Aromatic Oligoamides with a Rare ortho‐Connectivity: Synthesis and Study of ortho‐Arylopeptoids

Abstract

Even though aromatic oligoamides composed of aromatic amino acids in a “one‐way sequence” attract ever increasing research interest, backbones connected through ortho‐linked aromatics remain rare. Herein, we present the first synthesis and study of N‐alkylated ortho‐aminomethyl‐benzamides termed “ortho‐arylopeptoids”. The ortho‐arylopeptoids may, with a few exceptions, be synthesized either in solution or on solid‐phase using unique and highly efficient submonomer methods with similar levels of high generality and efficiency to those previously demonstrated for meta‐ and para‐arylopeptoids. NMR studies indicated a more restricted rotation about the amide bonds in ortho‐arylopeptoids, presumably due to a more congested backbone structure resulting from the ortho‐connectivity pattern. Intriguingly, tert‐butyl and phenyl side chains offer complete control over the amide conformations; whereas arylopeptoid residues with tert‐butyl side chains adopt a 100 % cis amide conformation, the opposite 100 % trans amide conformation was observed in arylopeptoids with phenyl side chains. The tert‐butyl moiety can furthermore serve as a protecting group during synthesis, which can later be removed to allow the amide to adopt a 100 % trans conformation instead.

Synthesis and complexing properties of cyclic benzylopeptoids – a new family of extended macrocyclic peptoids

“…Benzanilides, [11][12][13] paracyclophanamides, [14][15][16] and arylopeptoids [17][18][19][20][21][22][23][24][25] (Fig. 1) are examples of new types of compounds with promising potential due to their rigidified frame.…”

“…In particular, arylopeptoids offer an interesting case of a new artificial taxonomic class. With these oligomeric aminomethyl benzamides, attractive architectures emerge from E/Z peptoid bond conformational control 20,22,23,25 and cyclization. The last case has recently been examined by Hjelmgaard and Faure.…”

“…Preliminary theoretical calculations demonstrated that the formal addition of a benzylene group to the N-alkylglycine unit would have beneficial effects for both formation of the elusive para-substituted "extended" cyclic trimers and cyclization of the crowded ortho-substituted trimeric isomers. The ortho-substituted oligomers represent a challenging synthetic target and the scarce literature available on the subject 22,[36][37][38] illustrates the intrinsic difficulties in forging these sterically demanding aromatic oligoamides.…”

N‐Alkylated Aromatic Poly‐ and Oligoamides

“…The following year, the synthesis of the first arylopeptoids with ortho-backbones was then reported. [49] Examples of such ortho-linked "one-way sequence" aromatic oligoamides remain very rare. Nonetheless, the efficient synthesis of a wide variety of ortho-arylopeptoids both in solution and on solid phase was demonstrated.…”

Synthesis of Oligobenzamide α-Helix Mimetics

“…4,5 These oligomeric structures have been termed foldamers; 1,3 they are extended organic molecules that adopt a defined structure in solution, often through inter-or intramolecular hydrogen bonding. The foldamer family encompasses a broad range of backbones, including β-peptides, 6,7 mixed α/β or α/β/γ backbones, [8][9][10] oligoureas, 11 peptoids, [12][13][14][15] arylopeptoids, 16,17 other peptidic-based backbones, [18][19][20] and a range of nonpeptidic-based backbones. 2 Within the foldamer family, aromatic oligoamides [21][22][23][24][25][26] have been identified as interesting scaffolds, because folding is governed by the rotameric preference of the amide bond and by interactions with adjacent ortho groups (Scheme 1).…”