Large ring-forming alkylations provide facile access to composite macrocycles† †Electronic supplementary information (ESI) available: Fig. S1–S4, list of macrocycles prepared, experimental procedures, and spectroscopic data. CCDC 1023942. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc03848g Click here for additional data file. Click here for additional data file.

Macrocyclic compounds have potential to enable drug discovery for protein targets with extended, solventexposed binding sites. Crystallographic structures of peptides bound at such sites show strong surface complementarity and frequent aromatic side-chain contacts. In an effort to capture these features in stabilized small molecules, we describe a method to convert linear peptides into constrained macrocycles based upon their aromatic content. Designed templates initiate the venerable Friedel– Crafts alkylation to form large rings efficiently at room temperature – routinely within minutes – and unimpeded by polar functional groups. No protecting groups, metals, or air-free techniques are required. Regiochemistry can be tuned electronically to explore diverse macrocycle connectivities. Templates with additional reaction capabilities can further manipulate macrocycle structure. The chemistry lays a foundation to extend studies of how the size, shape and constitution of peptidyl macrocycles correlate with their pharmacological properties.