1. Introduction
Chirality is a common phenomenon in nature. The demand of enantiopure compounds has increased dramatically over the years in order to cover the research need of chiral drugs, agrochemicals, and materials [
1,
2,
3,
4,
5].
Asymmetric catalysis represents the most effective strategy for enantioselective synthesis, and it is built on three strategic pillars based on enzymes, metal complexes and small organic molecules [
6,
7].
The term organocatalysis was coined in 2000 by David W. C. MacMillan as the use of small organic molecules, with a low molecular weight, acting as catalysts in organic synthesis. Starting from these data, during the last decade, organocatalysis has proven to be an attractive synthetic tool for the development of enantiomerically enriched molecules [
8]. The prominent role of asymmetric organocatalysis, in modern research, has been recently underlined by the Nobel Prize in Chemistry being awarded for “the development of asymmetric organocatalysis” to Benjamin List and David MacMillan in 2021 [
9,
10].
The great interest of academia and industries towards asymmetric organocatalytic transformation regards the applications in medicinal chemistry for the drug discovery and the preparation of new active pharmaceutical compounds [
8].
The differentiation between two enantiomers is a fundamental task for living organisms. The most representative example is thalidomide, a drug firstly commercialized as a racemic mixture, but later, in the 1960s, it was withdrawn from the market due to the teratogenic activity of the (S) enantiomer, though the therapeutically effective molecule was the (R) enantiomer [
11].
Over the past decades, several peptide-based organocatalysts have been used as effective asymmetric catalysis for a wide range of synthetically useful reactions [
12,
13]. These catalysts have proven to be effective for asymmetric acylation reactions, C-C bond formations, and oxidations [
14,
15].
A variety of different strategies have been explored to synthetize new peptide-based catalysts [
16,
17,
18], nucleic acid derivatives [
19,
20] and DNA-based catalysts [
21,
22]; these systems have been deeply investigated due to their structural organization enabling enantioselectivity, regioselectivity and chemoselectivity.
Recently, an emerging topic regarded self-assembled short peptides acting as organocatalysts. Their efficiencies are comparable to those found in enzymes [
23,
24], and their supramolecular state can accelerate the organocatalysis activity [
25,
26,
27].
Despite the numerous advantages offered by peptide-based catalysts, they suffer some limitations, for example, the biostability in comparison with the parent peptidomimetics. Furthermore, the need of a system which permits a rational design and easy synthesis of libraries has encouraged the development of peptidomimetic-based asymmetric catalysts.
A peptidomimetic has been defined as ‘
compounds whose essential elements (pharmacophore) mimic a natural peptide or protein in 3D space and which retain the ability to interact with the biological target and produce the same biological effect’ [
28].
Peptidomimetics overcome the peptide limitations by displaying higher metabolic stability and enhanced receptor affinity and selectivity. The development of peptidomimetics represents a powerful tool not only for the drug discovery [
29] but also for the synthesis of novel catalysts using a rational design, with the purpose of positioning the catalytic site in the right position.
In this contribution, all the peptidomimetic-based asymmetric organocatalysts, reported in literature, with their synthesis and catalytic abilities, are discussed.
This review highlights recent developments up to 2022.
2. Foldamers in Asymmetric Catalysis
The first linear foldamer employed as enantioselective catalyst was reported by Kirshenbaum in 2009 [
30]. This approach relies on attaching an achiral TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) catalytic residue to a foldamer.
Foldamers are unnatural oligomers, (e.g., oligoureas, peptoids, β-peptides) able to adopt a well-defined secondary structure [
31,
32].
The classification of foldamers takes into account the chemical nature of their backbone: fully aliphatic (e.g., α-, β-, or γ-peptides, peptoids, peptidomimetic oligoureas), containing aromatic units (e.g., oligoaryl- or heteroarylamides), or results from the combination of aliphatic and aromatic residues. Starting from helices and β-sheets, the most widely found motifs, there are many foldamer backbones able to adopt rigid conformations, which exhibit molecular recognition processes (
Figure 1).
Taking advantage of the efficient synthesis of peptoids, Kirshenbaum and coworkers have described the incorporation, at the prescribed location, of an achiral catalytic center into the peptoidic helical scaffold.
