Mes remerciements vont également à toutes les personnes de l'équipe F9 de l'IBMM. J'en profite pour remercier chaleureusement le Docteur Matthieu Simon pour nos échanges sur ce projet mais également pour sa bonne humeur et ses encouragements. Viennent ensuite les remerciements aux doctorants, Christophe, mon fidèle voisin de bureau et de labo, tu as été le premier à m'accueillir dans ces locaux, grâce à toi, je me suis sentie un peu moins perdue dans ce dédale de labos. Barth, je pourrai faire un paragraphe juste pour toi mon ami ! Merci d'avoir été là, merci pour toutes les soirées qu'on a passé durant ces trois ans. Ces « Smash up » où j'ai enfin fini par gagner une partie, nos pas de danse déguisés devant la télé, … et j'en passe ! Bien sûr, je n'oublie pas tous les autres doctorants, Alice, Julie, Julien, Kevin, Laurent, Laurine, Prisca, Titouan et Yohan ainsi que Manon et Caro ! Merci à vous d'avoir permis à ces trois années d'être festives ! Un grand merci à l'équipe AM2N et au Professeur Jean-Marc Campagne de m'avoir accueillie dans son laboratoire. Je suis reconnaissante envers Julien qui m'a toujours offert une place sur sa paillasse pour mes manips. Jimmy, je te remercie pour ta gentillesse, ta disponibilité et ta volonté de toujours faire au mieux pour tout le monde, c'est aussi grâce à toi que mes passages chez vous étaient si réussis ! Enfin, j'aimerai remercier mes meilleures amies, Marie et Marjorie, toujours disponibles pour un coup de fil malgré la distance qui nous sépare. Merci pour votre soutien les filles ! Bien entendu, je n'aurai jamais accompli cela sans ma famille : mes parents Edith et Christophe, mes soeurs Manon et Clara, et mon frère Mattéo. Vous n'avez pas toujours compris en quoi consistaient mes études et mon travail, je pense que vous allez encore moins comprendre ma présentation le jour de la soutenance, mais vous avez toujours été à mes côtés et je vous en remercie ! NOMENCLATURE Amino acids will be designated by their full names, their 3-or 1-letter codes without difference. For the 3D-modelling studies, a nomenclature based on three characters was necessary; it can be found below each structure. For further information, the two first letters correspond to the amino acid used as a starting block for the design of the monomer (e.g., LF means L-Phenylalanine, LA: L-Alanine and etc). The digit refers to the chain carried by the thiazole ring, 1 for a methyl, 2 for (S)-pyrrolidine and so on. The nomenclature used for the ATC-oligomers in this document is defined as following: when ATC-oligomers contain Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OH (45i) and Fmoc-NH-{CH3;Bn}-ATC-OH (45a) residues, these are defined as ATCL-P-X, with L the length of the oligomer (3 for a trimer, 5 for a pentamer and etc), P the position along the chain of the ATC unit bearing the pyrrolidine group, from the N-Ter to the C-terminal extremity and X the C-terminal extremity (for example NHiPr or NH2).

Glycine

The pyrrolidine group in the ATC-oligomers is usually set in the (S) configuration, however, when the (R) configuration is used, a star (*) is added after the position number (P), such as ATCL-P*-X represents an ATC-oligomer bearing a pyrrolidine group of (R) configuration.

Finally, if the ATC-oligomer contains one residue that differs from (45a) and/or (45i) or (45j), it will be designated as a mutant and thus will be called M(n)-ATCL-P-X with n a number in order of appearance. industries are small molecules that might be poorly selective or even toxic. In contrast to small molecule catalysts, biocatalysts offer an attractive alternative to conventional chemical methods. Enzymes are 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. In this context, research to design peptides and peptide-based molecules to mimick enzymatic systems seems auspicious.

However, for a better efficiency, the enzyme-like catalysts should have a well defined structure, which is hard to control in peptides. [START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF] Recently, new synthetic systems named "foldamers", mimicking the protein secondary structures (helices, sheets and ribbons) were developed. They are defined as artificial oligomers with high conformational stability and structural predictabilities. [START_REF] Gellman | A Manifesto[END_REF] Substantial results were obtained and were patented for material and biomedical applications. Nevertheless, their potential for modular catalyst design has been studied little.

The work in this manuscript is devoted to the development of bio-inspired foldamer catalysts and how to adapt a small foldamer to achieve catalytic functions. After reviewing the different levels of protein structures, we will give an overview of some available structures obtained by oligomerization of β-and γ-amino acids. We will focus on the driving forces for the genesis of these structures. It will be shown from the literature that some of those foldamers could potentially be used as catalysts for different reactions. Thereafter, we will concentrate on enamine-type catalysis and how proline-containing peptides inspired the design of a catalytically competent 4-amino-(methyl)-1,3-thiazole-5-carboxylic acid (ATC) monomer.

The next two chapters will be devoted to the introduction of the ATC monomer, which bears the catalytic function, into a γ-peptide foldamer. A systematic exploration of the connection between foldamer sizes and/or shapes, and, both, reactivity and enantioselectivity will be detailed. Depiction of the global folding of ATC-based foldamers using the study of NMR, FTIR and circular dichroism experiments will be elucidated. Eventually, the development of a new script for NMR-based 3D-modelling, used for the structure determination at the atomic level of the synthesized ATC-oligomers, will be detailed.

CHAPTER 1:

BIBLIOGRAPHIC INTRODUCTION CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION
Proteins are defined by four levels of structure, the simplest one being the primary structure, corresponding to the amino acid sequence in a polypeptide chain. The next level is the secondary structure; it refers to the folding of structures that form within a polypeptide to become a α-helix or a β-pleated-sheet. Both structures are held in shape by hydrogen bonds, formed between the carbonyl oxygen of one amino acid and the amino hydrogen of another one. The tertiary structure is the overall three-dimensional structure of a polypeptide and is mostly due to the interactions between the lateral groups of the amino acids forming the protein.

Various bonds among which are hydrogen bonds, electrovalent bonds or disulfide bonds, maintain it. Finally, the quaternary structure corresponds to two or more polypeptide chains that can bond in a non-covalent way and thus create a bigger structure. It has now been widely accepted that the 3D structure of a protein determines its function. [START_REF] Berg | Chapter 3, Protein Structure and Function[END_REF] The correlation between the low conformational stability of many enzymes within temperature, pH or solvent conditions, and, the loss of catalytic activity is evidence correlating with the said fact. The catalytic site of an enzyme is composed solely of a small part of the protein in which only two to four amino acids, constituting the catalytic centre, are directly involved in the chemical transformation. The other residues in the catalytic site are useful for their orientations and dynamics as well as for the substrate recognition. In such a context, one major area to address is understanding the role of the peripheral residues, meaning those that do not constitute the active site. Indeed, by introducing catalytic centres into small peptides, the catalytic enzyme properties could be mimicked and, the molecular complexity of the catalyst could theoretically be reduced.

So far, many attempts have been made to recreate all the desired catalytic properties of the enzymes starting from short peptide sequences. However, outside a protein context, small to medium-size peptides are often highly flexible, meaning that they do not adopt a single conformation but more likely a dynamic conformational ensemble. In the proteins, the conformation of a small peptide sequence is directly related to its local environment, which is to the presence of other elements of the secondary structure close to each other. Therefore, mimicking the enzyme activity with a peptide is challenging as the folding of this peptide needs to be controlled to a certain extent.

Some progress was made in the field and the desire to control the structural properties of peptides is very prominent in research nowadays. [START_REF] Grauer | Peptidomimetics -A Versatile Route to Biologically Active Compounds[END_REF][START_REF] Qvit | Peptidomimetic therapeutics: scientific approaches and opportunities[END_REF] Hence, the concept of restricting the conformation of peptides in order to mimic the activity of another natural peptide or protein was adopted in the design of molecules called peptidomimetics. [START_REF] Gante | Peptidomimetics-Tailored Enzyme Inhibitors[END_REF] In order to reduce the flexibility of the peptide and control its shape, different approaches were considered. The most common approach is the incorporation of disulfide bridges, whereas, another possibility is to tie together several side chains, for example a glutamate and a lysine in an amide bridge in order to create a "multiple side chain knotting". [START_REF] Liskamp | Peptides and Proteins as a Continuing Exciting Source of Inspiration for Peptidomimetics[END_REF] Additionally, one can envisage using chemical elements, different from peptides able to mimic typical secondary structures, such as the αhelices, β-strands or turns, found in proteins. The structuration properties within an artificial oligomer, associated with the properties carried by its internal specificities would permit to access new functions, like catalysis, specific binding, or controlled crystallization of inorganic phases. This would not be conceivable if the molecule was only a covalent succession of monomers. Such molecules exhibiting those properties are called "foldamers". [START_REF] Gellman | A Manifesto[END_REF] After a short presentation of the secondary structures found in proteins, how it is possible to design fold artificial pseudo-peptides will be reviewed. Finally, the end of this section will be dedicated to the insertion of a catalytic function within such foldamers. An attempt to highlight the relationships existing between the structural behaviours and the pseudo-enzymatic activities will be made.

I. SECONDARY STRUCTURES ASSOCIATED WITH PROTEINS DIHEDRAL ANGLES

On a polypeptide chain, the amino acids are connected by an amide bond (in red, Figure 5). The geometry of this link is partially responsible for the structure of the proteins. Torsion angles are dihedral angles defined by four points in space; here ω is defined as the dihedral angle Cαi-CO-NH-Cαi+1. Two conformations for this specific bond are possible: the cis conformation, when ω = 0° and the trans conformation, when ω = 180° (Figure 5). Usually, since the lateral chains on the carbon α are sources of steric hindrance, the trans configuration is preferred. In addition, there is a partial double bond delocalized between the N-C-O bonds due to the resonance stabilization, leading to a planar and rigid geometry of the amide bond.

Consequently, the length of this bond is shorter than a simple C-N bond (1.33 Å against 1.47 Å) but longer than a C=N bond (1.28 Å). [START_REF] Allen | Tables of Bond Lengths determined by X-Ray and Neutron Diffraction. Part I . Bond Lengths in Organic Compounds[END_REF] In proteins, two torsion angles, φ and ψ, are noteworthy.

These describe the rotation of the polypeptide chain around the two bonds on both sides of the carbon α, as represented in Figure 6, where φ defines the torsion angle created by Ci-1-Ni-Cαi-Ci and ψ by Ni-Cαi-Ci-Ni+1. [START_REF] Pettersen | UCSF Chimera -A visualization system for exploratory research and analysis[END_REF] Because of the rigidity of the amide bond, it is impossible for the angles φ and ψ to take every single value between 0 and 180°. As part of this manuscript, we will only focus on the most common secondary structures allowed by the combination of these dihedral angles. Such possibilities are represented on the Ramachandran plot Figure 7. [START_REF] Hollingsworth | A Fresh Look at the Ramachandran Plot and the Occurrence of Standard Structures in Proteins[END_REF][START_REF] Horton | Principles of Biochemistry[END_REF] Figure 7: Ramachandran plot [START_REF] Horton | Principles of Biochemistry[END_REF] The representation in Figure 7 displays recurrent structures such as turns, β-sheets and helices are detected in proteins. Furthermore, several types of helices such as α-, 310-, πor even polyproline helices can be observed in nature, the most common one being the α-helix (32% of secondary structure of globular proteins). [START_REF] Barlow | Helix Geometry in Proteins[END_REF] The 310-helices represent only 3.4% of the secondary structure, comparable with polyproline II helices (2 to 4%) while the occurrence of π helices is even lower (less than 1%). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF][START_REF] Adzhubei | Polyproline-II Helix in Proteins: Structure and Function[END_REF] 1. The helical secondary structures In 1931, Astbury et al. performed X-ray studies of hair and wool structures. The data obtained showed strong differences in the diffraction of hair fibres or moist wool depending on whether it was stretched or unstretched. This study demonstrated that unstretched fibres take the shape of a helix with a vertical distance between two consecutive turns (pitch) of 5.1 Å, that Astbury called the α-form. Also, the existence of another form was shown, the β-strand, when the fibres are stretched. [START_REF] Astbury | X-Ray Studies of the Structure of Hair, Wool, and Related Fibres. I. General[END_REF] Afterwards, the exploration of intramolecular fold was pursued with the investigation of α-keratin and α-myosin. [START_REF] Astbury | Nature of the Intramolecular Fold in Alpha-Keratin and Alpha-Myosin[END_REF] Even though all the details provided by those articles were not entirely accurate as Atsbury's models involved clashes of atoms, [START_REF] Neurath | Intramolecular Folding of Polypeptide Chains in Relation to Protein Structure[END_REF] the elements of secondary structures, being the α-helix and the β-strand, were touched upon and gave Pauling, Corey and Branson the opportunity to characterize the α-helix in 1951. [START_REF] Pauling | The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain[END_REF] In theory, α-helices can be either a right-handed screw or a left-handed screw but are usually right-handed. [START_REF] Kabsch | Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features[END_REF][START_REF] Haimov | A Closer Look into the α-Helix Basin[END_REF] These are the most abundant structure inherent to proteins, the pitch of the helix is equal to 5.4 Å, each turn is composed of 3.6 amino acids and the rise per residue is of 1.52 Å. A pseudocycle of 13 atoms forms within the helix between the carbonyl oxygen, eleven backbone atoms and the amide hydrogen that closes the loop and gives one complete turn (Figure 8,A). In Bragg's nomenclature, the α-helix is called a 3.613-helix, based on its average number of residues per helical turn and the hydrogen-bonded loop size. [START_REF] Bragg | Polypeptide Chain Configurations in Crystalline Proteins[END_REF] The dihedral angles φ and ψ of the α-helix are -57° and -47° respectively. [START_REF] Barlow | Helix Geometry in Proteins[END_REF][START_REF] Arnott | Atomic Co-ordinates for an α-Helix: Refinement of the Crystal Structure of α-Poly-L-alanine[END_REF] Along the axis of the helix, each carbonyl oxygen (residue i) of the polypeptide backbone is hydrogen-bonded to the backbone amide hydrogen, four residues away towards the C-terminus (residue i+4). This way, the hydrogen bonds stabilize the structure by being almost parallel to the axis (Figure 8, A). The side chains are located around the cylinder of this helix, pointing outward. The length of a α-helix in a protein can range from about 4 or 5 residues to more than 40, but the average is 14 ± 5 amino acids. [START_REF] Kumar | Geometrical and Sequence Characteristics of alpha-Helices in Globular Proteins[END_REF] Each peptide bond within the helix has a dipole [START_REF] Astbury | X-Ray Studies of the Structure of Hair, Wool, and Related Fibres. I. General[END_REF] Astbury, W. T. et al., Philos. Trans. R. Soc. Math. Phys. Eng. Sci., 230, 75-101 (1932). [START_REF] Astbury | Nature of the Intramolecular Fold in Alpha-Keratin and Alpha-Myosin[END_REF] Astbury, W. T. et al., Nature, 147, 696-99 (1941). [START_REF] Neurath | Intramolecular Folding of Polypeptide Chains in Relation to Protein Structure[END_REF] Neurath, H., J. Phys. Chem., 44, 296-305 (1940). [START_REF] Pauling | The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain[END_REF] Pauling, L. et al., Proc. Natl. Acad. Sci., 37, 205-11 (1951). [START_REF] Kabsch | Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features[END_REF] Kabsch, W. et al., Biopolymers, 22, 2577-2637 (1983). 20 Haimov, B. et al., Sci. Rep., 6, 38341 (2016). [START_REF] Bragg | Polypeptide Chain Configurations in Crystalline Proteins[END_REF] Bragg, L. et al., Proc. R. Soc. Lond. Ser. Math. Phys. Sci., 203, 321-57 (1950). [START_REF] Arnott | Atomic Co-ordinates for an α-Helix: Refinement of the Crystal Structure of α-Poly-L-alanine[END_REF] Arnott, S. et al., J. Mol. Biol., 21, 371-83 (1966). [START_REF] Kumar | Geometrical and Sequence Characteristics of alpha-Helices in Globular Proteins[END_REF] Kumar, S. et al., Biophys. J., 75, 1935-44 (1998).

positioned from the oxygen to the nitrogen. Owing to that, the entire helix is a macrodipole oriented from the δ -C-terminus towards the δ + N-terminus (Figure 8, C). [START_REF] Maestro | Schrödinger Release 2019-1[END_REF] As previously reported, left-handed α-helices (φ and ψ are positive, opposite of the right-handed helix) also exist. However, they are less observed due to the dihedral angle ψ causing a higher steric hindrance between the carbonyl and the lateral chain.

Regarding other types of helices found in proteins, the 310-helix differs from the α-helix as 10 atoms compose a pseudocycle, with a hydrogen bond between COi and NHi+3. The 310-helix is also less regular, hence its dihedral angle values, φ and ψ, fluctuate. The observed values in proteins are respectively of -71° and -18°, giving a very compact helical structure with a small diameter. [START_REF] Toniolo | The Polypeptide 3.10-Helix[END_REF] Less frequent, but nonetheless present, are the π-helices. They are stabilized by a network of hydrogen bonds between COi and NHi+5. These long-distance interactions impose 4.4 amino acids per turn and a pitch of 5.0 Å. This is the largest helix in terms of diameter and is usually found within α-helices. Its dihedral angles φ and ψ are fixed at -57° and -70°, respectively. On average, such helices are composed of seven amino acids, usually aromatic amino acids (tryptophan and phenylalanine) for which the lateral chains stabilize the helix by π-π stacking. [START_REF] Cooley | Evolutionary Origin of a Secondary Structure: π-Helices as Cryptic but Widespread Insertional Variations of α-Helices That Enhance Protein Functionality[END_REF] Finally, polyproline helices occur in two different conformation: polyproline-I (PPI) and polyproline-II (PPII). The PPI helix is a right-handed helix composed of all peptide bonds in cis conformation, while the PPII helix has all its peptide bonds in trans conformation. Only the latter is found in globular proteins. [START_REF] Kakinoki | On the Stability of Polyproline-I and II Structures of Proline Oligopeptides[END_REF]

The β-sheets

A β-strand is a long and extended polypeptide chain, while, as previously discussed, the α-helix is tightly coiled. The distance between adjacent amino acids along the β-strand is of approximately 3.5 Å and the side chains project from the sheet alternating up and down directions. β-strands are usually drawn as wide arrows with the tip of the arrowhead representing the C-terminal end of the polypeptide chain (Figure 9). In proteins, it is quite rare to find single β-strands, as their structure is not very stable, and can be compared to a random coil in terms of their stability.

Figure 9: Representative structure of a β-strand [START_REF] Nelson | Principles of Biochemistry[END_REF] However, when two adjacent β-strands line up, they can form hydrogen bonds creating a very stable structure known as a β-sheet. Connected by turns, many strands can assemble in β-sheets.

Adjacent chains in a β-sheet can run in opposite directions (antiparallel β-sheet) or in the same direction (parallel β-sheet) (Figure 10). In the antiparallel arrangement (Figure 11), the NH group and the CO group of each amino acid are respectively hydrogen bonded to the CO and the NH of a partner on the adjacent chain. The dihedral angles of the amino acids in this type of sheet are φ = -139° and ψ = +135°. [START_REF] Lubell | Peptidomimetics II[END_REF] Figure 11: Representative structure of an antiparallel β-sheet. A/Top view. B/Side view [START_REF] Nelson | Principles of Biochemistry[END_REF] In the parallel arrangement (Figure 12), the hydrogen-bonding scheme is slightly more complicated. For each amino acid, their hydrogen amide is bonded to the carbonyl oxygen of one amino acid on the adjacent strand, whereas their carbonyl oxygen is bonded to the hydrogen amide of the amino acid two residues further along the chain of the adjacent strand. Usually, two strands of such structure are connected by a long non-structured polypeptide chain or, sometimes, a α-helix. The φ and ψ dihedral angles are then -119° and +113° respectively. [START_REF] Lubell | Peptidomimetics II[END_REF] Figure 12: Representative structure of a parallel β-sheet. A/Top view. B/Side view [START_REF] Nelson | Principles of Biochemistry[END_REF] Due to the optimum alignment of the donors and acceptors along the chains and the resulting parallelism given by the antiparallel conformation, it is the most common β-sheet conformation in proteins. The antiparallel β-sheet can be found at the surface of the proteins while, usually, the parallel arrangement tends to be found inside the core structure of proteins where the hydrogen bonds between strands are protected from competition with water molecules.

The turns

In addition to α-helices and β-strands, a folded polypeptide chain can contain two other types of secondary structure called loops and turns. They are the simplest and most irregular secondary structures. Loops are not well defined, but generally hold hydrophilic residues found on the surface of the protein. Initially, turns were described by Venkatachalam in 1968, they were designated as sites where the polypeptide chain folds back on itself. [START_REF] Venkatachalam | Stereochemical criteria for polypeptides and proteins. V. Conformation of a system of three linked peptide units[END_REF] Nowadays, a widely accepted definition of turns is when loops possess an internal hydrogen bond between the main-chain carbonyl group from the first residue of the loop and the main-chain amide group from the last residue of this loop. [START_REF] Chou | Prediction of Tight Turns and Their Types in Proteins[END_REF] Several types of turns exists (Table 1), they differ by the number of residues separating the pair connected via the hydrogen bond. [START_REF] Koch | Turns revisited: A uniform and comprehensive classification of normal, open, and reverse turn families minimizing unassigned random chain portions[END_REF] The δ and ε turns contrast from the other families as they are characterized by a hydrogen bond between the main-chain amide group of the first residue and the main-chain carbonyl group of the last 30 Venkatachalam, C. M., Biopolymers, 6, 1425-36 (1968). [START_REF] Chou | Prediction of Tight Turns and Their Types in Proteins[END_REF] Chou, K.-C., Anal. Biochem., 286, 1-16 (2000). [START_REF] Koch | Turns revisited: A uniform and comprehensive classification of normal, open, and reverse turn families minimizing unassigned random chain portions[END_REF] Koch, O. et al., Proteins Struct. Funct. Bioinforma., 74, 353-67 (2009).

CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION 34 residue (opposite to the γ, β, α and π turns). Therefore, in these conformations, a ''reverse'' hydrogen bond is observed. COi -NHi+5

We will focus, in the following paragraphs, on the most common turns, the β-turns and γ-turns.

i. β-turns

The β-turns are composed of four amino acids, their stabilization is based on the establishment of an intramolecular hydrogen bond between the carbonyl oxygen of the residue i and the amine hydrogen of the residue i+3 (Figure 13). They are called β-turns because they usually connect adjacent β-strands in an antiparallel β-sheet. They generally cause a change in direction of the polypeptide chain allowing it to fold back on itself to create a more compact structure. Several families of β-turns exist and were described in 1994 by Hutchinson and Thornton. [START_REF] Hutchinson | A Revised Set of Potentials for Beta-Turn Formation in Proteins[END_REF] Their classification relies on the dihedral angles of the central residues (i+1 and i+2) in the turn.

The main types of β-turns are summarized in the following table. 33 Hutchinson, E. G. et al., Protein Sci., 2207-16 (1994). VIb (cis) -120 +120 -60 0

Types I and II (Figure 14) are the most common turns found in proteins, types I' and II' are their mirror images and are significantly rarer. In these types of β-turns, it is quite typical to find proline in the position 2 and glycine as residue number 3. Indeed, in such configuration, the proline adds a high restraint in the structure, which is unconstrained by the following glycine.

ii. γ-turns

As reported in Table 1, γ-turns possess three amino acids and are stabilized by a hydrogen bond between the main chain COi and NHi+2.

Figure 15: γ-turn involving a hydrogen bond between i and i+2 [START_REF] Liskamp | Peptides and Proteins as a Continuing Exciting Source of Inspiration for Peptidomimetics[END_REF] In 1972, Matthews described the first example of a γ-turn in a protein at the end of a β-hairpin in thermolysin. [START_REF] Matthews | The γ Turn. Evidence for a New Folded Conformation in Proteins[END_REF][START_REF] Némethy | The γ Turn, a Possible Folded Conformation of the Polypeptide Chain. Comparison with the β Turn[END_REF] Afterwards, this type of turn was also reported in the early 80s by several groups. [START_REF] Smith | Reverse Turns in Peptides and Protein[END_REF][START_REF] Valle | Intramolecularly Hydrogen-bonded Peptide Conformations. Preferred Crystal-state and Solution Conformations of N-Monochloroacetylated Glycines Dialkylated at the a-Carbon Atom[END_REF][START_REF] Rose | Turns in Peptides and Proteins[END_REF] These occur as two types: inverse γ-turn and classic γ-turn. However, it is less common to find classic γ-turns in proteins. [START_REF] Milner-White | One type of gamma-turn, rather than the other gives rise to chain-reversal in proteins[END_REF] The values of dihedral angles for these two types of γ-turns are reported in the following table. Finally, it is quite frequent to find proline in the central position of the turn (Figure 16,A). It is to be noted that the intramolecular hydrogen bond is only possible if the proline adopts a cis conformation as represented in Figure 16, B. [START_REF] Matthews | The γ Turn. Evidence for a New Folded Conformation in Proteins[END_REF] Matthews, B. W., Macromolecules, 5, 818-19 (1972). [START_REF] Némethy | The γ Turn, a Possible Folded Conformation of the Polypeptide Chain. Comparison with the β Turn[END_REF] Némethy, G. et al., Macromolecules, 5, 755-58 (1972). 36 Smith, J. A. et al., Crit. Rev. Biochem., 8, 315-99 (1980). 37 Valle, G. et al., J Chem Soc Perkin Trans 2, 885-89 (1986). [START_REF] Rose | Turns in Peptides and Proteins[END_REF] Rose, G. D. et al., Adv. Protein Chem., 37, 1-109 (1985). [START_REF] Milner-White | One type of gamma-turn, rather than the other gives rise to chain-reversal in proteins[END_REF] Milner-White, E. J. et al., J. Mol. Biol., 204, 777-82 (1988).

Secondary structure predictions for the natural amino acids in protein conformation

As previously presented, proteins can adopt different secondary structures such as helices, βsheets or turns. These structures are amino acid dependent, meaning that each amino acid tends to direct towards one preferential structure. A statistic rank was proposed by Chou and Fasman in 1974 for the twenty natural amino acids, in regards of the three most common secondary structures (α-helices, β-sheets and turns). [START_REF] Chou | Conformational Parameters for Amino Acids in Helical, /3-Sheet, and Random Coil Regions Calculated from[END_REF] In this study, fifteen proteins with known conformations were crystallized and the theoretical data was compared with the crystalline data.

Using this procedure, the overall accuracy of prediction of the secondary structure of globular proteins was about 80%. [START_REF] Chou | Prediction of Protein Conformation[END_REF] In 1987, Williams et al. proposed a more precise model that is currently used as a reference in terms of structure prediction. [START_REF] Williams | Secondary structure predictions and medium range interactions[END_REF] These statistical data are presented in the Table 4. If the preferential score is higher than one, then this amino acid will likely be found within the corresponding structure. 40 Chou, P. Y. et al., Biochemistry, 13, 211-22 (1974). 41 Chou, P. Y. et al., Biochemistry, 13, 222-45 (1974). 42 Williams, R. W. et al., Biochim. Biophys. Acta, 916, 200-204 (1987). Among the natural amino acids, two of them are identified as "helix breakers": glycine and proline. The first is highly flexible and, therefore, disrupts the regularity of the α-helical backbone conformation, while the pyrrolidine ring of proline is too rigid and causes an important steric strain. Conversely, those two amino acids are commonly found in turns. [START_REF] Imai | Mechanisms of secondary structure breakers in soluble proteins[END_REF] Some others, such as methionine, alanine, leucine, glutamate and lysine, prefer to adopt helical conformations. Various amino acids like isoleucine, valine, threonine or large aromatic residues (tryptophan, tyrosine and phenylalanine), presumptively adopt β-strand conformations.

Therefore, it appears that the structuration properties depend on the primary structure of the polypeptide chains, due to specific values on the dihedral angles φ and ψ and interactions between lateral chains along the main-chains. Nonetheless, even if the sequence itself provides an indication of which amino acid could disrupt a structure or induce another one, these are not entirely reliable in predicting with exactitude the secondary structure.

In conclusion, structural complexity holds small, simple and randomly structured peptides as much as turns, helices and sheets. Structures with assemblies of helices, sheets and turns are also quite common in nature. The number of possibilities for the creation of proteins with these twenty amino acids is immense. Moreover, each of the amino acids carries some specific properties due to their side chain, it can then be established that the structural diversity will lead to an extensive variety in biological function. In this respect, it can be alleged that the biochemical functions carried out by the proteins must rely on their capacity to structure themselves. 43 Imai, K. et al., Biophysics, 1, 55-65 (2005).

II. FOLDAMERS AND CATALYSIS

Definition foldamer

The term "foldamer" was introduced for the first time by Samuel Gellman in 1996. He described it as "polymer with a strong tendency to adopt a specific compact conformation". [START_REF] Gellman | A Manifesto[END_REF] In 2001, Moore gave a more specific definition of a foldamer as being "any oligomer that folds into a conformationally ordered state in solution, the structures of which are stabilized by a collection of non-covalent interactions between non-adjacent monomer units". [START_REF] Hill | A Field Guide to Foldamers[END_REF] In other words, a

foldamer is an artificial oligomer, peptidic or not, for which, in solution, the backbone adopts a well-defined secondary structure, such as turns, helices or sheets. It is important to point out that these molecular objects must adopt only one conformational state.

Moreover, the interactions that provide the foldamer its structure ought not to be contained within adjacent repeating units, they must be immutable with the notion of secondary structure mimic. The conformational stability is required to be the result of the combination of steric hindrance, intrinsic rigidity of the backbone and non-covalent interaction between non-adjacent monomers. [START_REF] Hecht | Foldamers: Structure, Properties and Applications[END_REF] Hydrogen bonds, ionic interactions or hydrophobic effect are governing the stability of the structure, in the same manner as they stabilize the structure of proteins.

