catalysts

Review Catalytic : When the Structure Guides the Function

Baptiste Legrand 1 , Julie Aguesseau-Kondrotas 1, Matthieu Simon 2 and Ludovic Maillard 1,*

1 IBMM, Université de Montpellier, CNRS, ENSCM, 34093 Montpellier, France; [email protected] (B.L.); [email protected] (J.A.-K.) 2 Institute of Regenerative Medicine and Biotherapies, CARTIGEN, CHU Montpellier, 34090 Montpellier, France; [email protected] * Correspondence: [email protected]; Tel.: +33-04-1175-9604

 Received: 28 May 2020; Accepted: 18 June 2020; Published: 22 June 2020 

Abstract: are predominantly able to effectively and selectively catalyze highly complex biochemical reactions in mild reaction conditions. Nevertheless, they are limited to the arsenal of reactions that have emerged during natural evolution in compliance with their intrinsic nature, three-dimensional structures and dynamics. They optimally work in physiological conditions for a limited range of reactions, and thus exhibit a low tolerance for solvent and temperature conditions. The de novo design of synthetic highly stable enzymes able to catalyze a broad range of chemical reactions in variable conditions is a great challenge, which requires the development of programmable and finely tunable artificial tools. Interestingly, over the last two decades, chemists developed secondary structure mimics to achieve some desirable features of proteins, which are able to interfere with the biological processes. Such non-natural , so called foldamers, can adopt highly stable and predictable architectures and have extensively demonstrated their attractiveness for widespread applications in fields from biomedical to material science. science was more recently considered to provide original solutions to the de novo design of artificial enzymes. This review covers recent developments related to foldamers with catalytic properties and the principles that have guided their design.

Keywords: foldamer; peptidomimetic; cooperation; organocatalyst

1. Introduction Enzymes are incredible powerful catalysts, being typically non-toxic and environmentally friendly, while capable of performing remarkably difficult chemical transformations with relative ease, unmatched substrate, and product selectivity [1–3]. As such, they offer many opportunities in chemical industry, however, their intrinsic vulnerabilities related to their low thermal stability, low tolerance for solvent conditions, as well as their poor diversity of substrates and their high cost of production, seriously hamper their attractiveness. Besides, they display poor adaptability to abiotic chemical transformations, and the identification of suitable catalysts for a given reaction often remains a limiting step. In this context, there is a great demand for the development of enzyme mimics as proficient as their natural models but overcoming their limitations. To date, many types of enzyme mimics, ranging from polymeric [4,5] and dendritic scaffolds, supramolecular cyclodextrin and porphyrin hosts, nanoparticulates, [6–10] to catalytic antibodies [11] and natural proteins [12–14] have attempted to address some of these features. In recent decades, great achievements have been realized following a reductionist approach in constructing catalytic sites from short artificial . The discovery of short sequences as effective asymmetric catalysts for a variety of reactions is now well documented and has been

Catalysts 2020, 10, 700; doi:10.3390/catal10060700 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 700 2 of 20 extensively reviewed [15–19]. For instance, both combinatorial and de novo methods of catalyst design were demonstrated to successfully perform a variety of reactions including the kinetic resolutions of alcohols, aldol reactions, phosphorylation, Michael addition, and Morita–Baylis–Hillman reactions. In particular, S. Miller and H. Wennemers have emphasized the strong potential of short peptides in asymmetric [15,20]. The strength of peptide lies in the diversity and complexity that can be achieved from a small set of position-interchangeable building blocks allowing the easy access of high chemical diversity. However, the state of a short peptide in solution is generally characterized not by a single structure, but by an ensemble of conformations limiting their ability to re-create all the desirable properties for an enzyme-like catalyst. Indeed, a fundamental paradigm in enzymology is the close relationship between the enzyme functions and their three-dimensional structures, which in turn depends on their sequences [21,22]. Large proteins of a hundred amino acids are often arranged in compact and finely tuned three-dimensional structures. The folding of polypeptide chains ensures that the residues are spatially bunched with some precision. The active sites then emerge in restricted places among the structures, constrained by the folded topology [23]. The first-shell residues at the active site are oriented in such a way as to bind the substrate and stabilize the transition state (TS) for a given reaction. The second-shell amino acids also contribute to the active site charge distribution through cooperative interactions, i.e., electrostatic, steric and hydrogen bonds. Thus, the enzymatic activity results from a necessary chemical diversity of the constituent elements; however, a tight control of the folding propensity is also just as crucial in order to encode functionally important dynamics, such as cooperative motions. Among the chemical tools reported in recent years, synthetic short oligomers, so called foldamers, [24–26] seeking to mimic the structure-forming propensity of biomolecules even at short-chain length, has provided an original contribution to this concern. Due to periodic regular H-bond networks, electronic interactions, local conformational restriction and solvophobic effects, these molecules allow the formation of programmable secondary structures, generally helices but at times strand-like conformations or turns [27,28]. In addition, while the diversity of monomer units in proteins is confined to a relatively narrow “alphabet”, determined over the course of evolution, this is not the case in foldamer chemistry where the chemical diversity is only limited by the creativity of chemists. Hence, foldamers provide an infinite range of scaffolds for presenting complex sets of functional groups to reproduce the structure and function of biomacromolecules, making them attractive for broad applications ranging from nanotechnology to biomedical fields, biopolymer surface recognition and nanomaterials. These areas are well covered in reviews [29–33]. In comparison, the catalyst function has been much more elusive for a long period. However, recent developments have led to interesting convergences between the fields of peptidomimetic foldamers and catalysis. In this review, we mainly focus on the potential of peptidomimetic foldamers including, among others, β- and γ-peptides, and oligoureas peptides for organocatalysis. We describe how a strict control of the topology could serve the design of biomimetic catalysts.

2. Principles Sustaining the Design of Catalytic Peptide Foldamers To date, four distinct approaches have been considered in the context of organocatalysis to take advantage of the chiral microenvironment of peptidomimetic foldamers. (1) In the first one, a prosthetic group is added to the abiotic . Like enzymes requiring co-factors to exert their function, for its catalytic function, the enzyme mimic depends on a group whose chemical nature is fundamentally different to the rest of the scaffold. Such a conjugation process allows for the creation of hybrid catalysts with new features resulting from the combination of the molecular recognition properties of the folded molecule with the inherent activity of the adjunct catalytic center. This strategy has been proven particularly fruitful in designing supramolecular biomacromolecules (RNA, DNA, protein) and peptide hybrids of organic and inorganic catalysts [7,9,34], but has been little explored in the field of peptidomimetic foldamers. (2) In a second approach, the peptide-like architecture is used to ensure a precise three-dimensional positioning of several key lateral side-chains that work together Catalysts 2020, 10, 700 3 of 20 in cooperation in ligand-binding and/or TS stabilization. Cooperative catalysis, defined as the dual activation of two reacting partners, is a fundamental principle of enzyme catalysis [35–38] that has guided the rational design of generations of multifunctional organocatalysts [39–42]. Cooperative enantioselective reactions can involve as either strong (mainly covalent) or transient (non-covalent) catalyst substrate interactions [43], but whatever the mechanism, catalytic proficiency requires a very − precise spatial organization of two or more reactive groups. In enzymes, the proper spatial positioning of functional groups within their active sites relies on their specific tertiary structures. In peptide foldamers, the judicious placement of the recognition elements and catalytic functional groups is simplified due the high predictability and stability of the backbone structures, and could be achieved on either a single molecule or a supramolecular assembly. (3) Besides, as demonstrated by recent studies, the well defined hydrogen-bonding network, sustaining the folding, may act by itself as support of the catalytic activity. In this third approach, the catalytic center is not shaped by the projection of reactive substitutes but directly relies on the foldamer backbone structure. In contrast to the second family of catalysts, the mechanistic characterization of catalytic asymmetric reactions involves transient, noncovalent catalyst substrate interactions. (4) Finally, in contrast to fully artificial − peptidomimetic catalysts, it has been envisioned to incorporate foldamer secondary structures into natural enzymes in order to improve and/or modify their catalytic functions. We provided an outlook on recent developments in foldamer prosthesis strategies in the last section of this review.

