Alternating asymmetric self-induction in functionalized pyrrolidine oligomers

Artificial structurally well-defined polymers have excited interest as functional mimetics of natural biomacromolecules, exhibiting additional properties not occurring in the living world. Specific conformational organization of natural and synthetic polymeric objects leading to unique folding accounts for the molecular recognition, which is one of the driving principles in important natural processes. Some nonnatural oligomeric species adopt specific and well-defined conformations dictated by the structure of monomeric units and intramolecular interactions and are defined as foldamers. One of the most studied unnatural foldamer types are bpeptides that adopt stable folded helical, sheet, and turn-like conformations. b-Peptides are stable towards natural enzymes, and appropriate design leads to discovery of bpeptide ligands for complicated pharmaceutical targets, such as protein–protein interactions. The application of pyrrolidine-3-carboxylic acid (Pca) for the construction of bpolypeptide chain rigidifies the molecular backbone and provides additional stabilization of the secondary structure of the oligomer in solution. The typical synthesis of a b-peptide backbone is based on the arsenal of peptide chemistry methods, including routine sequences of amino group protection–deprotection steps and multiple activations of carboxylic functionality for amide bond construction. Herein we disclose a fundamentally novel synthetic method towards well-defined highly functionalized short b-peptides that avoids protection, deprotection, and activation procedures and allows to generate efficiently stereoregular oligomeric pyrrolidine-based molecules. The developed method, called cycloadditive oligomerization, has been used for the synthesis of a set of racemic and enantiopure oligomers containing a Pca backbone. The realized approach determines highly diverse structural characteristics of b-peptide oligomers, which are characterized by various physicochemical methods, including X-ray analysis. The oligomerization utilized azomethine ylide 1,3-dipolar cycloaddition as a chain-growth approach (Scheme 1). 5Arylpyrrolidine-2,4-dicarboxylate units serve both as linked elements and as auxiliaries to determine stereoand enantioselectivities of the cycloaddition process. The starting 5arylpyrrolidine-2,4-dicarboxylic acid diesters 3a (X=H, Br) for oligomer synthesis were obtained from iminoesters 1 and tert-butyl acrylate in racemic and enantiopure forms by 1,3-dipolar cycloaddition using Lewis acids for the azomethine ylide generation step (Scheme 1, Table 1). Asymmetric synthesis of the monomer ( )-3a-H was effectively conducted with the enantiopure ligand 4 on a gram scale, and single recrystallization provided the target compound with more than 99% ee. Subsequent N-acryloylation of monomers 3a with acryloyl chloride transformed them into dipolarophiles 2b with a sterically hindered amide residue connected to the ethylene fragment. We supposed that these unique dipolarophiles would induce good diastereoand enantioselectivities under iterative cycloaddition steps with iminoesters 1 (Scheme 1). Indeed, dimers 3b were effectively synthesized by cycloaddition of acrylamides 2b with Schiff bases 1 (X=H, Br) in presence of AgOAc as a Lewis acid agent for azomethine ylide generation (Table 1, entries 4–6). Comparison of H NMR spectra of the cycloaddition reaction mixtures and