Foldamers can be sorted in two classes: the single-stranded foldamers and the multiple-stranded foldamers (Figure 17). As the second class tends to access molecules presenting a level of structuration of the tertiary structure, we will focus on the following paragraphs on the singlestranded foldamers. Indeed, it is of great interest to create such foldamers as they are designed to organize themselves into defined secondary structures found in nature (helices, turns and sheets). 44 Hill, D. J. et al., Chem. Rev., 101, 3893-4012 (2001). 45 Hecht, S. et al. (John Wiley & Sons, 2007).

Figure 17: Illustrations of the different types of foldamer secondary structures in A/single-stranded foldamer or in B/multiple-stranded foldamers [START_REF] Hill | A Field Guide to Foldamers[END_REF] Foldamer-based chemical systems can be used for various applications if they are functionalized in a suitable manner. For instance, they could be adapted for different biological purposes such as protein-protein interaction inhibitors [START_REF] Bartus | De Novo Modular Development of a Foldameric Protein-Protein Interaction Inhibitor for Separate Hot Spots: A Dynamic Covalent Assembly Approach[END_REF][START_REF] Mándity | An overview of peptide and peptoid foldamers in medicinal chemistry[END_REF] or antimicrobial activity [START_REF] Schmitt | Unexpected Relationships between Structure and Function in α,β-Peptides: Antimicrobial Foldamers with Heterogeneous Backbones[END_REF][START_REF] Schmitt | Interplay among Folding, Sequence, and Lipophilicity in the Antibacterial and Hemolytic Activities of α/β-Peptides[END_REF] , their exploitation as polyfunctional platforms for synthetic glycocluster construction [START_REF] Simon | Can Heterocyclic γ-Peptides Provide Polyfunctional Platforms for Synthetic Glycocluster Construction?[END_REF] was investigated too. They also present possibilities to be used for further diverse applications like nanoarchitecture [START_REF] Li | Strong Stacking between F⋅⋅⋅H-N Hydrogen-Bonded Foldamers and Fullerenes: Formation of Supramolecular Nano Networks[END_REF] or catalysis. [START_REF] Maayan | Folded Biomimetic Oligomers for Enantioselective Catalysis[END_REF][START_REF] Bécart | Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions[END_REF] Single-stranded foldamers are composed of various numbers of different foldamer-based molecules. [START_REF] Hill | A Field Guide to Foldamers[END_REF][START_REF] Guichard | Synthetic foldamers[END_REF] In this document, we will focus on peptides and pseudopeptides foldamers that can be classified into four separated groups. The artificial oligomers composing these clusters are sorted by the number of atoms separating the CO from the NH within a monomer (Figure 18). Hence, the four families are constituted either with α-, β-, γ-or δ-peptides. For example, the α-peptides are oligomers created with α-amino acids connected by an amide bond; βand γ-peptides are obtained by oligomerization of βand γ-amino acids, which are homologated proteinogenic amino acid residues, with respectively one and two extra carbons in comparison to the α-amino acids. Also represented in the family tree of foldamers (Figure 18), we can distinguish subunits, sorted by the functional group classes such as aminoxy acids, ureas, vinylogous peptides and so on.

Figure 18: Structural lineage of existing artificial oligomers [START_REF] Hill | A Field Guide to Foldamers[END_REF] Historically, the first synthesized non-natural oligomers consisted of the same category of monomer in the succession along the backbone, therefore, they were qualified as homofoldamers. [START_REF] Gellman | A Manifesto[END_REF][START_REF] Seebach | β-Peptides: Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a β-Hexapeptide in Solution and Its Stability towards Pepsin[END_REF] Afterwards, new combinations between different types of monomers were attempted in order to reach new conformations, this category is known as heterofoldamers. [START_REF] De Pol | Surprisingly Stable Helical Conformations inα/β-Peptides by Incorporation ofcis-β-Aminocyclopropane Carboxylic Acids[END_REF][START_REF] Hayen | Two Helical Conformations from a Single Foldamer Backbone: "Split Personality" in Short α/β-Peptides[END_REF] In this manuscript, the objective is not to give a complete description of all the possible foldamers and their associated structures. The point here is to give an overview of the most common structures found on the α-, βand γ-peptides. Eventually, as the goal of this thesis is the design of bio-inspired catalysts based on a γ-peptide foldamer architecture, we will centre our interest on foldamers bearing specific functions that could lead to a catalytic activity. 55 Seebach, D. et al., Helv. Chim. Acta, 79, 913-41 (1996). 56 De Pol, S. et al., Angew. Chem. Int. Ed., 43, 511-14 (2004). 57 Hayen, A. et al., Angew. Chem. Int. Ed., 43, 505-10 (2004).

i. Considerations from the dynamics of α-peptides and peptoids

As previously discussed, α-amino acids are proteinogenic amino acid residues. In proteins, peptidic helices mainly correspond to the α-helices (3.613-helices) or the 310-helices. For most amino acids, the α-helical geometry (φ = -57°, ψ = -47°) is of lower energy than the 310 geometry (φ = -71°, ψ = -18°). [START_REF] Barlow | Helix Geometry in Proteins[END_REF] However there is no energetic barrier between the two conformations in the Ramachandran plot, and a peptide can therefore drive an easy transition from a α-helix to a 310-helix. [START_REF] Toniolo | The Polypeptide 3.10-Helix[END_REF][START_REF] Bolin | α and 3 10 : The Split Personality of Polypeptide Helices[END_REF] Interestingly, when a Cα,α-disubstituted amino acid, such as α-aminoisobutyric acid (Aib), is incorporated inside the peptide, the formation of a 310 helix tends to be favoured, demonstrating that a slight modification in a peptide sequence may have a great impact on the conformational behaviour. [START_REF] Karle | Perspectives in Biochemistry[END_REF] When no intramolecular hydrogen bonding network can be formed, for example in sequences consisting solely of proline, the peptide may adopt a new helical conformation called polyproline that could exist as both left-(PPII (φ, ψ, ω) = (-75°, +145°, +180°)) and right-handed (PPI (φ, ψ, ω) = (-75°, +160°, 0°)) helices. [START_REF] Chiang | Stereoelectronic Effects on the Transition Barrier of Polyproline Conformational Interconversion[END_REF] Polyproline type II peptides are constituted with only trans-configuration and are observed in aqueous conditions. By contrast, the all-cis polyproline I is favoured in hydrophobic solvents but has not been found in protein structures. Interestingly, a polyproline II helix can propagate through adjacent non-proline residues. Theoretical and experimental studies demonstrated that water molecules form carbonyl-water-carbonyl H-bond within the chain, which seems to be the driving force to favour the trans-configuration. [START_REF] Sreerama | Molecular Dynamics Simulations of Polypeptide Conformations in Water: A Comparison of α, β and poly(Pro)II Conformations[END_REF][START_REF] Adzhubei | Polyproline-II Helix in Proteins: Structure and Function[END_REF] By moving the side chain by one atom, from the α-carbon to the amide nitrogen, the resulting N-substituted glycine becomes a new monomer for the synthesis of α-peptoids (Figure 19).

Figure 19: Structure of a generic peptoid oligomer 58 Bolin, K. A. et al., Acc. Chem. Res., 32, 1027-33 (1999). 59 Karle, I. L. et al., Biochemistry, 29, 6747-56 (1990). 60 Chiang, Y.-C. et al., Protein Sci. Publ. Protein Soc., 18, 1967-77 (2009). 61 Sreerama, N. et al., Proteins Struct. Funct. Genet., 36, 400-406 (1999).

Due to the lack of amide backbone protons, peptoids are expected to be more flexible than their peptide counterparts as it is the inter-and intra-chain hydrogen bonding involving the amide proton in peptides that enables the formation of α-helices, β-sheets and so on. However, despite a low conformational stability of peptoids, many types of secondary structures such as turns (Figure 20, C), sheets (Figure 20, E) or even ribbons (Figure 20, F) were obtained. [START_REF] Sun | Peptoid Polymers: A Highly Designable Bioinspired Material[END_REF] Helices are probably the most interesting type of folding. The monomers constituting peptoids do no longer possess a chiral centre on the α-carbon nor do they still have the hydrogen bond donor hold by the NH on a proteinogenic amino acid making the αand 310-helices inaccessible. The only accessible helical structure is analogous to the polyproline type I like helices (Figure 20 A, B and D) [START_REF] Sun | Peptoid Polymers: A Highly Designable Bioinspired Material[END_REF] for which the electronic interactions backbone to side chains (n→π*) and the side chains bulkiness are the major driving force governing the folding. [START_REF] Sun | Peptoid Polymers: A Highly Designable Bioinspired Material[END_REF] All these examples are highlighting that the folding of an oligomer into a specific conformation is a multi-parametric problem. The free energy landscape is the result of repeating long-range intramolecular forces such as regular H-bond network or electronic interactions, local 62 Sun, J. et al., ACS Nano, 7, 4715-32 (2013).

conformational restriction, as in Aib-containing peptides, and in some cases of intermolecular interactions with the environment. Over the last two decades, chemists have tended to combine all these approaches to control the folding behaviour of abiotic oligomers.

ii. β-peptides β-peptides have probably been the most extensively studied foldamer series. They result from the oligomerization of β-amino acids. Those residues are homologues of proteinogenic amino acids. This adds to the molecule an extra torsion angle θi between the α-and β-carbons. [START_REF] Banerjee | Stereochemistry of Peptides and Polypeptides Containing Omega Amino Acids[END_REF] Due to this new angle, the angle φi is found between the Cβ and the NH, while ψi is the corresponding angle for the Cα-CO bond (Figure 21). Noticeably, the α-and β-carbons can be the starting point for functionalization. When the substituent is branched on the α-carbon relatively to the acid group, the residue is typically called β 2 -amino acid and the resulting oligomer is a β 2 -peptide. On the other hand, for β 3 -peptides, the lateral chain is on the β-carbon relative to the acid group. Di-substitutions are also possible (Figure 22). 63 Banerjee, A. et al., Curr. Sci., 73, 1067-77 (1997).

In the β-peptide family, the most common structures found are helical. Many groups have been working to describe them, resulting in various nomenclature to characterize the structures. [START_REF] Seebach | β-Peptides: Synthesis by Arndt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-ray Crystallography. Helical Secondary Structure of a β-Hexapeptide in Solution and Its Stability towards Pepsin[END_REF][START_REF] Bode | Poly(β-amino acid) Helices. Theoretical π-π* Absorption and Circular Dichroic Spectra[END_REF][START_REF] Bella | Conformation of the Helical Polyamide Poly(cu-isobutyl L-aspartate)[END_REF][START_REF] Appella | β-Peptide Foldamers: Robust Helix Formation in a New Family of β-Amino Acid Oligomers[END_REF] In this manuscript, we will use Gellman's nomenclature, which clearly indicates the number of atoms involved in a hydrogen-bonded pseudocycle, from the carbonyls towards the NH amide groups, in the C-terminal direction. [START_REF] Appella | β-Peptide Foldamers: Robust Helix Formation in a New Family of β-Amino Acid Oligomers[END_REF] For instance, if the pseudocycle is composed of 14 atoms, the helix is called "14-helix", "helix 14" or "C14-helix". This nomenclature is close to Bragg's nomenclature in which the number of atoms composing the hydrogen-bonded ring is indicated after the number of residues per turn, it would be "314" for a pseudocycle of 14 atoms, as observed for 3.613-and 310-helices in proteins. [START_REF] Bragg | Polypeptide Chain Configurations in Crystalline Proteins[END_REF] To Gellman's nomenclature, we will take the liberty to add, for clarity, the sense of rotation of the helix (right or left (respectively (P) or (M) in Seebach's nomenclature)).

The prevalent structures accessible to β-peptides are the helices 14, 12, 12/10, 10 and 8 (Figure 23).

Figure 23: Most common hydrogen bonds in a β-peptide [START_REF] Cheng | β-Peptides: From Structure to Function[END_REF] 14-helix

The first helical structure of β-peptides was simultaneously described by Gellman and Seebach in 1996. Seebach's team was working on the study of the hexa-β-peptide H-(β3-HVal-β3-HAla-β3-HLeu)2-OH (1) (Figure 24,A). [START_REF] Seebach | Probing the Helical Secondary Structure of Short-Chain β-Peptides[END_REF] By performing 1 H NMR studies in deuterated pyridine and methanol, they were able to confirm that it would adopt a 14-helix structure with dihedral angles φ = -134.3°, θ = +60°, ψ = -139.9° and ω = +102° (Figure 24,B). [START_REF] Cheng | β-Peptides: From Structure to Function[END_REF] This structure is characterized by the establishment of intramolecular hydrogen bonds between the NH in position i and the CO located on the residue i+2, leading to a 14 atoms pseudocycle. Due to the alignment of the hydrogen bonds along the main-chain, the net dipole of the helix is established 64 Bode, K. A. et al., Macromolecules, 30, 2144-50 (1997). 65 Bella, J. et al., Macromolecules, 25, 5225-30 (1992). 66 Appella, D. H. et al., J. Am. Chem. Soc., 118, 13071-72 (1996). 67 Cheng, R. P. et al., Chem. Rev., 101, 3219-32 (2001). 68 Seebach, D. et al., Helv. Chim. Acta, 79, 2043-66 (1996).

in an opposite direction to that of the α-helix. As represented in Figure 24 C, three residues are necessary to complete a full turn and the pitch is of 4.8 Å. The side chains are distributed around the helix every 120°, positioning them directly above one another every third residue along one face of the helix, giving three distinct sides on the foldamer (Figure 24, D). Only four β 3 -amino acids are necessary to lead to such structure but the 14-helix conformation is generally much less stable in water than in organic solvents.

The increase of the 14-helix stability was finally obtained by using the 6-member cyclic trans-2-aminocyclohexanecarboxylic acid, so called trans-ACHC β 2,3 -amino acid (2) (Figure 24,E), for which the constrained dihedral angles prefigure the oligomer folding. [START_REF] Appella | Residue-Based Control of Helix Shape in β-Peptide Oligomers[END_REF] Figure 24: A/Hexa-β-peptide (1) stabilized by hydrogen bonds. B/Superimposition of the conformations of (1) in methanol (green) and in pyridine (blue). C/Representative structure of the 14-helix. D/View N→C of the lefthanded 14-helix of (1) in pyridine solution. [START_REF] Seebach | Probing the Helical Secondary Structure of Short-Chain β-Peptides[END_REF][START_REF] Seebach | NMR-Solution Structures in Methanol of an α-Heptapeptide, of a β3/β2-Nonapeptide, and of an all-β3-Icosapeptide Carrying the 20 Proteinogenic Side Chains[END_REF] E/Monomer of trans-ACHC (2)

Afterwards, several other β-peptides folding into 14-helix were described and depending on the stereochemistry of the β-amino acids, the resulting helix is either right or left-handed. Usually, 69 Appella, D. H. et al., Nature, 387, 381-84 (1997). 70 Seebach, D. et al., Helv. Chim. Acta, 88, 1969-82 (2005).

when synthesized with β 3 -amino acid derived from naturally occurring L-amino acids, the oligomer adopts a left-handed (M) helix. [START_REF] Cheng | β-Peptides: From Structure to Function[END_REF] 12-helix angle values correspond to φ = +100°, ψ = +104° and ω = -182°. [START_REF] Degrado | The Twists and Turns of β-peptides[END_REF] This result is of prime importance since, for the first time, it demonstrated the possibility of changing the conformational behaviour of β-peptides by altering the cyclic constraint. H-N), C/Crystallographic structure of (4). D/Representation of the monomers repartition around the helical axis. E/Axial view N→C of (4) [START_REF] Cheng | β-Peptides: From Structure to Function[END_REF][START_REF] Appella | Synthesis and Structural Characterization of Helix-Forming β-Peptides: trans-2-Aminocyclopentanecarboxylic Acid Oligomers[END_REF] The 12-helix is a left-handed (M) helix stabilized by interwoven twelve-membered-ring hydrogen bonds between the CO of the residue i and NH of the residue i+3 (Figure 25,B). [START_REF] Cheng | β-Peptides: From Structure to Function[END_REF][START_REF] Appella | Synthesis and Structural Characterization of Helix-Forming β-Peptides: trans-2-Aminocyclopentanecarboxylic Acid Oligomers[END_REF] It is characterized by a pitch of 5.6 Å and 2.5 residues per turn. The orientation of the dipole is the same as for the α-helix (Figure 25, C, D and E).

Another
Even though most of the publications found in the literature were describing the 12-helix structure via sequences synthesized using five-membered-ring residues, other groups have been able to reproduce the 12-helical shape using other β-cyclic amino acids. For instance, Aitken et 71 DeGrado, W. F. et al., J. Pept. Res., 54, 206-17 (2008). 72 Appella, D. H. et al., J. Am. Chem. Soc., 121, 7574-81 (1999).

A/ C/ B/ D/ E/
al. used cyclobutane residues (5) named (R,R)-trans-ACBC in which the amine and acid groups are in trans configuration. [START_REF] Fernandes | 12-Helix Folding of Cyclobutane β-Amino Acid Oligomers[END_REF] The angle θ is -95.7° which is close to the one of the canonical 12-helix. Following a similar approach, Martinek et al. also obtained such 12-helix employing bicyclic monomers (6) (Figure 26). [START_REF] Hetényi | Sculpting the β-peptide foldamer H12 helix via a designed side-chain shape[END_REF] Figure 26: Other β-amino acids folding into 12-helix shape after oligomerization 12/10-helix

Early after beginning to study the conformational dynamic of β-peptides, Seebach et al.

demonstrated that unique structures may be obtained by alternating β 2 -and β 3 -amino acids. [START_REF] Seebach | Mixed' β-peptides: A unique helical secondary structure in solution. Preliminary communication[END_REF] For instance, heterochiral hybrid β 3 -HAxx-β 2 -HAxx peptides fold forming a 12/10-helix. [START_REF] Hecht | Foldamers: Structure, Properties and Applications[END_REF][START_REF] Wu | Theoretical Analysis of Secondary Structures of β-Peptides[END_REF] The structure results from intramolecular hydrogen bonds alternating in the forward and backward directions along the sequence. The twelve-membered-ring occurs between the NH of the residue i from a β 2 -amino acid and the COi-3 of a β 3 -amino acid while the ten-memberedring exists between the β 2 -NHi and the β 3 -COi+1 (Figure 27). [START_REF] Rueping | Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve-and Ten-Membered Hydrogen-Bonded Rings[END_REF] The sense of helicity is righthanded (P) with a pitch of 5.7 Å and 2.7 residues per turn. [START_REF] Wu | Theoretical Analysis of Secondary Structures of β-Peptides[END_REF] Finally, since the amide C=O bonds point alternately up and down the helix axis, the resulting dipole is strongly reduced in comparison to a 14-helix. [START_REF] Rueping | Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve-and Ten-Membered Hydrogen-Bonded Rings[END_REF] Figure [START_REF] Rueping | Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve-and Ten-Membered Hydrogen-Bonded Rings[END_REF] 73 Fernandes, C. et al., Org. Lett., 12, 3606-9 (2010). 74 Hetényi, A. et al., Chem Commun, 177-79 (2009). 75 Seebach, D. et al., Helv. Chim. Acta, 80, 2033-38 (1997). 76 Wu, Y.-D. et al., Acc. Chem. Res., 41, 1418-27 (2008). 77 Rueping, M. et al., Helv. Chim. Acta, 85, 2577-93 (2002).

27: β-peptide of Boc-(β 3 -HAxx-β 2 -HAxx)n-OBn (7) stabilized by hydrogen bonds i-3,i C=O• • •H-N and i,i+1 N-H• • •C=O

10-helix

In 2001, Fleet et al. described the structure of an hexamer of an oxetin β-amino acid derivative (Figure 28). [START_REF] Claridge | 10-Helical conformations in oxetane β-amino acid hexamers[END_REF] By comparison with the (R,R)-trans-ACBC (5), another four-member ring containing β-amino acid, the amine and acid groups in the oxetin residues are in cis configuration. Thus, the angle θ shifts from -95.7° to -12.1° driving the folding towards a new 10-helical conformation in organic solvents. [START_REF] Ragab | Cooperative 5-and 10-membered ring interactions in the 10-helix folding of oxetin homo-oligomers[END_REF] The latest value seems somewhat far from the model predicted by Hofmann for an idealized left-handed 10-helix hexapeptide (θ = -59°), but the two other dihedral angles (φ and ψ) compensate for this deviation (respectively -104.7° and -101.2° in solution versus -64° and -75° for the idealized model). [START_REF] Günther | Searching for Periodic Structures in β-Peptides[END_REF] foldamer. [START_REF] Gademann | The Fourth Helical Secondary Structure of β-Peptides: The (P)-2.8-Helix of a β-Hexapeptide Consisting of (2R,3S)-3-Amino-2-hydroxy Acid Residues[END_REF] The structure was studied in methanol and possessed a pitch of 4.7-4.9 Å with about 2 residues per turn. The eight-membered-ring hydrogen bonds were found to be between the NH group of the amino acid i and the CO group of the amino acid i-2. This structure was the result of the oligomerization of syn-(or unlike)-β 2,3 -amino acids, such as the (2R,3S)-3amino-2-hydroxy acid residues (9) (Figure 29). However, if a methyl group replaces the -OH group in position β 2 of the building blocks, the 8-helical structure is lost in favour of a pleatedsheet. This can be explained by the presence of a second hydrogen-bonding pattern between hydroxyl groups, borne by the β 2 -carbons, and the adjacent carbonyls. [START_REF] Gademann | The Fourth Helical Secondary Structure of β-Peptides: The (P)-2.8-Helix of a β-Hexapeptide Consisting of (2R,3S)-3-Amino-2-hydroxy Acid Residues[END_REF] 78 Claridge, T. D. W. et al., Tetrahedron Lett., 5 (2001). 79 Ragab, S. S. et al., Chem. Commun., 54, 1968-71 (2018). 80 Günther, R. et al., J. Phys. Chem. B, 105, 5559-67 (2001). 81 Gademann, K. et al., Angew. Chem. Int. Ed., 42, 1534-37 (2003). As reported previously, Aitken et al. were able to induce 12-helix structure using trans-ACBC monomers. This building block can be modified to display a strong tendency to form hydrazine turn by only changing one atom from the ring to create a N-aminoazetidine-2-carboxylic acid (AAzC) moiety. [START_REF] Altmayer-Henzien | Solution State Conformational Preferences of Dipeptides Derived from N-Aminoazetidinecarboxylic Acid: An Assessment of the Hydrazino Turn[END_REF] The hydrazine turn is a split H-bonded 8/5-ring that can behave as an inducer of an 8-helix into a peptide sequence. The first studies were performed by replacing the trans-ACBC residue of the N-terminal extremity by a trans-AAzC (10) (Figure 30, A) to induce the 8-helix, but after six residues, the 12-helix would take over and the 8-helix would not be found. [START_REF] Altmayer-Henzien | Fine Tuning of β-Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8-Helix to a 12-Helix[END_REF] This team did further research and, even if the result might be solvent dependant, they eventually depicted the trans-AAzC monomer as an 8-helix promoter over the entire length of the peptide, even when placed in the middle of a polypeptide. The octamer being the longest sequence to prove it yet (Figure 30,B). [START_REF] Declerck | Strategic C to N Replacement in β-Peptides: Atomic Level Control of Helical Folding[END_REF] Interestingly, the dihedral angles φ (≈ +86°) and θ (≈ -95°) of the trans-ACBC residues were similar for the 12-and 8-helices tough the dihedral angle ψ was found to be significantly altered (+95° for the 12-helix versus +35° for the 8helix). [START_REF] Altmayer-Henzien | Fine Tuning of β-Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8-Helix to a 12-Helix[END_REF] Finally, the AAzC residue displays a slightly different set of backbone dihedral angles (φ, θ, ψ) ≈ (+109°, -98°, +9°) without interfering with the 8-helix conformation along the chain. [START_REF] Declerck | Strategic C to N Replacement in β-Peptides: Atomic Level Control of Helical Folding[END_REF] Figure 30: A/trans-AAzC residue (10), B/Hydrogen bonding network in an octamer possessing one AAzC residue in its centre 82 Altmayer-Henzien, A. et al., J. Org. Chem., 78, 6031-39 (2013). 83 Altmayer-Henzien, A. et al., Angew. Chem. Int. Ed., 54, 10807-10 (2015). 84 Declerck, V. et al., J. Org. Chem., 83, 8793-8800 (2018).

A/ B/ A/ B/ CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION 51
In conclusion, despite a higher degree of freedom than in α-peptides, oligomers of β-amino acids may adopt stable 3D-structures (Figure 31). Due to numerous NMR, CD and X-ray investigations, reinforced by crystallography, different helical structures were observed in βpeptide series for which topologies are mainly driven either by establishment of regular H-bond networks and by dihedral angle restrictions. In the next sections, we will see that similar concepts are involved in the folding of higher order foldamers such as γ-peptides and related oligomers, including oligoureas.

Figure 31: Recap of the possible helix for β-peptide [START_REF] Wu | Theoretical Analysis of Secondary Structures of β-Peptides[END_REF] iii. γ-peptides γ-peptides are constituted of γ-amino acids, homologues of β-amino acids, giving a total of three methylene groups between the CO and NH of each monomer. Each of these carbons becomes then a possible starting point for functionalization. Depending on the nomenclature chosen, the position of the substituent is called α, β and γ, or γ 2 , γ 3 and γ 4 . The corresponding dihedral angles are φi, θi, ζi and ψi as represented in Figure 32. Because of this third carbon on the main-chain, the γ-peptides are allegedly more flexible than the αor β-peptides. Furthermore, the number of hydrogen-bond donors and acceptors, essential for the structuration of the helix, is lower for a γ-peptide than a βor α-peptide of the same number of atoms. These two parameters seem unfavourable regarding a possible structuration, but it does not mean that it is impossible, as proved by many researchers who designed folded γ-peptides.

9-and 14-helices: two structures accessible to acyclic γ-peptides Systematic prediction of the most stable periodic structures in unconstrained γ-peptides was first postulated by Hofmann et al. who used an ab initio molecular orbital (MO) method. [START_REF] Baldauf | Helix Formation and Folding in γ-Peptides and Their Vinylogues[END_REF] They computationally generated oligomers of γ-aminobutyric acid (GABA) by variations of the torsion angles φ, θ, ζ and ψ of the backbone. This generated 36,000 different conformations which were optimized at the ab initio Hartree-Fock MO level of theory (HF/6-31G*). This study provided various possible structures for the γ-peptides, all of them being helices or even flat ribbons with H-bonded pseudo-rings with atoms ranging from seven up to 24 in number.

From these calculations, the 9-and 14-membered-ring helices were recognized as the most stable conformations (Figure 33). The 7-membered-ring structure was also considered as accessible but corresponds to a ribbon due to its small pitch, giving a flat shape of the structure as represented in Figure 34. 85 Baldauf, C. et al., Helv. Chim. Acta, 86, 2573-88 (2003).

Figure 34: Most stable periodic structures of GABA hexamers obtained after MO theory optimization (Hx = number of atoms to complete the pseudocycle) [START_REF] Baldauf | Helix Formation and Folding in γ-Peptides and Their Vinylogues[END_REF] In fact, Hanessian et al. and Seebach et al. independently discovered, in 1998, the 14-helix by oligomerization of γ 4 -amino acids. [START_REF] Hanessian | Design of Secondary Structures in Unnatural Peptides: Stable Helical γ-Tetra-, Hexa-, and Octapeptides and Consequences of α-Substitution[END_REF][START_REF] Hintermann | γ-Peptides Forming More Stable Secondary Structures than α-Peptides: Synthesis and helical NMR-solution structure of the γ-hexapeptide analog of H-(Val-Ala-Leu)2-OH[END_REF] The folding is characterized by a right-handed helix connecting fourteen atoms by a hydrogen bond between NHi and COi-3, with a pitch of 5 Å and 2.6 residues per turn; this is why it is also called the 2.614-helix (Figure 35).

Figure 35: A/H-bonded pattern in Seebach's hexamer [START_REF] Hintermann | γ-Peptides Forming More Stable Secondary Structures than α-Peptides: Synthesis and helical NMR-solution structure of the γ-hexapeptide analog of H-(Val-Ala-Leu)2-OH[END_REF] B/Chemical structure of (αS)-methylated γ-peptide (11) and ( 12), (αS)-cinnamyl γ-peptide ( 13) and (αR)-methylated γ-peptide (14) [START_REF] Hanessian | Design of Secondary Structures in Unnatural Peptides: Stable Helical γ-Tetra-, Hexa-, and Octapeptides and Consequences of α-Substitution[END_REF][START_REF] Hanessian | Synthesis and Folding Preferences of γ-Amino Acid Oligopeptides: Stereochemical Control in the Formation of a Reverse Turn and a Helix[END_REF] Based on NMR experiments performed in pyridine-d5, NOE correlations were extracted from the ROESY spectra. These data provided distance restraints for 3D-modelling using NMR 86 Hanessian, S. et al., J. Am. Chem. Soc., 120, 8569-70 (1998). 87 Hintermann, T. et al., Helv. Chim. Acta, 81, 983-1002(1998).

refinement by simulated annealing. The 3D-models obtained showed that, in addition to the Hbond network, hydrophobic interactions between lateral chains projected perpendicular to the helical axis may stabilize the helix.

