Skeletal editing of 4-arylpyrimidines into diverse nitrogen heteroaromatics via four-atom synthons
Abstract Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. We present here a distinct scaffold hopping strategy for the skeletal editing of pyrimidines into a wide ran...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62547-7 |
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| Summary: | Abstract Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. We present here a distinct scaffold hopping strategy for the skeletal editing of pyrimidines into a wide range of heteroarenes through the addition of nucleophiles, ring-opening, fragmentation, and ring-closing (ANROFRC) processes. This method features the in situ generation of a vinamidinium salt intermediate, which serves as a unique N-C-C-C four-atom (A4) synthon that reacts with A1 and A2 synthons. Mechanistic studies reveal that C4-aryl substituents play a crucial role in stabilizing the vinamidinium salt intermediate. This work provides a powerful tool for the systematic construction and modification of nitrogen heterocycles, thereby expanding conventional molecular editing techniques. |
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| ISSN: | 2041-1723 |