Scanning nitrogen in sp(3)-rich scaffolds enabled by carbonyl-to-nitrogen atom swap
Summary
Medicinal chemistry campaigns routinely require access to series of saturated nitrogen heterocycle (SNH)-based analogs that place nitrogen at different positions to probe structure-activity relationships. However, systematic preparation of N-positional variants remains synthetically burdensome. In this work, we report a strategy for nitrogen scanning in sp3-rich scaffolds enabled by the exchange of a carbonyl group with an amine moiety, formally achieving a carbonyl-to-nitrogen (CO-to-N) a
Content
# Scanning nitrogen in sp(3)-rich scaffolds enabled by carbonyl-to-nitrogen atom swap
*Published: 2026 Apr 30*
Medicinal chemistry campaigns routinely require access to series of saturated
nitrogen heterocycle (SNH)-based analogs that place nitrogen at different
positions to probe structure-activity relationships. However, systematic
preparation of N-positional variants remains synthetically burdensome. In this
work, we report a strategy for nitrogen scanning in sp3-rich scaffolds enabled
by the exchange of a carbonyl group with an amine moiety, formally achieving a
carbonyl-to-nitrogen (CO-to-N) atom swap. Because ketone positional isomers can
be readily obtained through carbonyl transposition or carbon-hydrogen oxidation
from a common carbocyclic precursor, the CO-to-N atom swap greatly streamlines
the preparation of SNH positional analogs and obviates the need for multiple de
novo syntheses. The CO-to-N reaction exhibits exceptional functional group
compatibility and generality, which makes it well suited for late-stage
modification of complex bioactive molecules and for isotopic labeling.
DOI: 10.1126/science.aef0610