The Minisci reaction is one of the most valuable methods for directly functionalizing basic heteroarenes to form carbon–carbon bonds. Use of prochiral, heteroatom-substituted radicals results in stereocenters being formed adjacent to the heteroaromatic system, generating motifs which are valuable in medicinal chemistry and chiral ligand design. Recently a highly enantioselective and regioselective protocol for the Minisci reaction was developed, using chiral phosphoric acid catalysis. However, the precise mechanism by which this process operated and the origin of selectivity remained unclear, making it challenging to develop the reaction more generally. Herein we report further experimental mechanistic studies which feed into detailed DFT calculations that probe the precise nature of the stereochemistry-determining step. Computational and experimental evidence together support Curtin–Hammett control in this reaction, with initial radical addition being quick and reversible, and enantioselectivity being achieved in the subsequent slower, irreversible deprotonation. A detailed survey via DFT calculations assessed a number of different possibilities for selectivity-determining deprotonation of the radical cation intermediate. Computations point to a clear preference for an initially unexpected mode of internal deprotonation enacted by the amide group, which is a crucial structural feature of the radical precursor, with the assistance of the associated chiral phosphate. This unconventional stereodetermining step underpins the high enantioselectivities and regioselectivities observed. The mechanistic model was further validated by applying it to a test set of substrates possessing varied structural features.

中文翻译：

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手性磷酸催化的对映选择性微型反应中选择性起源的计算和实验研究

Minisci 反应是直接官能化碱性杂芳烃以形成碳-碳键的最有价值的方法之一。使用前手性、杂原子取代的基团导致在杂芳族系统附近形成立体中心，产生在药物化学和手性配体设计中有价值的基序。最近，使用手性磷酸催化开发了 Minisci 反应的高度对映选择性和区域选择性方案。然而，该过程运行的精确机制和选择性的起源仍不清楚，这使得更普遍地开发反应具有挑战性。在此，我们报告了进一步的实验机制研究，这些研究提供了详细的 DFT 计算，这些计算探讨了立体化学确定步骤的精确性质。计算和实验证据共同支持该反应中的 Curtin-Hammett 控制，初始自由基添加是快速且可逆的，并且在随后的较慢、不可逆的去质子化中实现对映选择性。通过 DFT 计算的详细调查评估了许多不同的可能性，用于确定自由基阳离子中间体的去质子化的选择性。计算表明，在相关手性磷酸酯的帮助下，酰胺基团产生了最初意想不到的内部去质子化模式，这是自由基前体的关键结构特征。这种非常规的立体确定步骤巩固了所观察到的高对映选择性和区域选择性。