Structural Diversity of Peptoids: Tube-Like Structures of Macrocycles

Abstract

Peptoids, or poly-N-substituted glycines, are characterised by broad structural diversity. Compared to peptides, they are less restricted in rotation and lack backbone-derived H bonding. Nevertheless, certain side chains force the peptoid backbone into distinct conformations. Designable secondary structures like helices or nanosheets arise from this knowledge. Herein, we report the copper-catalysed alkyne-azide cycloaddition (CuAAC) of macrocycles to form innovative tube-like tricyclic peptoids, giving access to host-guest chemistry or storage applications. Different linker systems make the single tubes tuneable in size and enable modifications within the gap. An azobenzene linker, which is reversibly switchable in conformation, was successfully incorporated and allowed for light-triggered changes of the entire tricyclic structure.

Keywords: CuAAC; foldamers; peptidomimetics; tricyclic peptoids.

Scheme 1

Conformational equilibrium of a peptoid backbone. (a) N-aryl sidechain enforcing trans-conformation [36] and (b) positively charged N-alkyl sidechain favouring cis-amide conformation [40].

Figure 1

Tricyclic peptoid reported by the group of Kirshenbaum in 2012 [37].

Scheme 2

A general approach for the stepwise synthesis of cyclic peptoids as derivatives of model structure 7a, including solid-phase synthesis on a chlorotrityl chloride resin (2) and cyclisation of the linear precursor in solution. (a) Bromoacetic acid, N,N’-diisopropylethylamine, methylene chloride (DCM), 21 °C, 1 h; (b) propargylamine, N,N’-dimethylformamide (DMF), 21 °C, 1 h; (c) bromoacetic acid, N,N’-diisopropylcarbodiimide, DMF, 21 °C, 30 min; (d) (1). Alternating coupling of a desired amine following (b) and bromoacetic acid following (c); (2). hexafluoroisopropanol, DCM, 21 °C, 30 min; (e) PyBOP, DIPEA, dry DCM, 21 °C, 16 h.

Figure 2

Molecular structure of cyclic peptoid 7b revealing the backbone topology c-c-t-t-c-c-t-t with both aliphatic azides located on the same side of the ring level. (a) Top view; (b) side view.

Figure 3

Molecular structure of one of the two independent molecules of the cyclic peptoid 7c decorated with two aromatic alkynes. The structural data coincide with those obtained for macrocycle 7b.

Scheme 3

CuAAC of peptoids 7a and 7b decorated with aliphatic functional groups. (a) 2,6-Lutidine, Cu(CH₃CN)₄PF₆, dry DCM, 21 °C, 3 days.

Scheme 4

Tricycle 9 as a product of the CuAAC of peptoids 7c and 7d decorated with aromatic functional groups. (a) 2,6-Lutidine, Cu(CH₃CN)₄PF₆, dry DCM, 21 °C, 3 days.

Scheme 5

CuAAC of the macrocyclic peptoid 7b and 1,4-diethynylbenzene (10). (a) 2,6-Lutidine, Cu(CH₃CN)₄PF₆, dry DCM, 21 °C, 3 days.

Scheme 6

CuAAC of the cyclic peptoid 7b and the azobenzene linker 12 revealed conjugate 13, but did not form the tricyclic structure 14. (a) 2,6-Lutidine, Cu(CH₃CN)₄PF₆, dry DCM, 21 °C, 3 days.

Figure 4

Switch experiment of conjugate 13, whose conformation change from trans (red) to cis (green) after irradiation with UV light was monitored via nuclear magnetic resonance (NMR).

Figure 5

Products of the CuAAC of peptoid 7b and a rigidified azobenzene linker (green). (a) Conjugate 15 displays the linker with one peptoid macrocycle attached to one alkyne moiety each. (b) CuAAC of both alkyne moieties led to the tube-like structure 16.

Figure 6

Switch experiment of the tricyclic structure 16, whose conformation change from trans (red) to cis (green) after irradiation with UV light was monitored via NMR.

Figure 7

UV-Vis spectra of compound 16 before (green) and after irradiation with UV light (365 nm) for 1 sec (red), indicating a conformational change from trans to cis. The reverse conformational change was induced via irradiation with UV light (365 nm), followed by irradiation with visible light (460 nm) for 1 min each (blue).