Catalysis

Site-selective Amide Functionalization by Catalytic Azoline Engrafting

Authors

Abstract

Amide activation is a challenging transformation due to 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 re-main scarce. Here, by combining the desired features from both catalytic regimes we designed an artificial cyclodehy-dratase, a catalytic system for site-selective modification of peptides and natural products by engrafting heterocyclic into their scaffolds. The catalytic system features molybdenum(VI) center that was decorated with a sterically congest-ed 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 direct func-tionalization of a single amide group in the presence of up to seven other chemically similar positions, and direct conversion into amines and thioamides. This new mechanistic paradigm may address an unmet need for a general method for selective and sustainable functionalization of peptides and natural products.

Content

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Supplementary material

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Supplementary Information
Detailed experimental protocols, copies of NMR spectra, computational details.