3. Installation of Catalytic Prosthetic Groups in Foldamers: The Example Kirshenbaum et al. pioneered the transfer of chiral information from a folded abiotic oligomer to an embedded prosthetic reactive center [44]. The asymmetric environment was provided by a peptoid scaffold, defined as oligomers of N-substituted glycine. Even though the peptoid backbone is intrinsically achiral, bulky chiral aromatic side chains such as 1-phenylethyl prompt stereocontrolled cis-amide helical structures resembling polyproline I [45,46]. The catalytic function was achieved by grafting (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl, commonly known as TEMPO, a competent group for oxidative transformation [47,48], at various sites along (S)-N-(1-phenylethyl)glycine oligomers. TEMPO is thus referred to as a redox covalently bound to helical peptoid backbones. The TEMPO peptoid hybrids were tested for oxidative kinetic resolution of a racemic mixture of − 1-phenylethanol. By modulating the position of the TEMPO group along the oligomer and by evaluating secondary structure content, the authors were able to correlate the enantioselectivity of the transformation to the helical propensity of the oligomer. In the best arrangement (Table1, entry 3), 1 mol% of catalyst gave excellent conversion (84%) with a selectivity towards the (S) enantiomer resulting in 99% enantiomeric excess (ee) of the less reactive (R)-enantiomer. In contrast, when the TEMPO group was not covalently linked to the peptoid oligomer, the catalytic system 2 was still active for the oxidation of 1-phenylethanol but did not produce a transfer of the chiral information. Besides, a mixture of the 4-amino-TEMPO catalyst and (S)-1-Phenylethylamine monomer was far less effective for oxidation and did not produce enantioselective transformation (Table1, entry 1). Collectively, these observations demonstrate a synergistic effect between the chiral environment provided by the helical peptoid scaffold, and the catalytic activity of TEMPO. The peptoid is likely to play a steric role, selectively preventing the exposure of one enantiomer to the oxidative action of the nitroxyl unit. Catalysts 2020, 10, 700 4 of 20 CatalystsCatalysts 2019 2019,, 9, x FORFOR PEER PEER REVIEW REVIEW 4 of 20 4 of 20 Catalysts 2019,, 9,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 20 TableTable 1. Conversion, enantioselectivities enantioselectivities and and enantiomeric enantiomeric excess excess for the for catalytic the catalytic oxidation oxidation of 1- of 1- Table 1.TableConversion, 1. Conversion, enantioselectivities enantioselectivities and and enantiomeric enantiomeric excess forexcess the catalytic for the oxidation catalytic of 1 oxidation- of phenylethanolphenylethanol byby the the TEMPO TEMPO−peptoid−peptoid hybrids. hybrids.[44].[44] . 1-phenylethanolphenylethanol by theby the TEMPO TEMPO−peptoid hybrids. hybrids[44] [.. 44]. −

a Catalytic system Conversiona Selectivity ee (%) CatalyticCatalytic Systemsystem system Conversion ConversionConversiona a (%)Selectivitya SelectivitySelectivity ee (%) (%) ee (%)(%) (%) (%) (%) (%) (%) (%) 1 1 22 22none nonenone none 1 22 none none 1 22 none none

2 86 none none 2 2 86 86none nonenone none 2 86 none none

3 84 60 (S) >99 (R) 3 3 84 8460 (S) 60 (S)>99 (R) >99 (R) 3 84 60 (S) >99 (R)

(a) Conversion values are based on 2 h of reaction time. (a) Conversion values are based on 2 h of reaction time.. (a) Conversion values are based on 2 h of reaction time. 4. Active sites Resulting from Spatially Preorganized Reactive Side Chains 4. Active sites Resulting from(a) Conversion Spatially P valuesreorganized are based Reactive on 2 h S ofide reaction Chains time . 4. Active4.a Sites—Enamine/ ResultingIminium from Mediated Spatially Catalysis Preorganized Reactive Side Chains 4.a—Enamine/Iminium Mediated Catalysis 4. ActiveCatalysis sites R byesulting chiral primary from S pat andially secondary Preorganized , calledReactive “aminocatalysis”, Side Chains comprises two Catalysis by chiral primary and secondary amines, called “aminocatalysis”, comprises two 4.1. Enaminedistinct/Iminium reactivity Mediated manifestos Catalysis for the functionalization of carbonyl compounds [49–53]. In iminium 4.adistinct—Enamine/ reactivityIminium manifestos Mediated for the Cfunctionalizationatalysis of carbonyl compounds [49–53].. In iminium catalysis, the condensation of a nucleophile with a carbonyl compound generates a tetrahedral Catalysiscatalysis, by the chiralcondensation primary of a nucleophi and secondaryle amine with amines, a carbonyl called compound “aminocatalysis”, generates a tetrahedral comprises two intermediate,Catalysis which by chi thenral converts primary in to and an iminium secondary ion. amines, Iminium calledsalts are “aminocatalysis”, more electrophilic than comprises the two intermediate, which then converts into an iminium ion. Iminium salts are more electrophilic than the distinctdistinctcorresponding reactivity reactivity manifestos aldehydes manifestos orfor ketones thefor the functionalization andfunctionalization provide a way of of for carbonyl carbonyl electrophilic compounds additions. [49 [When49–53]–53. the].In In iminium iminium corresponding aldehydes or ketones and provide a way for electrophilic additions. When the catalysis,catalysis,carbon the condensationyl thecomponent condensation is enolizable of a of nucleophile a nucleophi, the iminium aminele amine ion is with withtransient a a carbonyl carbonyl and evolves compound by deprotonation generates generates at a thetetrahedral a tetrahedral carbonyl component is enolizable,, the iminium ion is transient and evolves by deprotonation at the intermediate,α-carbon which atom toward then convertsa nucleophilic into enamine, an iminium which can ion. then Iminium trap electrophilic salts are substrates more electrophilic(Figure than intermediate,α-carbon atom which toward then a nucleophilic converts in enamine,to an iminium which canion. then Iminium trap electrophilic salts are more substrates electrophilic (Figure than the 1a). Such a reversible process referred to as enamine catalysis is routinely accomplished by enzyme the correspondingcorresponding1a).. Such a reversible aldehydes aldehydes process or or referred ketones ketones to as and enamine provide catalysis a a way way is routinely for for electrophilic electrophilic accomplished additions. additions. by enzyme When When the the catalytic machinery. It has been recognized since the 1960s, that natural enzymes, such as acetoacetate carboncatalyticyl machinery.component It ishas enolizable been recognized, the iminium since the ion1960 iss, thattransient natural and enzymes, evolves such by as deprotonation acetoacetate at the carbonyldecarboxylases component [54,55] is enolizable, and type I aldolases, the iminium [56,57] use ion the is  transient-amino group and of lysine evolves residues by deprotonationfor the at α-decarboxylasescarbon atom toward[54,55] and a nucleophilic type I aldolases, enamine, [56,57] usewhich the can-amino then group trap electrophilicof lysine residues substrates for the (Figure the α-carbonactivation atom of keto toward substrates. a nucleophilic Compared to lysine enamine, in aqueous which solution, can the then lysine trap of electrophilicthe Schiff base- substrates 1a)activation. Such a ofreversible keto substrates. process Compared referred toto lysine as enamine in aqueous catalysis solution, is routinely the lysine accomplishedof the Schiff base by- enzyme (Figure1forminga). Such enzymes a reversible has a significantly process lower referred pKa (<7.5 to versus as enamine 10.5), making catalysis them highly is routinely amenable accomplished for forming enzymes has a significantly lower pKa (<7.5 versus 10.5), making them highly amenable for catalyticcarbonyl machinery. condensation It. hasTheir been mechanism recognized characterization since the 1960 has s,established that natural that enzymes, the perturbation such as of acetoacetate the by enzymecarbonyl catalytic condensation machinery... Their m Itechanism has been characterization recognized has since established the 1960s, that the that perturbation natural of enzymes, the such decarboxylasespKa mainly results [54,55] from and electrostatic type I aldolases, interactions [56,57] due to use a nearby the - aminopositively group charged of lysine residue, residues often for the as acetoacetatepKa mainly decarboxylases results from electrostatic [54,55] interactions and type Idue aldolases, to a nearby [56 positively,57] use charged the ε-amino residue, groupoften of lysine activationanother lysine of keto or arginine substrates. residue. Compared This effect to is lysine further in enhanced aqueous if solution, the charged the r esidueslysine ofare the almost Schiff base- another lysine or arginine residue. This effect is further enhanced if the charged residues are almost residuesformingburied for the in enzymes the activation binding has pocket a ofsignificantly keto of the substrates. enzyme lower within pKa Compared a (<7.5 low dielectricversus to 10.5), lysineenvironment making in aqueous (Figure them highly 1b) solution, [58,59] amenable. the lysinefor buried in the binding pocket of the enzyme within a low dielectric environment (Figure 1b) [58,59].. of the Schicarbonylff base-forming condensation. enzymes Their mechanism has a significantly characterization lower has established pKa (<7.5 that versus the p 10.5),erturbation making of the them highlypKa amenable mainly forresults carbonyl from electrostatic condensation. interactions Their mechanismdue to a nearby characterization positively charged has establishedresidue, often that the perturbationanother lysine of theor arginine pKa mainly residue. results This effect from is electrostatic further enhanced interactions if the charged due to residues a nearby are positivelyalmost chargedburied residue, in the often binding another pocket lysine of the or enzyme arginine within residue. a low This dielectric effect environment is further enhanced (Figure 1b) if the[58,59] charged. residues are almost buried in the binding pocket of the enzyme within a low dielectric environment (Figure1b) [58,59]. These mechanistic studies have inspired Alleman and Benner for the design of lysine-rich amphiphilic α-helices as minimal oxaloacetate decarboxylase mimics [60,61]. They demonstrated a strong correlation of the catalytic activity with both the folding propensity of the peptide and the clustering of lysine side chains along one side of the helix. As in the enzyme catalytic site, placing the reacting amine close to the positively charged side chains depresses its pKa by up to two orders of magnitude due to the coulombic interactions and increases its reactivity. In 2009, Hilvert and Gellman transposed such a design onto helical β-peptides capable of forming helix bundles in aqueous media and explored their ability to catalyze the retroaldol cleavage of β-hydroxyketone [62]. β3-peptides typically adopt a 14-helix structure that can be further stabilized in water by the incorporation of the constrained cyclic trans-2-aminocyclohexanecarboxylic acid (ACHC) [63,64]. The resulting edifice exhibits three distinct faces enabling the perfect control of the spatial orientation of the appended functionalities. Catalysts 2020, 10, 700 5 of 20