Peptoids, oligomers of
N-substituted glycines, are one class of peptidomimetics. They are mimics of α-peptides in which the side chain is attached to the backbone amide nitrogen instead of the α-carbon (
Figure 2).
These oligomers are attractive scaffolds for a wide range of applications because they can be generated using a modular synthesis, based on the solid-phase approach, which allows for the incorporation of a wide variety of functionalities.
The library of catalytic foldamers was designed using benzylamine (pm), TEMPO, (
S)- or (
R)-1-phenylethylamine (spe o rpe, respectively) as submonomer synthons of the peptoid scaffolds (
Figure 3). The synthesis of linear peptoids was accomplished by the “sub-monomer” solid-phase approach on a Rink amide resin. The iteration of bromoacetylations and amine displacement steps gave the desired peptoid oligomers (
Scheme 1). In
Table 1, all the catalysts synthesized in that paper are reported.
Using the catalysts depicted in
Figure 4, the asymmetric catalysts were effectively used for the oxidative kinetic resolution of 1-phenylethanol, and some results are summarized in
Table 2 [
30].
The folded catalyst (1S) is characterized by a right-handed helical configuration with the TEMPO group that is covalently attached at the N-terminus; this compound was able to perform effective kinetic resolution, and the same behavior was revealed by the linear oligomer (1R) presenting a left-handed helical configuration.
Interestingly, when the TEMPO was attached on internal positions of the oligomer chain (e.g., 2S, 3S or 4S) no enantioselectivity was observed.
The highest levels of enantioselectivity were achieved for catalytic peptoids bearing the TEMPO group positioned at the
N-terminus (
Figure 5A), indicating a less-effective interaction with the asymmetric environment when the TEMPO is incorporated in the middle of the catalytic scaffold (e.g.,
4S) (
Figure 5B). In peptoid
4S, the catalytic site TEMPO is crowded so the π–π interactions with the substrate 1-phenylethanol are precluded. These could give a reasonable explanation of the different values of enantioselectivity between the catalyst
4S and
1S.
This paper underlined how the enantioselectivity depends on the handedness of the asymmetric environment derived from the helical scaffold, the position of the achiral catalytic center and the degree of conformational order of the peptoid.
Synthetic foldamers represent an opportunity to design sophisticated catalysts taking advantage of their easy synthesis. In fact, the construction of peptoid libraries permits rapid catalytic screening and the possibility of performing rapid systematic investigations of sequence–structure–function relationships in order to optimize the catalytic performances.
3. Peptide–Peptoid Hybrid Catalysts
Taking inspiration from the crucial role of combinatorial chemistry for peptide catalyst discovery and development [
15,
33,
34,
35,
36,
37], Paixão and coworkers reported the application of Ugi four-component reaction (Ugi-4CR) for the development of a combinatorial multicomponent synthesis of novel peptide–peptoid hybrid catalysts [
38].
In principle, the combinatorial multicomponent strategy allows for the possibility of combining four different starting materials, enabling the development of novel catalyst libraries. Paixão and coworkers described the synthesis with a fixed proline substrate, in order to perform enamine catalysis, modulating three elements of diversity—the amine, oxo and isocyanide components—as shown in
Table 3.
The catalytic performances of peptide–peptoid hybrid catalysts
17–
29 were tested in the asymmetric Michael addition of
n-butanal to
trans-β-nitrostyrene, as shown in
Table 4.
The screening of the enamine-type catalytic performance of peptide–peptoid hybrids
17–
29 revealed that the catalyst
25 was the best catalyst in terms of stereocontrol (98% ee, 94:6 dr). The simultaneous presence of the 2-aminoisobutyric acid (Aib) and the chiral
N-substituent (
S)-α-MeBn are crucial factors for the higher enantioselectivity in comparison with its congeners. It was evident that the conformational rigidity of catalyst
25 affected the stereocontrol of the conjugate addition. This was confirmed by NMR analysis of
25: this catalyst showed almost a single rotational isomer, while its congener, catalyst
23, bearing a Gly amino acid residue (R
2 = H), showed a mixture of
cis and
trans isomers in solution (
Figure 6) [
38]. The NMR behavior of both catalysts confirmed that different conformers of
23 affect the stereocontrol of the Michael addition, leading to 89% ee and 96:4 dr. The best catalyst
25 was also used to extend the scope of this conjugate asymmetric Michael addition exploring various solvents, reaction conditions and additives.
