Pirrung Michael C, Schreihans Ryan S
Department of Chemistry, University of California, Riverside, CA 92521 USA.
European J Org Chem. 2016 Dec;2016(34):5633-5636. doi: 10.1002/ejoc.201601148. Epub 2016 Nov 15.
This work develops serine peptide assembly (SPA), which complements and contrasts with classic native chemical ligation (NCL). Advances in reagent-less peptide bond formation have been applied to serine (and serine models) and a range of -terminal amino acids, including bulky residues that are not amenable to NCL. The particular appeal of SPA is preparative-scale segment condensations with zero racemization risk and favourable process mass intensity (PMI). Mechanistic studies support a previously proposed reaction pathway via an initial trans-esterification step. An understanding of the factors favouring this pathway relies on hard-soft acid-base theory, where mildly activated esters with the largest carbonyl positive charge are most reactive with hydroxy amines. Novel -terminal activators have been discovered that enhance reactivity and give harmless by-products.
这项工作开发了丝氨酸肽组装（SPA），它与经典的天然化学连接（NCL）互为补充且形成对比。无试剂肽键形成方面的进展已应用于丝氨酸（以及丝氨酸模型）和一系列N端氨基酸，包括不适合NCL的大位阻残基。SPA的特别吸引力在于制备规模的片段缩合，具有零消旋风险和良好的过程质量强度（PMI）。机理研究支持了先前提出的通过初始酯交换步骤的反应途径。对有利于该途径的因素的理解依赖于软硬酸碱理论，其中具有最大羰基正电荷的轻度活化酯与羟基胺反应性最高。已发现新型N端活化剂可提高反应性并产生无害副产物。
