Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous‐Flow
Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous‐Flow
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通过光氧化还原/钴肟催化生成氧鏻离子，用于批量和连续流中可扩展的酰胺和肽合成
DOI：
10.1002/anie.202112668
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Jiannan Zhao
中科院分区：
文献类型：
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作者：
Junqi Su;Jia-Nan Mo;Xiangyang Chen;Alex;er Umanzor;Zheng Zhang;Kendall N.Houk;Jiannan Zhao
膦介导的脱氧亲核取代反应，如Mitsunobu反应，在有机合成中具有重要意义。然而，传统的方案需要化学计量氧化剂来触发氧磷中间体的形成，以进行随后的亲核添加。通过光氧化还原和钴胺肟的双重催化，我们实现了一种催化形成酰基氧磷离子的激进策略，使直接酰胺化成为可能。脱氧协议具有广泛的范围，并已用于药物分子的后期酰胺化。除了间歇反应外，还开发了连续流反应器，使克级快速合成肽成为可能。四肽在固体载体上的成功组装进一步证明了该光催化体系的多功能性。此外，实验和计算研究都与酰基氧磷离子作为关键中间体形成的假设相一致。
Phosphine‐mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium intermediates for the subsequent nucleophilic additions. Through dual catalysis of photoredox and cobaloxime, we realized a radical strategy for the catalytic formation of acyloxyphosphonium ions that enables direct amidation. The deoxygenative protocol exhibits a broad scope and has been used in the late‐stage amidation of drug molecules. In addition to batch reactions, a continuous‐flow reactor was developed, enabling rapid peptide synthesis on gram scale. The successful assembly of a tetrapeptide on the solid support further demonstrated the versatility of this photocatalytic system. Moreover, experimental and computational studies are consistent with the hypothesis of acyloxyphosphonium ions being formed as the key intermediates.