Two-Component Redox Organocatalyst for Peptide Bond Formation
Two-Component Redox Organocatalyst for Peptide Bond Formation
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DOI：
10.1021/jacs.1c12798
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发表时间：
2022-03-02
影响因子：
15
通讯作者：
Arora, Paramjit S.
中科院分区：
文献类型：
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作者：
Handoko;Panigrahi, Nihar R.;Arora, Paramjit S.
肽是一种重要的治疗手段，其序列特异性合成可以实现自动化。然而，现代肽合成在原子经济性方面仍存在不足，并且为了高效形成酰胺键，需要过量的偶联剂和受保护的氨基酸。我们最近阐述了一种有机催化剂的合理设计，该催化剂可作用于Fmoc氨基酸（自动化肽合成中的标准单体，《美国化学会志》2019年，第141卷，第15977页）。催化循环的核心是将羧酸转化为硒代酯，后者通过一个氢键支架活化以实现与胺的偶联。硒代酯由二硒化物催化剂和化学计量的膦原位生成。尽管之前的体系能够在固相上催化寡肽合成，但它有两个显著的要求限制了其作为偶联剂替代物的实用性——它依赖化学计量的膦，并且需要分子筛作为脱水剂。在此，我们通过一种优化方法解决了这些限制，该方法仅需催化量的膦且无需脱水剂。这种新方法利用双组分有机还原剂/有机氧化剂循环策略来催化酰胺键的形成。
Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide synthesis remains atom uneconomical and requires an excess of coupling agents and protected amino acids for efficient amide bond formation. We recently described the rational design of an organocatalyst that can operate on Fmoc amino acids-the standard monomers in automated peptide synthesis (J. Am. Chem. Soc. 2019, 141, 15977). The catalytic cycle centered on the conversion of the carboxylic acid to selenoester, which was activated by a hydrogen bonding scaffold for amine coupling. The selenoester was generated in situ from a diselenide catalyst and stoichiometric amounts of phosphine. Although the prior system catalyzed oligopeptide synthesis on solid phase, it had two significant requirements that limited its utility as an alternative to coupling agents-it depended on stoichiometric amounts of phosphine and required molecular sieves as dehydrating agent. Here, we address these limitations with an optimized method that requires only catalytic amounts of phosphine and no dehydrating agent. The new method utilizes a two-component organoreductant/organooxidantrecycling strategy to catalyze amide bond formation.