Synthesis and conformational studies of alpha/beta(2,3)-peptides derived from alternating beta(2,3)-amino acids and L-Ala repeats

Cyclic beta(2,3)-amino acids though have been extensively used in foldamer designs, their acyclic analogues have received less attention. In view of strong backbone constraints imparted by the substituents, beta(2,3)-amino acids provide very attractive options for creating novel foldamers. In the present study, new C-linked carbo-beta(2,3)-amino acids (beta(2,3)-Caa) were prepared by the alkylation of C alpha-carbon (C2) with allyl and propargyl halides, and used with L-Ala to design regular 1 : 1 hybrid alpha/beta(2,3)-peptides. Extensive NMR and MD studies revealed the presence of right-handed 11/9-mixed helices in the peptides with the 'alpha-beta-alpha' sequence at the C-terminus, while, induction of 'turns' in the peptides with the 'beta-alpha-beta' motif at the C-terminus. Despite the strong backbone constraints due to the substitution at both the beta(2) and beta(3)-carbons, the folds of these alpha/beta(2,3)-peptides are less robust compared to foldamers of the alpha/beta(3)-family, reflecting the impact of C alpha-substitution.