Postelongation Strategy for the Introduction of Guanidinium Units in the Main Chain of Helical Oligourea Foldamers

Abstract

The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural γ-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group.

C-Terminal-Modified Oligourea Foldamers as a Result of Terminal Methyl Ester Reactions under Alkaline Conditions

“…Over the years the (oligo)urea backbone has undergone various modifications and the impact of these changes on the structural properties of the new analogs has been investigated. This has led to the conclusion that the 2.5-helical structures of oligoureas are robust and it is possible to substitute the urea residue with γ-amino acid [ 6 , 18 ], carbamate [ 18 , 19 ], thiourea [ 20 ], guanidinium [ 21 ] and also N-methylated [ 22 ] or urea residues with noncanonical substitution patterns [ 23 ] without the loss of the structural integrity of the new molecule. It has also been shown that urea fragments as short as three residues can induce a helical conformation when fused to a peptide too short to fold into a stable secondary structure [ 24 , 25 ].…”

Structural Consequences of N‐Methylation of N‐Terminus in Oligourea Foldamers

“…There are many examples of chemical modification within the urea group in foldamers of this type. There are oligomers where the oxygen atom has been substituted with sulfur or selenium, [35,36,37] or also with nitrogen [37,38] . The NH group, on the other hand, has been replaced with CH 2 [39,40] or oxygen [39,41] .…”

“…There are oligomers where the oxygen atom has been substituted with sulfur or selenium, [35,36,37] or also with nitrogen. [37,38] The NH group, on the other hand, has been replaced with CH 2 [39,40] or oxygen. [39,41] The influence of these modifications on the secondary structure has been investigated.…”