Site-Selective α-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis.
Site-Selective α-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis.
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DOI：
10.1021/jacs.1c07144
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发表时间：
2021-11-17
影响因子：
15
通讯作者：
Rovis T
中科院分区：
文献类型：
--
作者：
Shen Y;Funez-Ardoiz I;Schoenebeck F;Rovis T
三烷基胺广泛存在于天然生物碱、合成农用化学品、生物探针，尤其是药物制剂和临床前候选物中。尽管最近在二烷基胺的催化烷基化方面取得了突破，但广泛使用的三烷基胺支架的选择性α-C(sp3) -H键功能化有望简化复杂三烷基胺的合成，加速药物发现，并通过互补反应性进行后期药物修饰。然而，规范方法总是导致在不太拥挤的站点上实现功能化。在这里，我们描述了一种通过从根本上克服主导这类过程的空间控制来切换反应位点的解决方案。通过可逆氢原子转移快速建立α-氨基C(sp3) -H键与高亲电性硫醇自由基之间的平衡，我们利用缺电子烯烃较慢的自由基俘获步骤，在Curtin-Hammett原理的指导下，选择性地与更密集的α-氨基自由基形成C(sp3) -C （sp3）键。这一微妙的反应特征为从具有高水平选择性和制备效用的多种三烷基胺中锻造C-C键提供了直接碳氢功能化领域的新战略概念。位点选择性与13C核磁共振位移的简单相关性可作为定性预测指南。这种动态系统的广泛影响，加上形成n取代的季碳中心和实施后期功能化技术的能力，具有简化复杂三烷基胺合成和加速小分子药物发现的潜力。
Trialkylamines are widely found in naturally-occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and pre-clinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective α-C(sp3)–H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between α-amino C(sp3)–H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3)–C(sp3) bond with the more-crowded α-amino radical, with the overall selectivity guided by Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C–H functionalization arena for forging C–C bonds from a diverse set of trialkylamines with high levels of site-selectivity and preparative utility. Simple correlation of site-selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, holds potential to streamline complex trialkylamine synthesis and accelerate small-molecule drug discovery.
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影响因子：
18.3
作者：
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通讯作者：
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