Patil Mahendra
UM-DAE Centre for Excellence in Basic Sciences, Health Centre, University of Mumbai, Vidyanagari Campus, Kalina, Santacruz (East), Mumbai 400098, India.
Org Biomol Chem. 2017 Jan 4;15(2):416-425. doi: 10.1039/c6ob02057g.
Computational investigations of the α-ketoacid-hydroxylamine amide-forming (KAHA) ligation of O-unsubstituted (type-I) and O-benzoyl substituted (type-II) hydroxylamine have revealed a distinct mechanistic pathway for the KAHA ligation reactions. Instead of a pathway involving lactone and oxiridine intermediates for the reaction of O-unsubstituted hydroxylamine and ketoacids (type-I KAHA), as had been proposed in the experimental studies, the computational results favor the pathway which involves migration of the hydroxy group (-OH) to the adjacent carbon in one of the key steps. The new pathway for the type I KAHA reaction explains the distribution of the O label in the final product (amide) that is observed in O labeling experiments of type-I ligation reaction. A coherent mechanistic course is also identified for the reaction of O-benzoyl substituted hydroxylamine and ketoacid (type II KAHA) reactions. The proposed pathway for the type-II KAHA ligation reaction proceeds with the retention of an oxygen atom of the keto group of ketoacids rather than hydroxylamine in the final product (amide). These findings are consistent with the results of O labeling experiments performed by Bode and coworkers on the KAHA reactions.
对O-未取代（I型）和O-苯甲酰基取代（II型）羟胺的α-酮酸-羟胺酰胺形成（KAHA）连接反应的计算研究揭示了KAHA连接反应的独特机理途径。与实验研究中提出的O-未取代羟胺与酮酸反应（I型KAHA）涉及内酯和环氧乙烷中间体的途径不同，计算结果支持在关键步骤之一中羟基（-OH）迁移至相邻碳的途径。I型KAHA反应的新途径解释了在I型连接反应的O标记实验中观察到的最终产物（酰胺）中O标记的分布。还确定了O-苯甲酰基取代的羟胺与酮酸反应（II型KAHA）的连贯机理过程。II型KAHA连接反应的 proposed途径在最终产物（酰胺）中保留了酮酸酮基的一个氧原子，而不是羟胺的氧原子。这些发现与Bode及其同事对KAHA反应进行的O标记实验结果一致。