Disubstituted γ 2,4 -amino acids were also used for γ-peptide elaboration. This additional substitution reduces the number of accessible conformations for the backbone. Thus, Hanessian et al. compared the folding potential of sequences (11) to (14) having opposite relative configuration. [START_REF] Hanessian | Design of Secondary Structures in Unnatural Peptides: Stable Helical γ-Tetra-, Hexa-, and Octapeptides and Consequences of α-Substitution[END_REF][START_REF] Hanessian | Synthesis and Folding Preferences of γ-Amino Acid Oligopeptides: Stereochemical Control in the Formation of a Reverse Turn and a Helix[END_REF] Only peptides (11)-( 13) adopt a 14-helix formation, (αR)-methylated analogue (14) do not fold. When the 2,4 relative configuration is compatible with the 14-helix secondary structure, a supplementary substitution in position 3 could be supported without disturbing the overall folding. [START_REF] Seebach | Preparation and Determination of X-ray-Crystal and NMR-Solution Structures of γ2,3,4-Peptides[END_REF][START_REF] Seebach | γ2-, γ3-, and γ2,3,4-Amino Acids, Coupling to γ-Hexapeptides: CD Spectra, NMR Solution and X-ray Crystal Structures of γ-Peptides[END_REF] Interestingly, for the 14-helix, the macrodipole is orientated as for the α-helix, from the δ -Cterminus to the δ + N-terminus. Thus, the structure of the α-helix (13-membered-ring) and of the 14-helices of βand γ-peptides are quite similar. However, each homologation, from α-to βand then from β-to γ-amino acid leads to an inversion of the macrodipole of the helix (Figure 36). [START_REF] Seebach | The World of β-and γ-Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components[END_REF] Figure 36: Comparison of α 3.613-, β314-and γ 2.614-helices, all amino acids are in L-configuration [START_REF] Seebach | Helices and other secondary structures of βand γ-peptides[END_REF] 88 Hanessian, S. et al., Tetrahedron Lett., 40, 4925-29 (1999). 89 Seebach, D. et al., Chem. Commun., 207-8 (2001). 90 Seebach, D. et al., Chem. -Eur. J., 8, 573-84 (2002). 91 Seebach, D. et al., Chem. Biodivers., 1, 1111-1239(2004). 92 Seebach, D. et al., Pept. Sci., 84, 23-37 (2005).

The second most stable helical structure given by Hofmann's calculations is the 9-helix which was characterized in 2005 by Balaram et al., starting from an oligomer of gabapentin, the Boc-Gpn-Gpn-Gpn-Gpn-NHMe (15) (Figure 37). [START_REF] Vasudev | C9 Helices and Ribbons in γ-Peptides: Crystal Structures of Gabapentin Oligomers[END_REF] The disubstitution of the central β-carbon (or γ 3 -) limits the rotation around the Cα-Cβ (angle θ) and Cβ-Cγ (angle ζ) to two gauche conformations, where θ ≈ ζ ≈ ±60°. The H-bond pseudocycle is formed between COi-2 and NHi. 15), D/view of (15) down the axis [START_REF] Vasudev | C9 Helices and Ribbons in γ-Peptides: Crystal Structures of Gabapentin Oligomers[END_REF] After this description, Kunwar et al. also reported γ-peptides alternating carbo-γ 4 -amino acid (γ-Caa) (16) and γ-aminobutyric acid (GABA) as able to fold into 9-helices. [START_REF] Sharma | A Left-Handed 9-Helix in γ-Peptides: Synthesis and Conformational Studies of Oligomers with Dipeptide Repeats of C-Linked Carbo-γ4-amino Acids and γ-Aminobutyric Acid[END_REF] The 9-helix is found after only four residues and each turn is completed with 2.3 monomers (Figure 38). 93 Vasudev, P. G. et al., Angew. Chem. Int. Ed., 44, 4972-75 (2005). [START_REF] Sharma | A Left-Handed 9-Helix in γ-Peptides: Synthesis and Conformational Studies of Oligomers with Dipeptide Repeats of C-Linked Carbo-γ4-amino Acids and γ-Aminobutyric Acid[END_REF] Sharma, G. V. M. et al., Angew. Chem. Int. Ed., 45, 2944-47 (2006).

Structures accessible to cyclic aliphatic γ-peptides

As in β-peptide series, a cyclic conformational restriction may improve the stability of a specific folding or even favour the formation of a new secondary structure. Thus, Gellman et al. used a cyclohexyl-containing γ-amino acid [START_REF] Guo | Characteristic Structural Parameters for the γ-Peptide 14-Helix: Importance of Subunit Preorganization[END_REF] . The ring constraint and stereochemistry promote a gauche + , gauche + torsion-angle around the Cα-Cβ and Cβ-Cγ bonds favouring the 14-helix (Figure 39,A). In a similar manner, a C9-bend ribbon was obtained from oligomers of cis-γamino-L-proline (Figure 39,B). [START_REF] Farrera-Sinfreu | A New Class of Foldamers Based on cis-γ-Amino-l-proline1,2[END_REF] A C7-bend-ribbon was also observed for homochiral and heterochiral tartrate-derived peptides in benzene (Figure 39,C). [START_REF] Kothari | Bend-ribbon forming γpeptides[END_REF] Finally, cyclopropanecontaining γ-peptides were also studied by Smith. [START_REF] Smith | An Artificial Antiparallel β-Sheet Containing a New Peptidomimetic Template[END_REF] Such oligomers adopt a unique infinite parallel sheet structure at both the solid state and in chloroform solution. [START_REF] Jones | A Nonpeptidic Reverse Turn that Promotes Parallel Sheet Structure Stabilized by C-H...O Hydrogen Bonds in a Cyclopropane Gamma-Peptide[END_REF] Figure 39: A/Structure of cyclohexyl-containing γ-peptide (18) and its crystal structure, [START_REF] Guo | Characteristic Structural Parameters for the γ-Peptide 14-Helix: Importance of Subunit Preorganization[END_REF] B/ Chemical structure of the cis-γ-aminoproline peptide, [START_REF] Farrera-Sinfreu | A New Class of Foldamers Based on cis-γ-Amino-l-proline1,2[END_REF] C/Observed bend-ribbon solution conformation of tartrate-derived peptides [START_REF] Kothari | Bend-ribbon forming γpeptides[END_REF] ATC-based oligomers as prototype of aromatic γ-peptide foldamers

Over the last few years, our laboratory has been working on the study of aromatic γ-amino acid building blocks and the structural behaviour of their oligomers. This research program was inspired by the work of Baldauf and Hofmann, who explored, by ab initio calculations, the folding properties of vinylogous γ-peptides. They suggested that the introduction of a 95 Guo, L. et al., Angew. Chem. Int. Ed., 50, 5843-46 (2011). 96 Farrera-Sinfreu, J. et al., J. Am. Chem. Soc., 126, 6048-57 (2004). 97 Kothari, A. et al., Chem. Commun., 0, 2814-16 (2007). [START_REF] Smith | An Artificial Antiparallel β-Sheet Containing a New Peptidomimetic Template[END_REF] Smith, E. M. et al., J. Org. Chem., 62, 7906-7 (1997). 99 Jones, C. R. et al., Angew. Chem. Int. Ed Engl., 47, 7099-7102 (2008). (E)-double bond between the Cα and Cβ would lead to helical structures starting from 14-to up to 27-membered pseudocycles but, would not conduct to smaller helices. [START_REF] Baldauf | Helix Formation and Folding in γ-Peptides and Their Vinylogues[END_REF] On the other hand, the (Z)-configuration, with a ζ dihedral angle at 0°, would favour peptidic nearest-neighbour interactions heading to helices with 7-and 9-membered pseudocycles, with unique dihedral values. [100] This hypothesis was corroborated by Grison et al. who observed an intramolecular C9-pseudocycle in a hybrid tripeptide that contained a cis-vinylogous derivative of proline (Figure 40). [101] A similar C9-hydrogen bond was also described by Mann and Kessler in a oxazole-based peptidomimetic. [102] As in a (Z)-vinylogous γ-amino acid, the heterocycle imposes that the ζ dihedral angle is 0°. [101] In 2013, our group published the first structure of a heterocyclic γ-peptide. The monomer called 4-Amino-(methyl)-1,3-Thiazole-5-Carboxylic acid (ATC) (20) was built around a thiazole ring, providing a conformational limitation at 0° around the Cα and Cβ (Figure 41). [103] Figure

41: (Z)-vinylogous γ-amino acid (19) and ATC (20) pattern

NMR studies performed in CDCl3 and water showed well-dispersed signals associated with high downfield chemical shifts of the amide protons, higher than 9.10 ppm. Later, this high deshielding effect was unambiguously associated with the formation of a C9 intermolecular 100 Baldauf, C. et al., J. Org. Chem., 70, 5351-61 (2005). 101 Grison, C. et al., J. Org. Chem., 70, 10753-64 (2005). 102 Mann, E. et al., Org. Lett., 5, 4567-70 (2003). 103 Mathieu, L. et al., Angew. Chem. Int. Ed., 52, 6006-10 (2013).

hydrogen-bond. [104] The structure of the ATC oligomers was finally solved either by simulated annealing protocol (AMBER 10 [105] ) starting from NMR constraints or by XRD. The folding corresponds to a right-handed helix different from those of Balaram, [START_REF] Vasudev | C9 Helices and Ribbons in γ-Peptides: Crystal Structures of Gabapentin Oligomers[END_REF] stabilized by hydrogen bonds between the main-chain carbonyl at position i and the amide proton at position i+2, forming a series of interwove 9-membered pseudocycles (Figure 42,B). The crystal structure revealed the same H-bonding pattern in one direction, from the N-to the C-terminus (Figure 42,C). Each turn of the 9-helix is composed of three residues with a pitch of 11.8 Å. The riseper-residue is of 3.9 Å and each turn exhibits six substitution patterns, distributed around a 60°

angle along the axis (Figure 42, C and D). Interestingly, only two residues are needed to induce the C9 folding. The structure of the ATC oligomers is perfectly consistent with the 9-helix predicted by Baldauf and Hofmann for oligomers of (Z)-vinylogous γ-amino acids (Table 5 for comparison of dihedral angles). [100,105,106] However, it is not clear why ATC oligomers never adopt the 7-helical conformation which was calculated by the same authors as similar in energy as the 9-104 Bonnel, C. et al., Org. Biomol. Chem., 14, 8664-69 (2016). 105 Case, D. A. et al. (University of California, San Francisco, 2008).

A/ B/ C/ D/ helix. A partial answer can be found in recent studies on hybrid oligomers alternating either ATCs and α-amino acids, or (Z)-vinylogous γand α-amino acids which display different conformational behaviours. While the latter adopt a 12-helical shape, [106] The ATC-containing oligomers fold into C9/12-ribbons. [107] In ATC-based molecules, the carbonyls and double bonds are coplanar while for the 12-helix of (Z)-vinylogous γ-amino acids they are not. Whatever the sequences studied, the ATC carbonyl group point towards the sulfur atom of the thiazole ring suggesting a dipole-dipole interaction between the C=O and the heterocycle. Thus, conformational behaviour of the ATC oligomers seems to result from the establishment of a regular H-bonding network oriented by both a strict limitation of the ζ dihedral angle at 0° and a possible electronic interaction between the aromatic ring and the amide bond. As highlighted by circular dichroism, the 9-helical folding of ATC-based γ-peptides is, surprisingly, very stable in a wide range of solvents such as nonpolar chloroform or polar methanol or even more protic water from pH 3 to 11. In addition, the ATC-monomers present the advantage of an easy modulation of their side chains. Notably, the folding appeared of low dependency of the lateral chains flanking the backbone. For instance, we recently reported ATC-based foldamer as a template for the design of glycoclusters. [START_REF] Simon | Can Heterocyclic γ-Peptides Provide Polyfunctional Platforms for Synthetic Glycocluster Construction?[END_REF] The main purpose of this project was to flank sugar moieties on an original glycol-peptide scaffold in order to target lectins. The obtained results demonstrated that the overall shape of the ATC-oligomer was not affected by the mannosyl substituents.

Oligourea peptidomimetics

Although there are many peptidomimetics in which the peptide amide bond was replaced by another moiety, the exploration towards oligomeric synthesis, and study of the resulting properties of these larger peptidomimetics containing more than three residues was performed on only a very small subset of them. Among these are the urea peptidomimetics. In such oligomers, the number of atoms between two sequential carbonyl groups is similar to those found in γ-peptides. However, because of an additional nitrogen atom within each residue, a new H-bond pattern may be formed resulting in a different folding behaviour.

The first studies of oligoureas were performed by Nowick et al. in 1992, to mimic turns and β-sheets. [108,109] Thanks to the NMR and IR studies, they were able to prove that di-and triureas form intramolecular hydrogen bonds between their COi and NHi+3 so that their scaffold could be used for mimicking β-sheet-like structures. Even though it was demonstrated in 1995 that the synthesis of oligoureas is possible with solid phase peptide synthesis (SPPS) [110,111,112] their structural preferences had not been investigated much until the Guichard group started in 2002. [113,114] At first, they postulated that the substitution of the α-carbon by a NH group within a γ-amino acid would be compatible with a folding into a 14-helix, similar to that found in the γ [START_REF] Grauer | Peptidomimetics -A Versatile Route to Biologically Active Compounds[END_REF] -peptides (Figure 43,A). for the 14-membered-ring (in red, Figure 43,B) and COi• • •HN'i+2 regarding the pseudocycle 108 Nowick, J. S. et al., J. Org. Chem., 57, 3763-65 (1992). 109 Nowick, J. S. et al., J. Am. Chem. Soc., 117, 89-99 (1995). 110 Burgess, K. et al., Angew. Chem. Int. Ed. Engl., 34, 907-9 (1995). 111 Burgess, K. et al., J. Am. Chem. Soc., 119, 1556-64 (1997). 112 Kim, J.-M. et al., Tetrahedron Lett., 37, 5305-8 (1996). 113 Semetey, V. et al., Angew. Chem. Int. Ed., 41, 1893-95 (2002). 114 Hemmerlin, C. et al., Helv. Chim. Acta, 85, 3692-3711 (2002).

B/

A/ CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION 61 of 12 atoms (in blue, Figure 43,B). The pitch of this helix is of 5.1 Å and 2.5 residues are needed to complete a turn, therefore, this helix is also called the 2.512/14-helix. These helical parameters are quite close to the γ 4 -peptides corresponding 14-helix (5 Å and 2.6 residues per turn). Circular dichroism experiments were performed on this N,N'-linked oligoureas and it seemed that there is a specific signature for such 2.512/14-helix (Figure 44). Indeed, in methanol, a maximum band is found at 203 nm while γ 4 -peptides folding into 14-helices do not provide any specific CD signature. Further studies led to the conclusion that five residues were enough to stabilize the 2.512/14-helices. [115,116] Finally, one can notice that the first two urea-residues, located on the N-terminal extremity of the oligoureas chain were not involved in the intramolecular hydrogen-bonding pattern. [START_REF] Bécart | Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions[END_REF] Figure 44: NMR Structure of oligourea (23) in pyridine-d5: A/stereo view along the helix axis and B/top view. C/CD signature of (23) in MeOH at room temperature. [114] D/Representation of the extended chain of an N,Nlinked oligoureas and its folded behaviour illustrating the two accessible H-bond donor sites near the positive pole of the helix macrodipole [START_REF] Bécart | Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions[END_REF] Conclusion

Over the last two decades, many folded architectures mimicking protein secondary structures have been described. Earlier studies mainly focused on their structural properties. Advances in synthetic folded molecules, coupled with the discovery that oligomeric backbones can retain folding in water, opened the way for foldamers to interfere with biological functions. In this context, initial work focused on the design of polycationic amphipathic sequences to tailor the 115 Violette, A. et al., J. Am. Chem. Soc., 127, 2156-64 (2005). 116 Violette, A. et al., Chem. -Eur. J., 14, 3874-82 (2008). physicochemical characteristics of antimicrobial peptides (AMPs). [117] Peptidomimetic antimicrobials were made using β-peptides, [118,119,120,121,122] peptoids [123] and oligoureas [124,125] as scaffold. Unlike the α-peptide backbone of natural AMPs, they offer the additional advantage of being resistant to proteases. A more challenging application of peptidomimetic foldamers concerns their use for mimicking protein segments, particularly α-helix, involved in proteinprotein interactions. Prototype works were employed to target the intracellular p53/hDM2 [126,127] and Bcl-2/Bcl-xL, [128] interactions demonstrating the potential for foldamers to bind undruggable flat protein surfaces.

Although peptidomimetic foldamers were extensively explored for biomedical applications, their potential as asymmetric catalysts was little explored. One major question to be addressed is to what extent can a small foldamer sequence be adapted to achieve catalytic functions. The next section will review this literature.

Catalytic foldamers

The discovery of short peptide sequences that function as asymmetric catalysts for a variety of reactions is now well documented. Both combinatorial and de novo methods of catalyst design were demonstrated successfully to perform a variety of reactions including kinetic resolutions of alcohols, aldol reactions, phosphorylation, Michael addition, and Morita-Baylis-Hillman reactions. [129,130,131,132] Despite both combinatorial and rational design methods proved fruitful, it remains a need for robust systems that permit rational design of versatile peptide-based catalysts. In many cases, secondary structural elements showed to be crucial for catalytic activity and chemical, regio-, or enantio-selectivity. However, the state of a short peptide in solution is generally characterized not by one configuration but by an ensemble of CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION 63 structures limiting the ability to re-create all the desirable characteristics for an enzyme-like catalyst. Foldamer science may provide solutions to these problems.

i. Peptoids for enantioselective catalysis

In this context, a chiral environment associated with a competent catalytic functional group is the key elements for catalyst design. Therefore, one can imagine positioning reactive sites on the foldamer side chains. This was achieved by Maayan et al. who described peptoids substituted on their lateral chains with a 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) group (Figure 45). The oligomers were explored for oxidation of a racemic mixture of 1-phenylethanol and their activity were compared to those of the corresponding peptides. [START_REF] Maayan | Folded Biomimetic Oligomers for Enantioselective Catalysis[END_REF] Figure 45: 4-amino-TEMPO, Nspe monomer and peptoid sequences (24), (25) and(26) While (S)-phenylalanine monomer (spe) mixed with 4-amino-TEMPO led to a low conversion with no selectivity for one enantiomer (Table 6, entry 1), the peptoid counterpart TEMPO-N(spe)6 (25) showed excellent conversion with a selectivity towards the (S) enantiomer (Table 6, entry 3). Inversion of the chirality of the oligomer (compound (26)) led to a complete change of the enantioselectivity (Table 6, entry 4). Interestingly, no asymmetric induction was observed when the TEMPO group was not covalently linked to the peptoid backbone (Table 6, entry 2).

Table 6: Conversions, enantioselectivities, and enantiomeric excess for the catalytic oxidation of 1-phenylethanol by peptoids [START_REF] Maayan | Folded Biomimetic Oligomers for Enantioselective Catalysis[END_REF] Entry Catalytic system Conv. a (%) Selectivity b (%) ee (%) ii. β-Peptides as catalysts

Juliá-Colonna asymmetric epoxidation of enones

The first example of a catalytic pseudo-peptide foldamer was probably reported by Smith et al. [133] By analogy to the work of Juliá and Colonna, who used poly-α-leucines as catalytic species, they described poly-β 3 -leucines as able to catalyse the epoxidation of (E)-α,β-enones by H2O2 with significant enantioselectivity. The exact role of the α-and β-peptides in the reaction mechanism is not clear. Since the reaction occurred in a heterogeneous medium, it should be hypothesized that the substrate is adsorbed on the oligomer surface that induce a chiral environment for the action of H2O2. In this article, the authors did not study the conformational preference of the oligomers nor demonstrated any superiority of the β-peptides over the α-ones.

Retroaldol cleavage of β-hydroxyketones

In 2009, Hilvert et al. used β-peptides as platforms to create a foldamer that has an aldolase activity in aqueous buffer. [134] It was previously known that lysine rich amphiphilic α-helices can catalyse retroaldol cleavage of β-hydroxyketones through the formation of imine or enamine intermediates. Thus, a β-peptide sequence that contains multiple ACHC residues along with β 3 -homolysine (β 3 -hLys) residues in an i, i+3, i+6 array (catalyst (27)) was designed to 133 Coffey, P. E. et al., Chem. Commun. Camb. Engl., 2330-31 (2001). 134 Müller, M. M. et al., Angew. Chem., 121, 940-43 (2009).

lead to alignment of the amine-containing side chains along one side of a 14-helix (Figure 46).

The N-terminus was capped by a β 3 -hTyr residue to facilitate concentration determination and with an heptanoyl moiety to promote self-assembly of the oligomer. The β-peptide (27) was tested for its ability to promote the retroaldol cleavage of the 4-phenyl-4-hydroxy-2oxobutyrate, an anionic β-hydroxyketone expected to bind to the cationic catalyst. While (27)

showed high catalytic activity, a scrambled sequence that does not match the three-residue repeat ACHC-ACHC-β 3 -hLys of the 14-helix and, an analogue of (27) in which all of the preorganized ACHC residues are replaced by flexible β 3 -hVal residues, were relatively poor catalysts under identical reaction conditions. The authors also demonstrated a favourable effect of the β-peptide clustering for the aldolase activity. As highlighted in the article, this favourable effect may reflect a reduction in the pKa value of the β 3 -hLys side-chain ammonium group. This could be due to an increase in the hydrophobicity of the environment of catalytic amines or a high local positive-charge density. Finally, another effect that could actually operate jointly with the previous one is such that the interface between helical β-peptides would be acting as a primitive substrate-binding pocket.

Hydrolysis of trisulfonate esters

Independently to Hilvert and Gellman, Schepartz group rationally designed a β 3 -peptide bundle catalyst for hydrolysis of 8-acetoxypyrene-1,3,6-trisulfonate. [135] They modified the Zwit-EYYK sequence, known to fold in a bundle octamer, and introduced β 3 -hArg (= β 3 R, Figure 135 Wang, P. S. P. et al., J. Am. Chem. Soc., 136, 6810-13 (2014).

B/ A/ 47, A) at key positions to electrostatically orientate the recognition of the substrate in close proximity to a catalytic α-His residue. The helical stability of the architecture was essential to guide the design of a β 3 -peptide bundle. Despite the low propensity to self-assemble, the first generation of synthesized peptides, at 10 mol%, was increasing the background reaction rate by a factor of 20 to 30 while free histidine at 10 mol% enhanced the reaction rate by less than 5fold. More importantly, steady-state measurements revealed that hydrolysis was following Michaelis-Menten kinetics. To improve bundle stability, they synthesized a covalent dimer containing two βEst-2 monomers joined with a tetra-β-hGly linker (Figure 47,B). The βEst-2-sequence showed a propensity to structure in an octamer and displayed Kcat/KM = 5102 M -1 min -1 , almost two orders of magnitude greater than that for the βEst-2 monomer.

Based on XRD structure of the bundle catalyst, twenty potential active sites per assembly were recognized, this could explain the differences in activity between bundle forming and monomeric β 3 -peptide catalysts.

Figure 47: Helical schematic of A/βEst-2, B/ βEst-2 monomers joined with a tetra-β-hGly linker [136] Bifunctional catalysis A few other types of folded catalysts were investigated, one of the latest, developed by Gellman et al., relies on a β-peptide helix bearing pyrrolidine groups for cross aldol reactions. [137] As previously settled, this group showed the propensity for ACPC-oligomers to fold into 12-helices (Chapter 1, II, 1, ii.b), based on this evidence, they developed pyrrolidine derivative (APC) for introduction into oligomers (Figure 48,A). A geometric study of APC-containing foldamers was performed in order to get the best spatial arrangement to provide a favourable secondary amine diad for bifunctional catalysis. Hence, β-peptides of ACPC/APC and mixed α/β-peptides 136 Wang, P. S. P. et al., Chem. Commun., 52, 7420-32 (2016). 137 Girvin, Z. C. et al., J. Am. Chem. Soc., 140, 12476-83 (2018). B/ A/ CHAPTER 1: BIBLIOGRAPHIC INTRODUCTION 67 of α-residues Aib and ACPC/APC β-monomers were synthesized (Figure 48,B). It appeared that the 1:2 α/β-oligomer (31) provided a propitious geometry of the secondary amine diad, for bifunctional catalysis as this helix is stabilized by hydrogen bonds between the COi and the NHi+3. This helix contains three residues per turn, thus bringing the two APC residues of (31) above one another and exactly one turn apart. [137] iii. Aib-oligomers and oligoureas for the C-C bond formation and control of chirality Over the last decade, Clayden's group explored the concepts of screw-sense preference, that is the thermodynamic preference for a helix to adopt a specific left-or right-handedness, by building synthetic helices made from achiral monomers. [138] They demonstrated that if an Aiboligomer is connected to a chiral terminus extremity, its two screw-sense conformers might be desymmetrised and thus drive to an imbalance in the population of the two interconverting screw-sense conformers. To induce a screw-sense preference, the terminal residue must be connected to the organization of the final β-turn of the 310-helix (as Aib-oligomers of more than three residues are usually 310-helical (Chapter 1, II, 1)). This ability was used to control the chiral environment of an achiral aminothiourea moiety placed at the second extremity of the oligomer. The remotely inducible chiral thiourea centre was able to catalyse the nitro-Michael addition reaction of diethylmalonate to β-trans-nitrostyrene. The enantiomeric ratio is reflecting the screw-sense preference of the Aib-oligomer (Figure 50). 138 Le Bailly, B. A. F. et al., Angew. Chem. Int. Ed Engl., 55, 2132-36 (2016).

Figure 50: Catalytic foldamer with a remotely inducible catalytic site [138] Concerning the γ-peptides, Guichard et al. reported helical oligoureas foldamers as catalysts for C-C bonding formation. [START_REF] Bécart | Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions[END_REF] For a reminder, they demonstrated that their structure owns two hydrogen-bond donors sites on the N-terminal extremity (circled in red on the hexamer (32a), Figure 51,A). Therefore, they focused their efforts on a catalysis based on the principle of Hbond donor catalysts. Moreover, as demonstrated by Clayden and explained in the previous paragraph, the internally organized amine/thiourea catalyst was proved to be an efficient catalyst for asymmetric induction. Hence, the objective of this study was to demonstrate that this well-defined 2.5-helix of oligourea could act as chiral catalyst capable of forming extended intramolecular hydrogen bonds. This would then increase the H-bond donor ability of the thiourea and leave space for the substrate-catalyst coordination around this moiety. The study established that only 0.01 mol% of foldamer (32a), in association with an external Brønsted base, can catalyse the Michael addition reaction between enolizable carbonyl compounds and nitroolefins (Table 7, entries 1-3). The reaction is performed in toluene, various parameters were tested, such as the loading of the catalyst, the influence of the temperature and the length of the foldamer (Table 7).

With this work, the authors were able to promote an efficient aliphatic N,N'-linked oligourea as chiral catalyst. Moreover, they demonstrated the importance of the folding in such oligomers as almost no enantiocontrol was observed when the reaction took place in presence of monomers and dimers of ureas but the highest reactivity and selectivity were found for the penta-and hexamers (Table 7). a Yield of isolated product after chromatography, b Enantiomeric excess determined by chiral HPLC. [START_REF] Bécart | Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions[END_REF] As we have seen in this paragraph, exploring the propensity for folded unnatural oligomers as a scaffold for catalysis remains a challenging topic. Research in this area is ongoing and many breakthroughs remain to be achieved.

III. THESIS OBJECTIVES

As explored in this chapter, over the past several decades, peptides and peptide-based molecules have emerged as promising minimal enzymatic systems. Combinatorial methods and de novo designs have led to real successes for a large variety of reactions, such as aldolisation, phosphorylation, Michael addition or Morita-Baylis-Hillman reactions. [129] However, the difficulty to control their three-dimensional structure limits their use to re-create all the desirable characteristics for an enzyme-like catalyst. [START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF] As we have reviewed, recently it was proposed to build bio-inspired catalytic systems from artificial oligomers, called "foldamers", with high conformational stability and structural predictabilities, mimicking the protein secondary structures (helices, sheets and ribbons). [139,134,[START_REF] Maayan | Folded Biomimetic Oligomers for Enantioselective Catalysis[END_REF] Potentially, such catalysts could present numerous advantages and could be an original solution to answer both the economic and environmental issues faced in organic chemistry. Chemically accessible, they can, unlike the enzyme, be used in various organic solvents and within a large temperature and pressure scale. Furthermore, the activity and specificity of the catalyst can be easily modulated by changing the nature of it catalytic centre and/or by modulating the topology of the folded backbone and the microenvironment around the catalytic centre.

In this context, my work was devoted to the development of bio-inspired foldamer catalysts based on a heterocyclic γ-peptide scaffold and one major question to be addressed was to what extent a small foldamer can be adapted to achieve catalytic functions. The general aim was to use the ATC-based foldamers as a template for the development of modular enamine-type catalysts. In this context, the next chapter of this manuscript will provide a short overview of the use of peptides in enamine catalysis. Particularly, we will see how the proline-containing peptides reported by the group of H. Wennemers inspired us for the design of a catalytically competent ATC monomer. The next section will be devoted to the introduction of the ATC monomer bearing the catalytic function into a set of ATC-based oligomers. One central feature was to explore systematically the connection between foldamer sizes and/or shapes, and, both, reactivity and enantioselectivity. Consequently, a steady study of the catalytic properties of the synthesized oligomers will be performed. We will also focus on the reliable structural markers to assess the folding properties of the catalytic oligomers by combining NMR, FTIR and circular dichroism experiments. Finally, I will describe the development of a script for NMR-based 3D-modelling that was used to calculate the folding of the ATC oligomers on an atomic level.

In this document, we will use the following nomenclature for the ATC monomers:

PG

I. ENAMINE CATALYSIS

History: proline as a prototype for enamine catalysis

Enamine catalysis is defined as being the catalysis of electrophilic substitution reactions in the α-position of a carbonyl compound, by a primary or secondary amine via an enamine intermediate. This type of catalysis was subject to much discussion as it provides, in terms of the number of steps, an economical way for enantioselective synthesis and one of the most powerful methods for the stereoselective α-functionalization of aldehydes and ketones. It involves catalytically generated enamine intermediates formed via deprotonation of an iminium ion that can react with various electrophiles. There are two modes of enamine catalysis, determined by the class of electrophile used (Scheme 1). [140,141] Scheme 1: Enamine catalysis, arrows may be considered equilibria A primary or secondary amine reacts with a ketone or an aldehyde to create an iminium ion that spontaneously converts into an enamine through a tautomerism equilibrium. The resulting enamine then reacts in one of the two possible ways. In a first potential chemical route, a nucleophilic addition of the enamine, occurs when the electrophile contains double bonds, like aldehydes, imines or Michael acceptors and so on. The second possible pathway results from the nucleophilic substitution by the enamine of a single bond containing electrophiles such as alkyl halides.