Thus, the β-peptide sequence 11, containing multiple ACHC residues along with β3-homolysine (β3-hLys) residues in an i, i + 3, i + 6 array, aligns the amine-containing side chain along one side of a 14-helix (Figure2). Despite the absence of a true binding pocket, 11 was proficient in catalyzing with a Michaelis–Menten behavior, the retroaldol reaction of 4-phenyl-4-hydroxy-2-oxobutyrate. By adding a heptanoyl moiety at the N-terminus of the β-peptide, which promoted its self-assembly, the catalytic efficiency was enhanced by one order of magnitude. At pH 8.0 and 30 ◦C, the steady-state parameters 1 kcat and Km are 0.13 0.01 min and 5.0 0.6 mM, respectively. The comparison of the turnover ± − ± number with the rate constant for the uncatalyzed retroaldol reaction under identical conditions gives a rate acceleration of kcat/kuncat = 3000. This result highlights the benefit of clustering the β-peptides to increase both, the local positive-charge density and the hydrophobicity of the environment of catalytic amines, which in turn results in the reduction in the pKa value of the β3-hLys side-chain ammoniumCatalysts 2019, 9 groups., x FOR PEER REVIEW 5 of 20

Figure 1. 1. ((a)) SchematicSchematic mechanism mechanism of of thethe enamineenamine catalysis. catalysis. E E = = electrophile. electrophile. ( b) GeneralGeneral class I I aldolase mechanism. Reactivity of the Schiff base-forming lysine is enhanced by two principal ways, Catalystsaldolase 2019 mechanism, 9, x FOR PEER. Reactivity REVIEW of the Schiff base-forming lysine is enhanced by two principal6 ways, of 20 aa lowlow dielectricdielectric environmentenvironment andand electrostaticelectrostatic interactioninteraction withwith aa nearbynearby positivelypositively chargedcharged residue.residue.

a) b) + These mechanistic studies have inspired Alleman and Benner for the designNH3 of lysine-rich HO amphiphilic αO-helicesO as minimalO oxaloacetate decarboxylase mimics [60,61]. They demonstrated a R1 2 O O O strong correlationN N of theN catalyticN R activity with both the folding propensityO of the peptide and the H H H H RHN N 2 N N N NH2 clustering of lysine side chains along one side of the helix. As in Hthe enzymeH H catalyticH site, placing the 3 reacting amine close to the positively charged side chains depresses11: R = Ac its pKa by up to two orders of Foldamer 12: R = CH3(CH2)5CO magnitudec) due to the coulombic interactions and increasesd) its reactivity. In 2009, Hilvert and Gellman Self-assembly through transposed such a design onto helical -peptides capable of forming helix bundles inthe H eaqueousptanoyl group media OH O OH HN and explored their abilityONa to catalyze the retroaldolONa cleavage of β-hydroxyketone [62]. β3-peptides H N typically adopt a 14-helixO structure that can Obe further2 stabilized in waterH2 Nby the incorporation of the

NH2 +H N + constrained cyclic H trans2N -2F-oaminocyclohexanecarboxylicldamer H2O 3 acid (ACHC) [63,64]H3N . The resulting edifice + exhibits three distinct faces enabling theFold aperfectmer control of the spatial orientation of the appendedNH3 +H N + O 3 H3N CHO 3  +  functionalities. Thus+ , theONa -peptide sequence 11, containing multiple ACHC residues alongNH 3with - HN 3 O n homolysine (β -hLys) residues in an i, i + 3,ONa i + 6 array, aligns 11the amine-containing side chain along 12 one side of a 14-helix (Figure 2). DespiteO the absence of a true binding pocket, 11 was proficient in catalyzing with a Michaelis–Menten behavior, the retroaldol reaction of 4-phenyl-4-hydroxy-2- FigureFigure 2. 2. (a) Axis Axis view view of the of helix the structure helix structure of trans-2-aminocyclohexanecarboxylic of trans-2-aminocyclohexanecarboxylic acid (ACHC)- acid oxobutyrate. By adding a heptanoyl moiety at the N-terminus of the β-peptide, which promoted3 its (ACHC)-containingcontaining oligomers oligomers (CCDC: 1247870).(CCDC:[63] 1247870).[(b) Sequences63](b)of Sequences β-peptides of11–β12-peptides: (3-hLys)11 residues–12:(β in-hLys) self-assembly, the catalytic efficiency was enhanced by one order of magnitude. At pH 8.0 and 30 °C, residuesan i, iin + 3, an i + 6i,arrayi + led3, i to+an6alignment array led of the to anamine-containing alignment of side the chains. amine-containing (c) Retroaldol reaction side chains. cat m  −1  the steady(c) Retroaldolof - sodiumstate parameters 4-phenyl-4-hydroxy-2-oxobutyrate reaction of sodium k and 4-phenyl-4-hydroxy-2-oxobutyrate K are 0.13 catalyzed 0.01 by min the β-peptides and 5.0 catalyzed11 and0.6 12mM, by. (d the) respectively. Cartoonβ-peptides The comparison11 andshowing12 of.( dthe the) Cartoon 3D-turnoverorganization showing number of the β-peptides 3D-organizationwith the11 and rate 12 .constant of β-peptides for the11 and uncatalyzed12. retroaldol reaction under identical conditions gives a rate acceleration of kcat/kuncat = 3000. This result highlights the benefit ofAlthough clustering foldamers the β - havepeptides huge to promising increase potentialboth, the for local enamine-mediated positive-charge catalysis, density this and the hydrophobicityresearch area of has the grown environment relatively ofslowly catalytic until amines, the middle which of the in 2010s.turn results In the 2000s,in the Erkkiläreduction and in the pKaPihko value reportedof the β3 the-hLys use sideof pyrrolidine-chain ammonium as an effective groups. catalyst for the α-methylenation reactions of aldehydes. The reaction proceeds through a second-order dependence of catalyst concentration following a Knoevenagel–Mannich-type mechanism. The catalytic cycle thus involves the dual activation of both the nucleophilic aldehyde via the enamine formation, and the electrophilic formaldehyde via the iminium formation (Figure 3a) [65]. Based on these results, Gellman's group was prompted to consider helical foldamers containing pairs of pyrrolidine-derived β-amino acid residues (so called APC) as a basis for designing a reactive dyad for the crossed aldol condensation [66]. Like its cyclopentane analogue (ACPC), APC supports the formation of a β-peptide helix characterized by C=O(i)··· H-N(i + 3) H-bonds and provides access, when it associates with L-α-amino acid residues, to diverse helical secondary structures that feature C=O(i)···H-N(i + 3) or C=O(i)···HN(i + 4) H-bonds. By varying the proportions of cyclic β-amino acids and L-α-amino acid residues as well as positions of the APC within the sequences, Gellman’s group obtained distinct pyrrolidine diad geometries for the catalytic condensation of the α-methylenation reactions of aldehydes (Figure 3d). Among all the explored arrangements, the α/β/β-peptide 14 (Figure 3) led to the best catalytic efficiency with an initial rate enhancement of 143 relative to mono-APC α/β-peptide. Remarkably, structural investigations provide evidence that the i + 3 spacing for the two APCs positions the two pyrrolidines exactly one turn apart along the helix at 5.5  0.1 Å from each other. As all the other assessed geometries led to less active catalysts, such arrangement appeared to be crucial to the accommodation of a double enamine/iminium catalysis involving the two secondary amines (Figure 3). An impressive application of this concept has been a very recent achievement of the discovery of a bifunctional α/β/β-peptide catalyst proficient for the macrocyclization of bisaldehydes [67]. Peptide 15 acts in a dual mode, consisting of a double iminium/enamine activation of the aldehyde functions and a conformational pre-organization of the substrate so as to overcomes the entropic cost of intramolecular reaction. It differs from the former hybrid peptide in that one of the catalytic units is a primary amine, which is required to activate one of the two carbonyl groups as iminium rather than enamine. The efficient foldamer-catalyzed macrocyclization was demonstrated to be practical for the synthesis of large-ring natural products, e.g., nostocyclyne A. Catalysts 2020, 10, 700 6 of 20

