We envisioned that Lewis acids might also aid post-translational Friedländer macrocyclization reactions to generate products with a quinoline pharmacophore embedded within the peptide backbone. To test this idea, we prepared four linear peptides containing both an N-terminal β-keto amide and an internal 2-aminoarylcarbonyl side chain provided by the non-canonical amino acid kynurenine (Fig. and Supplementary Fig. ). The linear peptide LP1 is a heptapeptide related to the FDA-approved drug octreotide , while LP2 is a hexapeptide containing a turn-inducing L-proline, LP3 is a decapeptide bearing diverse functional groups, and LP4 is a longer diverse tridecapeptide related to the hormone somatostatin . All four linear peptides LP1-4 (1 mM) underwent intramolecular Friedländer reactions to generate macrocycles CP1-4 (Supplementary Fig. ) in the presence of 1-2 mM Yb(OTf) 3 in EtOH or MeCN at 60 °C, as supported by LC-HRMS (Fig. and Supplementary Fig. ) and NMR experiments (Supplementary Fig. and and Supplementary Data). The smaller peptides LP1 and LP2 cyclized cleanly and the macrocyclic products CP1 and CP2 could be isolated with efficiencies that tracked well with LC-MS and HPLC chromatograms of reaction progress. CP1 and CP2 were isolated as salts in complex with TFA employed in the isolation procedure (see Supplementary Material). Cyclization of the larger peptides LP3 and LP4 proceeded under analogous conditions to deliver their corresponding macrocycles with reduced, but still notable efficiency. For comparison, macrocyclization reactions of LP1-4 were also performed under aqueous conditions (80 mM glycine pH 2.8 at 60 °C); in all cases, cyclization proceeded faster using the Lewis acid Yb(OTf) 3 (Supplementary Fig. ). The isolated macrocycles CP1-CP4 were also characterized by MALDI-TOF MS to confirm the monomeric mass and the absence of significant quantities of higher order oligomers (Supplementary Fig 25 and Supplementary Data).