The independent discoveries in 1971, of Hajos and Parrish's group and Eder, Sauer and Wiechert's group, of L-proline enantioselectively catalysing 6-enolendo intramolecular aldol reactions of di-and triketones, is probably the fundamental to enamine catalysis (Scheme 2). [142,143,144] Scheme 2: Hajos-Parrish-Eder-Sauer-Wiechert reaction [145] Hajos and Parrish initially proposed two possible mechanisms for this reaction. The first hypothesis being the formation of a protonated enamine and an oxazolidone ring (Figure 53,A). The second one is based on the addition of the L-proline's zwitterionic form on one of the two carbonyls of the cyclopentanedione (Figure 53,B). Initially considered as true by Hajos, [146] the second hypothesis was rejected by List et al. In fact, when performed in [START_REF] Pauling | The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain[END_REF] O-labelled water, the latter obtained more than 90% of labelled oxygen incorporation in the final product, which is not compatible with the putative 142 Hajos, Z. G. et al., Ger. Pat. DE2102623 (1971). 143 Eder, U. et al., Ger. Pat. DE2014757 (1971). 144 Eder, U. et al., Angew. Chem. Int. Ed. Engl., 10, 496-97 (1971). 145 Clemente, F. R. et al., Angew. Chem. Int. Ed., 43, 5766-68 (2004). 146 Hajos, Z. G. et al., J. Org. Chem., 39, 1615-21 (1974).

mechanism. [147] In 1976, Jung proposed a third mechanism involving the formation of a C-C bond, together with the transfer of the carboxylic acid's proton on the carbonyl group (Figure 54,A). [148] This model was challenged in the 80s by Agami's group who proposed a mechanism based on the hydrogen transfer guided by a second molecule of proline (Figure 54,B). [149] Figure 54: Reaction intermediates proposed by A/Jung, B/Agami

However, because of the absence of dilution effect on the enantioselectivity and, secondly, due to the kinetics obtained during this reaction, List, Houk et al. showed, in 2003, that only one proline would be involved in the mechanism. [150] Subsequently, Jung's model became the most probable one. Eventually, helped with the Density Functional Theory (DFT), Houk brought new elements supporting the formation of an enamine intermediate. [145] i. Asymmetric aldol reaction

As proline can catalyse intramolecular aldol reactions, many groups were interested in whether proline would catalyse intermolecular aldol reactions or not. The first case of such reaction was reported by List et al. in 2000, in which L-proline catalysed the aldol condensation of acetone to p-nitrobenzaldehyde giving the aldol product with an enantiomeric excess of 76% (Scheme 3). [151] Scheme 3: The first proline-catalysed asymmetric intermolecular aldol reaction [151] 147 List, B. et al., Proc. Natl. Acad. Sci. U. S. A., 101, 5839-42 (2004). 148 Jung, M. E., Tetrahedron, 32, 3-31 (1976). 149 Agami, C., Bull. Société Chim. Fr., 499-507 (1988). 150 Hoang, L. et al., J. Am. Chem. Soc., 125, 16-17 (2003). 151 List, B. et al., J. Am. Chem. Soc., 122, 2395-96 (2000).

The resulting catalytic mechanism involving the proline would be, from then onwards, described as an enamine type reaction, very similar to the accepted mechanism of class I aldolases (Scheme 4). [140,152]

Scheme 4: Catalytic cycle of proline-catalysed aldolizations

Proline A reacts with a ketone or aldehyde to form the iminium ion B which evolves to the nucleophilic enamine C by imine-enamine tautomerism. In the transition state of the carboncarbon formation (D), the electrophile aldehyde R 3 CHO approaches in a way that permits a re-facial attack of the enamine to the carbonyl, leading to the anti-product. This transition state was widely studied, and it is suggested that the carboxylic acid acts as a Brønsted cocatalyst, replacing the several acid/base functional groups involved in the aldolase mechanism, making proline a "bifunctional catalyst". Finally, the iminium ion E is hydrolysed into a carbinolamine F to release the aldol product and the proline catalyst. [153] Supporting this mechanism, Marquez and Metzger isolated and characterized the intermediates C, E and F with an ESI-MS study. [154] With the success of the first proline-catalysed intermolecular reaction by List et al. and the non-152 Dalko, P. I. et al., Angew. Chem. Int. Ed., 43, 5138-75 (2004). 153 List, B. et al., Org. Lett., 3, 573-75 (2000). 154 Marquez, C. et al., Chem. Commun., 1539(2006).

existent steric constraints applied to proline compared to enzymes, a large scope of electrophiles were tested. As highlighted by some examples found on the literature, the yields and enantiomeric excesses depend on the aldehyde used for the reaction (Table 8). [155] Table 8: Examples of proline-catalysed aldol reactions [155] Entry R 1 R 2 Yield (%) anti:syn anti ee c (%)

1 a OH iPr 63 >20:1 >99 2 a OH Ph 83

ii. Asymmetric three-component Mannich reaction

The Mannich reaction represents a highly useful extension of aldol-type approaches. The most widely recognized form of this reaction consists of three components, those are two carbonyl compounds and an amine, condensing to form a β-amino-carbonyl product. [156] The concomitant formation of a carbon-carbon bond and a carbon-nitrogen bond makes the Mannich reaction an extremely useful synthetic transformation. This reaction can be either direct, when using unmodified ketone donors or indirect, with preformed enolates generated stoichiometrically either in situ or by prior synthesis (Scheme 5).

155 Tanaka, F. et al., in Enantioselective Organocatalysis, ed. by Peter I. Dalko, pp. 19-55 (Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA, 2007). 156 Kleinman, E. F., in Compr. Org. Synth., by Barry M. Trost et al., 2, 893-951 (Elsevier Ltd, 1991).

Scheme 5: Direct and indirect Mannich reactions [157] The first example of direct organocatalytic Mannich reaction with proline as a catalyst was described shortly after the first proline-catalysed aldol reaction. It depicted the reaction between proline, p-nitrobenzaldehyde, and p-anisidine in acetone/DMSO (1:4) over twelve hours. The corresponding Mannich product was formed with 50% yield and 94% enantiomeric excess (Scheme 6). [158] Scheme 6: The first highly enantioselective three component Mannich reaction

The L-proline-catalysed Mannich reaction also takes place with disymmetric ketones as donors, providing two regioisomers when aliphatic (Table 9, entry 2). When using α-hydroxy or αalkoxyketones, the reaction becomes regiospecific (Table 9, entries 3-4). Finally, enantioselectivities are generally better with aromatic aldehydes than with aliphatic ones (Table 9, entries 1, 5-8). [157,158,159] 157 List, B., Synlett, 2001, 1675-86 (2001). 158 List, B., J. Am. Chem. Soc., 122, 9336-37 (2000). 159 Córdova, A., Acc. Chem. Res., 37, 102-12 (2004). Noticeably, the products from proline-catalysed Mannich reactions have the opposite absolute configuration to those of the aldol products, meaning that Mannich and aldol reactions have opposite enantiofacial selectivities (si and re respectively). It is assumed that the proline imine and enamine intermediates have a fixed (E)-configuration leading to a selective attack of the enamine on the si-face of the imine. The access on the re-face is limited by unfavourable steric interactions between the pyrrolidine of the proline and the N-substituent of the imine. This does not exist in the aldol reaction, in which steric repulsion between aldehyde and enamine carbon substituents is dominant, leading to a re-facial attack (Scheme 7). [160] Scheme 7: Opposite enantiofacial selectivity in Mannich (left) and aldol (right) transition states

iii. Michael addition reaction

The Michael addition reaction is another efficient pathway to form carbon-carbon bonds. As the demand for optically active compounds grew, this reaction was widely studied to provide 1,4-addition adducts as valuable synthetic intermediates, such as γ-nitro ketones. Thus, the diversity of Michael acceptors used was broadly extended from malonic acid esters and βketoesters to nitroolefins. Regarding the Michael donors, ketones are usually used once activated into a more reactive species like enols or enamines even though this is not optimum in terms of atom economy. Therefore, a direct addition of unmodified carbonyl donors to Michael acceptors would make this reaction more advantageous. The first result of an enaminecatalytic asymmetric intermolecular Michael reaction was obtained by List et al. in 2001. [161] They first performed a proline-catalysed Michael addition between acetone and β-transnitrostyrene (Table 10, entry 1). Thereafter, they disclosed a variety of Michael addition between unmodified ketones and nitroolefins, even if this first enantioselecitivity was low (7% ee). In general, it appeared that proline-catalysed Michael reactions are less enantioselective than the aldol or Mannich reactions, but its high efficiency and simple process are noteworthy for enamine catalysis. Finally, a high syn selectivity was observed, explained by an acyclic synclinal transition state based on a re,re-approach (Figure 55). [162] In such model, the reaction is under kinetic control. [163,164] 160 List, B. et al., J. Am. Chem. Soc., 124, 827-33 (2002). 161 List, B. et al., Org. Lett., 3, 2423-25 (2001). 162 Seebach, D. et al., Helv. Chim. Acta, 64, 1413-23 (1981). 163 Enders, D. et al., Synlett, 2002, 0026-0028 (2002). 164 Sharma, A. K. et al., J. Org. Chem., 77, 10516-24 (2012). The reaction is general as it could be extended to many ketones and nitroolefins. However, the chiral controls appeared much less favourable than in the aldol-type reaction (Table 10).

Table 10: Michael reaction between unmodified carbonyl donors and nitroolefins [161] Entry Product Yield (%) ee a (%) (syn) dr b (syn/anti) catalysts. [165,166,167,168,169,170] They assumed that the peptide folding could drive a highly chiral local microenvironment thus, enhancing the chiral transfer. Considering both activity and selectivity, di-proline-containing tripeptides discovered by H. Wennemers are probably the most efficient catalysts for diastereo-and enantioselective aldol-type reactions and Michael additions of aldehydes to β-substituted nitroolefins.

1 97 7 - 2

Peptides in enamine catalysis

i. H-Pro-Pro-Asp-NH2 as a prototype catalyst for aldol reaction

In 2005, Wennemers's team identified two tripeptides, H-L-Pro-D-Ala-D-Asp-NH2 (33) and H- 34), as highly efficient catalysts on the aldol reaction between the nitro-benzaldehyde and the acetone (Figure 56). [171] Figure 56: Wennemers's peptides ( 33) and ( 34)

L-Pro-L-Pro-L-Asp-NH2 (
While the use of 30 mol% of proline is needed to catalyse this transformation in four hours at room temperature (y = 68%, ee = 76%), only 10 mol% of (33) are necessary to lead to 73% yield, after 72 hours, and an enantiomeric excess up to 70%. Moreover, only 1 mol% of peptide (34) gave, in 4 hours, 99% of the aldol product in 80% ee. These results were explained by a better aptitude for this second peptide to adopt a compact structure, in comparison with the first one. In fact, based on molecular dynamic studies, the authors highlighted that the peptides (33)

and (34) hold different conformations, a left-handed turn for the first one and a right-handed turn for the second. It is also interesting to note that the two peptides lead to two different enantiomers, even if the chirality of the catalytic N-terminus prolines are identical (Table 11).

This result is of prime importance as it demonstrates that the chirality of the transformation 165 Kofoed, J. et al., Bioorg. Med. Chem. Lett., 13, 2445-47 (2003). 166 Martin, T. J. et al., Synlett, 12, 1091-1902[START_REF] Horton | Principles of Biochemistry[END_REF]. 167 Jarvo, E. R. et al., Tetrahedron, 58, 2481-95 (2002). 168 Andreae, M. R. M. et al., Tetrahedron Asymmetry, 16, 2487-92 (2005).

169 Luppi, G. et al., J. Org. Chem., 70, 7418-21 (2005). 170 Tang, Z. et al., J. Am. Chem. Soc., 127, 9285-89 (2005).

171 Krattiger, P. et al., Org. Lett., 7, 1101-3 (2005).

might be driven not only by the catalytic centre but also by the overall conformational behaviour of the peptide catalyst. a Enantiomeric excess determined by chiral HPLC or GC analysis, (R) and (S) indicate the absolute configuration of the aldol product [171] On a mechanistic aspect, the amine and acid functions are essential. If the secondary amine is either acetylated (Ac-Pro-Pro-Asp-NH2 (35)) or methylated (Me-Pro-Pro-Asp-NH2 (36)), or if the carboxylic acid is replaced by an amide (H-Pro-Pro-Asn-NH2 (37)) or a sulfonic acid (H-Pro-Pro-Cys(SO3H)-NH2 (38)), the catalytic activity is drastically reduced (Figure 57 and Table 12). [172]

ii. Scope extension: from aldol reaction to nitro-Michael addition

An article from 2008 suggested that the distance between the N-terminal secondary amine and the carboxylic acid might play a determining role in the reaction control. [173] While such a distance is of 3.7 Å for proline, it reaches 7.3 Å in the tripeptide (34) (Figure 58, A and B).

Figure 58: A/Lowest-energy conformation for the proline as calculated by MacroModel 8.0 [173] B/Lowest-energy conformation of the (34) as calculated by MacroModel 8.0 [171,173] C/Transition state of aldol reactions catalysed by proline proposed by Houk and List [145,147] D/Transition state for the 1,4-addition catalysed by Wennemers's tripeptide, X and Y represent heteroatoms or carbon atoms [173] Thus, it was hypothesized that the tripeptide may be a better support for substrate recognition of 1,4-additions than proline. Tested on the nitro-Michael addition of n-butanal and β-transnitrostyrene, the tripeptide H-L-Pro-Pro-Asp-NH2 (34) and its diastereomeric version (H-D-Pro-Pro-Asp-NH2 (39)) led to 96 and 93% yields with a high preference for the syn product. The enantiomeric excesses (85 and 95%) were much higher than with proline. However, since the two catalysts led to products with opposite configurations, it appeared that the chirality of the transformation was driven by the absolute configuration of the N-terminal proline. This observation implies two different transition states resulting from an opposite approach of the nitroolefin to the enamine intermediate (Figure 59). ). [175,176] Although the acid group probably coordinates the nitronate function, its exact role as well as the protonation states along the catalytic pathway are not fully understood. Especially, its presence is not indispensable since a powerful catalytic tripeptide without acidic group was reported for the addition of nitro-Michael 174 Bächle, F. et al., Angew. Chem. Int. Ed., 52, 12619-23 (2013). 175 Duschmalé, J. et al., Chem. Sci., 4, 1312-18 (2013). 176 Duschmalé, J. et al., Chem. -Eur. J., 18, 1111-20 (2012).

B/ A/ C/ CHAPTER 2: INTRODUCTION OF A CATALYTIC FUNCTION ON AN ATC-OLIGOMER 88
between aldehydes and β,β-disubstituted nitro-olefins. [177] When the catalyst bears a carboxylic acid, the iminium nitronate B is intramolecularly protonated to form the iminium ion C which is then hydrolysed to release the expected product and the catalyst (Scheme 8, pink pathway).

This intramolecular protonation is fast and does not limit the reaction rate, suggesting again that the limiting step is the C-C bond formation, which depends on the concentration of the nitroolefin and the enamine but not on the external proton sources.

Scheme 8: Catalytic cycle proposed for 1,4-additions of aldehydes to nitroolefins using catalyst with (pink) or without (orange) a proton-donor [175] Alternative mechanisms were proposed for catalysts which do not own acidic hydrogen. For example, with chiral prolinol ether derivatives, cyclic intermediates such as dihydrooxazine and cyclobutane (respectively E and F in Scheme 8) were identified as resting states of catalysts [178,179,180,181,182] and the rate-determining step of the reaction was suggested to be the protonation of the dihydrooxazine oxide species, [183] instead of the iminium or enamine nitronates. For example, an analogous cyclobutane intermediate was found in the reaction of butanal and nitrostyrene with H-D-Pro-Pro-Asp(OMe)-NH2. [175] On the other hand, even though they are not populated to a significant extent, dihydrooxazine and cyclobutane intermediates could not exclude H-D-Pro-Pro-Asp-NH2 (39) as catalyst. [184] Further studies demonstrated that the related sequence H-D-Pro-Pro-Glu-NH2 ( 40) is also able to catalyse the nitro-Michael addition reaction between aldehydes and the nitroethylene as Michael acceptor. [185] The best result (yield ≥ 95%, ee ≥ 95%) was obtained after 15 hours at room temperature with 1 mol% of ( 40

iv. Structural modulation of the tripeptide catalyst

Effect of ring-size analogues of H-D-Pro-Pro-Glu-NH2

In 2017, Wennemers and her team accessed structurally related catalysts of (40) with different trans/cis amide bond ratio, by synthesizing analogues bearing the four-and six-membered ring, respectively azetidine carboxylic acid (Aze) and piperidine (Figure 60). [187] This study was 178 Patora-Komisarska, K. et al., Helv. Chim. Acta, 94, 719-45 (2011). 179 Seebach, D. et al., Helv. Chim. Acta, 95, 1064-78 (2012). 180 Burés, J. et al., J. Am. Chem. Soc., 133, 8822-25 (2011).

181 Burés, J. et al., J. Am. Chem. Soc., 134, 6741-50 (2012).

182 Burés, J. et al., J. Am. Chem. Soc., 134, 14264-14264 (2012). 183 Sahoo, G. et al., Angew. Chem. Int. Ed., 51, 13144-48 (2012). 184 Maillard, L. T. et al., ACS Omega, 4, 8862-73 (2019). 185 Wiesner, M. et al., J. Am. Chem. Soc., 130, 5610-11 (2008). 186 Rigling, C. et al., J. Am. Chem. Soc., 140, 10829-38 (2018). 187 Schnitzer, T. et al., J. Am. Chem. Soc., 139, 15356-62 (2017).

conducted to observe the influence of the trans/cis amide bond ratio on stereoselectivity. Based on NMR, they demonstrated that all the peptides adopt as similar β-turn with a hydrogen bond between the C=O of D-Pro and the C-terminal amide. However, whatever the considered solvent, the trans/cis amide bond ratio increased with the size of the central azacycle (Table 13, 3 rd column). Evaluation of the catalytic properties demonstrated a strong dependency of the diastereo-and enantioselectivities to the trans/cis ratio: the more the trans isomer is favoured, the better is the selectivity. In addition, since the trans/cis ratio is mainly related to the solvent (Figure 61), it is not surprising to find strong solvent effects on the reaction selectivity. [187] Figure 61: Correlation between the amount of trans conformer of peptides (40)-4, ( 40) and ( 40)-6 with their A/enantioselectivity and B/diastereoselectivity as examined in different solvents [187] Effect of β [START_REF] Berg | Chapter 3, Protein Structure and Function[END_REF]

-amino acids analogues of H-D-Pro-Pro-Glu-NH2

Finally, in a recent publication, Wennemers and Schnitzer explored the effects of conformational flexibility on catalytic performances by synthesizing β 3 -amino acid peptides analogues of (40) (Figure 62). [188] Based on computational analysis of the enamines derived from these four peptides, they observed that tripeptides (40)-αβα and (40)-ααβ tend to have a similar orientation of their enamine and carboxylic acid groups when compared to the all-αamino acids tripeptide (40). Tested on the conjugate addition reaction of butanal to β-transnitrostyrene, these two analogues showed a lower reactivity and stereoselectivity than H-D-Pro-Pro-Glu-NH2 (40) but the effect was not critical (Table 14, entries 1, 3 and 4). However, when the tripeptide bears an extra methylene group on its N-terminal side ((40)-βαα), a rotation of the β 3 -D-Pro residue occurred. This homologation leads to an important distance between the enamine and the carboxylic acid. In that case, the outcome is not too surprising; an increase of flexibility on the N-terminal proline can drive the nitroolefin to approach from both faces, hence it directs to a low enantioselectivity of the reaction (Table 14, entry 2). In conclusion, the catalytic properties of these tripeptides seem closely related to the balance between conformational flexibility and rigidity. [START_REF] Berg | Chapter 3, Protein Structure and Function[END_REF] -amino acids [188] Table 14: Peptide catalysed conjugate addition reaction of butanal to β-trans-nitrostyrene [188] Entry Catalyst Conv. a (%) dr b (%) ee b (%)

II. DESIGN AND SYNTHESIS OF COMPETENT ATCS FOR ENAMINE-TYPE CATALYSIS

ATC design

These insights, from the literature, provide a general guide for designing an enamine-type catalyst. It appeared that an ideal catalyst should combine two functionalities, i.e. a nucleophilic amine such as a pyrrolidine and a Brønsted acid. The average distance of the two key functions is of prime importance to establish the catalysed transformation. Finally, the chemo-and enantioselectivity of the reaction is drastically related to the dynamics of the folding and could be modulated by an appropriate choice of solvent.

Thus, the first objective of my thesis was to develop an ATC-monomer bearing a carboxylic acid on its -lateral chain and an azacycle on the position 2 of the thiazole ring. The general structure is presented in Figure 63. The chemical route ought to guarantee a strict control of the stereochemistry of the two asymmetric carbons.

ATC synthesis

In 2016, Dr. L. Mathieu and Dr. C. Bonnel reported a robust ATC synthesis pathway providing an easy way to modulate the lateral chains, either on the γ-carbon atom or on the thiazole core of the amino acids. [189] The synthetic strategy starts by a Cross-Claisen condensation between the N-Fmoc-amino acid and the 1,1-dimethylallyl acetate to access an N-Fmoc-amino-β-keto ester intermediate (42).

The use of a sterically hindered acetate is needed to preserve the orthogonality of the protections and to avoid any side reactions due to acetate autocondensation. Actually, the best conditions consist in the use of CDI (1.1 equiv.) and DMAP (3 mol%) to activate the N-protected-amino acid as an imidazolide intermediate, which is not isolated. The reaction is usually performed at 189 Mathieu, L. et al., Eur. J. Org. Chem., 2262-70 (2015).

room temperature, in dry THF. In parallel, the enolate is generated from the 1,1-dimethylallyl acetate using LiHMDS as base. Then, the activated amino acid is added dropwise to the enolate.

A strict temperature control, at -80°C is necessary to prevent any Fmoc deprotection. The N-Fmoc-amino β-keto esters are classically obtained in ten grams scales with overall yields of 34-80%, depending on the selected N-Fmoc-amino acid starting material. [189] A monohalogenation at the malonic position of compound (42) is then performed to give the -bromo-β-keto ester intermediate (43) (Scheme 9, A). The bromination is carried out under Yang et al.

conditions, [190] in presence of a catalytic quantity of Mg(ClO4)2 behaving as a Lewis acid, and N-bromosuccinimide (NBS), at -45°C. A Hantzsch cyclisation using a thioamide reactant leads to the formation of the fully protected ATC (44). The bromine substitution, the cyclisation and the spontaneous aromatisation are performed in ethanol, at 35°C. A chemoselective deprotection of the acid function is finally done using a catalytic amount of palladium tetrakis triphenylphosphine and phenylsilane as nucleophile.

The N-Fmoc-ATC-monomer (45) is orthogonally protected on the amino group by the basolabile Fmoc and on its lateral chain by an acido-labile group. Following this chemical route (Scheme 9), several monomers were synthesized with 26 to 65% yield. These monomers were used for the synthesis of a variety of foldamers described later in this manuscript.

190 Yang, D. et al., J. Org. Chem., 67, 7429-31 (2002).

Evaluation of the catalytic properties of the bifunctional ATC-monomer (46)

Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OCH3 (46) was first evaluated at 10 mol% in model enamine reactions: the cross condensation of acetone with p-nitrobenzaldehyde [153] , the amination of isovaleraldehyde with dibenzylazodicarboxylate [191] and the Michael addition reaction of cyclohexanone to β-trans-nitrostyrene (Scheme 12). [161] Scheme 12: Explored model reactions using (46) as catalyst

In the first case, using 10 mol% catalyst, less than 28% p-nitrobenzaldehyde was converted after 6 hours (66% after 7 days), and the reaction led to the Mannich-type product as a major species instead of the desired aldol-type compound (See SI, section IV). With the addition of isovaleraldehyde to dibenzylazodicarboxylate, the conversion rate was 67% after 2 hours (94% after 3.5 days) but no asymmetric induction was observed at 10 mol% catalyst (See SI, section IV). The effectiveness of ATC (46) was finally established in the nitro-Michael addition reaction of cyclohexanone to β-trans-nitrostyrene (Scheme 12). Initially performed in toluene at 30°C (Table 15, entry 1), the reaction led to a yield of 54% after 16 hours, with a good diastereoselectivity towards the syn product (syn/anti ratio 95/5) and a modest, but significant, enantiomeric excess of 27% in favour of the product with a ((S),(R)) configuration, determined by HPLC and optical rotation. This reaction has the advantage of being widely studied in organocatalysis since the resulting γ-nitroketones possess two stereogenic centres and can be 191 Kumaragurubaran, N. et al., J. Am. Chem. Soc., 124, 6254-55 (2002).

used for the synthesis of more complex molecules, such as chiral γ-amino acids, γbutyrolactams or polyketide natural products. [176,192,193,194]

Optimization of the nitro-Michael addition reaction catalysed by (46)

Having established the effectiveness of Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OCH3 ( 46) in the nitro-Michael addition reaction of cyclohexanone to β-trans-nitrostyrene, we then explored the reaction conditions. We have first tested the influence of the temperature and the solvent on the yield, the syn/anti diastereoselectivity and the enantioselectivity (Table 15).

The reaction was performed using 10 equivalents of cyclohexanone, 1.0 equivalent of β-trans-nitrostyrene and 10 mol% of catalyst (46) as TFA salt and 10 mol% N-methylmorpholine as base. The yields were estimated by HPLC at 214nm. [195] .

As highlighted in Table 15 (entries 2 to 6), when the reaction was performed in dimethyl sulfoxide, chloroform, tetrahydrofuran, acetonitrile or else hexane, the yield raised up to more 192 Belot, S. et al., Adv. Synth. Catal., 352, 667-95 (2010).

193 Roca-Lopez, D. et al., Tetrahedron Asymmetry, 21, 2561-2601 (2010). 194 Marcia de Figueiredo, R. et al., Eur. J. Org. Chem., 2007, 2575-2600 (2007). 195 Xu, Y. et al., Adv. Synth. Catal., 348, 418-24 (2006).

than 80%. However, the asymmetric induction was not significantly increased, reaching a limit of 31%. Methanol (Table 15, entry 7) was the solvent for which the conversion rate obtained was the lowest. This was quite an unexpected result, especially since under the same reaction conditions, ethanol led to a yield of 98% with an enantiomeric excess of 34%. Supported by the latest result, isopropanol was tested (Table 15, entries 9-10), giving the best yield with an ee of 41% at 30°C. By decreasing the temperature to 4°C, the asymmetric induction was increased, reaching 45% ee with a yield of 98%.

To conclude, we designed a bifunctional ATC, which, as proline or Wennemer's tripeptides, The pyrrolidine group in the ATC-oligomers is usually set in the (S) configuration, however, when the (R) configuration is used, a star (*) is added after the position number (P), such as ATCL-P*-X represents an ATC-oligomer bearing a pyrrolidine group of (R) configuration.

Finally, if the ATC-oligomer contains one residue that differs from (45a) and/or (45i)

(eventually (45j) when the pyrrolidine is in the (R) configuration), it will be designated as a mutant, thus will be called M(n)-ATCL-P-X where n is a number in order of appearance in the manuscript.

II. DESIGN AND SYNTHESIS OF FOLDED ATC-BASED CATALYSTS

We initially explored the relationship existing between the oligomer length and the catalytic properties. Therefore, we designed five ATC-based catalysts with an increasing number of ATC units. We first attempted to rigidify the monomeric catalyst (46) by introducing an isopropyl amide group to its C-terminal extremity and acetyl to its N-terminal extremity (Figure 65, compound (47)). Based on a previous study conducted within our laboratory, [104] we expected a stiffening of the ATC-scaffold resulting from a C9 intramolecular H-bond between the acetyl carbonyl and iPrNH. (47) was used as a reference catalyst. Then, we inserted the catalytic motif inside an ATC-trimer called ATC3-2-NHiPr and an ATC-pentamer named ATC5-3-NHiPr.

We believed that whatever the sequence, the oligomers would still conserve a C9-helical folding.

We also designed the trimer ATC3-2*-NHiPr, for which the pyrrolidine chiral centre was in the opposite configuration than in ATC3-2-NHiPr (Figure 65). The aim was to dissociate the effect of the folding to those from the pyrrolidine configuration on the asymmetric induction.

To test the role of the acidic lateral chain, we also prepared the methyl ester ATC3-2(OMe)-NHiPr. Finally, we planned the synthesis of the pentamer ATC5-3-NH2 differing from ATC5-3-NHiPr at the C-terminal extremity. The main goal was to explore the impact of the C-terminal extremity on both the folding and the catalytic properties of the oligomers.

Synthesis of (47)

The Ac-NH-{Pyrrolidine;propanoic acid}-ATC-NHiPr (47) was prepared from (45i) as depicted in Scheme 13. After activation by isobutylchloroformate (iBCF) and DIEA, the acid function was converted into isopropylamide. Treatment with diethylamine in DMF led to terminal amine deprotection which was then acetylated with acetic anhydride in DCM. Finally, the pyrrolidine and the propanoic acid lateral chains were deprotected by TFA (Scheme 13).

Synthesis of the ATC-trimers ATC3-2-NHiPr, ATC3-2*-NHiPr and ATC3-2(OMe)-NHiPr

The two diastereomers ATC3-2-NHiPr and ATC3-2*-NHiPr were synthesized in solution, following a step-by-step strategy, using a mix of EDCI and HOBt (1:1) as coupling agents.

During the procedure, the Fmoc groups were removed using a solution of diethylamine in DMF

Synthesis of the ATC-pentamer ATC5-3-NHiPr

In contrast, the pentamer ATC5-3-NHiPr was prepared following a convergent fragment approach (Scheme 15). As the first step, the monomer (44a) was quantitatively deprotected from its Fmoc group with a solution of diethylamine in DMF (2:8 vv) to obtain compound G.

