Unique Stereoselective Homolytic C-O Bond Activation in Diketopiperazine-Derived Alkoxyamines by Adjacent Amide Pyramidalization

Simple monocyclic diketopiperazine (DKP)-derived alkoxyamines exhibit unprecedented activation of a remote C-O bond for homolysis by amide distortion. The combination of strain-release-driven amide planarization and the persistent radical effect (PRE) enables a unique, irreversible, and quantitative tran -> scis isomerization under much milder conditions than typically observed for such homolysis-limited reactions. This isomerization is shown to be general and independent of the steric and electronic nature of both the amino acid side chains and the substituents at the DKP nitrogen atoms. Homolysis rate constants are determined, and they significantly differ for both the labile trans diastereomers and the stable cis diastereomers. To reveal the factors influencing this unusual process, structural features of the kinetic trans diastereomers and thermodynamic cis diastereomers are investigated in the solid state and in solution. X-ray crystallographic analysis and computational studies indicate substantial distortion of the amide bond from planarity in the trans-alkoxyamines, and this is believed to be the cause for the facile and quantitative isomerization. Thus, these amino-acid-derived alkoxyamines are the first examples that exhibit a large thermodynamic preference for one diastereomer over the other upon thermal homolysis, and this allows controlled switching of configurations and configurational cycling.