Framework Editing of Macrocycles Through Catalytic Olefin Metathesis

Bioactive macrocyclic compounds are valuable platforms in drug discovery.

More often than not, natural products represent attractive leads, the structures of which may be altered by chemical synthesis to enhance efficacy, lower toxicity, and superior physicochemical properties.

The proposed project aims to a practical and programmable strategy for precise skeletal editing of large ring structures by aligning catalytic ring-opening metathesis, site- and/or stereoselective modification of the linear intermediates, and formation re-formation of the macrocycle through catalytic ring-closing metathesis.

The advance will significantly enhance our ability to navigate hitherto unexplored chemical space, needed for drugs discovery. The proposed investigations are centered on epothilone C, an important naturally occurring compound.

We will to demonstrate the versatility of our approach by precise framework editing of this anticancer agent in a systematic way.

The first phase will entail Z-to-E isomerization of the macrocyclic alkene, an alteration that will significantly change the molecule’s three-dimensional shape.

This will be followed by site specific insertion of a methylene or a hydroxy methylene at one or both sides of the acyclic allylic sites. We will then re-close the ring. Similarly, ring contraction will be implemented through deletion of one or two methylene groups. Finally, ring expansion and ring contraction will be combined to achieve ring distortion.