Thereafter, a general coupling between monomers (45a) and G was performed using a mix of EDCI and HOBt (1:1) as coupling agents to lead to dimer H. Half of the amount of H was treated with Et2NH/DMF (2:8 vv) to remove the Fmoc group (compound I, 100% yield), the other half was deprotected on its acid group (compound J, 100% yield) under Tsuji-Trost conditions. J was coupled with the free amine group of K using EDCI and HOBt (1:1). The

Synthesis of ATC-pentamer ATC5-3-NH2

The synthesis of ATC5-3-NH2 was guided by two main objectives. As previously underlined, the first one was to explore the impact of the C-terminal extremity on both the folding and the catalytic properties of the oligomers. The second objective was to test the feasibility of a Fmoc/tBu Solid Phase Peptide Synthesis (SPPS) approach for the preparation of catalytic CHAPTER 3: CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 106 oligomers. In fact, because of the simplified procedures after coupling and deprotection steps, SPPS permits the parallel synthesis of multiple ATC-oligomers in a more convenient way than a solution phase strategy. Thus, ATC5-3-NH2 was synthesized step-by-step on a Rink amide ChemMatrix resin, following the procedure optimized by Dr. Bonnel three years ago. [196] Each coupling is effective after one night, in NMP (20 mL per gram of resin), using two equivalents of Fmoc-ATC-OH monomer, 2.0 equiv. of DIC and 2.0 equiv. of OxymaPure©, in NMP (20 mL per gram of resin). Other coupling reagents, such as BOP, PyBOP, HBTU, HATU and T3P had previously been evaluated. All had resulted in an incomplete reaction (around 70% yield). In the case of ATC5-3-NH2, each coupling was monitored by a Kaiser test to detect the presence of free amines and was followed by an acetylation step. Deprotections of the Fmoc groups were performed in three times ten minutes in a 20% piperidine solution in DMF.

Cleavages were achieved, after acetylation of the N-terminal extremity by acetic anhydride, using a solution of TFA/TIS/H2O 95/2.5/2.5 vvv, for three hours (Scheme 16). The peptide was finally purified by RP-HPLC, with a yield of 15%. 2). The trimer ATC3-2-NHiPr and pentamer ATC5-3-NHiPr retained a good catalytic activity (yields = 98% and 93% respectively) associated with an excellent syn/anti selectivity (Table 16, entries 3 and 4). The asymmetric induction was significantly increased to 74% for the trimer ATC3-2-NHiPr and 77% for the pentamer ATC5-3-NHiPr. Finally, it can be noted that ATC5-3-NHiPr and ATC5-3-NH2 produced similar results, demonstrating no real impact of the C-ter capping (H or iPr) on the catalysis (Table 16, entries 4-5). and ATC3-2*-NHiPr (Table 16, entries 3 and 6), that the pyrrolidine configuration mainly orients the chiral transfer, with the latter catalyst, the ((R),(S)) enantiomer was obtained as major compound. Finally, a total loss of reactivity was observed with ATC3-2(OMe)-NHiPr, demonstrating the crucial role of the acid group in the catalytic activity (Table 16,entry 7).

These results showed a dependency of the diastereo-and enantioselectivity of the reaction within the oligomer length. This also suggested an impact of the secondary structure on the catalytic properties which remained to be demonstrated by exploring the conformational behaviour of the molecules.

IV. EVALUATION OF THE OVERALL FOLDING OF THE CATALYSTS

The structure elucidation of the oligomers described within this document is based on the interpretation of several spectroscopic methods. Among them, the nuclear magnetic resonance (NMR) and the X-ray crystallography (XRC), which enable to determine the structure on an atomic level, respectively in solution-and solid-state. This will be the object of the last chapter of this manuscript. However, some NMR observables and other complementary methods, such as circular dichroism (CD) or Fourier-transform infrared spectroscopy (FTIR), can be used to give qualitative information on the global folding of the molecules.

Characteristic structural markers for ATC-based helical foldamers

The aim of this paragraph is to give to the reader an overview of the structural markers related to the C9-helical folding of the ATC oligomers.

i. Circular dichroism

Studying macromolecules by circular dichroism allows obtaining information about their folding. Circular dichroism (CD) spectroscopy measures differences in the absorption of lefthanded polarized light versus right-handed polarized light, which arise due to structural asymmetry. Dichroic spectra may be difficult to interpret because the dichroic signature depends not only on the structure of the object, but also on the nature of the monomeric units of which it is composed. Thus, CD is probably the most rapid method for evaluating the folding of non-natural oligomers, including ATC-based γ-peptides, provided that the spectrum pattern must be carefully established based on high resolution structural data. The CD signature for the C9-helical folding of the ATC oligomers in solvents such as methanol and water was described in 2013. [103] Whatever the solvent considered, the CD spectra displayed two minima, at around 195 and 230 nm, and a strong maximum at 263 nm. The two minima were assigned respectively to the π-π* and n-π* transitions of the amide chromophore, while the maximum could be attributed to the thiazole core. We generally observe a blue shift for the n-π* transition (226 nm) in aqueous solution certainly resulting from a stronger solutesolvent hydrogen bond interaction and/or to the higher water polarizability. A molar ellipticity value per residue (mre) around 80 000 deg.cm -2 .dmol -1 is characteristic of the 9-helix (Figure 66). Representative CD spectrum for an ATC-oligomer folding in 9-helix [103] ii. Nuclear Magnetic Resonance structural markers Nuclear Magnetic Resonance (NMR) spectroscopy is the second method used to explore the folding properties of ATC-oligomers.

Sequential attribution of protons in ATC polypeptides is performed by the combination of multi-dimensional experiments providing homonuclear 1 H/ 1 H n J-couplings and heteronuclear 13 C/ 1 H n J-couplings (Table 17). [197,198] 197 Diehl, B., in NMR Spectrosc. Pharm. Anal., pp. 1-41 (Elsevier, 2008). 198 Wagner, G. et al., Eur. J. Biochem., 114, 375-84 (1981). In 2016, our laboratory published a study related to NMR structural markers for ATCcontaining molecules. [104] Among them, it was recognized that a high deshielding effect (δ > 9.0 ppm) constitutes a confident 1 H NMR observable, representative of an ATC NH engaged in a C9-intramolecular hydrogen bond. In the ATC C9-helix, only the N-terminal NH is not engaged in a H-bond and appears at δ = 8.0 to 8.5 ppm.

The 3 J(NH, γ CH) values constitute a second indicator of the C9-helical folding. The coupling constants can be derived from the 1 H (or from the 2D COSY [199] ). Vicinal coupling constants 3 J(NH, γ CH) are used for the deduction of the possible values for the torsion angle θ (H-N-Cγ-Hγ), using the Karplus equation:

3 J = A.cos 2 (θ) -B.cos(θ) + C
where A, B and C are empiric values (which differ depending on the authors [200,201,202] ). Usually, ). [203] When ATC-oligomers 199 Marion, D. et al., Biochem. Biophys. Res. Commun., 113, 967-74 (1983). 200 Cung, M. T. et al., Macromolecules, 7, 606-13 (1974). 201 Ramachandran, G. N. et al., Biopolymers, 10, 2113-31 (1971). 202 Bystrov, V. F., Prog. Nucl. Magn. Reson. Spectrosc., 10, 41-82 (1976). 203 Pardi, A. et al., J. Mol. Biol., 180, 741-51 (1984).

adopt the C9-helical folding, the φ angles are around -78°, making the 3 J(NH, γ CH) values in the range of 6.0 to 7.0 Hz.

iii. Mid infrared spectroscopy

Mid infrared spectroscopy is one of the most effective methods to establish the folding as well as the amide hydrogen bonding state in peptides and pseudo-peptide molecules. [204,205] The amide groups of polypeptides and proteins possess nine characteristic vibrational modes or group frequencies, named A, B, and from I to VII. [206] Three of them, Amide A, I and II are the most explored in the infrared spectra of proteins because these arise from the amide bonds that link the amino acids. [207] Frequencies of Amide A (mainly ν(NH)), Amide I (dominated by ν(CO)) and Amide II (mix of NH bending and CN stretching) vibrations, which are highly influenced by the state (free or bound) and the strength of hydrogen bonds involving amide groups, may provide unambiguous structural assignments of the H-bonding states of the oligomers. In peptides, as well as in ATC-oligomers, the Amide A band corresponding to the NH stretching is located between 3450 and 3200 cm -1 , making experiments in water or methanol usually quite hard to interpret as they strongly absorb in this spectral region. Nonetheless, the frequency associated with this band typically depends on whether the NH is involved in the establishment of an intramolecular hydrogen bond (absorption band around 3450-3400 cm -1 ) or not (around 3300-3250 cm -1 ). For example, a change in hydrogen bonding distance of only 0.002 Å shifts the wavenumber of the Amide A band of a polypeptide by approximately 1 cm -1 . [208] However, it was demonstrated, from the ATC-oligomers, a strong deviation of the molar absorption coefficient between the free and bound Amide A bands. Consequently, Amides A are not considered as quantitative markers of the H-bonding state of ATC-oligomers.

The absorption associated with the Amide I band is due to the stretching vibrations of the C=O bond of the amide, coupled with in-plane NH bending and CN stretching modes (Figure 69).

This band is located between 1800 and 1600 cm -1 . For instance, ν(CO) and ν(NH) are downshifted when hydrogen bonds are reinforced. Based on a careful comparison of ATColigomers and other 1,3-thiazole-containing molecules, it was established that a bounded ATC carbonyl leads to a ν(CO) ≈ 1618-1630 cm -1 , while a free carbonyl gives a band at ν(CO) > 1645 cm -1 . By contrast to Amide A, the Amide I bands in ATC-molecules are particularly relevant as the molar absorption coefficients are similar for the free and the bound C=O.

Decomposition of the spectrum into individual Gaussian functions and quantitative analysis of each contribution enables to estimate the number of carbonyls involved in a hydrogen-bonding pattern (Figure 70). Finally, the Amide II band, which corresponds primarily to the NH bending and CN stretching vibrations (Figure 69), is positioned around 1575-1480 cm -1 . If the band is shifted towards the highest wavenumber of the region, it implies that the proton of NH is involved in a hydrogen bond. However, since the Amide II bands overlap the stretching bands of the thiazole rings, they are not suitable to the study of the folding of ATC-based peptides.

Fourier Transform InfraRed (FTIR) brings structural indications but the resolution with such method is not always optimum, especially in the Amide I region, as that can lead to misinterpretation due to a superposition of the absorption bands. Consequently, FTIR experiments must be correlated with other spectroscopic techniques to provide a bundle of irrefutable structural markers.

Structural markers associated to the ATC-catalysts

i. Global folding of (47)

We started to explore the folding behaviour of the N-acetyl-ATC-carboxamide (47). We had hypothesized that the higher enantiomeric excess observed with the N-acetyl-ATC- Isopropanol was chosen as solvent because it was considered as the best one for the catalysis.

Circular dichroism signatures

All compounds shared comparable CD signatures with a strong positive band centred at 263 nm and a negative maximum at 232 nm. These signatures indicated that all sequences had adopted a similar conformational preference, consistent with the above-described right 9-helix structure for ATC oligomers. [104,209] As clearly visible on the1 H NMR spectrum of ATC5-3-NHiPr (Figure 72, A), we observed strong NH deshielding (> 9.8 ppm) as well as 3 J(NH,  CH) values ≈ 6.5 Hz (Figure 72)

previously recognized as a structural marker related to the formation of the poly-ATC C9-helix pattern. [104,107] The less deshielded proton was attributed to the N-terminal ATC NH, an indication that this hydrogen was not engaged in such hydrogen bond network. Similar NH behaviours were observed for the trimer ATC3-2-NHiPr.

On the ROESY spectrum of ATC5-3-NHiPr (Figure 72,B), canonical correlations between the Hγ of the residues i and the NH of the residues i+1 were detected. Some other correlations between Hγ of the residues i and the protons of the lateral chains worn by the thiazole rings of the residues i+1 were also observed (Figure 72,C). Once again, these features, also appearing on the ROESY spectrum of ATC3-2-NHiPr, are characteristic of a C9-helical structure. In the case of ATC5-3-NH2, we observed one major conformer and two minor species contributing to 82 %, 16% and 2%, suggesting that ATC5-3-NH2 is more dynamic than ATC5-3-NHiPr. However, as for the other oligomers, most of the amide protons were highly deshielded which was consistent with the previously set hypothesis of intramolecular hydrogen

Fourier transform infrared indicators

It was decided to conduct FTIR experiments on ATC-oligomers in isopropanol at room temperature. Considering that the Amide I frequencies (1600-1800 cm -1 ) were formerly recognized as structural markers of the C9 H-bond network for ATC-containing oligomers in a previous work performed in the laboratory, [104,107] thus, we focused our efforts on the interpretation of signals in this area.

In the 9-helix model, oligomer ATC5-3-NH2 should display five bounded CO corresponding to the acetyl group and to ATCs 1-4 and two free carbonyls resulting from the ATC 5 and the acid lateral chain COOH. In addition, since ATC5-3-NH2 was obtained as a salt, a band corresponding to the carbonyl of the TFA was also expected.

The FTIR spectrum exhibited three absorption components in ν(CO) region (Table 18). The shoulder contribution at 1705-1710 cm -1 is tied to the free acidic lateral chain as reported in the literature. [210] Based on the C9-helix model and on our previously reported studies on ATC 210 Max, J.-J. et al., J. Phys. Chem. A, 108, 3324-37 (2004).

CHAPTER 3: CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 118 oligomers, [104,107] the band at 1674 cm -1 should correspond to a combination of the C-terminal carboxamide (ATC 5) and of the TFA counter ions. [211] Finally, the low frequency band at 1631 cm -1 was attributed to five bounded CO, i.e. the acetyl group at the N-terminus of the sequence, as well as to the four carbonyls of ATCs 1-4, which are engaged in the H-bond network. After deconvolution of the spectrum into individual Gaussian functions (Table 18), the experimental ratio of free and H-bonded NHs was 3/5 in accordance with the C9-helix model. In conclusion, all the CD, NMR and FTIR data were consistent with the folding model. Despite that, based on 1 H NMR spectra, ATC5-3-NH2 appeared more dynamic than the isopropylamide terminated counterpart ATC5-3-NHiPr, but should likely adopt the expected C9-topology. In addition, as previously underlined, the capping of the C-terminal extremity did not influence the reactivity nor the enantiomeric excess in the nitro-Michael addition reaction. Consequently, the following studies were performed on oligomers with a primary amide, being more readily available than the NHiPr homologues.

V. MODULATION OF THE POSITION OF THE CATALYTIC CENTRE

Synthesis of ATC-pentamers ATC5-P-NH2 (1 ≤ P ≤ 5)

We then explored the impact of the position of the catalytic NH2-{Pyrrolidine;propanoic acid}-ATC-OH residue along the sequence. The length was fixed at five ATC units. Thus, the oligomers, so called ATC5-1-NH2, ATC5-2-NH2, ATC5-3-NH2, ATC5-4-NH2 and ATC5-5-NH2, have a CO-NH2 extremity and can be prepared by SPPS, as previously presented (Scheme 16). After elongation and cleavage, each oligomer was purified using semi-preparative HPLC.

After lyophilisation, the five foldamers were isolated as TFA salts.

The modest yields obtained (around 15%) were explained afterwards by some difficulties encountered during the cleavage phase. In fact, we found out later that, after a cleavage of three hours in a solution of TFA/TIS/H2O 95/2.5/2.5 vvv, the resin was only partially cleaved.

Another cleavage was then performed on the resin, giving the possibility to recover as much product as obtained from the first cleavage; then yields were doubled.

Comparison of the catalytic properties with the position of the competent ATC moiety

The catalytic properties of all the oligomers ATC5-P-NH2 (with 1 ≤ P ≤ 5) were evaluated on the nitro-Michael addition reaction, using three different substrates: β-trans-nitrostyrene, trans-4-methyl-β-nitrostyrene and trans-4-methoxy-β-nitrostyrene. Based on the previous optimizations, all the reactions were performed at 4°C in isopropanol. Whatever the substrate considered, oligomer ATC5-3-NH2, in which the catalytic centre is in the middle of the sequence, led to the best yield after 16 h reaction (> 95%, Figure 76). We observed a slight decrease in the conversion speed when using the electron rich trans-4-methoxy-β-nitrostyrene as reactant, and especially for the ATC-oligomers bearing the competent moiety on another position other than the middle of sequence.

Finally, with the exception of the peptide ATC5-1-NH2, in which the catalytic ATC was positioned at the N-terminus, the asymmetric induction was almost similar for all the peptides (ee = 77-82%) demonstrating that the location of the active site along the backbone had little effect on the stereocontrol (Figure 76).

VI. CONCLUSION

As emphasised by the Wennemers' group, the catalytic activity is mainly guided by the average distance between the pyrrolidine and the Brønsted acid functions. Thus, the next objective was to study the impact of the relative position of the lateral carboxylic chain with respect to the pyrrolidine on the catalysis properties. Therefore, the next chapter will be dedicated to this exploration and of the effects driven by the modification of the microenvironment around the catalytic centre. All these oligomers shared the same CD signature as the previous synthesized oligomers, with a strong positive band centred at 265 nm and a negative maximum at 232 nm (Figure 78). The NMR NOE data sets as well as the FTIR spectra were similar to those described previously for ATC5-3-NH2. These are all presented in the supporting information (section VI, 10 to 12).

Consequently, we concluded that the C9-helical structure was conserved, regardless of the modifications applied. The catalytic activities of the three pseudo-peptides were compared to those of ATC5-3-NH2.

After a 16 hour reaction, M(1)-ATC5-3-NH2 led to only 45% yield with β-trans-nitrostyrene as substrate. This result was quite surprising since with p-methyl-nitrostyrene or p-methoxynitrostyrene, the conversions were almost quantitative. Nevertheless, in all cases the asymmetric induction remained lower than with ATC5-3-NH2 (Figure 79).

The separation of the acidic chain from the pyrrolidine provided two types of profiles. Whatever the olefin considered, the yields obtained with M(2)-ATC5-3-NH2 were around 94% and the enantiomeric excess varied slightly, from 59 to 63%. On the other hand, when the acidic chain was closer to the C-terminus (M(3)-ATC5-3-NH2), the yields were lower, (70 to 90%), but the asymmetric induction was higher, around 75% (Figure 79). Nonetheless, ATC5-3-NH2 still produced the best results in terms of conversions and enantiomeric excesses.

Local modifications of the remote lateral chains

In order to modulate the steric hindrance around the catalytic site, we planned to modify the nature of the side chains that are distant from the catalytic residue. Starting from the canonical ATC-helix, we built a 3D-model of the oligomer ATC5-3-NH2. This provided us with an insight about the lateral chains that share the same face of the helix as the catalytic functions (in red, Figure 80). Two of those chains are carried by the thiazole ring of the residues 1 and 5, the third one corresponds to the γ-lateral chain of the residue 2. Therefore, a series of mutated ATC5-3-NH2 oligomers was designed (Figure 81). The methyl groups of the thiazole rings of residues 1 and 5 were replaced by a branched aliphatic chain such as isobutyl, an aromatic substituent like benzyl, or a polar function like an amine or a butyl amine group. The benzyl group on the γ-chain of the ATCs 1 and 2 were also modified by and isobutyl or a methyl. The ATC-monomers used for those syntheses are the ones discussed at the beginning of this manuscript (Chapter II, 2). All the oligomers were synthesized following the SPPS approach previously described.

Removal of the steric hindrance induced by the benzyl lateral chains

Finally, we sought to remove all the possible steric interactions that could occur between the lateral chains. Thus, all the benzyl lateral chains were replaced by methyl groups. Following the same reasoning as the benzyl series, five oligomers with four identical ATC-monomers NH2-{CH3;CH3}-ATC-OH, and one catalytic centre NH2-{Pyrrolidine;propanoic acid}-ATC-OH were synthesized by SPPS, with the position of the catalytic centre varying along the pentameric structure (Figure 84). Eventually, we synthesized a trimer and a heptamer of this series, with the catalytic centre in the middle of the chain (Figure 84). The nitro-Michael addition reaction between cyclohexanone and the three defined nitroolefins was performed using these four latter oligomers as catalysts. At first, even though the number of catalytic moieties was higher than ATC5-3-NH2, it was decided to realize the reaction under the same conditions, with 10 mol% of oligomers. The reactivity for all four oligomers was, as expected, exceptional (Figure 89). On the other hand, the enantioselectivity did not rise with the number of catalytic moieties. Actually, it seems that the trimer and pentamer bearing solely the catalytic moiety obtained the worst results in terms of enantiomeric excesses (41 to 65%).

Regarding the oligomer bearing three catalytic residues, M(20)-ATC5-1,3,5-NH2, the enantiomeric excess was of about 71% (Figure 89). In contrast, the oligomer M(21)-ATC5-2,4-NH2, bearing only two catalytic moieties, presented a similar enantioselectivity than ATC5-3-NH2 (ee = 79%) (Figure 89).

nitro-Michael addition reaction using β-trans-nitrostyrene (R=H), trans-4-methyl-(R=CH3) and trans-4-methoxy-β-nitrostyrene (R=OCH3) and oligomers ATC5-3-NH2, M(18)-ATC3-1,2,3-NH2, M(19)-ATC5-1,2,3,4,5-NH2, M(20)-ATC5-1,3,5-NH2 and M(21)-ATC5-2,4-NH2 as catalysts

Finally, to evaluate the possibility of a cooperation, a kinetic study was performed using the pentamer M(19)-ATC5-1,2,3,4,5-NH2 at 10 mol% and at 2 mol%, which corresponds to a 5/10 a 1/10 ratio of ATC units with respect to β-trans-nitrostyrene. The kinetics were compared to the reaction catalysed by the pentamer ATC5-3-NH2 at 10 mol% (catalytic ratio ATC/β-transnitrostyrene = 1/10) (Figure 90). As represented in the figure above, when the catalyst bearing only competent moieties was used at 10 mol% (green), the reaction was nearly completed after 8 hours (yield = 93%). On the contrary, when 2 mol% were used (yellow), after 8 hours, the yield reached only 45%. This latest result was similar to using 10 mol% of ATC5-3-NH2 (purple), thus, catalytic moieties do not appear to act in a cooperative way, the activity is only correlated with the amount of catalytic function used for the reaction.

IV. CONCLUSION

On the one hand, the systematic evaluation of the twenty-six synthesized ATC-oligomers as catalysts for the nitro-Michael addition reaction between cyclohexanone and three different olefins permitted to demonstrate their activity in an enamine-type reaction.

Contrary to the expectations, it seems that the correlation between the sequence and the asymmetric induction is quite weak, as the enantiomeric excesses remained mostly greater than 75% but reached their maximum around 80%. On the other hand, the catalytic activity appears highly interrelated with the remote lateral chains, especially when the lateral chains are modulated on the N-terminal extremity. Even if these effects are not totally understood, this is Finally, low resolution circular dichroism and FTIR spectroscopies provided clues for the overall folding of the oligomers. Some NMR data have also corroborated the helical topology generally associated with ATC-oligomers. Nevertheless, structures at the atomic level have not been discussed yet. Therefore, the next chapter will be devoted to the description of the simulated annealing protocol that we used to generate 3D-models from NMR restraints. Some of the obtained structures in the solution state were then compared to crystallographic data.

CHAPTER 5:

STRUCTURE DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS

Due to the NMR studies, we imposed experimental restraints and, using the software AMBER16 [212] , performed NMR refinements by simulated annealing. A part of my thesis consisted of improving the method of 3D-model generation by NMR refinement. The way to computationally build oligomers was modified as well as different force fields were applied to the models. Details of this research and enhancement will be explained in the following paragraphs.

I. GENERALITIES ON NMR REFINEMENT

It is now well established that three-dimensional structures of small proteins can be determined using a combined approach of multidimensional NMR spectroscopy and computational techniques. [213,214,215] Developments in NMR methodology make it possible to extract a large number of structural information, including estimations of interproton distances and vicinal scalar coupling constants. Most internuclear distance constraints come from NOESY data, while scalar coupling constants are more useful for confirming secondary structural features. 214 Clore, G. et al., Science, 252, 1390-99 (1991). 215 Gronenborn, A. M. et al., Proteins Struct. Funct. Genet., 19, 273-76 (1994). Molecular dynamic (MD) simulations provide the means to solve the equation of motion of the particles to obtain trajectories for the molecular system. The Newton equation of motion for a molecule consisting of N atoms is:

Structure analysis and validation

𝑚𝑎 𝑑 2 𝑟 𝑖 𝑑𝑡 2 = 𝜕 𝜕𝑟 𝑖 𝑈[𝑡|𝜎(𝑟 1 , … , 𝑟 𝑁 )]
where 𝑈[𝑡|𝜎(𝑟 1 , … , 𝑟 𝑁 )] is the potential energy at the moment t, for the complete set of 3N atomic coordinates. The basic functional form of potential energy includes bonded terms for interactions of atoms that are linked by covalent bonds, and noncovalent terms, that describe the long-range electrostatic and van der Waals forces. Because each interacting force depends on the atoms involved and the environment, the potential must be adapted locally. The force fields define a set of parameters for different types of atoms, chemical bonds, dihedral angles, and so on. The parameter sets are usually empirical but can also be derived from ab-initio calculations.

In MD, the presence of kinetic energy allows the molecule conformations to cross potential surface barriers. In structural determination of peptides and pseudo-peptides, MD is usually combined with simulated annealing (SA) protocols. The kinetic energy provided in terms of temperature defines the maximum height of energy barrier that can be overcome in MD simulations. During the SA calculations, temperature is varied along the MD simulation to illustrate a broad conformational space of the molecule. In a second step, the molecule reaches its minimum energy configuration by slow cooling. To consider the experimental data, a hybrid energy function is defined that incorporates the potential energy function combined with an appropriate force field and NMR structural restraints as pseudopotential energy terms.

One could conclude that there is no single recipe to the "best NMR refinement" since it is highly correlated to quality and interpretation of the NOE data set, the force field optimisation and of common sense, trials and errors.

Eventually, based on the ROESY spectra, NOE cross-peaks were integrated and assigned within the NMRView software. [216] The signal intensity (Iij) depends on the distance r between two nuclei i and j. Therefore, distances rij by r -6 averaging were obtained using these integration 216 Johnson, B. A. et al., J. Biomol. NMR, 4, 603-14 (1994).

values. Comparison was made with an integrated known reference distance rref using the following equation:

𝑟 𝑖𝑗 = 𝑟 𝑟𝑒𝑓 * ( 𝐼 𝑟𝑒𝑓 𝐼 𝑖𝑗 ) 1/6
Distances obtained were grouped into three classes and each of them is defined by an upper and a lower bound of distance.

II. 3D-MODELLING UNDER NMR RESTRAINTS

Method 1: Simulated annealing protocol and limitation of the NMR refinements

The first methodology used to generate 3D-models of our oligomers was based on previous 3D modelling studies performed before my arrival within our team. The ATC-oligomers were built using Maestro [START_REF] Maestro | Schrödinger Release 2019-1[END_REF] and UCSF Chimera [START_REF] Pettersen | UCSF Chimera -A visualization system for exploratory research and analysis[END_REF] and the parameter files were generated using the General AMBER Force Field, so called GAFF. The reference for the volume of a NOE was taken between methylene pair protons (1.8 Å). The lower bound for all restraints was fixed at 1.8 Å and upper bounds at 2.7, 3.3, and 5.0 Å, for strong, medium, and weak correlations, respectively. Structure calculations were performed with AMBER 16 [212] in two stages: cooking and simulated annealing (SA) in vacuum. The cooking stage was performed at 1000 K to generate 100 initial random structures. SA calculations were carried during 20 ps (20,000 steps, 1 fs long). First, the temperature was raised quickly and was maintained at 1000 K for the first 5000 steps, then the system was cooled gradually from 1000 K to 100 K from steps 5001 to 18,000. Finally, the temperature was brought to 0 K over the 2000 remaining steps. For the 3000 first steps, the force constant of the distance restraints was increased gradually from 2.0 kcal.mol -1 .Å -2 to 20 kcal.mol -1 .Å -2 . For the rest of the simulation (step 3001 to 20,000), the force constant was kept at 20 kcal.mol -1 .Å -2 . The calculations were launched on the Hawkins, Cramer, Truhlar (HCT) form of pairwise generalized Born model for solvation. [217] The 20 lowest energy structures with no violations greater than 0.3 Å were considered as representative of the oligomer structure. The representation and quantitative analysis were carried out using MOLMOL [218] and UCSF Chimera.

Using the integration of the observed NOE cross-peaks, three major restraints between NHi and NHi+1, Hγi and NHi+1, and, Hγi and Hτ1i+1 were set as weak, strong and weak, respectively. In addition to this basic set, we also included, when visible on the NOE spectrum, some weak restraints between the γ-lateral chains of the residue i and the lateral chains born by the thiazole ring of the residue i+1. In the case of ATC5-3-NH2, the 20 structures of lowest energy converged towards the expected C9-helix with a Root-Mean-Square Deviation (RMSD) of 1.175 Å (Figure 92). The dihedral angle values were consistent with those expected for the canonical 9-helix. However, we can observe that some dihedral angles were somewhat shifted from the expected canonic C9-helix values (Table 19). 4) and the barycentre of the two H from NH2 on the C-terminus However, starting from the same set of NOEs, some oligomers did not converge towards the helical shape. As a representative example, M(10)-ATC5-3-NH2 led to a rotation around two dihedral angles (Figure 93), hence the well-established C9 hydrogen-bonding pattern was unbalanced (Table 20). The first issue we addressed was wether this result disproved our well-defined C9-helical structure hypothesis, or that it resulted from a bias due to the simulated annealing procedure.

According to the first hypothesis, we should have observed more NOE cross-peaks, especially between ATC-lateral chains around the flip, though this was not the case. Consequently, two other options were considered:

1.

A possible over-estimation of some NOE cross peaks, leading to a misfolding of the oligomers.

2.

An incorrect setting of the applied force field.

