Direct peptide and protein activation is a challenging transformation because of the stabilizing effect of the amide group. While enzymes can be considered as prototypical systems that have evolved to achieve high selectivity and specificity, small-molecule catalysts that functionalize the amide group may accommodate a much larger selection of substrates but currently remain scarce. Here, by combining the desired features from both catalytic regimes we designed an artificial cyclodehydratase, a catalytic system for the site-selective modification of peptides and natural products by engrafting heterocycles into their scaffolds. The catalytic system features a molybdenum(VI) center that was decorated with a sterically congested tripod ligand. The optimized catalyst can introduce azolines into small molecules, natural products, and oligopeptides with high efficiency and minimal waste. We further demonstrate the utility of the new protocol in the direct functionalization of a single amide group in the presence of up to seven other chemically similar positions and in the direct conversion of these groups into amines and thioamides. This new mechanistic paradigm may address an unmet need for a general method for the selective and sustainable functionalization of peptides and natural products.

中文翻译：

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通过催化唑啉接枝进行位点选择性酰胺功能化

由于酰胺基团的稳定作用，直接激活肽和蛋白质是一项具有挑战性的转化。虽然酶可以被认为是已经进化以实现高选择性和特异性的原型系统，但功能化酰胺基团的小分子催化剂可以容纳更多的底物选择，但目前仍然稀缺。在这里，通过结合两种催化机制的所需特征，我们设计了一种人工环化脱水酶，这是一种催化系统，用于通过将杂环化合物移植到它们的支架中来对肽和天然产物进行位点选择性修饰。该催化系统具有钼 (VI) 中心，该中心装饰有空间拥挤的三脚架配体。优化后的催化剂可以将唑啉引入小分子、天然产物、和寡肽具有高效率和最小的浪费。我们进一步证明了新方案在存在多达七个其他化学相似位置的情况下直接功能化单个酰胺基团以及将这些基团直接转化为胺和硫代酰胺的效用。这种新的机制范式可以解决对肽和天然产物的选择性和可持续功能化的通用方法的未满足需求。