This study demonstrates that the combinatorial approach represents a convenient tool for the discovery of new asymmetric catalyst and provides new elements to detect the structure–catalytic activity relationship. This small collection of prolyl peptide–peptoid hybrids provides good-to-excellent stereocontrol and catalytic efficiency in the asymmetric conjugate addition of aldehydes to nitroolefins. In order to extend the scope of the asymmetric Michael addition with the best catalyst
25, various aldehydes and different trans-β-Nitrostyrenes were screened (
Scheme 2).
Peptide–peptoid hybrids represent a new platform to design sophisticated catalysts taking advantage of the combinatorial multicomponent strategy. In particular, the introduction of a specific aminoacid, such as Aib, provided greater conformational rigidity and guaranteed good-to-excellent stereocontrol in the asymmetric Michael addition. All these features have paved the way for new insights into their structure−catalytic activity relationship.
4. β-Turn Peptoid Scaffolds
It has been reported that many peptide-based asymmetric organocatalysts adopt a β-turn-like structure, an important structural feature for high efficiency and selectivity [
39].
However, to the best of our knowledge, there are really few examples of β-turn-like peptoid structures [
40].
All these reasons motivated Mayaan and coworkers to develop a small library of β-turn-like pyrrolidine-based peptoids exploring the conjugate Michael addition [
41], one of the most useful C-C bond forming reaction, important for the pharmaceutical production of enantiopure synthetic intermediates [
42,
43,
44].
The sequences of five designed tripeptoids (
44–
48) consist of an
S- or
R-pyrrolidine group at the
N-terminus and two consecutive
S-,
R- or achiral naphthyl-ethyl side chains. The structure of
44 bears an
S-pyrrolidine group at the
N-terminal and two chiral
R-naphthylethyl side chains (Nr1npe). The structures of peptoids
45–
48 were designed having a piperazine group at the C-terminus to enhance their water solubility. The synthesis of linear peptoids was accomplished by the “sub-monomer” solid-phase approach on Rink amide resin. The preparation of
44 required a bromoacetylation step followed by an amine displacement step. Bromoacetylation and amine displacement steps were repeated until the desired peptoid was obtained (
Scheme 3a). For peptoids
45–
48, the synthetic procedure was extended by the initial insertion of the piperazine moiety, achieved by a chloroacylation followed by a cyclic diamine displacement. Once desired sequences have been obtained, the peptoids were cleaved from the resin and characterized (
Scheme 3b).
The ability of peptoid-based catalysts summarized in
Figure 7 has been tested for the asymmetric Michael addition between aldehydes and nitro-olefins resulting in γ-nitro aldehydes, which are important building blocks leading to γ-aminoacids [
45,
46,
47,
48]. The catalytic performances of peptoids
44–
48 were initially tested in the reaction between β-nitrostyrene and pentanal (
Table 5).
The ee was highly dependent on the chirality and structures of catalysts: the best catalyst 45 has a β-turn structure and mechanicistic studies have revealed that the enamine can approach selectively the Si-face of the β-nitrostyrene.
Deep investigation of timing, catalyst loading, helical structure of peptoids, and substrate scope was carried out (
Scheme 4). This investigation confirmed that the β-turn structure plays a key role in this highly enantioselective reaction. This work represents the first example of β-turn-like peptoid structure acting as asymmetric catalyst.
The β-turn-like structure has been formed only when the naphthylethyl side-chains have the reverse chirality of the pyrrolidine residues.
5. Peptidomimetic Triazole-Based Organocatalysts
The triazole ring, considered as an amide bond surrogate, is an important structural tool for the peptidomimetic chemistry [
49,
50]. Incorporation of this heterocycle into the structure of a peptidomimetic catalyst may rigidify its conformation, improving its selectivity. Moreover, the high number of nitrogen atoms can influence the basicity of the corresponding catalysts.