Variation of the NOE restraints

As previously mentioned, while NMR refinements usually works fine, the quality of the results is highly dependent on interpretation of the NMR data. One major limitation with NOESY-NMR is the fact that only an average distance over time is measured meaning that experimental observations are thus driven by population statistics. Significant fluctuation of internuclear distances between non-sequential 1 H nuclei on the NOESY timescale is likely to be found within peptide foldamers. Consequently, calculation of distances from NOE cross-peaks can give the wrong impression of a fixed distance but still might be used to describe the conformational behavior of the molecule in solution. A cautious analysis is thus required to select the relevant NOE cross-peaks associated with a single conformational cluster. In the worst case, a set of NOE cross-peaks observed in an unstructured foldamer may map to a single incorrect structural interpretation, resulting in spurious conclusions.

CHAPTER 5: STRUCTURE DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 149 Therefore, to explain the differences in the calculation outcomes, we hypothesized that some of the restraints could be irrelevant and/or overvalued. Therefore, we decided to categorize restraints in two sets: the "mandatory" and the "optional" restraints.

From the past observations, we noticed that the NOE cross-peaks between Hγi and NHi+1 and the ones corresponding to NHi-NHi+1 were necessary for the establishment of the helical structure so these two were classified as "mandatory" restraints. Usually, the distances between Hγi and NHi+1 are below 2.7 Å and the ones corresponding to NHi-NHi+1 are greater than 3.3 Å, this can be verified on the NOESY experiments. Furthermore, NOE cross-peaks between Hγi and Hγi+1 are not always visible so this restraint was categorized as "optional" and is set above 3.3 Å (Figure 94A). In some cases, other correlations could be found, between Hγi and Hδi+1 for instance, or between Hγi and the protons carried by the lateral chain of the thiazolering of the residue i+1. Cross-peaks can also be integrated between protons in position δ or further along the gamma lateral chain of the residue i and the protons carried by the lateral chain of the thiazole-ring of the residue i+1. All these restraints were categorized as "optional"

(Figure 94B). Eventually, a systematic generation of the foldamer 3D-models was performed with one parameter being changed after another, as represented in the Table 21 for the foldamer M(10)-ATC5-3-NH2. Values filling this table correspond to the values set in the script for the generation of the structure. "o" indicates "off", where no restraint were imposed between the two atoms, "w" is for "weak", the value is set at 5.0 Å, "m" for "medium is fixed at 3.3 Å and "s" for "strong" at 2.7 Å. Some restraints had a penalty of "+1" applied to them because several protons were in competition (e.g. Ac-1.NH: "s+1" as there are 3 hydrogens on the acetyl group and if we had restrained the distance at "s" only, it would have locked an equal distance for the three protons while they are not equidistant to the amide hydrogen and the restraint would then have been too restrictive). Each number in italics corresponds to the residue numbers along the chain, from the N-to the C-terminal extremity. In entry 1 all the observed NOE cross-peaks have been considered. In entry 2, we added some optional restraints between lateral chains. In entries 3 to 6, we kept open the mandatory restraints and closed each of the optional ones. These changes of parameterization have led to new structures (Table 21). One can see that by adding restraints between lateral chains, the structure seems to converge more towards the 9-helix (Table 21, entry 2). On the other hand, when removing restraints observed in the ROESY spectrum, the structures became less well organized (Table 21, entries 3 to 5). Also, when only "mandatory" restraints were taken into account (Table 21, entry 6), the structre became a lot more compact and the canonic C9-helical structure was not observed.

Therefore, eventhough the structure tends toward a C9-helix, the "mandatory" set is not enough on its own to provide the canonic C9-helix, the "optional" restraints must be taken into consideration as well. It seems that all the observed NOE cross-peaks are relevant and therefore should be taken into consideration during the generation of the 3D-sequences.

As the hypothesis of a misinterpretation of the NOE cross-peaks was lifted, we decided to focus on the applied force field. Indeed, as we were working on pseudopeptide oligomers, one could argue that the applied force field was not relevant for such structure. Indeed, a significant challenge in the use of computation to study pseudo-peptide systems is force-field accuracy.

Setting the force field

Force fields are composed of a molecular-mechanics energy function with empirical parameters, which are typically obtained from fitting to experimental or high-level quantum mechanical data. These approximations may lead to inaccuracies in calculated kinetic and/or thermodynamic properties. AMBER force fields such as ff99SB have a good reputation in the study of proteins and nucleic acids. However, they are not suitable for other organic molecules.

A general set of parameters to allow simulations for small organic molecules is provided by the General AMBER Force Field (GAFF). Compared to the traditional AMBER force field, atom properties in GAFF include element type, hybridization, aromaticity and chemical environment for most of the organic chemical space. [219] Parameters exist for almost all the molecules made of C, N, O, H, S, P, F, Cl, Br, and I, and are compatible with the AMBER functional forms. The partial atomic charges are derived by fitting the gas phase electrostatic potential calculated at the Hartree-Fock 6-31G* level. GAFF also includes parameters for bond lengths, bond angles and torsional angles. Classically, recognition of the atom and bond types as well as assignment of the atomic equivalence and of the force field parameters is automatically performed by Antechamber, a set of auxiliary programs for molecular mechanic studies. However, this General Amber Force Field is known to be efficient for molecules up to 100 or 200 atoms. The problem for bigger molecules is that a quantum calculation is needed to obtain partial charges 219 Wang, J. et al., J. Comput. Chem., 25, 1157-74 (2004). In contrast to the previously explained method (Method 1), the atomic charges were calculated independently for each monomer using GAFF. We also intended to optimize the force field for the ATC monomers, using high-level quantum mechanical method for charge assignments (Method 3). The three methods used to generate the AMBER parameter files is depicted in Figure 95.

Generation of ATC monomer 3D-structures

The 3D-structures of ATC-monomers were generated using the USCF Chimera software. The dihedral angle values were defined from the ATC oligomer crystal structure CCDC 922304

(Table 22 and supporting information, section IX). [103] Each ATC was capped using an acetyl group (called Ace) at the N-terminus and an N-methylamide (Nme) at the C-terminus, resulting in Ace-ATC-Nme. This was done to mimic the environment of an oligomer backbone for an ATC-monomer.

Application of the GAFF force field on the ATC monomers and generation of the AMBER file t ypes

To generate the Amber model parameter file types such as '.prepin', '.inpcrd', '.frcmod', '.pdb' and '.prmtop', we used the LEaP program. LEaP is an Antechamber module that collects parameters in order to make a complete description of a molecule. Each of the parameter files generated by LEaP contained pieces of information needed for the construction of a simulation, whether for energy minimization or for molecular dynamics. For instance, the '.inpcrd' and '.prepin' files hold initial coordinates and periodic box size.

Datasets of new parameters assigned for the ATC building-blocks are consigned in '.frcmod'.

The '.prmtop' regroups all the informations as it contains the molecular topology, force field, atom and residue names. '.mol2' files and used as input files. In lines 5 to 14, the force field GAFF ff99SBnmr was applied using antechamber, generating four out of the five parameter and coordinate output files needed for the rest of the process. Line 16 permitted to generate the '.pdb' file from the '.prmtop' (Figure 98). A second script was then used to remove the acetyl and amine capping groups from the parametrized Ace-ATC-Nme monomer (Figure 102). The output files could then be used as an ATC library to generate an oligomer sequence. For the method 3, it was decided to perform an intermediate step where the electrostatic potential was taken into consideration to generate atom charges on ATC-monomers (Figure 100). Force field libraries for ATC fragments were generated using the restrained electrostatic potential (RESP) method. [220] After having locally optimized the geometry, the atom charges

were derived from the electrostatic potential obtained by DFT calculations with Gaussian 09 [221] at the M062X/6311++g(d) level of theory in vacuum (See SI, section VI, 31). The M06-2X is a global hybrid functional, meaning a class of approximations to the exchange-correlation energy functional in density functional theory, that has shown good performance in predicting noncovalent interactions of small molecules and structures and relative stabilities of biological compounds such as peptides. [222] 220 The basic structure of a Gaussian input file includes several different sections:

# M062X/6-311++g(d) geom=connectivity Method and basis set that specifies the model chemistry used.

Pop=MK iop(6/33=2) iop(6/42=6) iop(6/50=1)

Calculated molecular properties:

Pop refers to the atomic charges while MK refers to the Merz-Singh-Kollman method. [223] iop values define the resolution of the charge distribution calculated around the molecule. 223 Singh, U. C. et al., J. Comput. Chem., 5, 129-45 (1984). The script, which had been edited to remove the extremities of the monomer, was then used. In the generated ".pdb" file, verification could be performed to ensure that the extremities were removed on the ATC-monomer and that the nomenclature of the atoms had remained the same as the one that had been implemented at the beginning of the process (Figure 102).

Amber parameter files

Whatever the methods 2 or 3 considered, ATC-sequences were generated by the assembly of ATC-residues (Figure 102). Again, we developed a special script to link the ATC monomers (Figure 103). The parameter files for each ATC residue were entered in the lines 9 to 24 of the script. The oligomer sequence defined in line 29 was constructed using LEaP. Finally, the related '.prepin', '.prmtop' and '.inpcrd' AMBER files that were to be used in the simulated annealing protocol were generated. to the C9-helix with method 1. However, by looking at the structures, one could not conclude regarding the differences and improvements between methods 2 and 3. RMSD values were lower using Method 2, meaning a higher convergence in the calculated structures than with Method 3. However, using Method 2 we observed a significant deviation from the canonic C9-helix dihedral angles (values in red). In contrast to Method 2, for Method 3, the average dihedral angles were completely consistent with the establishment of a 9-helix structure (Table 24).

Table 24: Comparison of dihedral angle values obtained for the 20 best structures obtained after NMR refinement for foldamers ATC5-3-NH2, M(10)-ATC5-3-NH2 and M(1)-ATC5-3-NH2 built with monomers created with or without ATC-optimized GAFF

Canonic C9-helix -78° +127° 0° -41° Oligomer Method a Res. b φ (°) θ (°) ζ (°) ψ (°) H-bond c (Å)

ATC5-3-NH2

Method 2 GAFF -73.5 ± 36.1 120.8 ± 12.6 -9.6 ± 3.4 -23.8 ± 10 In summary, the procedure could be divided into 8 steps:

1

• Design of ATC-monomers using dihedral angles found on an ATC-monomer crystal (Software UCSF Chimera)

• Assignment of atomic charges by DFT calculations at the M062X/6311++g(d) level of theory (Gaussian)

• Generation by Antechamber of the AMBER parameter files for each ATC monomer by combining the atomic charges obtained by DFT and the other atom properties as defined in GAFF ff99SBnmr (AMBER16)

• Construction of the oligomer sequences using LEaP (AMBER16)

• Introduction of the distance restraints resulting from the study of the NMR spectra and NOE cross-peaks (TopSpin and NMRView)

• Cooking and simulated annealing in vacuum of each oligomer (AMBER16) 25). Its folding is defined by an intramolecular hydrogen-bonding pattern found between the carbonyl of the residue i and the proton amide of the residue i+2, the C9-helix seems preserved in both states.

As previously described (Chapter 4, I and SI, VII and VIII), the folding is perfectly consistent with the data obtained by CD and FTIR. Ultimately, Method 3 was used for the structural determination of other catalytic ATColigomers as it had been recognized as being the most relevant method for their 3D-modelling.

Structures according to the position of the catalytic residue

We first solved the structures of ATC5-2-NH2, ATC5-3-NH2, ATC5-4-NH2 and ATC5-5-NH2.

Whatever the position of the catalytic residue along the backbone, the oligomers displayed the same 9-helical structure (Figure 107). Once again, these results were in accordance with the FTIR and CD data. In the case of ATC5-1-NH2, the structure was not solved since it precipitated into iPrOH, making the NMR study impossible. Nevertheless, based on FTIR and CD experiments, it was assumed that it adopted the same overall folding as the other oligomers.

Limitations of the method

As presented previously, M(1)-ATC5-3-NH2 displayed the same C9-helical folding in both the solution and the solid state. The two oligomers, M(2)-and M(3)-ATC5-3-NH2, in which the catalytic pyrrolidine and the carboxylic acid are born by two different ATC monomers, also folded into a C9-helix. However, the backbones curved around the 3 rd residue (Figure 108). A careful analysis of the dihedral angles of M(2)-ATC5-3-NH2, presented in the supporting information (section VI, 34), showed that φ of residue 3 was equal to -12.8 ± 30°. This value is far from the expected -78° for a canonic C9-helix. However, a variation around the 3 rd residue was confirmed by looking at the coupling constant 3 J(NH, γ CH), which was of 4.7 Hz, instead of 6.0-7.0 Hz in other oligomers (SI, section VI, 11). In addition, analysis of the 20 lowest energy structures calculated from NMR data suggests some labilities of the C9-H bond around ATC 3. This is in agreement with the FTIR data (SI, section VIII), in which the contribution of bound CO (50% of all the C=O) is lower than those expected (62.5% of all the C=O). It is actually unclear whether the folding dynamic around ATC 3 could explain the observed decrease of the enantiomeric excess (ee < 70%) in the nitro-Michael addition reaction catalysed by M(2)-ATC5-3-NH2.

In M(3)-ATC5-3-NH2, the dihedral angle φ of ATC 3 also differed from the expected -78° (-34.5 ± 27.4°). The coupling constant 3 J(NH, γ CH) was measured at 7.6 Hz, meaning that this angle should be around -87°. In the same manner, M(8)-ATC5-3-NH2 had its ATC 3 dihedral angle φ at -34.7 ± 72.6°, moreover, its 3 J(NH, γ CH) was measured at 7.8 Hz. In those cases, the comparison between the coupling constant of this residue 3, associated with its dihedral angle φ, is not relevant for the expected models. We believe that we might have reached the limitations of the method and that the observed coupling constant would not reflect a single conformational state but more a dynamic one around the ATC 3.

Structural validation of other M(X)-Mutant oligomers

Eventually, other ATC-oligomers were studied using 3D-modelling and M( 5)-, M( 9)-and M(10)-ATC5-3-NH2 were fully consistent with the canonic C9-helix (Figure 109). Furthermore, trimer M( 16)-ATC3-2-NH2, pentamer M( 13)-ATC5-3-NH2 and heptamer M( 17)-ATC7-4-NH2 adopted the same 9-helical structure, regardless of the length of the oligomer (Figure 110). In the figure it might be challenging to visualize perfectly the shape of this helix on the trimer, however, it really folds into a well-defined 9-helical structure even though, in such a case, the helix is only one turn long. Finally, the last four oligomers (M( 18)-to M(21)-), which bear several catalytic ATC residues did not entirely converge towards the C9-helix (Figure 111). In fact, the definition of the ROESY spectra of these four oligomers was not sufficient to provide substantial NOE crosspeaks and most of them overlapped, making them almost impossible to integrate. Hence, these models probably cannot fully reflect the structures of these molecules.

IV. CONCLUSION

During this whole project, it was quite challenging to investigate the relationship between the structure and the catalytic activity. However, in this last section, I will try to provide some elements to enable the correlation of the obtained results to some extent.

In fact, the X-ray structure of oligomer M(1)-ATC5-3-NH2 provided information regarding the distance between the pyrrolidine NH and the carboxylic acid, being of about 7.1 Å (Figure 112). In contrast, it seems that Wennemers tripeptide H-D-Pro-Pro-Glu-NH2 is quite flexible. In fact, from the crystallographic data provided by Wennemers et al., it appeared that the distance between the nitrogen of the 1 st proline and the oxygen of the carboxylic acid was of 9.9 Å (structure in green, Figure 113,A).

On the other hand, a conformational exploration of the peptide along the reactional pathway lead by DFT calculations [184] permitted to observe that when the tripeptide was in presence of the substrates, a different conformation was adopted. Regarding the ATC-oligomers, there was not an obvious correlation between the pyrrolidinecarboxylic acid distance and the observed enantioselectivity in the nitro-Michael reaction (Table 26). Nevertheless, we can notice that for M(2)-ATC5-3-NH2, the enantiomeric excesses were lower for any considered substrate than for the other oligomers. This could have been due to a lack of flexibility between the chains and therefore the substrates might not have had a proper access to the catalytic site. If we have a close look at the 3D-models (Figure 114), we can observe that for M(2)-ATC5-3-NH2, the key functions were completely above one another, while for the other oligomers, these functions were not located on the same face of the oligomer. This could be a part of the explanation for the drop in enantioselectivity. In conclusion, it appears that the ATC-oligomers have less flexibility regarding their catalytic centre than the tripeptides proposed by Wennemers. This lack of adaptability could explain, to some extent, why the ATC catalysts were less enantioselective than their peptidic counterpart.

Hence, the distance and flexibility between the key functions appear to be of prime importance.

In 2016, our team reported a robust ATC synthesis pathway providing an easy way to modulate the lateral chains, either on the γ-carbon atom or on the thiazole core of the amino acids. These monomers were designed to exhibit a conformational limitation around the Cα and Cβ, blocking the angle ζ at about 0° to reduce the flexibility of the residue. Moreover, it was established that ATC monomers bearing a pyrrolidine on their thiazole ring and a carboxylic acid on their γlateral chain were able to catalyse enamine-type reactions and especially the nitro-Michael addition reaction. We were first able to prove that a rise of the structuration on an ATC monomer bearing catalytic functions was increasing the asymmetric induction in the reaction of cyclohexanone to β-trans-nitrostyrene. Therefore, the main objective of this project was to develop foldamers bearing a catalytic activity and observe the influence of their size and/or shape, on both, reactivity and enantioselectivity.

A large number of ATC-monomers was synthesized in solution, they differed in their lateral chains, either on their γ-lateral chain or at the position 2 of their thiazole ring. We then obtained, by solid phase peptide synthesis, twenty-six different ATC-oligomers which were tested on the nitro-Michael addition reaction of cyclohexanone to β-trans-nitrostyrene, p-methylnitrostyrene and p-methoxy-nitrostyrene. They showed a potential as catalysts. Yields were generally around 95% after 16 hour reaction, and the selectivity was towards the syn compound, regardless of the pyrrolidine configuration. For the pentamers, the enantiomeric excesses were around 79%. The modulation of the remote lateral chains displayed a chemoselectivity that we had not expected at the beginning of this project but demonstrated a substrate selectivity for some oligomers, mimicking some enzymes properties.

A study combining NMR, FTIR and circular dichroism permitted to evaluate the structural markers characteristic of the ATC-oligomers. This enabled to show that ATC-oligomers fold into a C9-helix, stabilized by hydrogen bonds between COi and NHi+2. NMR studies demonstrated that a high unshield of the amide protons (> 9 ppm) is associated with this structure, and FTIR experiments showed that the study of Amide I band was relevant to quantify the bounded and free carbonyls of the sequence. A study of the circular dichroism signatures confirmed to us the conformational stability of these oligomers.

Finally, the creation of a script pipeline for molecular dynamic associated with simulated annealing, based on the integration of NOE cross-peaks allowed to determine the structure of the foldamers on an atomic level. Moreover, an X-ray study of an ATC-oligomer proved that the C9-helix adopted by ATC-oligomers was conserved in a solid state.

Eventually, it was established that not only the length of the oligomer and the microenvironment around the catalytic centre influence the catalysis, but also the distance between the carboxylic acid and the pyrrolidine seems to play a role in the activity and the enantiomeric excess. It appears that a balance between flexibility and rigidity must be found within the catalytic functions.

Since ATCs are built around a thiazole ring, the scaffold can be modified for the construction of thiazolium containing oligomers that could be of value to design a new family of NHCorganocatalysts. The use of a coenzyme chimera in the form of an ATC building block to mimic thiamine diphosphate dependent enzymes could be an interesting outlook for this project. In fact, the development of such a prosthetic strategy would offer a straightforward way to implement catalytic functionality into foldamer constructs. Thiazolium ATC analogues, also named ATzCs could be included in reverse-turns or twist-turns folded α-γ-α-α hybrid tetrapeptides. Their catalytic activities could, for instance, be evaluated on benzoin condensation and Stetter reaction.

Finally, it could be possible to study ATC-based systems that adopt a tertiary structure mimicking proteins, not only in terms of their structure but also in size. Therefore, a design of a true substrate-binding pocket represents the next challenge for the conception of an enzymelike catalyst.

I. INTRODUCTION ET OBJECTIFS DE LA THESE

Les contraintes environnementales, économiques et sociologiques actuelles invitent nos sociétés à repenser les structures et technologies de production afin de favoriser l'utilisation de ressources renouvelables, de proposer des procédés économes en énergie et de limiter la production de déchets. Dans un tel contexte, ces nouvelles exigences passent en particulier par la mise au point et l'exploitation de nouveaux systèmes catalytiques pour la chimie. L'une des approches pour développer ces catalyseurs verts consiste à s'inspirer de la nature pour inventer, en mariant biologie et chimie, des biocatalyseurs et des systèmes de catalyse dits biomimétiques ou bio-inspirés. [START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF] Ainsi, au cours des dernières décennies la détermination structurale d'un nombre toujours croissant de protéines a mis en exergue l'importance du contrôle conformationnel pour expliquer l'activité et la sélectivité des enzymes. En résumé, la structure est le support de l'activité. Actuellement, on compte plus d'une centaine de procédés industriels faisant intervenir des biocatalyseurs. Cependant, dans de nombreux cas, l'instabilité enzymatique limite leur utilisation et les enzymes doivent alors être remplacées par des catalyseurs artificiels, souvent moins sélectifs et parfois toxiques pour l'environnement. Aspirant à imiter l'efficacité enzymatique, un des objectifs actuels de la chimie vise à concevoir des catalyseurs artificiels reproduisant certaines propriétés de structure et de fonction des enzymes. Les peptides se sont révélés être des candidats prometteurs pour développer de telles plateformes de catalyse bioinspirée. Les méthodes combinatoires et le design de novo ont conduit à de réels succès pour une large variété de réactions, comme les résolutions cinétiques d'alcools, réactions d'aldolisation, de phosphorylation, d'addition de Michael, réactions de Morita-Baylis-Hillman, etc. [129] Toutefois, l'activité catalytique et la sélectivité de la réaction sont souvent limitées par la difficulté à contrôler précisément la topologie du catalyseur peptidique. Plus récemment, il a été proposé de construire des systèmes de catalyse bio-inspirée à partir de plateformes hautement structurées, appelés foldamères, différents des peptides et oligonucléotides que la nature n'a pas explorés, ni sélectionnés. [134,139,[START_REF] Maayan | Folded Biomimetic Oligomers for Enantioselective Catalysis[END_REF] Mon projet de thèse a concerné le développement de catalyseurs artificiels reproduisant certaines propriétés de structure et de fonction des enzymes. Nous avons ainsi cherché à mimer les éléments de structures secondaires des protéines, i.e. feuillet-β et hélice-α pour présenter de manière contrôlée en trois dimensions des éléments clés pour la catalyse.

Durant les années précédent mon arrivée, l'équipe que j'ai intégrée a décrit la synthèse et la structure d'une nouvelle famille de γ-aminoacides hétérocycliques contraints, des acides 4amino(methyl)-1,3-thiazole-5-carboxyliques, appelés ATCs (Figure 52). Ces monomères sont construits autour d'un thiazole afin de contraindre, aux alentours de 0°, la flexibilité de la liaison α C-β C. [103] De plus, ces monomères présentent l'avantage de pouvoir être modifiés en deux positions, sur leur chaine γ et en position 2 du thiazole. que la conformation en C9 avait été prédite par modélisation moléculaire par Hofmann et al. [START_REF] Baldauf | Helix Formation and Folding in γ-Peptides and Their Vinylogues[END_REF] pour des oligomères de γ-aminoacides Z-vinylogues, c'est-à-dire présentant une insaturation entre les carbones  et . Une hélice 7 avait aussi été proposée mais elle n'a pas encore été mise en évidence pour les ATCs. Il est possible qu'une interaction dipolaire ou une délocalisation électronique n→* entre les carbonyles et les thiazoles (Figure 116, A) orientent le repliement vers la formation de l'hélice 9. [142,143,144,146] Dans les années 1980, le groupe de C. Agami a démontré que ce type de mécanisme implique la formation d'un intermédiaire énamine. [149] Par la suite, de nombreuses études ont permis de démontrer que la L-Proline possédait la capacité de catalyser, de manière asymétrique, des réactions telles que les α-alkylations, réactions de Mannich, additions de Michael et α-aminations de cétones. [155,157] Schéma 1 : Réaction de Hajos-Parrish-Eder-Sauer-Wiechert [145] Ce type de mécanisme a été exploré par Houk en 2004 pour des réactions de cyclisations intramoléculaires d'aldols catalysées par la proline [145] et également étudié, la même année, par l'équipe de List. [147] Figure 117: a) Conformation de plus basse énergie pour la proline [173] . b) Etat de transition de la proline proposé par Houk et List [145,147] . c) Conformation de plus basse énergie du tripeptide de Wennemers. [171,173] d) Etat de transition pour l'addition 1,4 catalysée par le tripeptide de Wennemers [173] .

En 2005, l'équipe de H. Wennemers a identifié deux tripeptides H-L-Pro-D-Ala-D-Asp-NH2 et H-L-Pro-L-Pro-L-Asp-NH2 comme catalyseurs hautement efficace de la réaction d'aldolisation entre le nitro-benzaldehyde et l'acétone. [171] Il est intéressant de noter que les deux peptides conduisent à des énantiomères différents.

Dans un article de 2008, cette même équipe suggère que la distance entre la fonction acide carboxylique portée par l'aspartate et l'amine secondaire de la proline N-terminale puisse jouer un rôle majeur dans le contrôle réactionnel. [173] Dans le cas de la proline, cette distance est de 3,7Å tandis que pour le tripeptide, cette même distance est de 7.3Å (Figure 117) permettant d'envisager, outre des réactions d'additions de type 1,2 (réaction d'aldolisations), des additions de type 1,4.

Il a ainsi été démontré que les tripeptides H-D-Pro-Pro-Glu-NH2 ou H-D-Pro-Pro-Asp-NH2 sont capables de catalyser, de manière asymétrique, des réactions entre des aldéhydes et le nitroéthylène, utilisé comme accepteur de Michael [185] . Le meilleur résultat, avec une conversion ≥ 95% et un ee > 95%, a été obtenu après 15h à température ambiante avec 1mol% de H-D-Pro-Pro-Glu-NH2, 1mol% de NMM, 1,5 équiv d'aldéhyde et de nitro-éthylène à 0,1M dans le chloroforme. Les deux fonctions amine et acide sont nécessaires à l'activité : lorsque l'amine de la proline est acétylée ou méthylée, l'activité catalytique est perdue. De plus, la réactivité est diminuée lorsque l'acide carboxylique du tripeptide est substitué par un carboxamide.

Des études cinétiques ont permis de démontrer que la réaction de l'énamine (A, Schéma 2) avec l'électrophile est limitante et de suggèrer un double rôle de la fonction acide. Premièrement, elle orienterait la réactivité et la stéréosélectivité et, deuxiemement, la réaction serait accélérée du fait de la protonation de l'iminium nitronate (B, Schéma 2). [175,176] Un mécanisme alternatif a été proposé lorsque le catalyseur ne possède pas d'hydrogène acide (chemin orange, Schéma 2).

Schéma 2: Cycle catalytique proposé par l'équipe de Wennemers pour la réaction d'un aldéhyde sur une nitro oléfine [175] .

Comme nous l'avons vu dans cette succincte étude bibliographique, la proline mais aussi de petits peptides de séquence Pro-Pro-Glu ou Pro-Pro-Asp sont capables de catalyser des et peuvent servir à la construction de molécules plus complexes. [192,176] Schéma 3 : Structure générale du monomère catalytique

Synthèse des monomères d'ATC

La voie de synthèse très robuste développée par les Dr. L. Matthieu et C. Bonnel garantit l'accès à une large diversité d'ATC énantiopures, permettant de facilement moduler la nature des chaînes latérales décorant les oligomères. [189] La stratégie de synthèse repose sur l'utilisation d'un N-Fmoc-aminoacide comme précurseur

Evaluation des propriétés de catalyse du monomère d'ATC (46)

Schéma 6: NFmoc-{Pyrrolidine;acide propanoïque}-ATC-OCH3

Nous avons cherché dans un premier temps à explorer les propriétés de catalyse de l'ATC (46)

dans la réaction de nitro-Michael. Celui-ci a été obtenu à partir du N-Fmoc-ATC-OH (45i) par traitement au diazométhane et déprotection au TFA des chaînes latérales (Schéma 6).

Premièrement, nous avons évalué l'influence de la température et du solvant sur la conversion, la diastéréosélectivité syn/anti et sur l'énantiosélectivité pour la réaction d'addition de la cyclohexanone sur le β-trans-nitrostyrène (Schéma 7). La réaction a été effectuée avec 10 cyclohexanone déterminée par rotation optique and comparaison avec les données reportées dans la littérature [195] Dans le toluène à 30°C (entrée 1), la réaction a conduit à une conversion de 54%, une bonne diastéréosélectivité syn/anti de 95/5 et un excès énantiomérique, modeste mais significatif, de 27% en faveur du produit de configuration ((S),(R)). Afin d'améliorer la conversion ainsi que l'induction asymétrique, plusieurs solvants ont été testés. Le diméthylsufoxide, le chloroforme, le tétrahydrofurane, l'acétonitrile ou encore l'hexane (entrées 2 à 6) ont permis d'accroitre le taux de conversion jusqu'à 88%. Cependant, l'induction asymétrique n'a pas été significativement augmentée, plafonnant à 31%. Le méthanol (entrée 7) est le solvant pour lequel le taux de conversion obtenu a été le plus faible. Ce résultat est plutôt inattendu, d'autant plus que l'éthanol a conduit à une conversion de 98% et un excès énantiomérique de 34%.

L'étude des alcools comme solvant a donc été poussée et le solvant donnant les meilleurs résultats en termes d'induction asymétrique a été l'isopropanol (entrée 9) pour lequel, à 30°C, l'excès énantiomérique obtenu est alors de 41%. A plus basse température (4°C), le rendement a été légèrement amélioré (98%) du fait de moins de produits de dégradation. Par ailleurs, l'induction asymétrique a été augmentée à 45%.

