Synthetic Receptors Based on Abiotic Cyclo(pseudo)peptides

Abstract

Work on the use of cyclic peptides or pseudopeptides as synthetic receptors started even before the field of supramolecular chemistry was firmly established. Research initially focused on the development of synthetic ionophores and involved the use of macrocycles with a repeating sequence of subunits along the ring to facilitate the correlation between structure, conformation, and binding properties. Later, nonnatural amino acids as building blocks were also considered. With growing research in this area, cyclopeptides and related macrocycles developed into an important and structurally diverse receptor family. This review provides an overview of these developments, starting from the early years. The presented systems are classified according to characteristic structural elements present along the ring. Wherever possible, structural aspects are correlated with binding properties to illustrate how natural or nonnatural amino acids affect binding properties.

Keywords: amino acids; cyclic pseudopeptides; cyclopeptides; molecular recognition; supramolecular chemistry; synthetic receptors.

Scheme 1

Structures of cyclopeptides 1a,b and of valinomycin 2.

Figure 1

Calculated structures of the preferred conformation of 1a in polar solvents (a), in nonpolar solvents (b), and structure of the 1:1 complex with Ca²⁺ (c). The calculations were performed by the author of this review based on the reported results by using Spartan 20 (Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). Protons, except acidic ones, are omitted for reasons of clarity. For the proposed 2:1 structure of the Mg²⁺ complex, no C₃ symmetric structure could be obtained.

Figure 2

Crystal structure of the Rb⁺ complex of 1b (CSD Entry: CPRGLR) (a), and side and top view of the crystal structure of the K⁺ complex of 2 (CSD Entry: TEFBAH) (b). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 2

Structures of the cyclic pseudopeptides 3, 4, and 5 containing α-aminoxy acid subunits.

Figure 3

Calculated structures of uncomplexed 3 (a) and its chloride complex (b), and of uncomplexed 4 (c) and its chloride complex (d). The calculations were performed by the author of this review based on the reported results by using Spartan 20 (Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). The side chains of both cyclic pseudopeptides are truncated and protons, except acidic ones, are omitted for reasons of clarity.

Figure 4

Structure of the cyclic peptoid 6 and calculated structure of its Na⁺ complex. The calculations were performed by the author of this review based on the reported results by using Spartan 20 (Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). Protons are omitted for reasons of clarity.

Scheme 3

Structures of the cystine-containing macrocyclic pseudopeptides 7–10.

Figure 5

Crystal structures of 7a (CSD Entry: NOSQIV) (a) and 8 (CSD Entry: TUHRAP) (b). Solvent molecules and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 4

Structures of the dithiols 11a–d used to generate macrocycles by oxidative disulfide formation and disulfide exchange.

Figure 6

Structures of the cyclic pseudopeptides 12a,b and crystal structure of 12a (CSD Entry: ZARZOH). Solvent molecules and protons, except acidic ones, are omitted for reasons of clarity.

Figure 7

Structures of the cyclic peptides 13a,b (a), crystal structure of 13a (CSD Entry: XEHMUW) (b), and calculated structure of the benzenesulfonate complex of 13a (c). The calculations were performed by the author of this review based on the reported results by using Spartan 20 Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Figure 8

Structures of the cyclic peptides 14a–c (a), crystal structure of 14a (CSD Entry: KIQXUD) (b), and crystal structure of the N-methylquinuclidinium iodide complex of 14a (CSD Entry: KIQYAK) (c). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 5

Structures of cyclopeptides 15 and 16a–c.

Figure 9

Crystal structures of 16a (CSD Entry: TIFKIC) (a), the sandwich-type iodide complex of 16a (CSD Entry: TIFKOI) (b), and of 16c (CSD Entry: XITDIN) (c). Solvent molecules, counterions, and protons, except acidic ones, and the H(α) protons in (a) are omitted for reasons of clarity.

Scheme 6

Structures of the cyclic pseudopeptides 17–19.