From these perspectives, Mainkar and co-workers focus their research on the development and synthesis of new peptidomimetic catalysts based on 1,2,3-disubstituted triazole motive [
51]. The scaffold of the new pyrrolidine-linked triazole catalyst was enriched with the presence of isoasparagine residue, responsible for providing hydrogen bonding, as enlightened by early investigations of Wennemers et al. [
18].
The authors reported the synthesis of two novel catalysts bearing a peptide bond surrogate triazole interpose between a pyrrolidine methylene and an isoaspargine moiety.
Scheme 5 reports the synthetic route towards new catalysts. The preparation of target molecules was accomplished by exposing the known azidopyrrolidine (
62) to a thermal Huisgen [3 + 2] cycloaddition with ethyl propiolate to provide two, chromatographically separable, isomeric triazoles,
63 and
63a, in a 28:72 ratio. Both regioisomers (1,5- and 1,4-disubstituted triazoles) were independently transformed to the corresponding acid
64 or
64a. The following coupling with isoaspargine
65 under
N-(3-dimethylaminopropyl)–
N-ethyl-carbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt) conditions furnished pyrrolidine-triazole
66 or
66a. Hydrogenation of benzyl ester to
67 or
67a with subsequent TFA-mediated deprotection furnished
68 or
68a.
Prior to the examination of the catalytic efficiency of
68 and
68a, an extensive structural study was performed to understand the hydrogen-bonding properties and turn pattern. The NMR investigations in combination with ROE-restrained molecular dynamics revealed that catalyst
68 (1,5-triazole catalyst) adopts a turn-like compact structure (
Figure 8a), while the 1,4-disubstituted isomer, catalyst
68a is characterized by an extended conformation (
Figure 8b).
The efficiency of these new catalysts was tested in the Michael addition of ketones onto nitroolefins (
Table 6). The authors hypothesized that the turn structure of the 1,5-triazole catalyst
68 could promote the hydrogen bonding between the terminal isoasparagine and the nitro group of nitrostyrene improving its catalytic efficacy.
In order to confirm this assumption, cyclohexanone was reacted with nitrostyrene in the presence of catalyst 68 (5 mol%) and CH2Cl2 as the solvent, resulting in the formation of the corresponding adduct in 55% yield and >99% ee.
Subsequent screening of reaction conditions revealed that methanol is the optimal solvent for enhancing efficiency and selectivity of chemical transformation. After a deeper screening of solvents and catalyst loading, the results prompted the authors to examine the substrate scope for broader applications. The outcome of this study demonstrated that the presence of both electron-donating and electron-withdrawing groups marginally affects the stereoselectivity of the reaction, ensuring a wide applicability of the catalysts. Moreover, it is worth emphasizing that catalyst 68a, having no turn structure, resulted to be just slightly less effective than 68.
In the light of the computational results, a mechanism was proposed. According to the study, the compound
68 acts as a bifunctional catalyst. Firstly, an enamine is formed as the proline ring reacts with the cyclohexanone carbonyl group with the assistance of acidic co-catalyst. Afterwards, owing to the turn structure of
68, the carboxylic group is able to participate in hydrogen-bonding interaction with the nitro group of nitrostyrene. The transition state arising from
Re-face attack on the
Anti-enamine resulted to be energetically lower than alternative ones (
Anti-
Si,
Syn-
Re and
Syn-
Si). On the other hand, the catalyst
68a, lacking the crucial hydrogen-bonding interaction, responsible for an extra stabilization, resulted in a higher-energy transition states compared to
68 (
Figure 9). The significant energy difference of the two-transition states (>10 kcal mol
−1) did not justify the slightly lower efficiency of
68a in comparison with
68. These results suggest that the catalyst
68, forming hydrogen bonding and having turn-inducing properties, acts following the mechanism established for tripeptides by a turn-like conformation while the catalyst
68a acts following a mechanism of proline-derived catalyst.
The study performed by Mainkar et al. demonstrates a considerable potential of these new peptidomimetic catalysts containing a peptide bond surrogate triazole in Michael-addition reactions. These results open interesting perspectives on the possibility of designing new triazole-based peptidomimetics for organocatalytic applications.
