A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist (1) was the S_N2 reaction with a highly functionalized lactamide electrophile and a unique difluoropiperidine nucleophile containing a pyridine N-oxide moiety. Initial reactions with sulfonate leaving groups exhibited superb stereoselectivity, but yields were very low due to side reactions originated from competitive Kornblum reactions of the pyridine N-oxide and the sulfonates. Markedly improved reaction profiles were achieved by including stoichiometric lithium triflate. NMR data provided insights into how the lithium cation impacted the pyridine N-oxide through coordination and attenuating its nucleophilicity, leading to the inhibition of the undesired Kornblum reactions. Our approach is highly relevant to preservation of the N-oxide, a structural motif known to several marketed products and emerging as an important class in drug discovery in nucleophilic substitutions. Application of this method enabled the production of the target (1 and its HCl salt 1a) up to multikilogram scale with high selectivity and in much improved yield.

中文翻译：

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在磺酸盐和含有吡啶 N-氧化物基团的亲核试剂的 SN2 反应中抑制锂盐与 Kornblum 反应：MRGPRX2 拮抗剂的趋同和选择性合成


开发 MRGPRX2 拮抗剂趋同合成 （1） 的关键步骤是 S_N2 反应，反应具有高度官能化的乳酰胺亲核试剂和含有吡啶 N-氧化物部分的独特二氟哌啶亲核试剂。与磺酸盐离去基团的初始反应表现出极好的立体选择性，但由于吡啶 N-氧化物和磺酸盐的竞争性 Kornblum 反应引起的副反应，产量非常低。通过加入化学计量三氟甲酸锂，实现了显著改善的反应曲线。NMR 数据有助于了解锂阳离子如何通过配位和减弱其亲核性来影响吡啶 N-氧化物，从而抑制不需要的 Kornblum 反应。我们的方法与保存 N-氧化物高度相关，N-氧化物是几种市售产品已知的结构基序，并成为亲核取代药物发现中的重要类别。该方法的应用能够生产高达数公斤级的目标物（1 及其 HCl 盐 1a），具有高选择性和大大提高的产量。