Deconstructive diversification of cyclic amines

Deconstructive functionalization involves carbon–carbon (C–C) bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis 1 and olefin metathesis 2 , 3 have allowed each carbon in C=C double bonds to be viewed as a functional group. Despite the substantial advances in deconstructive functionalization involving the scission of C=C double bonds, there are very few methods that achieve C( sp 3 )–C( sp 3 ) single-bond cleavage and functionalization, especially in relatively unstrained cyclic systems. Here we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, which are important moieties in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C( sp 3 )–N and C( sp 3 )–C( sp 3 ) single-bond cleavage followed by C( sp 3 )–halogen bond formation. The resulting acyclic haloamines are versatile intermediates that can be transformed into various structural motifs through substitution reactions. In this way we achieve the skeletal remodelling of cyclic amines, an example of scaffold hopping. We demonstrate this deconstructive strategy by the late-stage diversification of proline-containing peptides. The silver-mediated deconstructive functionalization of saturated nitrogen heterocycles via acylic haloamine intermediates provides access to various acyclic amines as well as enabling ring contraction and skeletal remodelling.