Ring closing metathesis of α- and β-amino acid derived dienes

Three new classes of conformationally constrained peptidomimetics, derived from modified α- and β-amino acids, have been prepared by ring closing metathesis (RCM). The first involves Cα–N′ cyclisation of the peptidic diene (23, 24, 26), the second Cβ2–N′ cyclisation (27, 28, 29), and the third N–Cβ2 cyclisation (30). The key C-centred olefin of the dienes was introduced by stereoselective α-allylation of either an α- or β-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by significant steric congestion, and the combination of a secondary amide linker and α,α-disubstitution promotes ring contraction on RCM.

Graphical abstractThree new classes of conformationally constrained (Cα–N′, Cβ2–N′, and N–Cβ2 cyclisation) peptidomimetics have been prepared by ring closing metathesis (RCM). The key C-centred olefin of the precursor diene was introduced by stereoselective α-allylation of an α- or β-amino acid. The normal favourable influence of a tertiary amide linker in the diene towards RCM is negated by significant steric congestion, and the combination of a secondary amide linker and α,α-disubstitution promotes ring contraction on RCM.Figure optionsDownload full-size imageDownload as PowerPoint slide