Although foldamers have huge promising potential for enamine-mediated catalysis, this research area has grown relatively slowly until the middle of the 2010s. In the 2000s, Erkkilä and Pihko reported the use of pyrrolidine as an effective catalyst for the α-methylenation reactions of aldehydes. The reaction proceeds through a second-order dependence of catalyst concentration following a Knoevenagel–Mannich-type mechanism. The catalytic cycle thus involves the dual activation of both the nucleophilic aldehyde via the enamine formation, and the electrophilic formaldehyde via the iminium formation (Figure3a) [ 65]. Based on these results, Gellman’s group was prompted to consider helical foldamers containing pairs of pyrrolidine-derived β-amino acid residues (so called APC) as a basis for designing a reactive dyad for the crossed aldol condensation [66]. Like its cyclopentane analogue (ACPC), APC supports the formation of a β-peptide helix characterized by C=O(i) H-N(i + 3) ··· H-bonds and provides access, when it associates with L-α-amino acid residues, to diverse helical secondary structures that feature C=O(i) H-N(i + 3) or C=O(i) HN(i + 4) H-bonds. By varying the ··· ··· proportions of cyclic β-amino acids and L-α-amino acid residues as well as positions of the APC within the sequences, Gellman’s group obtained distinct pyrrolidine diad geometries for the catalytic condensation of the α-methylenation reactions of aldehydes (Figure3d). Among all the explored arrangements, the α/β/β-peptide 14 (Figure3) led to the best catalytic e fficiency with an initial rate enhancement of 143 relative to mono-APC α/β-peptide. Remarkably, structural investigations provide evidence that the i + 3 spacing for the two APCs positions the two pyrrolidines exactly one turn apart along the helix at 5.5 0.1 Å from each other. As all the other assessed geometries led to less active ± catalysts, such arrangement appeared to be crucial to the accommodation of a double enamine/iminium catalysis involving the two secondary amines (Figure3). An impressive application of this concept has been a very recent achievement of the discovery of a bifunctional α/β/β-peptide catalyst proficient for the macrocyclization of bisaldehydes [67]. Peptide 15 acts in a dual mode, consisting of a double iminium/enamine activation of the aldehyde functions and a conformational pre-organization of the substrate so as to overcomes the entropic cost of intramolecular reaction. It differs from the former hybrid peptide in that one of the catalytic units is a primary amine, which is required to activate one of the two carbonyl groups as iminium rather than enamine. The efficient foldamer-catalyzed macrocyclization was demonstrated to be practical for the synthesis of large-ring natural products, e.g., nostocyclyne A. In recent years, our group explored a class of constrained heterocyclic γ-amino acids built around a thiazole ring, so called ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids). Thanks to the planar conformation of the γC-βC-αC-C(O) torsion angle imposed by the heterocyles, ATC oligomers adopt a nine-helix structure resulting from the formation of a highly stable C9 hydrogen-bonding pattern [68,69]. These foldamers could be readily functionalized [70] and the helical structure showed a low dependency on the appended side chains. Among other applications [71,72], we were interested in addressing ATC molecules for enamine-type catalysis [73]. We first established the effectiveness of a dual ATC monomer catalyst 16 on the nitro-Michael addition reaction of cyclohexanone and β-trans-nitrostyrene (Figure4). With a nucleophilic pyrrolidine in position 2 of the thiazole core and a propanoic chain on the γ carbon lateral chain, ATC 16 could be viewed as a structural analog of the H–D–Pro–Pro–Glu–NH2 tripeptide, which is probably the most efficient catalyst for such a transformation [74–77]. Catalysts 2020, 10, 700 7 of 20 Catalysts 2019, 9, x FOR PEER REVIEW 7 of 20

HO a) b) C NH H2N O O O O + 10 mol % R1 H H H H NH CH2Cl2 O R1

HN O N N N O H H H H i+3 H H NH H X- O R1 R1 R1 + H O + HX 2 HN O i N O H N H N H H NH HX H N H R1 O X-

HN O N O N R1 R1 HX H H H NH O O 13 c) d) O HO HO O H H O H N 1 mol% 14 H2N 2 N + CH2 O O O O H Ph Ph NH NH N H Ph O OH O O 14

HN HN O H N O 2 CHO H N ACPC HN 2 H CHO CHO NH NH O N O O n n n 15 10 mol% n HN HN O OH O O N n = 2 to 5 O O O 55 to 97% NH 15 NH NH H2N O O APC NH NH CHO O O OHC O HN HN O O 10 mol% 15 O OHC + O O NH NH O O OHC 14 15

FigureFigure 3. 3.(a) Mechanism(a) Mechanism of the pyrrolidine- of the pyrrolidine-catalyzedcatalyzed α-methylenationα-methylenation of aldehydes of [65] aldehydes. (b,c) α/β/β [65-]. α β β peptide(b,c) / bifunctional/ -peptide bifunctional catalysts 14 catalystsand 15 were14 and designed15 were based designed on the based helical on secondary the helical structures secondary adoptedstructures by adopted the ACPC-containing by the ACPC-containing foldamer foldamer13 (CSD:13 (CSD: PUCDEX). PUCDEX). (d) Foldamer- (d) Foldamer-catalyzedcatalyzed α- α methylenation-methylenation and and macrocyclization macrocyclization (reaction (reaction conditions: conditions: 2 equiv. 2 equiv.triethylamine, triethylamine, 2 2equiv. equiv.p propionicropionic acid,acid, 4 4 vol vol % % w water,ater, ii--PrOH,PrOH, 37 37°◦CC..

In recent years, our group explored a class of constrained heterocyclic γ-amino acids built around a thiazole ring, so called ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids). Thanks to the planar conformation of the γC-βC-αC-C(O) torsion angle imposed by the heterocyles, ATC oligomers adopt a nine-helix structure resulting from the formation of a highly stable C9 hydrogen- bonding pattern [68,69]. These foldamers could be readily functionalized [70] and the helical structure showed a low dependency on the appended side chains. Among other applications [71,72], we were interested in addressing ATC molecules for enamine-type catalysis [73]. We first established the effectiveness of a dual ATC monomer catalyst 16 on the nitro-Michael addition reaction of cyclohexanone and β-trans-nitrostyrene (Figure 4). With a nucleophilic pyrrolidine in position 2 of the thiazole core and a propanoic chain on the γ carbon lateral chain, ATC 16 could be viewed as a Catalysts 2019, 9, x FOR PEER REVIEW 8 of 20 structuralCatalysts 2020 analog, 10, 700 of the H–D–Pro–Pro–Glu–NH2 tripeptide, which is probably the most efficient8 of 20 catalyst for such a transformation [74–77].

