Synthesis and structural study of highly constrained hybrid cyclobutane-proline γ,γ-peptides

Two diastereomeric series of hybrid γ,γ-peptides derived from conveniently protected derivatives of (1 R ,2 S )- and (1 S ,2 R )-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and cis -4-amino- l -proline joined in alternation have efficiently been prepared through convergent synthesis. High-resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. ( R,S )-cyclobutane containing peptides adopt more twisted conformations than ( S,R ) diastereomers. In addition, all these γ-peptides have high tendency to aggregation providing vesicles of nanometric size, which were stable when allowed to stand for several days, as verified by transmission electron microscopy.