Solid-Phase Synthesis and Circular Dichroism Study of β-ABpeptoids

Abstract

The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated β2-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were shown to adopt folding conformations. Here, we report β-ABpeptoids having chiral methyl group at β-positions rather than α-positions as a different class of peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the synthesis of β-ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR studies. Overall, these results suggest that β-ABpeptoids represent a novel class of peptidomimetic foldamers that will find a wide range of applications in biomedical and material sciences.

Per-Residue Program of Multiple Backbone Dihedral Angles of β-Peptoids via Backbone Substitutions

“…Here, we report a strategy for per-residue control of two backbone dihedral angles, ω and φ, of β-peptoids and a unique loop shape adopted by the β-peptoid with the dihedral controls. Recently, we and others proposed that the introduction of substituents on backbone carbons of β-peptoids would be useful for constraining the conformation of β-peptoids. − However, preliminary NMR analysis conducted in these studies suggests that small methyl substituents at these positions do not bias ω-angles of β-peptoids. In addition, circular dichroism (CD) spectroscopic analysis conducted in these studies does not provide concrete evidence for strong folding of the oligomers.…”

Oligo(β-peptoid)s with Backbone Chirality from Aspartic Acid Derivatives: Synthesis and Property Investigation

“…As shown in Figure 3 a, P( N MeP-Asp-OMe) 10 displayed characteristic CD signals with intense minima around 208 nm and shallow minima around 230 nm at pH ∼ 7, which were identical in shape to those of oligo(β-peptoid)s prepared by solid-phase synthesis. 15 , 16 The diblock copolypeptoids of mPEG 45 - b -P( N MeP-Asp-OMe) 13 and mPEG 113 - b -P( N MeP-Asp-OMe) 22 showed nearly identical CD signals to P( N MeP-Asp-OMe) 10 , indicating the similarly ordered structure ( Figure S11b,c ). Also, mPEG 45 - b -P( N t BuP-Asp-OMe) 9 and mPEG 113 - b -P( N t BuP-Asp-OMe) 18 presented ordered structures with intense minima around 195 nm and shallow minima around 228 nm ( Figure S11d,e ).…”

“… 12 , 13 Furthermore, the extra C–C bond in the β-peptoid backbone would greatly expand the potential diversity of the peptoid shape as compared to α-peptoids. 5 , 14 − 16 In this regard, a great deal of effort has been made to develop poly(β-peptoid) materials with interesting structures for property investigation and biological applications in recent years. 14 − 19 …”

“…Besides, β-ABpeptoids with chiral groups at β-positions rather than α-positions were prepared via a submonomer solid-phase strategy. 14 , 16 , 21 Very recently, Morimoto and co-workers reported that the introduction of bulky substituents at β-carbon- would strongly promote the folding of β-peptoids. 14 All of the abovementioned β-peptoids are synthesized by the monomer or unique “submonomer” method, 4 where the β-peptoid chain is extended in an iterative and stepwise manner.…”

Solid‐Phase Synthesis of Peptidomimetics with Peptide Backbone Modifications

“…Next, solid-phase synthesis of β-ABpeptoids was reported by Sable et al (Scheme 6, Path 3). [48] The N-benzyl and N-naphthyl monomers with a chiral methyl group at the β position of 81 were prepared in solution phase and β-ABpeptoid elongation proceeded in a similar fashion to the previous reports.…”