Abstract
Efforts to emulate biological oligomers have given rise to a host of useful technologies, ranging from solid-phase peptide and nucleic acid synthesis to various peptidomimetic platforms. Herein we introduce a novel class of peptide-like oligomers called "peptidines" wherein each carbonyl O-atom within poly-N-alkyl glycine oligomers is replaced with a functionalized N-atom. Compared to peptoids or peptides, the presence of this amidine N-substituent in peptidines effectively doubles the number of diversification sites per monomeric unit, and can decrease their overall conformational flexibility. We have developed iterative solution- and solid-phase protocols for the straightforward assembly of peptidines containing diverse backbone and amidine substituents, derived from readily available primary and secondary amines. We have also performed crystallographic and computational studies, which demonstrate a strong preference for the trans (E) amidine geometry. Given their straightforward synthetic preparation and high functional group density, peptidines have the potential to serve as useful tools for library generation, peptide mimicry, and the identification of biologically active small molecules.
Highlights
Oligomer-based synthesis is central to all known life processes
Signi cant efforts to incorporate N2-aryl substituents into solid-phase oligomers proved unsuccessful, and yielded either unreacted, resin-bound starting material or complex mixtures. These results indicate that a diverse range of N1 substituents, and electronwithdrawing N2 substituents are compatible with the solidphase peptidine synthesis platform
Our synthesis platform is currently incompatible with such electronrich groups on N2, the possibility exists that the s geometry can we have introduced a novel class of glycine-amidinebased oligomers, which we term “peptidines” readily afforded through modular synthetic approaches using both solid and solution phase chemistry
Summary
Oligomer-based synthesis is central to all known life processes. In particular, the structural and functional variety found in proteins is derived from the assembly of only 20 amino acid building blocks. Crystallographic and computational studies have demonstrated that amidines present within the peptidine scaffold prefer the trans(E) geometry of the N1 substituent with respect to the N2 nitrogen.
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