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杂氮芳烃C–H键的距离、几何和手性的分子编辑
作者:小柯机器人 发布时间:2022/8/11 13:58:31

美国斯克里普斯研究所Yu Jin-Quan团队报道了杂氮芳烃C–H键的距离、几何和手性的分子编辑。相关研究成果于2022年8月9日发表在国际顶尖学术期刊《自然》。

通过连续选择性C–H官能化直接分子编辑杂芳烃碳-氢(C–H)键,有可能快速进入不同的化学空间;在医药化学领域,这是一项有价值但往往具有挑战性的尝试。与电子偏压杂环C–H键相比,双环氮杂芳烃上的远端苯并环C–H键由于缺乏固有的立体/电子偏压而特别难以区分。

该文中,研究人员报告了两种概念上不同的定向模板,通过仔细调节模板设计中的距离、几何结构和先前未考虑的手性,实现了双环氮杂芳烃上相邻远端(C6 vs.C7)和位置相似位置(C3 vs.C6)的模块化区分和功能化。该策略可在空间上与C7相似的竞争C3位置存在的情况下,在喹啉的相邻C6和C7位置直接进行C–H烯烃化、炔基化和烯丙基化。值得注意的是,此类含喹啉药效团的位点选择性、迭代和后期C–H编辑可按不同顺序模块化进行,以适应定制的合成应用。该文结合先前报道的补充方法,现在完全建立了统一的后期“分子编辑”策略,以不同顺序直接修饰任何给定位点的双环氮杂芳烃。

附:英文原文

Title: Molecular Editing of Aza-arene C–H Bonds by Distance, Geometry and Chirality

Author: Fan, Zhoulong, Chen, Xiangyang, Tanaka, Keita, Park, Han Seul, Lam, Nelson Y. S., Wong, Jonathan J., Houk, K. N., Yu, Jin-Quan

Issue&Volume: 2022-08-09

Abstract: Direct molecular editing of heteroarene carbon-hydrogen (C–H) bonds through consecutive selective C–H functionalization has the potential to grant rapid access into diverse chemical space; a valuable but often challenging venture to achieve in medicinal chemistry1. Contrasting with electronically-biased heterocyclic C–H bonds2-9, remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate due to lack of intrinsic steric/electronic biases10-12. We herein report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 vs. C7) and positionally-similar positions (C3 vs. C7) on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C–H olefination, alkynylation, and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative, and late-stage C–H editing of quinoline-containing pharmacophores can be modularly performed in different orders to suit bespoke synthetic applications. This report, in combination with previously reported complementary methods, now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify bicyclic aza-arenes at any given site in different orders.

DOI: 10.1038/s41586-022-05175-1

Source: https://www.nature.com/articles/s41586-022-05175-1

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:42.778
官方网址:http://www.nature.com/