Abstract：
Amidations employing mixed (carbonic) anhydrides have long been favoured in peptide synthesis because of their cost-effectiveness and less waste generation. Despite their long history, no study has compared the effects of additives on the activation of mixed anhydrides and carbonic anhydrides. In this study, we investigated the amidation of mixed (carbonic) anhydride in the presence of a base and/or Brønsted acids. The use of NMI⋅HCl significantly improved the conversion of the mixed carbonic anhydride, while expediting nucleophilic attacks on the desired carbonyl group. In contrast, in the case of mixed anhydrides, neither the conversion nor the desired nucleophilic attack improved significantly. We developed a C-terminus-free N-methylated peptide synthesis method using mixed carbonic anhydrides in a micro-flow reactor. Fourteen N-alkylated peptides were synthesized in moderate to high yields (55-99 %) without severe racemization (<1 %). Additionally, a significant enhancement in the amidation between mixed carbonic anhydrides and bis-TMS-protected N-methyl amino acids with the inclusion of NMI⋅HCl was observed for the first time. In addition, we observed unexpected C-terminal epimerization of the C-terminus-free N-methyl peptides.
摘要：
使用混合(碳)酸酐的酰胺化由于其成本效益和较少的废物产生而在肽合成中一直是有利的。尽管他们历史悠久,没有研究比较添加剂对混合酸酐和碳酸酐活化的影响。在这项研究中,我们研究了在碱和/或布朗斯台德酸存在下混合（碳酸）酸酐的酰胺化。NMI·HCl的使用显著提高了混合碳酸酐的转化率,同时加快对所需羰基的亲核攻击。相比之下,在混合酸酐的情况下，转化率和所需的亲核攻击都没有明显改善。我们在微流反应器中使用混合的碳酐开发了无C末端的N-甲基化肽合成方法。以中等至高产率(55-99%)合成了14种N-烷基化肽,而没有严重的外消旋化(<1%)。此外,首次观察到包含NMI·HCl的混合碳酸酐和双TMS保护的N-甲基氨基酸之间的酰胺化作用显着增强。此外,我们观察到C-末端游离N-甲基肽的意外C-末端差向异构化。
