A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.
A Computational and Experimental Investigation of the Origin of Selectivity in the Chiral Phosphoric Acid Catalyzed Enantioselective Minisci Reaction.
复制标题
手性磷酸中选择性起源的计算和实验研究催化了对映选择性的Minisci反应。
DOI：
10.1021/jacs.0c09668
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发表时间：
2020-12-16
影响因子：
15
通讯作者：
Goodman JM
中科院分区：
文献类型：
--
作者：
Ermanis K;Colgan AC;Proctor RSJ;Hadrys BW;Phipps RJ;Goodman JM
Minisci反应是直接官能化碱性杂环芳烃形成碳-碳键最有价值的方法之一。使用前手性，杂原子取代自由基导致在杂芳体系附近形成立体中心，产生在药物化学和手性配体设计中有价值的基序。最近开发了一种高度对映选择性和区域选择性的Minisci反应方案，使用手性磷酸催化。然而，这一过程运作的确切机制和选择性的起源仍然不清楚，这使得更普遍地发展反应具有挑战性。在这里，我们报告了进一步的实验机制研究，这些研究提供给详细的DFT计算，以探测立体化学决定步骤的精确性质。计算和实验证据共同支持该反应中的Curtin-Hammett控制，初始自由基加成是快速可逆的，而在随后较慢的不可逆去质子化中实现了对映选择性。通过DFT计算进行的详细调查评估了许多不同的可能性，以确定自由基阳离子中间体的选择性去质子化。计算表明，在相关的手性磷酸盐的帮助下，酰胺基团（这是自由基前体的关键结构特征）明显倾向于最初意想不到的内部去质子化模式。这种非常规的立体决定步骤支持观察到的高对映选择性和区域选择性。将该力学模型应用于具有不同结构特征的衬底测试集，进一步验证了该模型的有效性。
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.
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