We also revisited the synthesis of mixed residue MPs with ring sizes greater than 24 atoms. It is possible that the fall off in yield for substrates containing more than five consecutive alanine residues (Figure ) is due to a propensity to form helices that hinder cyclization. Therefore, we constructed linear peptides in which more flexible units (Ahx and Ipa) were placed between the reactive amine and Oxo residues. As seen in Figure , this indeed resulted in efficient macrocyclization for compounds (MP18 and MP19) with 37 and 39 atoms, respectively, in the ring (see Supplementary Figures ). Based on these data, we speculate that the IP+ chemistry will be useful for the efficient synthesis of macrocycles spanning a much wider range of ring sizes than might have been suggested from the data shown in