We hypothesized that Friedländer reactions of β-keto amide-containing peptides could be optimized using mild Lewis acid-catalyzed conditions, thus allowing for good reactivity with ribosomal peptides generated by IVT. Indeed, Lewis acids such as the chloride salts of Ce(III) and Fe(III) as well as the triflate salts of Yb(III) , Y(III) , and Zn(II) , can promote Friedländer reactions of β-ketoesters . To evaluate if they could improve atropisomer-forming reactions of β-keto amide 2-P1, we screened their effect (at 20 mol%) on the Friedländer reaction of dipeptide 5 and (2-aminophenyl)(o-tolyl)methanone (26) to generate the quinoline 27 (Supplementary Fig. and Supplementary Table ). Of all Lewis acids tested, the highest yields were obtained with Yb(OTf) 3 in ethanol. Yb(OTf) 3 was versatile, performing well in DCM, MeCN, THF, and AcOH. Although strong Brønsted acids such as triflic acid, sulfuric acid, phosphoric acid, and trifluoroacetic acid also out-performed acetic acid, these conditions are far less mild. When the Friedländer reaction of 28 and 26 was repeated, this time in the presence of 20 mol% Yb(OTf) 3 in EtOH at 60 °C for 48 h, we isolated the product 29 in 65% yield with a similar diastereomeric ratio (Fig. ). The diastereomers could be separated and subsequently characterized by H NMR (Supplementary Fig. ) and X-ray structure determination (Fig. , Supplementary Fig. & 11, and Supplementary Tables &), revealing that the (P, S) diastereomer is the major product. The stability of the atropisomeric axis was assessed by heating a pure sample of the minor diastereomer (i.e., (M, S)-29) in DMSO-d 6 at 100 °C for 18 h . Subsequent 1 H NMR analysis revealed minimal epimerization (< 1%, Supplementary Fig. ). With optimized conditions in hand, we again attempted modification of a ribosomal peptide generated by IVT. Indeed, when treated with 26 in EtOH containing Yb(OTf) 3 , the IVT synthesized β-keto amide peptide 2-P1 was transformed cleanly into the quinoline-peptide hybrid Q26-P1 after 24 h at 40 °C (Fig. and Supplementary Fig. ). Q26-P1 is presumed to exist as a mixture of atropisomers in analogy to 29, but chromatographic separation of distinct isomers by reverse phase UPLC-MS was not observed on this larger IVT peptide.