III. INCORPORATION DES MONOMERES DANS DES OLIGOMERES

Le deuxième point abordé dans ce manuscrit a été l'étude de l'impact du contrôle conformationnel sur la chimio et l'énantiosélectivité.

Nous avons tout d'abord cherché à rigidifier le catalyseur en introduisant un groupement isopropylamide du côté C-terminal et un acétyle sur l'extrémité N-terminale (Figure 4). Dans une étude antérieure du laboratoire, [104] ces deux groupements s'étaient avérés compatibles avec l'établissement d'une liaison hydrogène intramoléculaire en C9. Alors que le composé (47)

semble moins encombré que le catalyseur (46) protégé par un Fmoc, l'induction asymétrique a été légèrement améliorée (ee = 52%). Néanmoins, alors que la conversion était excellente > 99%, la sélectivité syn/anti s'est avérée légèrement moins bonne (93/7).

Validation de la structure de l'oligomère

Après la synthèse du premier oligomère, il a été nécessaire de valider sa structure en solution.

En effet, un foldamère est un oligomère artificiel qui doit présenter une structure définie et Dans une seconde approche, nous avons envisagé de modifier la nature des chaines latérales et de moduler les contraintes stériques autour du centre catalytique. Les monomères utilisés pour la synthèse de ces foldamères sont ceux qui ont été présentés en début de ce résumé. Tous ces oligomères ont été synthétisés comme précédemment selon une approche SPPS. 33.4; 42.3; 47.3; 51.6; 53.6; 59.7; 66.8; 82.7; 113.5; 120 4.20 (t, J = 6.9 Hz, 1H); 4.24 (s, 2H); 4.29 (dd, J = 6.9 Hz and 3.3 Hz, 1H); 4.39 (dd, J = 6.9 7.76 (d, J = 7.5 Hz, 2H). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 26.9 (2C); 40.0; 42.3; 43.2; 47.5; 51.5; 66.8; 76.8; 83.2; 113.4; 120.1 (2C); 125. ). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 26.9 (2C); 27.1; 28.6 (3C); 29.6; 33.3; 40.3; 42.4; 47.4; 51.7; 66.9; 77.2; 78.8; 83.2; 113.5; 120 19.5; 22.3; 23.3; 25.1; 26.7; 26.8; 45.1; 47.4; 48.8; 66.7; 83.3; 113.5; 120.0 28.3 (3C); 31.1; 32.5; 47.5; 50.2; 66.9; 80.2; 83.3; 113.6; 120 To a solution of the thiazoline (9.14mmol) dissolved in 100ml dry THF, DMAP (9.141mmol, 1 equiv.) and TFAA (36.56mmol, 4 equiv.) were added. After cooling at 0°C, DIEA (77.7mmol, 8.5 equiv.) dissolved in 50ml dry THF was added drop-wise. After stirring at 0°C for 2 hours, 26.8 (2C), 28.3 (3C), 23.5 and 28.6 (3C), 31.4, 32.9, 34.0, 46.8, 47.5, 50.4, 59.4, 59.9, 67.0, 80.5, 80.7, 83.5, 113.7, 120.1 (2C), 123.6, 125.4 (2C), 127.2 (2C), 127.8 (2C), 141.5, 142.0 (2C), 144.1, 144.3, 156.0, 160.5, 161.3 (2C), 172.6, 179.3 ). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ ppm 23.3 and 24.0; 26.8 (2C); 28.3 (3C); 23.5 and 28.6 (3C); 31.4; 32.9; 34.0; 46.8; 47.5; 50.4; 59.4; 59.9; 67.0; 80.5; 80.7; 83.5; 113.7; 120.1 (2C); 123.6; 125.4 33.3, 41.5, 46.9, 47.3, 47.8, 50.4, 59.6, 67.0, 78.0, 80.5, 83.5, 113.7, 120.1 (2C), 124.0, 125.4 (2C) 7.4 Hz, 2H). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ =21.0; 22.7; 23.5; 26.6 (2C); 28.6 (3C); 33.4; 42.1; 46.8; 47.4; 51.3; 59.5; 66.8; 80.6; 83.2; 112.6; 113.5; 120.1 (2C); 125. Force field libraries for ATC fragments were generated using the restrained electrostatic potential (RESP) method. Atom charges were derived from the electrostatic potential obtained by DFT calculations with Gaussian 09 [221] at the M062X/6-31+G(d) level of theory in vacuum.

The computed electrostatic potential (ESP) was fit using RESP charge fitting in antechamber.

Structure calculations. [START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF] H chemical shifts were assigned according to classical procedures.

NOE cross-peaks were integrated and assigned within the NMRView software [216] . The volume of a ROE between methylene pair protons or ortho phenyl protons was used as a reference of 1.8 Å or 2.48 Å respectively. The lower bound for all restraints was fixed at 1.8 Å and upper bounds at 2.7, 3.3 and 5.0 Å, for strong, medium and weak correlations, respectively. Pseudoatoms corrections of the upper bounds were applied for unresolved aromatic, methylene and methyl protons signals as described previously. [213] Structure calculations were performed with AMBER 16 [212] in three stages: cooking, simulated annealing in vacuum and refinement in a solvent box. The cooking stage was performed at 600 K to generate 100 initial random structures. SA calculations were carried during 20 ps (20 000 steps, 1 fs long) as described elsewhere. First, the temperature was risen quickly and was maintained at 600 K for the first SUPPORTING INFORMATION S50 5000 steps, then the system was cooled gradually from 600 K to 100 K from step 5001 to 18 000 and finally the temperature was brought to 0 K during the 2000 remaining steps. For the 3000 first steps, the force constant of the distance restraints was increased gradually from 2.0 kcal.mol -1 Å to 20 kcal.mol -1 Å. For the rest of the simulation (step 3001 to 20 000), the force constant is kept at 20 kcal.mol -1 Å. The calculations were launched using the generalized born solvation model. The 20 lowest energy structures with no violations > 0.3 Å were considered as representative of the peptide structure. The representation and quantitative analysis were carried out using Ptraj and MOLMOL [218]. Res. 2 5.9

Nomenclature and torsion angles description

NMR analyses of ATC3-2-NHiPr

NMR analyses of ATC3-2*-NHiPr

NMR analyses of ATC5-3-NHiPr

Res. 3 6.9

Res. 4 5.6

Res. 5 6.5

NHiPr

7.4

Table S9 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in CD3OH at 293K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

NOE correlations Intensity

NMR analyses of ATC5-1-NH2

ATC5-1-NH2 precipitated in few minutes in deuterated isopropanol making NMR characterization impossible. < 3.3 Å, 3.3 Å < Weak (w). < 3.3 Å, 3.3 Å < Weak (w). < 3.3 Å, 3.3 Å < Weak (w). Res. 4 5.7

NMR analyses of ATC5-2-NH2

NOE correlations Intensity

NMR analyses of ATC5-3-NH2

NOE correlations Intensity

NMR analyses of ATC5-4-NH2

NOE correlations Intensity

NMR analyses of ATC5-5-NH2

NMR analyses of M(1)-ATC5-3-NH2

NMR analyses of M(2)-ATC5-3-NH2

NMR analyses of M(3)-ATC5-3-NH2

NMR analyses of M(4)-ATC5-3-NH2

Res. 5 6.8

NMR analyses of M(5)-ATC5-3-NH2

NMR analyses of M(6)-ATC5-3-NH2

The yield obtained for M(6)-ATC5-3-NH2 was too small to perform NMR analysis. We used all the compound for the nitro-Michael addition reaction tests. < 3.3 Å, 3.3 Å < Weak (w). < 3.3 Å, 3.3 Å < Weak (w).

NMR analyses of M(7)-ATC5-3-NH2

NMR analyses of M(8)-ATC5-3-NH2

NMR analyses of M(9)-ATC5-3-NH2

NMR analyses of M(10)-ATC5-3-NH2

NMR analyses of M(11)-ATC5-1-NH2

NMR analyses of M(13)-ATC5-3-NH2

NMR analyses of M(14)-ATC5-4-NH2

NMR analyses of M(16)-ATC3-2-NH2

NMR analyses of M(18)-ATC3-1,2,3-NH2

NMR analyses of M(19)-ATC5-1,2,3,4,5-NH2

NMR analyses of M(20)-ATC5-1,3,5-NH2

NOE correlations

NOE correlations

Script for NMR solution calculations

An example of the script used will be given here, of course, name of residues are arbitrary chosen here and the name of the folder in which files are saved are given for understanding of the script but can be renamed. 5/ Copy in Bureau/Julie the folder named "minimisation-igb1" containing file 5 empty folders named "init", "min", "prep", "sa1" and "sa2" and parametrizing files ("cook_heat.in", "min.in", "map.C71" and "sa.in", scripts will be given at the end of this procedure) "map.C71" -All the atom names must be generated, the script is quite long to cover every possible atom given, a specific selection could actually, a short example will be provided here.

  propres ailes. Pour ta confiance en moi, ta disponibilité et tes précieux conseils, je te suis grandement reconnaissante. Renata, toujours disponible et volontaire, je te remercie d'avoir accepté d'encadrer mon travail et de m'avoir accueillie occasionnellement dans votre laboratoire. Tous deux, vous m'avez permis d'acquérir de nouvelles connaissances, techniques et scientifiques, et vos qualités humaines n'ont fait que renforcer mon enthousiasme et mon envie de développer ce projet. Merci. Je tiens sincèrement à remercier les Docteurs Gilles Guichard et Grégory Chaume qui me font l'honneur d'être les rapporteurs de mon jury de thèse ainsi que le Professeur David Aitken qui a gentiment accepté d'examiner mon travail. I would like to address my special thanks to Doctor Michael Thormann who accepted to evaluate my work and who has always encouraged me through the years. I am looking forward to working with you again! Je remercie le Professeur Jean-Louis Bantigniès et David Maurin d'avoir pris le temps de m'accueillir au sein de leur laboratoire et m'avoir formée pour les acquisitions en spectroscopie infrarouge. J'adresse mes remerciements au Docteur Baptiste Legrand pour son implication dans les analyses structurales de nos oligomères.

Figure 1 :

 1 Figure 1: The twenty amino acids found in the standard genetic code

Figure 2 :

 2 Figure 2: Nomenclature of ATC-monomers

Figure 3 :

 3 Figure 3: Nomenclature of ATC-oligomers

Figure 4 :

 4 Figure 4: The four levels of protein structure

Figure 5 :

 5 Figure 5: Peptide bond, cis and trans conformations

Figure 6 :

 6 Figure 6: Ball and stick model of a polypeptide chain indicating the distances Cα-C, C=O and C-N and the rotations defined by the torsion angles of φ and ψ. Figure created with UCSF Chimera (University of California)[START_REF] Pettersen | UCSF Chimera -A visualization system for exploratory research and analysis[END_REF]

Figure 8 :

 8 Figure 8: A/Hydrogen bonds stabilizing a right-handed α-helix. B/An end view showing the coiled backbone as the inside of the helix and the side chains projecting outward. C/Macrodipole oriented to the δ -C-terminus towards the δ + N-terminus. Figures created with Maestro, Schrödinger software[START_REF] Maestro | Schrödinger Release 2019-1[END_REF]

Figure 10 :

 10 Figure 10: Antiparallel β-sheet versus parallel β-sheet

Figure 13 :

 13 Figure 13: β-turn connected by hydrogen bond between residue i and i+3

Figure 14 :

 14 Figure 14: β-turns type I and II

Figure 16 :

 16 Figure 16: A/Isomerism of the proline's amide link. B/Representative structure of a γ-turn with proline in position 2

Figure 20 :

 20 Figure 20: Peptoid helix from a homopolymer of N-(S)-(1-phenylethyl)glycine A/predicted by molecular mechanics, B/determined by solution-phase 2D NMR. C/N-aryl peptoid reverse turn. D/N-(S)-(1naphthylethyl)glycine based peptoid helix looking down along the helix axis. E/N-hydroxyamide sheet-likestructures determined by X-ray crystallography. F/alternating N-aryl/N-1-naphthylethyl peptoid ribbon structure[START_REF] Sun | Peptoid Polymers: A Highly Designable Bioinspired Material[END_REF]

Figure 21 :

 21 Figure 21: Nomenclature of carbons and dihedral angles on a β-peptide

Figure 22 :

 22 Figure 22: Possible substitutions for the β-amino acids

  type of stable secondary structure, the 12-helix, was discovered in 1997 by Gellman et al. who used a new pre-organized cyclic β 2,3 -amino acid (3) amino acid named trans-2aminocyclopentanecarboxylic acid or trans-ACPC (Figure 25, A). The cyclopentane ring restrains the value of θ at about -95°, appearing as favouring the 12-helix. The other dihedral

Figure 25 :

 25 Figure 25: A/Monomer of trans-ACPC (3) B/β-peptide of (R,R)-trans-ACPC (4) stabilized by hydrogen bonds i,i+3 C=O• • •H-N), C/Crystallographic structure of (4). D/Representation of the monomers repartition around the helical axis. E/Axial view N→C of (4)[START_REF] Cheng | β-Peptides: From Structure to Function[END_REF][START_REF] Appella | Synthesis and Structural Characterization of Helix-Forming β-Peptides: trans-2-Aminocyclopentanecarboxylic Acid Oligomers[END_REF]

Figure 28 :

 28 Figure 28: A/Analogue of cis-oxetane β-amino acid (8). B/β-peptide of the (8) stabilized by H-bond i,i+1 N-H• • •C=O

Figure 29 :

 29 Figure 29: A/(2R,3S)-3-amino-2-hydroxy acid residue (9), B/β-peptide of (9) stabilized by hydrogen bonds i-2,i C=O• • •H-N

Figure 32 :

 32 Figure 32: Nomenclature of carbons and dihedral angles on a γ-peptide and examples of its possible substitutions

Figure 33 :

 33 Figure 33: Most common hydrogen bonds in a γ-peptide

Figure 37 :

 37 Figure 37: A/Amino acid gabapentin, B/Oligomer (15) stabilized by hydrogen bonds i-2,i C=O• • •H-N, C/9-helix formed by (15), D/view of (15) down the axis[START_REF] Vasudev | C9 Helices and Ribbons in γ-Peptides: Crystal Structures of Gabapentin Oligomers[END_REF]

Figure 38 :

 38 Figure 38: Structure of (16) and tetramer (17) stabilized by hydrogen bonds i-2,i C=O• • •H-N

Figure 40 :

 40 Figure 40: Schematic and stereoscopic view of the crystal molecular structure of the cis-vinylogous tripeptide Boc-Ala-"Pro cis "-Ala-NH-Me with a DCM molecule joining the N-and C-terminal extremities[101]

Figure 42 A

 42 Figure 42 A/ATC-based γ-peptides (21) synthesized in solution, B/Representation of the intrahelical H-bonding pattern on hexamer (22), C/X-ray structure of (21b), D/Axial projection of the ATC-oligomers

Figure 43 :

 43 Figure 43: A/γ 4 -oligomer versus γ 4 -oligourea, B/Structure of heptaurea (23) stabilized by hydrogen bonds i,i+3 C=O• • •H-N and i,i+2 C=O• • •H-N'

Figure 46 :

 46 Figure 46: A/Helical wheel diagram of β-peptide (27) (left) and a cartoon showing β-peptide self-assembly (right; the partial protonation state shown is purely hypothetical) B/Retroaldol reaction of sodium 4-phenyl-4-hydroxy-2-oxobutyrate catalysed by (27)

Figure 48 :

 48 Figure 48: A/Cyclic β-amino acid pyrrolidine derivative APC, B/Foldamers to evaluate different APC diad geometries

Figure 49 :

 49 Figure49: Proposed catalytic cycle for the foldamer-catalysed crossed aldol reaction[137]

Figure 51 :

 51 Figure 51: A/Oligoureas foldamers (32a) the free H of the hexamer are circled in red, B/X-ray structure of (32a) along the axis, C/down the axis, D/Oligoureas foldamers (32b-e)

  -NH-{Rτ;Rγ}-ATC-OH. Chemset numbering is related to the lateral chains Rτ, Rγ, where Rτ corresponds to the substituent bore by the thiazole ring in position 2 and Rγ to the γ lateral chain. OH means that the acidic function on the C-terminal extremity is unprotected and PG-NH corresponds to the amine function on the N-terminal side, with its protecting group.

Figure 52 :

 52 Figure 52: General structure of an ATC-monomer

Figure 53 :

 53 Figure 53: A/Formation of a protonated enamine; B/Addition of the L-proline's zwitterionic form

Figure 55 :

 55 Figure 55: Proposed transition state for the diastereoselective Michael-addition of (E)-enamines to (E)-nitroolefins

a

  Enantiomeric excess determined by chiral HPLC, b Determined by 1 H NMR of crude mixture.In conclusion, following the pioneer work of Hajos, Parrish, Eder, Sauer and Wiechert, List's group opened the possibility of proline-based enamine catalysis. They demonstrated its potential for aldol-type condensation and nitro-Michael addition reactions. However, despite a worthy diastereoselectivity and regioselectivity in the addition of ketones to nitroolefins, the level of enantioselectivity was disappointing. Thus, different groups imagined using prolinecontaining peptides as an alternative to the low complexity of proline CHAPTER 2: INTRODUCTION OF A CATALYTIC FUNCTION ON AN ATC-OLIGOMER 84

Figure 57 :

 57 Figure 57: Peptides (35) to(38)

Figure 59 :

 59 Figure59: A/Wennemers's peptides(39). Proposed transition-state structures for B/(34) and C/(39) leading to enantiomeric syn products

  ), 1 mol% of NMM, 1.5 equivalent of aldehyde and nitroethylene in chloroform. Recently, Rigling et al. investigated the conformational preferences of H-D-Pro-Pro-Glu-NH2 (40) and its enamine intermediate (A) obtained by reaction with phenylacetaldehyde in a solution of CDCl3/CD3OH (9:1). [186] NMR data support the formation of a β-turn conformation with a H-bond between the carbonyl group of the D- Proline in position 1 and one amide proton of the C-terminal group. The side chain of the glutamic acid points towards the D-Pro-Pro moiety. Moreover, it was found that the enamine intermediate A also adopts a β-turn conformation, even though its overall folding appeared more flexible than H-D-Pro-Pro-Glu-NH2 (40). The higher flexibility of the glutamic side chain and of the backbone in A was suggested to be essential to handle the incoming nitroolefin, which would allow a very stereoselective C-C bond formation.

Figure 60 :

 60 Figure 60: H-D-Pro-Yaa-Glu-NH2 catalysts

Figure 62 :

 62 Figure62: Analogues of H-D-Pro-Pro-Glu-NH2 (40) bearing β 3 -amino acids[188]

Figure 63 :

 63 Figure 63: General structure of the catalytic ATC monomer

  Scheme 9: A/Short route for the synthesis of ATC-monomers. B/Synthesized ATC-monomers, yields are calculated from both bromination and Hantzsch cyclisation steps

Scheme 11 :

 11 Scheme 11: Access to Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OCH3 (46)

  bears a nucleophilic pyrrolidine and a Brønsted acid lateral chain. After a slight modification of the chemical procedure, we were able to prepare the catalyst on a multigram scale. We established its effectiveness on the nitro-Michael addition reaction of cyclohexanone and βtrans-nitrostyrene and optimized the reaction conditions. At 10 mol% of Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OCH3 (46) in iPrOH at 4°C, the 2-[2-Nitro-1phenylethyl]cyclohexanone was obtained in 98% yield with a selectivity towards the syn product (dr > 95:5) and an enantiomeric excess of 45%. The next step of the project was to introduce the catalytic monomer in ATC oligomers to explore how a folded γ-peptide environment may modulate the catalytic properties. CHAPTER 3: CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 99 CHAPTER 3: CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC POSITION OF THE COMPETENT ATC 101 I. NOMENCLATURE USED FOR THE ATC-OLIGOMERS Most of the oligomers described in this section alternate two ATC monomers, consisting on the Fmoc-NH-{Pyrrolidine;propanoic acid}-ATC-OH (45i) and Fmoc-NH-{CH3;Bn}-ATC-OH (45a). The sequences are named based on the following nomenclature: ATCL-P-X, where L is related to the length of the oligomer (3 for a trimer, 5 for a pentamer, and so on), P corresponds to the position along the chain of the ATC unit bearing the pyrrolidine group, from the N-Ter to the C-terminal extremity. X pertains to the C-terminal extremity (for example NHiPr or NH2).

Figure 64 :

 64 Figure 64: Illustration of this nomenclature

Figure 65 :

 65 Figure 65: Structured ATC-monomer (47), trimers ATC3-2-NHiPr, ATC3-2*-NHiPr and ATC3-2(OMe)-NHiPr and pentamers ATC5-3-NHiPr and ATC5-3-NH2

Scheme 13 :

 13 Scheme 13: Access to Ac-NH-{Pyrrolidine;propanoic acid}-ATC-NHiPr (47)

( 2 :

 2 Scheme 14: Synthesis of ATC3-2-NHiPr, ATC3-2*-NHiPr and ATC3-2(OMe)-NHiPr

  Scheme 15: Solution synthesis of ATC5-3-NHiPr

CHAPTER 3 :

 3 CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 109

Figure 66 :

 66 Figure 66: Representative CD spectrum for an ATC-oligomer folding in 9-helix[103]

  the ATC-oligomer folding is preferably described by the torsion angle φ (H-N-Cγ-Cβ) instead of θ (H-N-Cγ-Hγ). Though, the two torsion angles are linked by the equation θ = | φ -60 |. The graph relative to the Karplus equation for the φ (H-N-Cγ-Cβ) torsion angle is drawn Figure 67, using the values given by Pardi et al (A = 6.4, B = 1.4 and C = 1.9

Figure 67 :

 67 Figure 67: The empirically-derived Karplus relationship between the vicinal three-bond coupling constant 3 J(NH, γ CH)and φ

Figure 68 :

 68 Figure 68: Recurrent NOE cross-peaks in an ATC-oligomer

Figure 69 :

 69 Figure 69: The vibrations responsible for the Amide A, I and II bands in the infrared spectra of proteins

Figure 70 :

 70 Figure 70: Representation of the carbonyls involved or not in a hydrogen-bonding pattern for an ATC-oligomer

carboxamide ( 47 )

 47 compared to the ATC catalyst (46) might be a result of a stiffening of the CHAPTER 3: CATALYTIC PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 114 ATC scaffold. Such increase in the rigidity of the scaffold could be explained by a C9 intramolecular H-bond between the acetyl carbonyl and the iPrNH in (47). The intramolecular hydrogen bond was supported by the strong chemical shift (δ = 9.64 ppm) of the iPrNH extremity. , in the solution state, of oligomers ATC3-2-NHiPr, ATC5-3-NHiPr and ATC5-3-NH2 were then explored by combining circular dichroism, NMR and FTIR.

Figure 71 :

 71 Figure 71: Overlay of the far-UV circular dichroism spectra of compounds ATC3-2-NHiPr, ATC5-3-NHiPr and ATC5-3-NH2. All experiments were performed at 4°C with a 50 µM peptide solution in iPrOH

Figure 72 :

 72 Figure 72: A/NMR 1 H spectrum of ATC5-3-NHiPr in CD3OH at 293K, with the coupling constants 3 J(NH, γ CH) in purple. B/Superimposition of ROESY (blue) and TOCSY (red) spectra of ATC5-3-NHiPr in CD3OH at 293K. C/Representation of the observable NOE cross-peaks.

  PROPERTIES ACCORDING TO THE OLIGOMER LENGTHS AND THE POSITION OF THE COMPETENT ATC 117 bonds forming C9 pseudocycles (Figure73). We also detected weak NHi/  CHi-1 and γ CHi/  CHi+1 sequential NOE connectivities characteristic of the ATC helix, all along the backbone.

Figure 73 : 1 H

 731 Figure 73: 1 H NMR of ATC5-3-NH2: A/full spectrum, B/NH zone: zoom between 8.0 and 11.0 ppm, C/Hγ zone: zoom between 6.4 and 7.5 ppm

CHAPTER 3 :Figure 74 :

 374 Figure 74: Foldamers ATC5-P-NH2 with P = 1 to 5, yields are in italics

Figure 75 :

 75 Figure 75: Overlay of the far-UV circular dichroism spectra of compounds ATC5-P-NH2 with 1 ≤ P ≤ 5. All experiments were performed at 4°C with a 50 µM peptide solution in iPrOH

Figure 76 :

 76 Figure 76: Evaluation of the nitro-Michael addition reaction using β-trans-nitrostyrene (R=H), trans-4-methyl-(R=CH3) and trans-4-methoxy-β-nitrostyrene (R=OCH3) and oligomers ATC5-P-NH2 as catalysts

  OF THE DISTANCE BETWEEN THE PYRROLIDINE AMINE AND THE CARBOXYLIC ACIDThe first modification we applied to the sequence was done to evaluate the importance of the distance between the pyrrolidine amine and the carboxylic acid. Thus, three ATC-oligomers were synthesised using SPPS as previously reported (Scheme 16), using the ATC-monomers presented in Chapter 3. The modification of the length of the lateral chain carrying the carboxylic acid is symbolized by the foldamer M(1)-ATC5-3-NH2 (Figure77). The separation of the pyrrolidine and the carboxylic acid on two different ATC-monomers is represented by foldamers M

Figure 77 :

 77 Figure 77: Modulation of the position and the nature of the lateral chain carrying the carboxylic acid, yields are in italics

CHAPTER 4 :Figure 78 :

 478 Figure 78: Overlay of the far-UV circular dichroism spectra of compounds M(1)-to M(3)-ATC5-3-NH2. All experiments were performed at 4°C with a 50 µM peptide solution in iPrOH

CHAPTER 4 :Figure 79 :CHAPTER 4 :

 4794 Figure 79: Evaluation of the nitro-Michael addition reaction using β-trans-nitrostyrene (R=H), trans-4-methyl-(R=CH3) and trans-4-methoxy-β-nitrostyrene (R=OCH3) and oligomers ATC5-3-NH2 and M(1)-to M(3)-ATC5-3-NH2 as catalysts

Figure 80 :

 80 Figure 80: 3D-model of ATC5-3-NH2 with the most likely interaction zones between the catalytic centre and its environment represented in red

Figure 81 :

 81 Figure 81: Modulation of the microenvironment around the catalytic centre on a series of foldamers, yields are in italics

CHAPTER 4 :Figure 82 :Figure 83 :

 48283 Figure 82: Overlay of the far-UV circular dichroism spectra of compounds M(4)-to M(10)-ATC5-3-NH2. All experiments were performed at 4°C with a 50 µM peptide solution in iPrOH

CHAPTER 4 :

 4 MODULATION OF THE MICROENVIRONMENT AROUND THE CATALYTIC CENTRE 132

Figure 84 :

 84 Figure 84: Foldamers M(11)-to M(17)-ATCL-P-NH2, with P from 1 to 5 and L = 3, 5 or 7, yields are in italics

Figure 85 :

 85 Figure 85: Overlay of the far-UV circular dichroism spectra of compounds M(11)-to M(15)-ATC5-3-NH2. All experiments were performed at 4°C with a 50 µM peptide solution in iPrOH

Figure 86 :

 86 Figure 86: Evaluation of the nitro-Michael addition reaction using β-trans-nitrostyrene (R=H), trans-4-methyl-(R=CH3) and trans-4-methoxy-β-nitrostyrene (R=OCH3) and oligomers ATC5-3-NH2 and M(10)-to M(17)-ATCL-P-NH2 as catalysts

Figure 87 Figure 88 :

 8788 Figure 87: Foldamers M(18)-ATC3-1,2,3-NH2, M(19)-ATC5-1,2,3,4,5-NH2, M(20)-ATC5-1,3,5-NH2 and M(21)-ATC5-2,4-NH2 bearing several catalytic centres, yields are in italics

CHAPTER 4 :Figure 89 :

 489 Figure 89: Evaluation of the nitro-Michael addition reaction using β-trans-nitrostyrene (R=H), trans-4-methyl-(R=CH3) and trans-4-methoxy-β-nitrostyrene (R=OCH3) and oligomers ATC5-3-NH2, M(18)-ATC3-1,2,3-NH2, M(19)-ATC5-1,2,3,4,5-NH2, M(20)-ATC5-1,3,5-NH2 and M(21)-ATC5-2,4-NH2 as catalysts

Figure 90 :

 90 Figure 90: Evolution of the yield in the nitro-Michael addition reaction between cyclohexanone and β-transnitrostyrene in function of amount of catalyst used.

Figure 91 :

 91 Figure 91: Typical scheme for NMR structure determination

  DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 144 A variety of algorithms were developed to use NOE cross-peaks for structural determination.

Figure 92 :

 92 Figure 92: Superimposition of the 20 lowest energy structures and isolated structure to observe the H-bonds of ATC5-3-NH2, RMSD (backbone without capping) = 1.175 Å

Figure 93 :

 93 Figure 93: Superimposition of the 20 lowest energy structures and isolated structure to observe the H-bonds of M(10)-ATC5-3-NH2, RMSD (backbone without capping) = 0.818 Å

Figure 94 :

 94 Figure 94: Distance restraints: A/Mandatory, B/ Optional

CHAPTER 5 :

 5 STRUCTURE DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 152 and one does not know what sort of performance are to be expected with large systems. Since Antechamber has to infer the bonding characteristics from the geometry, the number of possibilities grows with the size of the molecule. Therefore, we decided to develop a homemade script to generate the ATC-oligomer sequences from individually parametrized ATCmonomers (Method 2).

Figure 95 :

 95 Figure 95: Comparison of the 3 methods employed to generate the AMBER parameter files of ATC sequences

  +127 ± 14° 0 ± 3° -41 ± 4°For simplicity in the construction and analysis of the sequences, we applied the same nomenclature code for the atoms of each monomer backbone. The amide extremity was identified as following: N for the nitrogen, HN for the amide proton. The carbons δ, γ, β and α were named respectively CD, CG, CB and CA while the carbon between the nitrogen (NT) and the sulfur (S) of the thiazole ring was called CT1. The first carbon on the chain held by the thiazole was named CT. The atoms of the acetyl group were named CX, OX, CX2, HH31, HH32 and HH33. Atoms constituting the NH-CH3 group on the C-terminal extremity were called NX, HNX, CX3, HH34, HH35 and HH36 (Figure96).