O NH2 NH2 OMe S S a) H S O O N N Bn Bn N N NHFmoc H NH NH , TFA O S O S 16 HOOC N N Bn Bn NHiPr NH NH S H H O O S H N O S H N N Bn N N , TFA , TFA NH HOOC HOOC H NH NH O S H N O O (S) S S N , TFA N N HOOC NH Bn Bn NH NH O S O S O S N Bn N N NH Bn Bn NH NH 17 O 18 19 O O R b) c) R C at (10 mol%) O O NMM (10mol%) NO2 NO + 2 IPrOH, 4°C, 16h

R = H , C H 3, OC H 3 Catalyst R Yield syn/anti ee (%) 16 H 93 96/4 45 17 H 91 >99/1 74 H 99 >99/1 79 18 CH3 99 >99/1 79 OCH3 97 >99/1 79 H 31 >99/1 77 19 CH3 11 >99/1 79 OCH3 81 >99/1 80 18

Figure 4. (a) ATC (4-amino(methyl)-1,3-thiazole-5-carboxylic acids)-based catalysts. (b) Lowest Figure 4. (a) ATC (4-amino(methyl)-1,3-thiazole-5-carboxylic acids)-based catalysts. (b) Lowest energy NMR solution structures of 18 in iPrOH. Catalytic groups are in light blue. (c) Nitro-Michael energy NMR solution structures of 18 in iPrOH. Catalytic groups are in light blue. (c) Nitro-Michael addition reaction of cyclohexanone to β-trans-nitrostyrene (R=H), trans-4-methyl- (R=CH3) and addition reaction of cyclohexanone to β-trans-nitrostyrene (R=H), trans-4-methyl- (R=CH3) and trans- trans-4-methoxy-β-nitrostyrene (R=OCH3) using ATC-based catalysts. 4-methoxy-β-nitrostyrene (R=OCH3) using ATC-based catalysts. Compound 16 showed a high catalytic activity toward the syn isomer, up to 45% ee for the (S, RCompound) enantiomer.16 Includingshowed a thehigh catalytic catalytic residue activity in toward a folded theγ-peptide syn isomer, (peptides up to17 45%and ee18 for, Figure the (S,4)  Renhanced) enantiomer. the asymmetricIncluding the induction catalytic (residuesyn/anti in= a96:4; folded ee =-peptide79%), highlighting (peptides 17that and the18,nine-helix Figure 4) enhancedstructure theis likely asymmetric to contribute induction to the (syn/anti enantioselectivity = 96:4; ee = [73 79%),]. Structure highlighting/activity that studies the nine-helix revealed structurethat side is chains likely distantto contribute from the to the catalytic enantioselectivity residue had [73]. a somewhat Structure/activity surprisingly studies effect revealed on substrate that sideselectivity. chains For distant instance, from sequence the catalytic19 with residue a branched had lateral a somewhat chain at surprisingly the N-terminus effect showed on substrate a marked selectivity.preference For for trans instance,-4-methoxy- sequenceβ-nitrostyrene19 with a branched while it was lateral poorly chain active at the for N-terminus the transformation showed ofa markedβ-trans -nitrostyrene, preference for and transtrans-4-methoxy--4-methyl-ββ-nitrostyrene.-nitrostyrene Such while a feature, it was reminiscent poorly active of biological for the transformationcatalysts, is not of really β-trans understood-nitrostyrene, but and underlinestrans-4-methyl- the effectβ-nitrostyrene. of a complex Such environment a feature, reminiscent in orienting ofsubstrate biological selectivity. catalysts, is not really understood but underlines the effect of a complex environment in orienting substrate selectivity. 4.2. Bundle Foldamers as Artificial Esterase 4.b—Bundle Foldamers as Artificial Esterase Engineering entirely new enzymes from scratch still remains an inaccessible challenge owing in Engineering entirely new enzymes from scratch still remains an inaccessible challenge owing in part to the difficulty in predicting the atomic level conformation of a polypeptide sequence. However, part to the difficulty in predicting the atomic level conformation of a polypeptide sequence. However, over the last decade, seminal works on coiled-coil proteins [78–81] have opened up the prospect of Catalysts 2020, 10, 700 9 of 20

Catalysts 2019, 9, x FOR PEER REVIEW 9 of 20 designing globular protein-like helix-bundle quaternary structures based on β-peptide [82–85] and oligoureaover the foldamers last decade, [86 –seminal88]. Among works the on reportedcoiled-coil structures, proteins [78 the–81] group have opened of A. Schepartz up the prospect described of the 3 mostdesigning thermally globular and kinetically protein-like stable helix-bundleβ -peptide quaternary bundle structures characterized based on to β date-peptide [89]. [82 The–85] octameric and bundleoligourea assembly foldamers (Figure [865–a)88]. named Among Zwit-EYYK the reported structures,20 consists the of group parallel of A. andSchepartz antiparallel described 14-helices, the well packedmost thermally by a leucine-rich and kinetically core stable and arrays β3-peptide of salt–bridge bundle characterized interactions to involving date [89].β The3-homoornithines. octameric In 2014,bundle Zwit-EYYK assembly was (Figure considered 5a) named as a Zwit-EYYK starting point20 consists for the rationalof parallel design and antiparallel of an esterase 14-helices, mimic using 3 8-acetoxypyrene-1,3,6-trisulfonatewell packed by a leucine-rich core23 andas arrays a model of salt substrate–bridge interactions [90]. In theinvolving first step, β the-homoornithines peptide sequence. In 2014, Zwit-EYYK was considered as a starting point for the rational design of an esterase mimic was modified to create binding sites for the anionic substrate. This was achieved by mutating the two using 8-acetoxypyrene-1,3,6-trisulfonate 23 as a model substrate [90]. In the first step, the peptide β3-homoornithine residues sharing one face of the helix (positions 3 and 9) by two β3-homoarginines sequence was modified to create binding sites for the anionic substrate. This was achieved by knownmutating to interact the two favorably β3-homoornithine with sulfonate residues groups. sharing one Secondly, face of the the helix hydrolytic (positions activity 3 and 9) was by two installed by addingβ3-homoarginines a basic histidine known residue to interact at the favorably N-terminus with ofsulfonate the peptide. groups. Considering Secondly, the that hydrolytic each bundle comprisesactivity four was parallel, installed two by antiparallel, adding a basic and four histidine tetramer residuetetramer at the helical N-terminus contacts, of and the peptidethere are. two − activeConsidering sites per interhelical that each bundle interface, comprises there four are theoreticallyparallel, two antiparallel, 20 intermolecular and four active tetramer−tetramer sites per bundle. helicalThe resulting contacts, foldamer and there21 arewas two able active to catalyze sites per the interhelical hydrolysis interface, of 23 in a there Michaelis–Menten are theoretically behavior 20 intermolecular active sites per bundle. 1 1 with a turnover 588-times faster than the uncatalyzed reaction (kcat/Km = 54 M− min− ). However, the bundleThe self-assembly resulting foldamer was impaired 21 was ableat the to concentration catalyze the hydrolysis chosen for of the 23 steady-statein a Michaelis kinetics–Menten studies behavior with a turnover 588-times faster than the uncatalyzed reaction (kcat/Km = 54 M−1 min−1). (25 mM) but was restored by covalently joining two monomers via a tetra-β-homoglycine linker However, the bundle self-assembly was impaired at the concentration chosen for the steady-state (compound 22, Figure5c). At low concentration of substrate ( <200 µM), the catalytic efficiency was kinetics studies (25 mM) but was restored by covalently joining two monomers via a tetra-β- 1 1 improvedhomoglycine by nearly linker two (compound orders of magnitude22, Figure (k 5c).cat /AtKm low= 5102 concentration M− min − of), substrate compared (<200 to the µM), monomeric the speciescatalytic21. The efficiency enhancement was improved of the by reaction nearly showedtwo orders to be of magnituderelated to an(kcat increase/Km = 5102 in M affi−1 nitymin−1 for), the substratecompared (Km to= the4 and monomeric 345 µM species for 22 21and. The21 enhancementrespectively), of the which reaction can showed be explained to be related by the to an greater numberincrease of functional in affinity for esterolytic the substrate active (Km sites= 4 withinand 345 theµM supramolecularfor 22 and 21 respectively), architecture which relative can be to the singleexplained chain catalyst. by the greater However, number at high of functional concentration esterolytic of substrate,active sites the within kinetic the failedsupramolecular to follow the Michaelis–Mentenarchitecture relative model to andthe single the hydrolytic chain catalyst. rateHowever, decreased at toward high concentration an asymptote. of substrate, This unexpectedthe behaviorkinetic was failed interpreted to follow asthe a Michaelis substrate–M inhibitionenten model phenomenon, and the hydrolytic which rate is commonlydecreased toward observed an as a asymptote. This unexpected behavior was interpreted as a substrate inhibition phenomenon, which regulatory mechanism of natural enzymes. The origin of the inhibition is actually not understood but is commonly observed as a regulatory mechanism of natural enzymes. The origin of the inhibition is revealed nonproductive catalyst–substrate interactions. actually not understood but revealed nonproductive catalyst–substrate interactions.

