One step synthesis of foldamers with tridimensional catalytic center for C-C bond formation

Peptides have been extensively exploited as efficient catalysts in a variety of reactions. Their structures and functionalities can be varied by changing amino acid components and by rationally designing their secondary structures, such as α-helix, β-turn and β-sheet, in order to build suitable reaction environments around catalytic centers. Foldamers have emerged as synthetic, conformationally well-defined mimics of proteins and other biopolymers, in the way to allow chemists to expand the narrow range of structural components that build up natural proteins. Thus, foldamers have been designed to carry out protein-like functions of binding, catalysis and signal relay. Recently, Gellman and co-workers, exploiting a combination of α- and β-amino acids, developed a set of foldamers carrying on their surface one primary amine and one secondary amine functions at varying sequence positions. A foldamer featuring the two functionalities spaced by one helical turn proved to be a potent catalyst for macrocycle formation from linear dialdehyde precursors through carbon-carbon bond formation. The high efficiency of the system is related to the rigid foldamer conformation, which allows spatial control of the relative positioning of the catalytic diad. We speculated that if one of the functionalities of the catalytic diad can be placed directly into the backbone of a helical foldamer rather than at a side-chain position, then the versatility of the system could be expanded, possibly opening the way to catalytic triads. To this aim, peptide-based foldamers containing a -CH2-NH- moiety as replacement of one peptide bond ([CH2NH] in the notation for peptide bond surrogates) represent suitable candidates. Concerning the helical foldameric scaffold, we relied on the well documented ability of α-aminoisobutyric acid (Aib), to promote stable and highly populated α-/310-helical conformations when combined with protein amino acids in α-peptides even of limited main-chain length. In this work, we report on the catalytic properties of foldamers designed on the basis of the considerations outlined above, which displayed high efficiency to template a C-C bond macrocyclization mediated by primary/secondary amine via imine-enamine chemistry, as well as examples of aldol condensation reactions.