Department of Chemistry New York University , New York , New York 10003 , United States.
J Am Chem Soc. 2019 Oct 9;141(40):15977-15985. doi: 10.1021/jacs.9b07742. Epub 2019 Sep 26.
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.
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：由于高效偶联剂的存在，酰胺键可以相对容易地合成。然而，人们需要一种不需要过量试剂的方法。一种可以缩合氨基酸的催化剂，如果能够减少肽合成过程中产生的大量废物，将产生重要的影响。我们描述了一种仿生催化剂的合理设计，该催化剂可以有效地偶联带有标准保护基团的氨基酸。该催化剂的设计结合了从酶、肽生物合成和有机催化剂中学到的经验。在优化条件下，5 mol%的催化剂可以有效地偶联 Fmoc 氨基酸，而没有明显的外消旋化。重要的是，我们证明了该催化剂在固相上合成寡肽是有效的。这一结果意义重大，因为它说明了该催化剂在具有多种酰胺键的底物上发挥作用的潜力，这可能会抑制氢键催化剂的作用。