a) b) O - O3S O R

- - O3S SO3 23 90°

H2O

- O3S OH

- - O3S SO3

+ + 3 3 NH3 NH3 β -G β -G c β3-G β3-G )β3-E α-H β3-L β3-L α-H 3 α-H β3-L β3-O β -R β3-L β3-R β3-R β3-Y β3-Y β3-Y β3-L β3-L 3 3 β -Y β3-L β3-D β -D β3-L 3 3 β3-D β3-D β -Y β -Y 3 3 3 3 β -Y β -L 3 β -L 3 β -Y 3 β -O β -R 3 β -L β -L 3 3 3 3 β -R β -R β -K β -K 3 3 3 3 β -K β -L 3 β -L 3 β -K 3 β -D β -D 3 β -L β -L β3-D β3-D -O -O -O + 20 O 21 O 22 NH3 O

FigureFigure 5. ( a 5.) Structure(a) Structure of of the the octameric octameric Zwit-EYYK Zwit-EYYK bundle bundle (CCDC (CCDC 804 687 804 687).). Key Key residues residues for the for the bundlebundle stabilization stabilization are are depicted depictedas as follows:follows: o orange:range: β3-hLeuβ3-hLeu;; blue: blue: β3-hOrnβ3-hOrn;; and red: and β3-hAsp red: .β (3b-hAsp.) (b) Hydrolysis of 8-acetoxypyrene-1,3,6-trisulfonate 23, chosen as a model reaction. (c) Helical net diagrams of Zwit-EYYK 20 and esterolytic-active β3-peptides 21-22. Catalysts 2020, 10, 700 10 of 20

5. Hydrogen-Bond Catalysis Directed by the Main Chain Atoms A deeper understanding of the enzyme-catalyzed processes has extensively highlighted the crucial role of hydrogen bonding as both a structural and catalytic determinant of enzyme active sites. For instance, the stabilization of negatively charged oxygens in transition states often takes place via two, or sometimes even three, hydrogen bonds directed at the substrate oxygen atom [91,92]. This is referred to as an oxyanion hole-based mechanism. Generally, the oxyanion holes pre-exist in the unliganded enzymes, thus considerably lowering the entropic cost of redirecting the H-bond donors in the active site. From these observations, the concept of hydrogen-bonding catalysis has been formulated. This review will not attempt to exhaustively examine the extensive literature on hydrogen-bond catalysis and the interested reader is invited to read selected reviews [93–95]. The aim here is to explore how short folded oligomers can be used as control elements for directing H-bond catalysis. The first work in this field dates back to 40 years ago, with the publication of the asymmetric poly-L-leucine (PLL)-catalyzed nucleophilic epoxidation of electron deficient olefins, such as α, β-unsaturated ketones (Figure6a). The reaction referred to as the Julia–Colonna epoxidation consists of a bi- or triphasic system comprising the insoluble PLL peptide, H2O2 as an oxidant, and a base in a water-immiscible solvent [96–98]. Extensive kinetic explorations demonstrated that the PLL behaves as an enzyme-like catalyst with a first-order dependence on both the hydroperoxide anion (KM = 30 mM) and the enone substrate (KM = 110 mM) [99,100]. Oxidation takes place through a steady-state random bireactant mechanism, which implicates that all substrates must bind to the catalyst to generate a tertiary complex (PLL–HOO−–enone). The rapid equilibrium enabling the complex formation is followed by the rate-limiting formation of the peroxide enolate. However, for a long time, the precise location of the catalytic site remained elusive. Structural investigations provided evidence for the α-helix propensity of PLL. Interestingly, only five amino acids, which correspond to one helical turn, are sufficient to catalyze the epoxidation reaction [101]. In α-helix, the four N-terminal N–H groups of the polypeptide chain are not engaged in intra-chain hydrogen bonds (Figure6b), and subsequently, are available as acceptors for hydrogen bonding with the enone and the peroxide enolate. In addition, the resulting oxyanion hole benefits from the cooperative charge stabilization by the α-helix macrodipole [102]. Molecular mechanics calculations confirmed the binding mode of a chalcone peroxyenolate to NH-2, NH-3 and NH-4 (Figure6b). This structural framework proved to be general. Other folded polyamino acids [100] and helical β3-peptides [103] also catalyzed the epoxidation of chalcones. Despite the different structural features from α-peptides, poly-β3-leucines are able to catalyze the epoxidation of (E)-α, β-enones with enantioselectivity up to 85%. The exact mechanism by which β3-peptides interplays with the substrates to transfer the chiral information is not described. It is likely that similarly to PLL, the main-chain atoms are involved in the catalysis. However, the orientation of the N–H bonds within the typical β3-peptidic helices is opposite to those of α-helices, which excludes the binding site at the N-terminus and makes the C-terminus extremity a possible active site. Catalysts 2020, 10, 700 11 of 20 Catalysts 2019, 9, x FOR PEER REVIEW 11 of 20

Poly-L-Leu a) or Poly-L-β3-Leu H O , base, solvent R2 R1 R2 R1 2 2 O O O up to 98% ee

R2 R1 O O- HO

b) N-terminus C-terminus n n-1

1 2 n-2

4 3

C-terminus N-terminus

Poly-L-Leucine Poly-L-β3-Leucine

Figure 6. (a) Scheme of the poly-L-leucines and poly-L-β3-peptides-catalyzed oxidation of α, 3 βFigure-unsaturated 6. (a) Scheme ketones byof hydrogenthe poly-L-leucines peroxide under and poly-L-basic conditions.β -peptides-catalyzed The reaction proceeds oxidation through of α,β a- resonance-stabilizedunsaturated ketones by peroxide hydrogen enolate peroxide intermediate. under basic (b) conditions. Left: model The for reaction the binding proceeds of the through chalcone a peroxyenolateresonance-stabilized to the peroxide NH-2, NH-3 enolate and intermediate. NH-4 of PLL (b (forest) Left: green model chalcone for the binding enolate hydroperoxide;of the chalcone builtperoxyenolate using UCSF to Chimera the NH-2, according NH-3 and to [NH-4100]). of Right: PLL the (forest proposed green bindingchalcone site enolate of poly-L- hydroperoxide;β3-peptides involvesbuilt using the UCSF amide Chimera protons according n, n-1 and to n-2[100] at the). Right: C-terminus the proposed extremity. binding site of poly-L-β3-peptides involves the amide protons n, n-1 and n-2 at the C-terminus extremity. The intrinsic reactivity of helical peptides has long been confined to chalcone epoxidation, but in recentThe years, intrinsic there hasreactivity been renewed of helical interest peptides in this has field long with been the confined discovery to of chalcone new reaction epoxidation, possibilities. but Thisin recent includes years, the there work has of beenTanaka renewed et al. who interest described in this helical field with peptide-catalyzed the discovery enantioselective of new reaction Michaelpossibilities. addition This reactions includes [104 the,105 work]. As of in theTanaka Julia–Colonna et al. who epoxidation, described mechanistic helical peptide-catalyzed considerations supportedenantioselective the participation Michael addition of the N reactions-terminal amide[104,105]. protons As in in the the activation Julia–Colonna of the epoxidation, nucleophile speciesmechanistic through considerations H-bonding supported coordination. the Very participation recently, of Guichard the N-terminal et al. extended amide protons the concept in the of backbone-mediatedactivation of the nucleophile catalysis tospecies aliphatic throughN,N0 -linkedH-bonding oligoureas coordination. [106]. Over Very the recently, last decade, Guichard this group et al. establishedextended the the concept propensity of backbone-mediated of these oligomers catalysis to fold intoto aliphatic a 2.5-type N,N′ helix-linked promoted oligoureas by a network[106]. Over of three-centeredthe last decade, hydrogen this group bonds established between the C =propensityO(i) and urea of these HN(i oligomers3) and HN to (foldi 2) into [107–a109 2.5-type]. Since helix the − 0 − firstpromoted two ureas by a atnetwork the positive of three end‐centered of the oligourea hydrogen helix bonds macrodipole between doC notO( participatei) and urea inHN( intra-chaini−3) and hydrogenHN′(i−2) [107 bonding–109]. (Figure Since the7a), first it has two been ureas proposed at the positive that they end may of providethe oligourea an ideal helix set macrodipole of acceptors do to createnot participate an oxyanion in intra-chain hole. Their ehydrogenfficiency in bonding binding (Figure anions confirmed 7a), it has this been hypothesis, proposed paving that they the mayway forprovide developments an ideal of set oligoureas of acceptors in the to field create of catalysis an oxyanion (Figure hole.7b) [ Their110]. Among efficiency H-bond in binding donor groupsanions actingconfirmed as oxyanion this hypothesis, hole mimics, paving (thio) the ureas way have for showndevelopments to be highly of oligoureas effective, promoting in the field carbon–carbon of catalysis and(Figure carbon–heteroatom 7b) [110]. Among bond H-bond formation, donor eithergroups as acting monofunctional as oxyanion catalyst hole mimics, with the (thio) assistance ureas ofhave an externalshown to base be or highly as an effective, integral part promoting of a bifunctional carbon–carbon Brønsted and base-H-bond carbon–heteroatom catalyst [ 111 bond–114 formation,]. Helical oligoeither (thio) as monofunctional urea foldamers catalyst have thus with naturally the assistance been considered of an external for the base catalysis or as an of integral enantioselective part of a carbon–carbonbifunctional Brønsted bond formation base‐H‐bond reactions. catalyst Foldamer [111–114].23a, Helicalin association oligo (thio) with urea an external foldamers Brønsted have base,thus wasnaturally extraordinarily been considered effective for in the the enantioselective catalysis of enantioselective conjugate addition carbon reaction–carbon of bond malonate formation esters andreactions. nitroalkenes Foldamer even 23 ata, ain charge association of catalyst with asan low external as 0.01 Brønsted mol% (Figure base, was7a). extraordinarilyAs in PLL, [ 101 effective,102] the reactivityin the enantioselective of the hydrogen conjugate bond donor addition sites is enhancedreaction of by malonate the cooperative esters charge and nitroalkenes stabilization even provided at a bycharge the directionalof catalyst as hydrogen low as 0.01 bond mol% network (Figure spreading 7a). As in along PLL, [101,102] the foldamer the reactivity (Figure7c).[ of the102 hydrogen,115,116] bond donor sites is enhanced by the cooperative charge stabilization provided by the directional network spreading along the foldamer (Figure 7c).[102], [115], [116] Hexamer 23b, Catalysts 2020, 10, 700 12 of 20

