Rational Design of an Organocatalyst for Peptide Bond Formation
Rational Design of an Organocatalyst for Peptide Bond Formation
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DOI：
10.1021/jacs.9b07742
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发表时间：
2019-10-09
影响因子：
15
通讯作者：
Arora, Paramjit S.
中科院分区：
文献类型：
--
作者：
Handoko;Satishkumar, Sakilam;Arora, Paramjit S.
酰胺键普遍存在于肽、蛋白质、药物和聚合物中。酰胺键的形成是一个简单的过程：由于有效偶联剂的可用性，酰胺键可以相对容易地合成。然而，对于不需要过量试剂的方法存在实质性需求。缩合氨基酸的催化剂可以通过减少肽合成过程中产生的大量废物而产生重要影响。我们描述了一种仿生催化剂的合理设计，可以有效地耦合具有标准保护基团的氨基酸。催化剂设计结合了从酶、肽生物合成和有机催化剂中吸取的经验教训。在优化的条件下，5摩尔%的催化剂有效地偶联Fmoc氨基酸没有显着的外消旋。重要的是，我们证明了催化剂是功能性的寡肽固相合成。该结果是重要的，因为它说明了催化剂在具有大量酰胺键的基底上起作用的潜力，这可以预期抑制氢键催化剂。
Amide bonds are ubiquitous in peptides, proteins, pharmaceuticals, and polymers. The formation of amide bonds is a straightforward process: amide bonds can be synthesized with relative ease because of the availability of efficient coupling agents. However, there is a substantive need for methods that do not require excess reagents. A catalyst that condenses amino acids could have an important impact by reducing the significant waste generated during peptide synthesis. We describe the rational design of a biomimetic catalyst that can efficiently couple amino acids featuring standard protecting groups. The catalyst design combines lessons learned from enzymes, peptide biosynthesis, and organocatalysts. Under optimized conditions, 5 mol % catalyst efficiently couples Fmoc amino acids without notable racemization. Importantly, we demonstrate that the catalyst is functional for the synthesis of oligopeptides on solid phase. This result is significant because it illustrates the potential of the catalyst to function on a substrate with a multitude of amide bonds, which may be expected to inhibit a hydrogen-bonding catalyst.