Ribosomal Synthesis of Ketone-containing Peptide Backbone via O to C Acyl Shift

Despite tremendous efforts to engineer translational machinery, replacing the encoded peptide backbone with new-to-Nature structures remains a significant and largely unmet challenge. C, H, O, and N are the elements of life, and yet ribosomes are only capable of forming C–N bonds as amides, C–O bonds as esters, and C–S bonds as thioesters; there is no current strategy to form C–C bonds as ketones embedded in the backbone of ribosomal products. We discovered that peptides containing a dehydrolactic acid motif rapidly isomerize to generate a backbone-embedded α,γ-diketoamide via a spontaneous formal O to C acyl shift. The dehydrolactic acid motif can be introduced into peptides ribosomally or via solid-phase synthesis using α-hydroxy phenylselenocysteine followed by oxidation. Subsequent incubation at physiological pH produces an α,γ-diketoamide that can be diversified using a variety of nucleophiles, including hydrazines and hydroxylamines to form pyrazoles and oximes, respectively. All of these groups remain embedded directly within the polypeptide backbone. This general strategy, predicated on an intricate cascade of acyl rearrangements, provides the first example of a C–C bond forming reaction to take place within the peptide backbone, as well as the first ribosomal strategy for generating protein-like materials with diverse, backbone-embedded heterocycles. The genetically encoded, new-to-nature biopolymers produced should accelerate the discovery of genetically encoded molecules whose properties better resemble those of bioactive natural products.