Catalysts 2019, 9, x FOR PEER REVIEW 12 of 20 Hexamer 23b, which contains a thiourea in the first position, also performed well but was systematically which contains a thiourea in the first position, also performed well but was systematically less less effective than 23a in the addition of malonate to the nitroolefine. This result is unintuitive but one effective than 23a in the addition of malonate to the nitroolefine. This result is unintuitive but one plausible explanation given by the authors is that the benefit of increasing the acidity by replacing the plausible explanation given by the authors is that the benefit of increasing the acidity by replacing oxygen of the first urea by a sulfur atom is counterbalanced by unfavorable conformational change the oxygen of the first urea by a sulfur atom is counterbalanced by unfavorable conformational and dynamics at the positive pole of the helix where catalysis takes place. change and dynamics at the positive pole of the helix where catalysis takes place.

O O 23a or 23b O O NO2 NEt , toluene a) + 3 EtO OEt NO EtO OEt -20°C, 48h 2

Yield (%) ee (%) 23a (0.01 mol%) 98 82 23b (0.1 mol %) 98 80

CF3 X O O O H H H H H H N N N N N N F3C N N N N N N N N H H H H H H H H O O O 23a: X = O 23b: X = S δ+ δ- b) c) Site 1

Site 2

Figure 7. (a) Conjugate addition of diethylmalonate to nitroalkenes catalyzed by N,N0-linked oligoureas Figure23a–b . 7. The (a H-bond) Conjugate network addition (dashed of curve) diethylmalonate evidences the to disponibility nitroalkenes of thecatalyzed two ureas by atN,N′ the-linked positive

oligoureasend of the 23 oligourea.a–b. The H-bond (b) Model network for the (dashed binding curve) of anion evidences to N,N 0the-linked disponibility oligoureas of [the110 ].two (c )ureas X-ray atcrystal the positive structure end of of23a theshowing oligourea. the accessibility(b) Model for of H-bondthe binding donor of sitesanion (Picture to N,N′ from-linked [106 ]).oligoureas [110]. (c) X-ray crystal structure of 23a showing the accessibility of H-bond donor sites (Picture from [106]In the). former example, the chirality of the transformation is intimately guided by the asymmetric folding of the oligomer, which depends on the stereochemistry of the monomer units. The inversion of enantioselectivityIn the former example, requires the thechirality switching of the oftransformation all the stereochemical is intimately centers, guided making by the theasymmetric synthesis foldingtedious. of Anthe interestingoligomer, which approach depends to overcome on the stereochemistry this concern is toof usethe anmonomer achiral oligomerunits. The and inversion induce ofsymmetry enantioselectivity breaking requires by an external the switching stimulus. of all This the concept stereochemical was explored centers, by makingClayden the et al.synthesis on Aib tedious.oligomers An as interesting support of approach the catalysis. to overcome Aib oligomers this concern are intrinsically is to use achiralan achiral and oligomer they mainly and populate induce symmetrytwo 310-helical breaking conformations by an external in opposite stimulus. screw This senses. concept However, was explored adding aby chiral Clayden residue et inal. either on Aib the oligomersN- or C terminal as support position of the or catalysis. even by Aib using oligomers chiral groups are intrinsically that bind theachiral helix and in athey non-covalent mainly populate manner twolead 310 to-helical an imbalance conformations in the population in opposite of screw the two senses. interconverting However, screw-senseadding a chiral conformers residue [in117 either–120]. theThis N- ability or C wasterminal used position to control or the even stereochemical by using chiral environment groups that of a bifunctionalbind the helix achiral in a aminothioureanon-covalent mannermoiety placedlead to atan the imbalance N-terminus in the of thepopulation oligomer of [121 the]. two The interconverting remotely inducible screw-sense chiral thiourea conformers center [117was– proficient120]. This inability the catalysis was used of theto control enantioselective the stereochemical nitro-Michael environment addition reaction of a bifunctional of diethylmalonate achiral aminothioureato β-trans-nitrostyrene. moiety placed Adding at the a photoswitchable N-terminus of the AlaBni oligomer residue [121]. at theThe C-terminus remotely inducible of the oligomer chiral thioureamade the center photo-induced was proficient inversion in the catalysis of the helix of the screw-sense enantioselective possible, nitro-Michael which in addition turn changed reaction the ofenantioselectivity diethylmalonate of to the β-trans-nitrostyrene. reaction (Figure8). Adding a photoswitchable AlaBni residue at the C- terminus of the oligomer made the photo-induced inversion of the helix screw-sense possible, which in turn changed the enantioselectivity of the reaction (Figure 8). Catalysts 2020, 10, 700 13 of 20 Catalysts 2019, 9, x FOR PEER REVIEW 13 of 20

FigureFigure 8. (a 8.) Catalytic(a) Catalytic oligourea oligourea with with a a remotely remotely inducible chiral chiral catalytic catalytic site site for forthe thenitro-Michael nitro-Michael additionaddition reaction reaction of diethylmalonate of diethylmalonate to β -trans-nitrostyrene. to β-trans-nitrostyrene. (b) Photochemical(b) Photochemical refolding refolding of a of catalytic a foldamercatalytic with foldamer the consequent with the consequent inversion ofinversion the sense of the of sense asymmetric of asymmetric induction induction [121]. [121].