6. Cyclic Peptoids as PTC in Asymmetric Catalysis
Linear peptoids lack conformation rigidity in comparison to their parent α-peptides; macrocyclic constrains has been employed to rigidify the conformation of these flexible oligomers obtaining the corresponding cyclic peptoids (e.g., using the head-to-tail cyclization strategy) (
Figure 10) [
52,
53].
In fact, it is well known that cyclization can enhance the selective binding and stability compared to the corresponding linear oligomer and can pre-organize the structure in a well-defined active conformation, which is a key element in designing new enantiopure therapeutic agents [
54].
Since 2007, when Kirshenbaum and co-workers reported the first cyclopeptoid hetero oligomers [
55], a great deal of research interest has been devoted to the synthesis of novel cyclopeptoids. Macrocyclic peptoids have shown remarkable biological properties [
56] such as antitumor [
57,
58,
59], antimicrobial [
60,
61,
62,
63,
64], glycosidase inhibition [
65,
66,
67] and ionophoric activities [
68,
69,
70]. Some of these features are a direct consequence of the cation-binding ability of the macrocyclic scaffold [
71,
72,
73,
74,
75,
76].
The cation-binding ability encouraged Izzo, Della Sala and coworkers to test their catalytic efficiency as phase-transfer catalysts. The synthesis of five catalysts
71–
75 was accomplished using the “sub-monomer”solid-phase method (
Scheme 6).
As enlightened by early investigation, concerning achiral cyclopeptoids [
77], these macrocycles proved to be able to promote the nucleophilic substitution of 4-nitrobenzyl bromide with NaSCN and KSCN (
Scheme 7).
More recently, the same research group have developed chiral cyclopeptoids able to catalyze the enantioselective alkylation of
N-(diphenylmethylene)glycine esters under phase-transfer catalysis (PTC) conditions [
78]. A library of chiral catalysts has been used in the synthesis of cyclopeptoid with different cavity size containing L-proline residues alternating with
N-substituted glycines (prolinated hexamer and tetramer macrocycles). The chiral library was realized using a mixed sub-monomeric/monomeric approach. The modular synthesis is based on a solid-phase process characterized by quick preparation and easy workup/purification. The first step is the loading of bromoacetic acid on a chlorotrityl resin; this step is followed by a nucleophilic substitution with a primary amine to build the first monomer. Then, there is a coupling reaction with a chiral monomer, in this case L-Proline, in the presence of a coupling reagent such as HATU followed by a deprotection step. The repetition of the steps described above affords a linear peptoid oligomer, attached on the resin. Cleavage reaction, in mild acidic conditions, affords the free linear hexapeptoid. No purification steps are required, and by-products are eliminated by easy filtration. The next step is a cyclization reaction that involves a head-to-tail connection in high dilution conditions (
Scheme 8).
After an extensive investigation of substrates, solvents, temperatures, catalyst loading, the asymmetric alkylation of cumyl
N-(diphenylmethylene)glycine ester was efficiently performed by the cyclohexapeptoid
79a (
Scheme 9) [
79]. Good-to-excellent ees and yields in the alkylation reaction were achieved using a small amount of the chiral catalyst (1.0–2.5 mol%). Furthermore, the cumyl ester group is convenient in the transformation of the glycine derivatives to the corresponding free amino acid, as it could be cleaved by hydrogenolysis without affecting acid-labile groups in the molecule.
The same prolinated catalysts, described above in
Scheme 8, were also applied to the enantioselective alkylation of 2-phenyl-2-oxazoline-4-carboxylate ester under PTC conditions [
80,
81]. The alkylation reaction was catalyzed by the cyclic hexapeptoid decorated with alternated residues of L-Proline and 4-methoxybenzyl side chains,
79h, in a toluene/50% aq NaOH liquid-liquid biphasic system. The enantiomeric excesses were moderate to good (48–75%) (
Scheme 10).
This methodology enables the achievement of important synthetic analogues of α-alkylserines, which are widespread in peptidomimetics and bioactive natural products [
82].