Self‐Assembled Chiral Dimeric Capsules from Difunctionalized N,C‐Linked Peptidocalix[4]arenes: Scope and Limitations

Abstract

In this paper we report the synthesis of the first examples of upper (wide) rim calix [4]arene amino acids 5 and 27, together with the conformational, self-assembly and molecular inclusion properties of the N,C-linked peptidocalix[4]arenes obtained from them. Whereas the dipropyl derivative 5 readily undergoes peptide synthesis allowing a small library of calix[4]arene pseudopeptides 12-21 to be obtained, the tetrapropoxy compound 27 preferentially gives upper-rimbridged derivatives (e.g., 28) which are formed through an intramolecular condensation reaction. The tetrapropoxycalix[4]arene pseudopeptide 33 shows conformational and self-assembly properties quite different to those of the dipropoxy derivatives 12-21. The observed differences are explained on the basis of the different conformational flexibilities of the two calix[4]arene scaffolds. Calixarene 5 is more rigid than 27 thanks to the presence of two OH groups at the lower (narrow) rim that are involved in strong intramolecular hydrogen bonds. Only peptidocalix[4]arenes 12-21 but not

5,11,17,23‐Tetrakis[(p‐carboxyphenyl)azo]‐25,26,27,28‐tetrahydroxy Calix[4]arene: Crystal Structure and pH Sensing Properties

“…The calix [4]arene core of 2 adopts a flattened cone conformation in which opposed phenyl rings have parallel or sharply inclined positions (Figure 2), which were observed in some calix- [4] (Figure 3a). Furthermore, each chain is linked via evident π…π interactions (3.459 Å) 33,34 between each phenyl group of azobenzene moieties, thereby forming a 2D H-bonded wave-like network (Figure 3b). …”

Solid-phase synthesis of linear and cyclic peptides containing a calix[4]arene amino acid

“…This is a peculiar reaction of dipropoxy calixarene amino acid 1, since the rigid structure of the calixarene cone prevents the intramolecular reaction and the low reactivity of the aromatic amine hinders intermolecular calixarene-calixarene condensation. 6 Coupling of the intermediate 9 to the immobilized peptide was subsequently achieved using the same conditions (PyBOP is not strictly necessary, but it proved to be useful to improve the yield in case a small amount of hydrolysis of the active ester takes place). After condensation of the final amino acid, the resin was subdivided into two portions.…”

“…The calix [4]arene amino acid 1 was functionalized with an Fmoc-Ala moiety prior to insertion in the peptide sequence since we had observed that a small amount of degradation of calixarene 1 can take place in basic solutions due to oxidation of the p-aminophenol ring to a benzoquinone imine species, promoted by deprotonation of the phenolic OH. 6 The reaction of 1 with Fmoc-Ala in the presence of PyBOP (Scheme 2) afforded intermediate 9,10 which is characterized by the presence of a benzotriazolyl active ester on the calixarene carboxylic acid. This is a peculiar reaction of dipropoxy calixarene amino acid 1, since the rigid structure of the calixarene cone prevents the intramolecular reaction and the low reactivity of the aromatic amine hinders intermolecular calixarene-calixarene condensation.…”

“…Their structure, which combines the presence of an aromatic cavity with spatially preorganized polar groups, makes them versatile receptors for polar organic molecules and peptides 3,4 or for the recognition of protein surfaces. 5 Recently, we synthesized the first examples of calix [4]arene amino acids 1 and 2, which allowed us to obtain the new class of N,C-linked peptidocalixarenes (e.g., [3][4][5][6]. 6 In contrast to the Nlinked and C-linked derivatives, these new compounds can indeed be considered as peptides, characterized by the presence of a nonnatural amino acid which is potentially able to transfer new properties to the resulting oligomers.…”

“…5 Recently, we synthesized the first examples of calix [4]arene amino acids 1 and 2, which allowed us to obtain the new class of N,C-linked peptidocalixarenes (e.g., [3][4][5][6]. 6 In contrast to the Nlinked and C-linked derivatives, these new compounds can indeed be considered as peptides, characterized by the presence of a nonnatural amino acid which is potentially able to transfer new properties to the resulting oligomers. For example, we showed that the different flexibilities of the 1,3-dipropoxycalix [4]arene amino acid 1 and of the tetrapropoxy derivative 2 (two hydrogen bonds between the phenolic OH and O propoxy groups make the aromatic macrocycle of 1 rigid, while 2, lacking these interactions, retains residual flexibility) are reflected in the conformational and assembly properties of the corresponding peptides 3-5 and 6.…”