The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N′-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an S_NAr substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical S_NAr reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N′-aryl group, hugely accelerating ipso-substitution.

中文翻译：

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通过构象加速的分子内亲核芳族取代 (SNAr) 进行 C(sp3)-芳基化

在天然产物、治疗剂、农用化学品和催化剂中普遍存在的大量取代的苄基立体中心的不对称合成是一项持续的挑战。在这个帐户中，我们概述了我们对这项工作的贡献，描述了我们发现的一系列新反应，这些反应不仅具有综合适用性，而且还具有重要的机械阴谋。这个故事源于我们对功能化有机锂的立体化学和反应性的长期兴趣。在研究尿素（更成熟的酰胺和氨基甲酸酯的“灰姑娘”姐妹）的锂化化学时，我们注意到了一个意外的休战-微笑 (TS) 重排，涉及尿素N '-芳基的 1,4-N → C 转座组到相邻N的 α-碳负离子-苄基。尽管该反应形式上构成了 S _N Ar 取代，但我们发现它对迁移的芳基取代基的电子特性和碳负离子的取代度具有显着的耐受性。此外，与经典的 S _N Ar 反应相比，重排足够快，以至于它发生在与有机锂中间体中的构型稳定性相容的条件下，从而能够在苄基立体中心进行对映体特异性芳基化。实验和计算研究证实，由于对尿素N的反式排列的强烈偏好，芳基迁移的低动力学障碍'-芳基和羰基，填充了一个反应性构象异构体，其中碳负离子和N'-芳基之间的空间接近，极大地加速了同位取代。