De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost.
De Novo Synthesis of Dihydrobenzofurans and Indolines and Its Application to a Modular, Asymmetric Synthesis of Beraprost.
复制标题
DOI：
10.1021/jacs.3c04582
复制
发表时间：
2023-06-28
影响因子：
15
通讯作者：
Aggarwal, Varinder K. K.
中科院分区：
文献类型：
--
作者：
Wang, Ze-Shu;Bennett, Steven H. H.;Kicin, Bilal;Jing, Changcheng;Pradeilles, Johan A. A.;Thai, Karen;Smith, James R. R.;Bacos, P. David;Fasano, Valerio;Saunders, Carla M. M.;Aggarwal, Varinder K. K.
二氢苯并呋喃和吲哚啉是重要的药物成分。在这里，我们描述了一种新的策略，其建设中，芳香环从头创建通过反电子需求狄尔斯-阿尔德反应和螯合挤出序列的2-卤代噻吩-1，1-二氧化物与烯醇醚/烯酰胺，然后芳构化。不寻常的是，芳构化过程被证明是非常具有挑战性的，但发现用碱处理卤代环己二烯会影响α-消除芳构化反应。使用氘标记的研究表明，这一步骤的机制调查的中间体的卡宾进行1，2-氢转移和随后的芳构化。该方法被应用到抗血小板药物贝前列素的模块化和立体选择性的全合成，只有8个步骤，从一个关键的烯醛内酯。这种内酯提供了贝前列素的核心，其两个侧链可以通过1，4-共轭加成过程（下部ω-侧链）附加到贝前列素的核心上，然后使用我们新开发的方法从头构建贝前列素的二氢苯并呋喃（上部α-侧链）。此外，我们已经证明了我们新建立的协议在合成功能化的吲哚啉，这发生在高水平的区域控制的广度。根据密度泛函理论（DFT）计算，高选择性源于吸引伦敦分散相互作用的TS的Diels-Alder反应。
Dihydrobenzofurans and indolines are important constituents of pharmaceuticals. Herein, we describe a novel strategy for their construction in which the aromatic ring is created de novo through an inverse-electron demand Diels–Alder reaction and cheletropic extrusion sequence of a 2-halothiophene-1,1-dioxide with an enol ether/enamide, followed by aromatization. Unusually, the aromatization process proved to be highly challenging, but it was discovered that treatment of the halocyclohexadienes with a base effected an α-elimination–aromatization reaction. Mechanistic investigation of this step using deuterium-labeling studies indicated the intermediacy of a carbene which undergoes a 1,2-hydrogen shift and subsequent aromatization. The methodology was applied to a modular and stereoselective total synthesis of the antiplatelet drug beraprost in only 8 steps from a key enal-lactone. This lactone provided the core of beraprost to which both its sidechains could be appended through a 1,4-conjugate addition process (lower ω-sidechain), followed by de novo construction of beraprost’s dihydrobenzofuran (upper α-sidechain) using our newly developed methodology. Additionally, we have demonstrated the breadth of our newly established protocol in the synthesis of functionalized indolines, which occurred with high levels of regiocontrol. According to density-functional theory (DFT) calculations, the high selectivity originates from attractive London dispersion interactions in the TS of the Diels–Alder reaction.
登录
查看更多内容
影响因子：
15
作者：
Iosub AV;Stahl SS
通讯作者：
Stahl SS
影响因子：
15
作者：
Ikeda, S;Mori, N;Sato, Y
通讯作者：
Sato, Y
影响因子：
15
作者：
BAILEY, WJ;CUMMINS, EW
通讯作者：
CUMMINS, EW
影响因子：
4.5
作者：
Hayashi, Yujiro;Kojima, Masahiro;Sato, Itaru
通讯作者：
Sato, Itaru
影响因子：
15
作者：
Johnson ER;Keinan S;Mori-Sánchez P;Contreras-García J;Cohen AJ;Yang W
通讯作者：
Yang W