2018-05-06760DDeconstructive diversification of cyclic amines

Deconstructive functionalization involves 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 significant advances in deconstructive functionalizations involving scission of C–C double bonds, there are very few methods that achieve C(sp(3))–C(sp(3)) single bond cleavage/functionalization, especially in relatively unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, important moities in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp(3))–N/C(sp(3))–C(sp(3)) single bond cleavage followed by C(sp(3))–halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.