期刊
ACS CATALYSIS
卷 -, 期 -, 页码 7789-7797出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.2c019387789
关键词
peptides; molybdenum; site-selective functionalization; azoline; azole
资金
- National Institutes of Health [R01GM138682]
- University of Colorado Boulder
- National Science Foundation [ACI-1532235, ACI-1532236]
- Colorado State University
By designing an artificial cyclodehydratase, we achieved siteselective modification of peptides and natural products, efficiently introducing heterocycles into these molecules with minimal waste. This new mechanistic paradigm may address the need for selective and sustainable functionalization of peptides and natural products.
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 siteselective 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.
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