General Installation of (4H)-Imidazolone cis-Amide Bioisosteres Along the Peptide Backbone

Imidazolones represent an important class of heterocycles present in a wide-range of pharmaceuticals, metabolites, naturally-occurring bioactive natural products, and serve as the active chromophore in green fluorescent protein (GFP). Recently imidazolones have received attention for their ability to act as an amide bond bioisotere to improve pharmacokinetic properties. Herein we present a tandem amidine installation and subsequent cyclization with an adjacent ester to yield (4H)-imidazolone products. By using amino acid building blocks, we can access the first examples of alpha-chiral imidazolones which have been previously inaccessible. Additionally, our method is amenable to on-resin installation and can be integrated seamlessly into existing solid-phase peptide synthesis (SPPS) protocols. Finally, we show that imidazolones can act as \textit{cis}-amide bond surrogates to assist in pre-organizing linear peptides for head-to-tail macrocyclization. This work represents the first general approach to backbone and side-chain insertion of imidazolone bioisosteres at various positions in linear and cyclic peptides.