Zhou Xueting, Huang Qingqin, Guo Jiami, Dai Lei, Lu Yixin
Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, Fuzhou, Fujian 350207, China.
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.
ACS Cent Sci. 2023 Aug 15;9(9):1758-1767. doi: 10.1021/acscentsci.3c00812. eCollection 2023 Sep 27.
Heterocyclic scaffolds are commonly found in numerous biologically active molecules, therapeutic agents, and agrochemicals. To probe chemical space around heterocycles, many powerful molecular editing strategies have been devised. Versatile C-H functionalization strategies allow for peripheral modifications of heterocyclic motifs, often being specific and taking place at multiple sites. The past few years have seen the quick emergence of exciting "single-atom skeletal editing" strategies, through one-atom deletion or addition, enabling ring contraction/expansion and structural diversification, as well as scaffold hopping. The construction of heterocycles via deconstruction of simple heterocycles is unknown. Herein, we disclose a new molecular editing method which we name the skeletal recasting strategy. Specifically, by tapping on the 1,3-dipolar property of azoalkenes, we recast simple pyrroles to fully substituted pyrroles, through a simple phosphoric acid-promoted one-pot reaction consisting of dearomative deconstruction and rearomative reconstruction steps. The reaction allows for easy access to synthetically challenging tetra-substituted pyrroles which are otherwise difficult to synthesize. Furthermore, we construct N-N axial chirality on our pyrrole products, as well as accomplish a facile synthesis of the anticancer drug, Sutent. The potential application of this method to other heterocycles has also been demonstrated.
杂环骨架常见于众多生物活性分子、治疗剂和农用化学品中。为了探索杂环周围的化学空间，人们设计了许多强大的分子编辑策略。通用的C-H官能化策略允许对杂环基序进行外围修饰，这种修饰通常具有特异性且能在多个位点发生。在过去几年中，令人兴奋的“单原子骨架编辑”策略迅速涌现，通过单原子的删除或添加，实现环的收缩/扩展、结构多样化以及骨架跃迁。通过解构简单杂环来构建杂环的方法尚属未知。在此，我们公开了一种新的分子编辑方法，我们将其命名为骨架重塑策略。具体而言，通过利用偶氮烯烃的1,3-偶极性质，我们通过一个由去芳香化解构和再芳香化重建步骤组成的简单磷酸促进的一锅反应，将简单吡咯重塑为全取代吡咯。该反应能够轻松获得合成上具有挑战性的四取代吡咯，而这些吡咯用其他方法难以合成。此外，我们在吡咯产物上构建了N-N轴手性，并且实现了抗癌药物索坦的简便合成。该方法在其他杂环上的潜在应用也得到了证明。