Figure 10

Crystal structures of 17 (CSD Entry: HADVIT) (a), 18a (CSD Entry: EYUKUG) (b), the 2:3 dihydrogenphosphate complex of 18a (CSD Entry: EYUTEZ) (c), and the 2:4 dihydrogenphosphate complex of 19 (CSD Entry: XAZQAT) (d). Solvent molecules, counterions, and protons, except acidic ones, and the H(α) and the triazole H(5) protons in (b–d) are omitted for reasons of clarity.

Figure 11

Structures of building blocks 20 and 21 (a), acetylcholine-templated synthesis of a macrocyclic trimer from 20 (b), and of a [2]catenane comprising two macrocyclic trimers from 21 (c).

Scheme 7

Structures of the cyclic pseudopeptides 22–27.

Figure 12

Crystal structures of 22a (CSD Entry: UHUSUL) (a), 23a (CSD Entry: UHUSOF) (b), and 27a (CSD Entry: XUYBAX) (c). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Figure 13

Strategy of the [2 + 2] macrocyclization by reacting diamines with flanking amino acid subunits with terephthalaldehyde via an intermediate tetraimine that is reduced to afford the stable tetraamine product (a), and structure of building blocks 28, 29, and 30 that afford the respective macrocyclic pseudopeptides 31, 32, and 33 (b).

Figure 14

Crystal structures of the phenylalanine-derived analogs of 32·4HCl (CSD Entry: QOJREN) (a) and 33·4HCl (CSD Entry: EHEMAG) (b). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Figure 15

Examples of natural cyclopeptides containing oxazoline, thiazoline, or thiazole residues (a), and crystal structures of the dicopper(II) complex of ascidiacyclamide (CSD Entry: POHKOM) (b), and the tetrasilver(I) complex of westiellamide (CSD Entry: WICZAJ) (c). Solvent molecules, counterions, and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 8

Examples of patellamide and westiellamide analogs investigated in the Comba group as ligands for transition metals, mainly copper(II).

Figure 16

Structures of the ascidiacyclamide analogs 34a–d. The Ca²⁺ affinity in 5 vol% water/acetonitrile is specified below each compound with the respective log K_a value.

Figure 17

Structures of cyclopeptides 35a–g, 36, and 37 (a), and crystal structures of 35a (CSD Entry: LUBKEY) (b), 35b (CSD Entry: HAHNEK) (c), and 36 (CSD Entry: XIBDES) (d). Solvent molecules, and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 9

Structures of the cyclopeptide-based molecular hinges 38, 39, and 40, the molecular pushing motor 41, the molecular pendulum 42, and the four-stroke motor 43.

Scheme 10

Structures of the anion-binding azole-containing cyclopeptides 44a–c.

Scheme 11

Structures of the phosphate-binding cyclopeptides 45a–d and 46a,b containing zinc-DPA moieties, and 48a,b containing urea and thiourea groups in the side chains.

Figure 18

Structure of indicator 47 and picture of solutions containing equimolar mixtures of 46a and 47 (20 μM in 5 mM HEPES buffer at pH 7.4 containing 145 mM NaCl). The vial on the left-hand side contains no additional salt while the other vials contain the sodium salts of PPi, ATP, ADP, AMP, cAMP, phosphothreonine, phosphoserine, phosphotyrosine, HPO₄²⁻, and citrate (5 equiv each) (from left to right). The picture is reprinted from Ref. [170] with permission from the Royal Society of Chemistry.

Figure 19

Structures and preferred calculated conformations of the furan-containing cyclopeptides 49a–d (a) and 50 (b). The structures of 49a and 50 were calculated by the author of this review based on the reported results by using Spartan 20 (Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). The side chains of 50 are truncated and protons, except acidic ones, are omitted for reasons of clarity.

Scheme 12

Structures of the cyclopeptides 51–55.

Figure 20

Calculated structures of cyclopeptides 52 (a) and 53 (b). The calculations were performed by the author of this review based on the reported results by using Spartan 20 (Wavefunction, Inc., Irvine, CA, USA) and the MMFF force-field (see Supporting Information). The side chains of all cyclopeptides are truncated and protons, except acidic ones, are omitted for reasons of clarity.