HOAt

HOAt is a coupling reagent that promotes peptide bond formation between carboxylic acids and amines by first reacting with the acid to generate an activated intermediate, which then reacts with the amine to form the amide^[1]. The nitrogen at the 7-position in HOAt provides a classic neighboring group effect that can both increase the reactivity and reduce racemization^[2]. In combination with 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) and N,N′-diisopropylethylamine (DIPEA), HOAt can be employed to promote the amide-bond-forming step between amino-modified DNA and carboxylic acids during the construction of DNA-encoded combinatorial libraries^[3]. HOAt functions as a non-mutagenic pharmaceutical reagent, a common drug impurity and a metal-binding pharmacophore, while also exhibiting pronounced corrosion-inhibition activity toward mild steel^[4-5]. HOAt can be used with HOBt in a relay fashion to catalyze the route from α-reducible aldehydes and amines to α-reduced amides^[6].

References:
[1] Nicolette J, Neft RE, Vanosdol J, Murray J. Peptide bond-forming reagents HOAt and HATU are not mutagenic in the bacterial reverse mutation test. Environ Mol Mutagen. 2016 Apr;57(3):236-40. doi: 10.1002/em.21997.
[2] Subirós-Funosas R, Prohens R, Barbas R, El-Faham A, Albericio F. Oxyma: an efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion. Chemistry. 2009 Sep 21;15(37):9394-403.
[3] Li Y, Gabriele E, Samain F, et al. Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries. ACS Comb Sci. 2016;18(8):438-443.
[4] Liu X, Yan W, Yang G, et al. 1-hydroxy-7-azabenzotriazole-cinnamic esters as anti-Toxoplasma gondii agents. Nat Prod Res. Published online May 8, 2025.
[5] Gao L, Peng S, Gong Z, Chen J. A combination of experiment and theoretical methods to study the novel and low-cost corrosion inhibitor 1-hydroxy-7-azabenzotriazole for mild steel in 1 M sulfuric acid. RSC Adv. 2018;8(67):38506-38516.
[6] Vora HU, Rovis T. Nucleophilic carbene and HOAt relay catalysis in an amide bond coupling: an orthogonal peptide bond forming reaction. J Am Chem Soc. 2007 Nov 14;129(45):13796-7. doi: 10.1021/ja0764052.

HOAt是一种偶联试剂，通过与羧酸先反应生成活性中间体，再与胺反应形成酰胺，从而促进羧酸与胺之间肽键的形成^[1]。HOAt的7位氮原子提供经典的邻基效应，可同时提高反应活性并减少消旋^[2]。在1-乙基-3-(3-二甲氨基丙基)碳二亚胺（EDC）和N,N′-二异丙基乙胺（DIPEA）的协同下，HOAt可用于促进DNA编码组合文库构建过程中氨基修饰DNA与羧酸之间的酰胺键形成步骤^[3]。HOAt兼具非致突变药用试剂、常见药物杂质和金属结合药效团的身份，同时对低碳钢具有显著的缓蚀作用^[4-5]。HOAt可与HOBt接力使用，催化α-可还原醛和胺生成α-还原酰胺的路径^[6]。