Deconstructive diversification of cyclic amines.

Abstract

Deconstructive functionalization involves C–C bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2, 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(sp3)–C(sp3) 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(sp3)–N/C(sp3)–C(sp3) single bond cleavage followed by C(sp3)–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.