D环和B环的尝试未成功。本文报道的新型异喹啉三酮,以及通过迈克尔加成连接CE环和A环合成子的一般策略,可能有助于其他吡咯并吖啶和吡啶并吖啶的合成,特别是抗癌先导化合物新两性霉素及其类似物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1ca4/9202020/93c64d9bdbf1/ao2c02117_0002.jpg

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