Deconstructive diversification of cyclic amines

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Deconstructive functionalization typically involves cleaving carbon-carbon double bonds.
• Methods for cleaving and functionalizing carbon-carbon single bonds, especially in cyclic systems, are limited.
• Nitrogen heterocycles are crucial scaffolds in many bioactive molecules.

Purpose of the Study:

• To develop a deconstructive strategy for saturated nitrogen heterocycles.
• To achieve C(sp³)-N and C(sp³)-C(sp³) single-bond cleavage and functionalization.
• To generate versatile halogen-containing acyclic amine derivatives.

Main Methods:

• Sequential C(sp³)-N and C(sp³)-C(sp³) single-bond cleavage of nitrogen heterocycles.
• Functionalization via C(sp³)-halogen bond formation.
• Application to late-stage diversification of proline-containing peptides.

Main Results:

• Successful transformation of piperidines and pyrrolidines into acyclic haloamines.
• Demonstration of skeletal remodeling of cyclic amines (scaffold hopping).
• Generation of versatile intermediates for further synthetic modifications.

Conclusions:

• The developed method provides a new route for functionalizing saturated nitrogen heterocycles.
• Acyclic haloamines serve as valuable building blocks for diverse molecular structures.
• This strategy facilitates late-stage diversification in drug discovery and development.