6. Foldamers6. Foldamers as Proteinas Protein Prosthesis Prosthesis The wholeThe whole foldamers foldamers presented presented in the in above the sectionsabove sections were designed were designed through through bottom-up bottom-up approaches. The edificesapproaches were. The able edifices to catalyze were a able specific to catalyze transformation, a specific transformation,taking advantage taking of the advantage topological of the control of thetopological oligomer control scaffolds. of the However, oligomer compared scaffolds. However, to natural compared enzymes, to they natural lacked enzymes well, definedthey lacked binding well defined binding pockets, thus limiting their proficiency and selectivity. The group of A. pockets, thus limiting their proficiency and selectivity. The group of A. Schepartz attempted to remedy Schepartz attempted to remedy this issue through foldamer bundle assemblies [90]. As a result, the this issue through foldamer bundle assemblies [90]. As a result, the protein-like particle displayed protein-like particle displayed multiple active sites differing in their local microenvironments and multiplecatalytic active aptitudes. sites di Inff eringrecent inyears, their consideration local microenvironments was given to the andsubstitution catalytic of aptitudes.whole secondary In recent years,structure consideration elements was of a givenprotein to with the topographical substitution ofmimics, whole whilst secondary retaining structure the function elements of the ofparent a protein withprotein topographical [122–124]. mimics, Such an whilstapproach retaining has been the termed function “protein of- theprosthesis” parent proteinor “bionic [122 proteins”–124]. and Such an approachhas been has been recently termed investigated “protein-prosthesis” in designing foldamer-enzyme or “bionic proteins” hybrids and withhas been true recently binding pocketsinvestigated in designing[125,126]. foldamer-enzyme hybrids with true binding pockets [125,126]. In a seminalIn a seminal example, example S. Gellman, S. Gellman and D. and Hilvert D. Hilvert developed developed a functional a functional heterodimeric heterodimeric chorismate mutasechorismate (CM) throughmutase (CM) the non-covalent through the non-covalent association association of a α/β of-peptide a α/β-peptide foldamer foldamer with with an inactivean inactive three-helix domain of the enzyme. In the native protein from Methanococcus jannaschii, the three-helix domain of the enzyme. In the native protein from Methanococcus jannaschii, the CM catalytic CM catalytic site is formed at the interface of a four -helix bundle (Figure 9a). It was previously site is formed at the interface of a four α-helix bundle (Figure9a). It was previously showed that showed that cleaving the dimer-spanning N-terminal helix to yield a one-helix and a three-helix cleavingfragment the dimer-spanning abolishes enzyme N-terminal function. However, helix to yield attaching a one-helix a leucine and zipper a three-helix dimerization fragment domain abolishes to enzymethe two function. polypeptides However, results attaching in the spontaneous a leucine zipper assembly dimerization of the two domain fragments, to the returning two polypeptides a split resultsenzyme in the with spontaneous wild-type-like assembly activities of the [127]. two This fragments, property returning was used a as split a starting enzyme point with to wild-type-like develop activitiesfoldamer- [127].hy Thisbrid propertyvariants of was the usedsplit CM, as a startingin which pointthe one-helix to develop domain foldamer-hybrid was substituted variants by α/β- of the splitpeptide CM, in surrogates which the differing one-helix in the domain number, was location substituted and/or by typeα/ βof-peptide β3-residues. surrogates Attaching di aff leucine-ering in the number,zipper location dimerization and/or domain type of toβ the3-residues. foldamers Attachingensured their a leucine-zipperassociation with dimerizationthe triple helix domainfragment to the foldamers(Figure ensured 9b). While their the association α/β-peptides with alone the triple were unable helix fragment to catalyze (Figure the conversion9b). While of the chorismate,α/β-peptides enzyme-like activities were observed with the hybrid assemblies. A similar demonstration of the alone were unable to catalyze the conversion of chorismate, enzyme-like activities were observed with the hybrid assemblies. A similar demonstration of the functional plasticity of proteins to the introduction of artificial segments has been recently described by Wilson starting from a split version Catalysts 2020, 10, 700 14 of 20 Catalysts 2019, 9, x FOR PEER REVIEW 14 of 20 of RNasefunctional S as plasticity protein scaof proteinsffold [126 to ].the An introductionα-helix segmentof artificial of segm theents catalytic has been site, recently bearing described one of the two histidineby Wilson residues starting from required a split for version acid-base of RNase catalyzed S as protein hydrolysis scaffold of [126] the phosphodiester. An α-helix segment linkage of in RNA,the was catalytic successfully site, bearing replaced one of by the an two aromatic histidine oligoamide residues required foldamer for a [cid126-base]. The catalyzed proteomimetics hydrolysis were shownof to the display phosphodiester first-order linkage kinetics in with RNA enzymatic, was successfully efficiency replaced dependent by on an both aromatic the concentration oligoamide of proteomimeticfoldamer [126] and. RNA,The proteomimetics but, with an e ffi wereciency shown>10 to4-fold display lower first than-order for kinetics the fully with functional enzymatic RNase S-proteinefficiency/S-peptide dependent complex. on both the concentration of proteomimetic and RNA, but, with an efficiency >104-fold lower than for the fully functional RNase S-protein/S-peptide complex. r a) r e e p p p p i i z z

e e n n i i c c u u e e L L

s i

s t e n h e t s m o g r a p r

f

e x d i l r r r r r e e e e e e p p p h p p p

e p p p p p i i i i i e p z z z z z

-

n e e e e e β o n n n n n i / i i i i c c c c c α u u u u u e e e e e L L b) L N L N L

C C C C

N N N Chorismate Mutase (CM) Split CM inac ve 3-helix domain Hybrid enzyme with

CM-like ac vity FigureFigure 9. (a) 9.Ribbon (a) Ribbon diagrams diagrams of the of monomeric the monomeric chorismate chorismate mutase mutase (PDB ( codePDB 2gtv) code [2gtv128)]. [128] (b) Schematic. (b) representationSchematic representation of chorismate of mutase chorismate (CM) mutase and its(CM) split and variant. its split Exchangevariant. Exchange of the oneof the helix one fragmenthelix (green)fragment with a (green)α/β-peptide with a surrogate/-peptide (orange) surrogate led (orange) to a hybrid led to enzymea hybrid withenzyme CM-like with CM activity.-like activity The active. site isThe symbolized active site byis symbolized a red circle by [121 a red]. circle [121].

7. Conclusions7. Conclusions FoldamersFoldamers can can mimic mimic the the structural structural and and biologicalbiological properties properties of of biopolymers biopolymers and and interesting interesting applicationsapplications were were developed developed in in various various fields fields from from lifelife to material material science. science. They They were were more more recently recently consideredconsidered as valuable as valuable sca scaffoldsffolds as as catalysts catalysts ableable to mimic complex complex reactions reactions as n asatural natural enzymes. enzymes. TheseThese latter latter are quiteare quite sophisticated sophisticated and and finely finely tunedtuned machines and and the the de denovo novo designdesign of artificial of artificial enzymes remains highly challenging. Fortunately, we showed herein that the use of peptidomimetic enzymes remains highly challenging. Fortunately, we showed herein that the use of peptidomimetic foldamers is particularly relevant to address this challenge since they putatively exhibit an infinite foldamersrange isof particularlystructures and relevant a huge tochemical address diversity. this challenge The high since stability they and putatively the predictability exhibit anof the infinite rangefoldamer of structures architectures and a huge allow chemical to accurately diversity. position The and high maintain stability chemical and the functions predictability at ideal of the foldamerdistances, architectures while their allow overall to accurately fold can positionconfine the and substrate maintain into chemical a reactive functions conformation, at ideal distances, thus whileovercoming their overall the fold entropic can confinecost of intramolecular the substrate reactions into a reactive mimicking conformation, the enzyme active thus overcomingsites. If such the entropicaptitudes cost ofare intramolecular actually out of reach reactions with mimickingsmall molecule the cataly enzymests, the active development sites. If suchof real aptitudes binding are actuallypockets out of using reach foldamers with small to re molecule-create the catalysts, natural enzymes the development microenvironments of real binding remains pockets a major using foldamersobstacle to re-createto override the the natural enzyme enzymess’ performances microenvironments while operating remains in various a major conditions obstacle (including to override the enzymes’temperature, performances solvent and while concent operatingration). in Moreover various conditions, the cooperativity (including is temperature, probably the solvent central and paradigm for future achievements in the design of proficient catalytic foldamers. Nevertheless, concentration). Moreover, the cooperativity is probably the central paradigm for future achievements research in this field has just begun and chemists are far from exhausting the potential of in thepeptido designmimetic of proficient foldamers catalytic in catalysis. foldamers. Nevertheless, research in this field has just begun and chemists are far from exhausting the potential of peptidomimetic foldamers in catalysis. Author Contributions: All authors have read and agreed to the published version of the manuscript.

Funding:Funding:This research This research received received no external no external funding. funding Conflicts of Interest: The authors declare no conflict of interest.

Catalysts 2020, 10, 700 15 of 20

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