Recently, we reported that linear peptides with a β-dicarbonyl functionality at the N-terminus could be synthesized ribosomally using in vitro translation to generate novel β-dicarbonyl-peptide hybrid molecules . Other β-dicarbonyl functionality could be introduced into polypeptides using orthogonal aminoacyl-tRNA synthetases . In both cases, the β-dicarbonyl species reported were derivatives of malonic acid, which are among the least reactive of all 1,3-dicarbonyl species, especially under mild conditions. We hypothesized that if we could ribosomally incorporate a more reactive β-dicarbonyl species at the N-terminus, then the resulting peptide or protein could be modified post-translationally into a heterocyclic pharmacophore using any one of a number of classic or modern chemical transformations. If the post-translational modification made use of a side chain as a co-substrate, then the resulting macrocycle would contain an embedded heterocycle. Such a macrocyclization strategy embodies the post-translational modification logic of RiPP natural products while appropriating chemical intermediates produced by polyketide synthase modules.