Figure 96 :

 96 Figure 96: Creation of an ATC-monomer on UCSF Chimera by forcing dihedral angle values and implementing a nomenclature on the backbone atoms

Figure 97 :

 97 Figure 97: Generation of the parametrized 3D-ATC monomers with the input/output files and the software used for each step

Figure 98 :

 98 Figure 98: Script of the parameters and coordinates files generation using Antechamber

Figure 99 :

 99 Figure 99: Script permitting the removal of the Ace and Nme extremities

Figure 100 :

 100 Figure 100: Generation of the parametrized 3D-ATC monomers with the input/output files and the software used for each step

  DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 158 At the end of the calculation, Gaussian generated an output '.LOG' or '.out' file depending on the software version. It contained all the calculated molecular properties, including the electrostatic surface potential (ESP) values. It is important to notice that Gaussian modified the nomenclature code for the atoms so a new 'gaussian.mol2' file had to be saved. The script that we developed is depicted in Figure 101. The Gaussian '.out' file that contains the charge distribution information as ESP values, the '.mol2' and 'gaussian.mol2' files were used as inputs. Derivation of RESP charges (Atomic charges) from ESP values was done in Lines 6 and 7 of the script. In Line 13, the match_atom command used the '.mol2' and 'gaussian.mol2' files as input and permitted to return to the initial atom code nomenclature. Finally, lines 15 to 25 provided the Amber model parameter files for the Ace-ATC-Nme molecule.

Figure 101 :

 101 Figure 101: Renaming ATC-monomer's atoms and generation of the parameter's files

Figure 102 :

 102 Figure 102: Example of an ATC-monomer without its N-ter and C-ter extremities after application of the ATCoptimized GAFF using Gaussian

Figure 103 : 3 A

 1033 Figure 103: Generation of an ATC-sequence

Figure 104 :

 104 Figure 104: Superimposition of the lowest energy structures generated using methods 1 (pink), 2 (beige) and 3 (blue), for ATC5-3-NH2, M(10)-ATC5-3-NH2 and M(1)-ATC5-3-NH2

CHAPTER 5 :•

 5 STRUCTURE DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 162 Selection of the 20 lowest energy structures without the violations being greater than 0.3 Å (MOLMOL) • Exploitation and observation of the structures (UCSF Chimera) ii. Validation of the calculated 3D models by comparison with the XRD structure, CD and FTIR data Finally, the foldamer M(1)-ATC5-3-NH2 crystallized by slow evaporation of an isopropanol solution (crystallographic data of this oligomer can now be obtained free of charge from The Cambridge Crystallographic Data Centre CCDC 1894172). Therefore, a careful comparison of the XRD structure permitted to validate the calculated models. This ATC-oligomer selfassembled into infinite columns linked together by hydrogen bonds between the acid and pyrrolidine side chains (Figure 105 and SI, section IX). It cannot be discounted that such intermolecular association could have occurred in solution, thus explaining the minor species observed in NMR spectra as previously discussed.

Figure 105 :

 105 Figure 105: Part of the crystal packing of M(1)-ATC5-3-NH2. A/The view highlights the asymmetric unit of M(1)-ATC5-3-NH2 that consists of two independent ATC oligomers (grey and green) and one iPrOH (wireframe). Hydrogen atoms are not indicated for clarity. B/ATC oligomers self-assemble in infinite columns linked together by hydrogen bonds between the acid and pyrrolidine side chains.

Figure 106 :

 106 Figure 106: Superimposition of the XRD (blue) and lowest energy NMR structures of M(1)-ATC5-3-NH2 generated by the Method 3 (coral)

Figure 107 :

 107 Figure 107: Superimposition of the 20 lowest energy NMR solution structures of ATC5-2-NH2, ATC5-3-NH2, ATC5-4-NH2 and ATC5-5-NH2 in iPrOH-d7. RMSD (Å) corresponds to the root mean square deviation value calculated on the heavy backbone atoms.

Figure 108 :

 108 Figure 108: Superimposition of the 20 lowest energy NMR solution structures of M(1)-, M(2)-, M(3)-and M(8)-ATC5-3-NH2 in iPrOH-d7. RMSD (Å) corresponds to the root mean square deviation value calculated on the heavy backbone atoms. M(1)-ATC 5 -3-NH 2 RMSD = 0.711

Figure 109 :

 109 Figure 109: Superimposition of the 20 lowest energy NMR solution structures of M(5)-, M(9)-and M(10)-ATC5-3-NH2 in iPrOH-d7. RMSD (Å) corresponds to the root mean square deviation value calculated on the heavy backbone atoms.

Figure 110 :

 110 Figure 110: Superimposition of the 20 lowest energy NMR solution structures of trimer M(16)-ATC3-2-NH2, pentamer M(13)-ATC5-3-NH2 and heptamer M(17)-ATC7-4-NH2 in iPrOH-d7. RMSD (Å) corresponds to the root mean square deviation value calculated on the heavy backbone atoms.

Figure 111 :

 111 Figure 111: Superimposition of the 20 lowest energy NMR solution structures of M(18)-ATC3-1,2,3-NH2, M(19)-ATC5-1,2,3,4,5-NH2, M(20)-ATC5-1,3,5-NH2 and M(21)-ATC5-2,4-NH2 in iPrOH-d7. RMSD (Å) corresponds to the root mean square deviation value calculated on the heavy backbone atoms.

FurthermoreFigure 112 :

 112 Figure 112: Representation of the distance between pyrrolidine NH and carboxylic acid in crystal structures of M(1)-ATC5-3-NH2 (CCDC 1894172)

  Figure 113 displays the conformations adopted at a resting state (B, in beige), during the enamine formation (C, in blue) and for the C-C bond formation (D, in pink). Therefore, the distances between the key functions are quite different when looking at the crystal structure or at the catalytic process.

Figure 113 :

 113 Figure113: A/Representation of the distance between pyrrolidine NH and carboxylic acid in crystal structures of H-D-Pro-Pro-Glu-NH2 (CCDC 1556800)[187] , Plausible pathways for the H-D-Pro-Pro-Glu-NH2-catalyzed conjugate addition reaction of butanal to β-nitrostyrene into (2S,3R)-2-ethyl-4-nitro-3-phenylbutanal in chloroform B/Resting state, C/Enamine formation, D/C-C bond formation[184]

Table 26 :a

 26 Enantiomeric excesses obtained for the nitro-Michael addition reaction of cyclohexanone to trans-, pmethyl-and p-methoxy-nitrosytrene in respects to the distance between pyrrolidine NH and carboxylic acid for ATC5Average distance between pyrrolidine NH and carboxylic acid from the 20 lowest energy structures, b distance taken from crystal structure

Figure 114 :

 114 Figure 114: Position of the two key functions on the oligomers ATC5-3-NH2 and M(1)-to M(3)-ATC5-3-NH2, along the axis (up) and above the axis (down), with the "catalytic site" circled in black.

Figure 115 :

 115 Figure 115: Structure générale d'un monomère d'ATC

Figure 116 :

 116 Figure 116 : A/ Réseau de liaisons hydrogènes au sein des oligomères d'ATCs. B/ Structure cristallographique d'un tétramère d'ATC. C/ Structure obtenue par RMN d'un hexamère d'ATCs dans l'eau.

  réactions de type énamine. Cette réactivité résulte à la fois de la présence d'une amine secondaire, sous forme de pyrrolidine et d'une fonction acide à proximité de l'amine. L'objectif de ma thèse étant d'introduire une activité catalytique sur un foldamère d'ATCs, c'est ainsi que nous avons cherché dans un premier temps à développer un monomère d'ATC présentant à la fois une pyrrolidine sur la position 2 du thiazole et une chaine latérale en position  comportant une fonction acide carboxylique (Schéma 3). Nous avons ensuite vérifié ses capacités à catalyser une réaction modèle, la réaction d'addition de Michael de la cyclohexanone sur des nitrostyrènes. Cette réaction présente l'avantage d'avoir été largement étudiée en organocatalyse. Par ailleurs, les γ-nitroaldéhydes obtenus possèdent deux centres stéréogènes

  d'un premier intermédiaire de type β-cétoester (42). La formation du β-cétoester (42) se fait selon un mécanisme de condensation croisée de Claisen entre le N-Fmoc-aminoacide et l'acétate de 1,1-diméthylallyle. L'utilisation d'un acétate encombré est nécessaire pour éviter des réactions secondaires d'auto-condensation de l'acétate. Le composé (42) subit ensuite une réaction de mono-bromation sur la position malonique selon les conditions de Yang et al. en présence de Mg(ClO4)2, en quantité catalytique agissant comme un acide de Lewis, et du Nbromosuccinimide, à -45°C, pour donner le -bromo-β-cétoester (43).[190] Une cyclisation de Hantzsch avec un thioamide permet la formation du thiazole 3 protégé de manière orthogonale sur les fonctions amine et acide ainsi que sur la chaîne latérale. Une déprotection chimiosélective de l'ester de 1,1-diméthylallyle en présence de phénylsilane conduit au monomère d'ATC (44) protégé par un groupement acido-labile sur les chaînes latérales. Selon cette voie de synthèse, plusieurs monomères ont été synthétisés avec des rendements variant de 26 à 65%. Ces monomères ont servi à la synthèse de foldamères qui seront présentés par la suite. Schéma 4 : A/ Voie de synthèse des monomères d'ATCs. B/ Monomères d'ATCs synthétisés. Les rendements sont calculés sur les étapes de bromation et de cyclisation de Hantzsch. Pour accéder aux ATCs comportant le motif pyrrolidine sur la position 2 du noyau thiazole, nous avons modifié le protocole (Schéma 5). Nous avons choisi de cycliser l'α-bromo-βcétoester afin de former les thiazolines en présence de Boc-Proline thioamide synthétisée au laboratoire (2 étapes, rdt 75%). Puis, une réaction d'aromatisation des thiazolines par l'anhydride trifluoroacétique en présence de DIEA à 0°C a été effectuée, conduisant au composé (44'). Une déprotection sélective selon les conditions de Tsuji-Trost a enfin été réalisée afin d'obtenir les monomères d'ATC (45i-l). Cyclisation de Hantzsch en 2 étapes. B/ Monomères d'ATCs synthétisés après cyclisation puis aromatisation. Les rendements sont calculés sur les étapes de bromation et de cyclisation de Hantzsch

Figure 4 : 2 -

 42 Figure 4 : ATC-monomer structuré (47), trimères ATC3-2-NHiPr et ATC3-2(OMe)-NHiPr, et pentamère ATC5-3-NHiPr

  conservée dans différentes gammes de températures et de solvants. Ainsi, afin de confirmer notre hypothèse, le pentamère ATC5-3-NHiPr a été soumis à des analyses RMN dans le méthanol d3.Grâce à l'étude du spectre RMN 1 H de ATC5-3-NHiPr, nous avons observé que les signaux des NH et Hγ étaient très dispersés et très déblindés pour des protons amides, autour de 10ppm. D'après des travaux antérieurs réalisés au laboratoire, cela signifie que ces protons sont engagés dans des liaisons hydrogènes intramoléculaires à 9 chainons.[104,107] Par ailleurs, nous avons pu remarquer que le proton NH du résidu 1 est moins déblindé (à 9ppm), signe que ce proton n'est pas engagé dans une liaison intramoléculaire en adéquation avec le modèle d'hélice C9. Afin de confirmer cette structure, nous avons procédé à l'étude des spectres ROESY. Nous avons ainsi pu détecter des corrélations canoniques entre les Hγ des résidus i et les NH des résidus i+1. Des corrélations secondaires entre les Hγ des résidus i et les protons des chaines latérales portés par les thiazoles des résidus i+1, caractéristiques de l'hélice 9 ont également été mises en évidence (Figure118).

Figure 118 :TFASchéma 8 :

 1188 Figure 118 : Représentation des correlations NOE observables.

Figure 120 :

 120 Figure 120: Modulation de la position et de la nature de la chaine portant l'acide carboxylique, les rendements sont en italiques

Figure 121 :

 121 Figure 121 : Modulation du microenvironnement autour du centre catalytique sur une série de foldamères, les rendements sont en italiques

Figure 122 :

 122 Figure 122 : Conversion et excès énantiomérique pour les réactions d'addition de la cyclohexanone sur le β-transnitrostyrène (bleu foncé), le p-methyl-nitrostyrène (bleu) et le p-méthoxy-nitrostyrène (vert) pour les foldamères d'ATC

Figure 123 :

 123 Figure 123 : Différentes methodes explorées pour la modélisation d'oligomères d'ATC sous contraintes RMN

Hz and 3 . 3

 33 Hz, 1H); 5.10 (d, J = 10.9 Hz, 1H); 5.18 (d, J = 17.4 Hz, 1H); 5.94 (m, 2H); 6.08 (dd, J = 10.9 Hz and 17.4 Hz, 1H); 7.06 (m, 2H); 7.15-7.21 (m, 3H); 7.28 (m, 2H); 7.30 (m, 3H); 7.35 (m, 2H); 7.40 (t, J = 7.5 Hz, 2H); 7.55 (d, J = 7.5 Hz, 1H); 7.58 (d, J = 7.5 Hz, 1H);

  Scheme S2

  the reaction was completed (HPLC monitoring). The crude was extracted with 120ml DCM, washed with 100ml water and 100ml saturated NaHCO3 and 3×100ml brine. The organic layer was dried, filtered and evaporated. Purification by flash column chromatography gave pure (44'). Flash purification: Cyclohexane/Ethyl Acetate 80/20 for 1CV then gradient from 80Yellowish solid. Yield: 40%. [α]D 20°C = -62.5° (c 1.5, CHCl3). 1 H NMR (CDCl3, 400 MHz): δ = 1.30 (s, 4.6H, conformer 1), 1.40 (s, 9H), 1.47 (s, 4H, conformer 2), 1.63 (s, 6H), 1.92 (m, J = 8 Hz, 2H), 2.03 (m, J = 8 Hz, 2H), 2.05-2.30 (m, J = 8 Hz, 4H), 3.40-3.50 (m, 1H), 3.58 (br, 1H), 4.19 (t, J = 6.5 Hz, 1H), 4.34 (t, J = 6.5 Hz, 2H), 5.02 (d, J = 6.0 Hz, 1H), 5.12 (d, J = 10.5 Hz, 1H), 5.24 (d, J = 17.5 Hz, 1H), 5.55 (m, 1H), 5.98 (d, J = 9.0 Hz, 1H), 6.15 (dd, J = 17.5 Hz, J = 10.5 Hz, 1H), 7.28 (t, J = 8.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.56 (t, J = 7.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H) ppm. 13 C NMR (CDCl3, 100 MHz): δ = 23.3 and 24.0,

  ; 4.35 (t, J = 6.5 Hz, 2H); 5.05 (d, J = 6.0 Hz, 1H); 5.15 (d, J = 10.5 Hz, 1H); 5.26 (d, J = 17.5 Hz, 1H); 5.59-5.69 (m, 1H); 5.97 (d, J = 9.0 Hz, 1H); 6.18 (dd, J = 17.5 Hz, J = 10.5 Hz, 1H); 7.29 (t, J = 8.5 Hz, 2H); 7.39 (t, J = 7.5 Hz, 2H); 7.61 (t, J = 7.5 Hz, 2H); 7.76 (d, J = 8.5 Hz, 2H

Figure S6 :

 S6 Figure S6: Nomenclature and torsion angles description for ATC units

Figure S9 - 1 H

 1 Figure S9 -1 H NMR spectrum of ATC3-2*-NHiPr in CD3OH at 298K

  Figure S11 -1 H NMR spectrum of ATC5-3-NHiPr in CD3OH at 293K

  with the solvent signals, nd: not detected.

Figure S13 - 1 H

 1 Figure S13 -1 H NMR spectrum of ATC5-2-NH2 in iPrOH-d7 at 298K

  Figure S15 -1 H NMR spectrum of ATC5-3-NH2 in iPrOH-d7 at 298K (red) and 343K (blue)

S68Figure S 18 -

 18 Figure S17 -1 H NMR spectrum of ATC5-4-NH2 in iPrOH-d7 at 298K

Figure S21 - 1 H

 1 Figure S21 -1 H NMR spectrum of M(1)-ATC5-3-NH2 in iPrOH-d7 at 298K

  Figure S23 -1 H NMR spectrum of M(2)-ATC5-3-NH2 in iPrOH-d7 at 298K

  Figure S25 -1 H NMR spectrum of M(3)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S27 - 1 H

 1 Figure S27 -1 H NMR spectrum of M(4)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S29 - 1 H

 1 Figure S29 -1 H NMR spectrum of M(5)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S31 - 1 H

 1 Figure S31 -1 H NMR spectrum of M(7)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S33 - 1 H

 1 Figure S33 -1 H NMR spectrum of M(8)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S35 - 1 H

 1 Figure S35 -1 H NMR spectrum of M(9)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S37 - 1 H

 1 Figure S37 -1 H NMR spectrum of M(10)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S41 - 1 H

 1 Figure S41 -1 H NMR spectrum of M(12)-ATC5-2-NH2 in iPrOH-d7 at 298K

Figure S43 - 1 H

 1 Figure S43 -1 H NMR spectrum of M(13)-ATC5-3-NH2 in iPrOH-d7 at 298K

Figure S47 - 1 H

 1 Figure S47 -1 H NMR spectrum of M(15)-ATC5-5-NH2 in iPrOH-d7 at 298K

Figure S51 - 1 H

 1 Figure S51 -1 H NMR spectrum of M(17)-ATC7-4-NH2 in iPrOH-d7 at 298K

Figure S53 - 1 H

 1 Figure S53 -1 H NMR spectrum of M(18)-ATC3-1,2,3-NH2 in iPrOH-d7 at 298K

  Figure S57 -1 H NMR spectrum of M(20)-ATC5-1,3,5-NH2 in iPrOH-d7 at 298K

  Figure S59 -1 H NMR spectrum of M(21)-ATC5-2,4-NH2 in iPrOH-d7 at 298K

molmol 12 /

 12 Save the models as .pdb "cook_heat.in" Cook from heating up the system equilibration stage 1 &cntrl nstlim=200000, dt=0.002, ntx=1, irest=0, ntpr=2000, ntwr=2000, ntwx=2000, nmropt=0, tempi =1000.0, temp0=1000.0, ntt=1, tautp=2.0

Table 1 :

 1 Different turn types: number of residues and hydrogen bond pattern

	Turn name	Number of residues	H bond type
	δ	2	NHi -COi+1
	ε	3	NHi -COi+2
	γ	3	COi -NHi+2
	β	4	COi -NHi+3
	α	5	COi -NHi+4
	π	6

Table 2 :

 2 Dihedral angles of β-turn types

	Turn type	φi+1	Dihedral angles (°) ψi+1 φi+2	ψi+2
	I	-60	-30	-90	0
	I'	+60	+30	+90	0
	II	-60	+120	+80	0
	II'	+60	-120	-80	0
	VIa (cis)	-60	+120	-90	0

Table 3 :

 3 Dihedral angles of γ-turns

		Dihedral angles (°)
		φi+1	ψi+1
	Classic	+70 to +85	-60 to -70
	Inverse	-70 to -85	+60 to +70

Table 4 :

 4 Conformational preferences of the amino acids

	Amino acid	Glu	Ala	Leu	Met	Gln	Lys	Arg	His
	α-helix	1.59	1.41	1.34	1.30	1.27	1.23	1.21	1.05
	β-sheet	0.52	0.72	1.22	1.14	0.98	0.69	0.84	0.80
	turn	1.01	0.82	0.57	0.52	0.84	1.07	0.90	0.81
	Amino acid	Val	Ile	Tyr	Cys	Trp	Phe	Thr
	α-helix	0.98	1.09	0.74	0.66	1.02	1.16	0.76
	β-sheet	1.87	1.67	1.45	1.40	1.35	1.33	1.17
	turn	0.41	0.47	0.76	0.54	0.65	0.59	0.90

Table 5 :

 5 Average backbone torsion angles for (Z)-vinylogous γ-oligomers and ATC-based foldamers (

21a,b,c) and (22). The

  ψ angles of the last residue of the NMR and XRD structures were omitted.

	Oligomers	φ	θ	ζ	ψ
	Predicted (Z)-vinylogous γ-oligomers	-79.8°	122.8°	0.1°	-46.5°
	ATC-oligomers (21a), (21b), (21c)	-76 ± 16°	128 ± 12°	-6 ± 5°	-28 ± 6°
	XRD structure of (22)	-78 ± 3°	127 ± 14°	0 ± 3°	-41 ± 4°

Table 7 :

 7 Impact of the oligourea catalyst loading, chain length and temperature

	Entry	Catalyst Cat. loading (mol%) Temp. (°C) Yield a (%)	ee b (%)
	1	(32a)	0.1	-20	86	95
	2	(32a)	0.1	rt	75	89
	3	(32a)	0.01	-20	82	91
	4	(32b)	0.1	rt	83	87
	5	(32c)	0.1	rt	47	36
	6	(32d)	0.1	rt	44	6
	7	(32e)	0.1	rt	55	5

Table 9 :

 9 Three-component direct Mannich reaction with different ketones and aldehydes

	Entry	(ketone) R 1	(aldehyde) R 2	Product	Yield (%)	ee a (%)
	1	H			50	94
						99 (de>95%)
	2	CH3			96 (ratio 2.5:1)
						94%
	3	OCH3			93	98
	4	OH			92	>99
	5	H			35	96
	6	H			90	93
	7	H			74	73
	8	H			58	70

a Enantiomeric excess determined by chiral HPLC

Table 11 :

 11 Aldol reactions catalysed by Wennemers's peptides[171,151]

	Entry	R	10 mol% (33) yield (%) ee a (%)	1 mol% (34) yield (%) ee a (%)	30 mol% Proline yield (%) ee a (%)
	1	4-NO2Ph	73	70 (R)	99	80 (S)	68	76 (R)
	2	Ph	58	66 (R)	69	78 (S)	62	60 (R)
	3	c-Hex	56	83 (R)	66	82 (S)	63	84 (R)
	4	i-Pr	75	91 (R)	79	79 (S)	97	96 (R)
	5	neo-Pent	24	70 (S)	28	73 (R)	22	36 (S)

Table 12 :

 12

Aldol reaction between p-nitrobenzaldehyde and acetone catalysed by peptides (

34) to (38)

	Entry	Catalyst	mol %	Time (h) Yield (%)	ee a (%)
	1	(34)	1	4	99	80
	2 b	(34)	5	24	67	77
	3	(35)	10	72	≤5	nd
	4	(36)	10	72	≤5	nd
	5	(37)	10	24	39	54
	6	(38)	10	24	26	53

a Enantiomeric excess determined by chiral HPLC, b Reaction was performed in the absence of NMM

Table 13 :

 13 Conjugate addition reaction of butanal to β-trans-nitrostyrene catalysed by H-D-Pro-Yaa-Glu-NH2peptides[187]

	Entry	Catalyst	Kt/c a	Conv. b (%) dr c (%)	ee c (%)
	1	(40)-4	10	>95	26:1	92
	2	(40)	46	>95	35:1	97
	3	(40)-6	71	>95	50:1	99

a Trans/cis conformer ratio in CDCl3/CD3OH 9:1, b Conversion determined by

[START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF]

H NMR of the crude material c Determined by chiral stationary phase

Table 15 :

 15 Optimization of nitro-Michael addition reaction, using catalyst(46)

	Entry a	Solvent	T (°C)	Yield b (%)	syn/anti	ee c (%)
	1	Toluene	30	54	95/5	27
	2	DMSO	30	82	87/13	29
	3	CHCl3	30	81	93/7	27
	4	THF	30	80	94/6	28
	5	CH3CN	30	80	92/8	22
	6	Hexane	30	88	94/6	31
	7	MeOH	30	18	95/5	nd
	8	EtOH	30	98	92/8	34
	9	iPrOH	30	92	96/4	41
	10	iPrOH	4	98	96/4	45
	a Reaction performed over 16 hours with 0.1mmol nitroolefin, 1mmol cyclohexanone, 0.01mmol NMM and
	0.01mmol catalyst in 400 µL solvent;

b Determined via RP-HPLC at 214 nm; c Determined via chiral HPLC (CHIRALPAK IC column; Hex/iPrOH 8:2 vv, d=1 ml/min, =214 nm). Selectivity towards (2S)-2-[(1R)-2-Nitro-1-phenylethyl]cyclohexanone determined by optical rotation and comparison with reported data in literature

Table 16 :

 16

	Entry a	Catalyst	Yield b (%) syn/anti ratio c ee d (%)
	1	(46)	92	96/4	45
	2	(47)	94	93/7	52
	3	ATC3-2-NHiPr	91	>99/1	74
	4	ATC5-3-NHiPr	>99	>99/1	77
	5	ATC5-3-NH2	>99	>99/1	79
	6	ATC3-2*-NHiPr	93	98/2	65 e
	7	ATC3-2(OMe)-NHiPr	<5	nd	nd

Comparison of different ATC-catalysts in the nitro-Michael addition reaction between cyclohexanone and β-trans-nitrostyrene a

Reaction performed over 16 hours with 0.1mmol nitroolefin, 1mmol cyclohexanone, 0.01mmol NMM and 0.01mmol catalyst in 400 µL solvent; b Determined via RP-HPLC at 214 nm; c Determined via chiral HPLC (CHRALPAK IC column; Hex/iPrOH 8:2 vv, d=1 ml/min, =214 nm). e ((R),(S)) enantiomer was obtained as major compound.

Table 17 :

 17 Most common scalar and bidimensional experiments

		Homonuclear through-bond correlation methods
	Name	Nuclei 1	Coupling	Nuclei 2
	COSY	1 H	2 J and 3 J (between geminal and vicinal protons)	1 H
	TOCSY	1 H	J, J, J… (multiple transfer, up to 3 bonds)	1 H
	NOESY/ROESY	1 H	NOE (dipolar interactions between H up to 5 Å)	1 H
		Heteronuclear through-bond correlation methods
	Name	Nuclei 1	Coupling	Nuclei 2
	HSQC	13 C or 15 N	1 JCH and 1 JNH	1 H
	HMQC	13 C	1 JCH	1 H
	HMBC	13 C	2 JCH and 3 JCH

1 H

Table 18 :

 18 FTIR spectrum of ATC5-3-NH2 at 2 mM in iPrOH. Band positions, intensities, widths, and areas in the region of 1800-1500cm -1 are reported in the table

	Absorption bands	Wavenumbers

(cm -1 ) Intensity (a.u.) Width (a.u.) Area (a.u.)

  breakthroughs of this work. It clearly demonstrates the possibility of modulating the substrate specificity which is an inherent property of the enzyme catalysts.

	CHAPTER 4: MODULATION OF THE MICROENVIRONMENT AROUND THE CATALYTIC CENTRE
	10 mol% ATC5-3-NH2 probably the biggest	2 mol% M(19)-ATC5-1,2,3,4,5-NH2
	10 mol% M(19)-ATC5-1,2,3,4,5-NH22
		139

Table 19 :

 19 Average dihedral angle values observed for the 20 best structures obtained after NMR refinement for

	foldamers ATC5-3-NH2
	Canonic C9-helix		-78	+127	0	-41
	Oligomer	Res. a	φ (°)	θ (°)	ζ (°)	ψ (°)	H-bond b (Å)
		1	-71.3 ± 14.9	+122.2 ± 6.1	-5.1 ± 1.7	-28.5 ± 10.8	1.92
		2	-121.9 ± 34.7 +53.7 ± 87.4	-1.6 ± 3.0	-6.8 ± 16.4	1.94
	ATC5-3-NH2	3	-108.0 ± 29.1 +107.1 ± 13.3	-2.9 ± 2.8	-19.8 ± 7.8	1.98
		4	-77.1 ± 23.8	+120.4 ± 9.6	-4.6 ± 1.6	-25.4 ± 3.7	1.94
		5	-111.5 ± 22.1 +115.6 ± 18.5	-0.6 ± 3.3	-3.2 ± 15.4	2.21 c
	a Residues are ordered from N to C-terminal extremities, b Average length of H-bond formed between COi and
	NHi+2, c Average length between O of CO(

Table 20 :

 20 Average dihedral angle values observed for the 20 best structures obtained after NMR refinement for foldamers M

(10)-ATC5-3-NH2

	Canonic C9-helix		-78	+127	0	-41
	Oligomer	Res. a	φ (°)	θ (°)	ζ (°)	ψ (°)	H-bond b (Å)
		1	-115.9 ± 49.5 +110.1 ± 32.8	-3.4 ± 3.6	-14.3 ± 6.2	2.85 c
	M(10)-ATC5-	2 3	-67.2 ± 6.8 -137.0 ± 14.6 +94.6 ± 16.4 +126.4 ± 10.6	-2.6 ± 7.3 -3.5 ± 3.6	-12.0 ± 16.0 -13.5 ± 5.9	1.91 2.50 c
	3-NH2	4	-97.0 ± 24.6 +114.1 ± 13.6	-6.8 ± 2.8	-20.0 ± 5.3	1.90
		5	-118.3 ± 18.8 +112.1 ± 15.6	-1.9 ± 6.7	-7.4 ± 19.6	2.20 d
	a Residues are ordered from N to C-terminal extremities, b Average distance of H-bond formed between COi and
	NHi+2, c Average distance between O of COi and H of NHi+2, d Average length between O of CO(4) and the
	barycentre of the two H from NH2 on the C-terminus

Table 21 :

 21 Variation

		of the parameters for M(10)-ATC5-3-NH2 and superimposition of the 20 structures of lowest
	energy for each entry
	Entry	1	2	3	4	5	6
	1.NH-2.NH	w	w	w	w	w	w
	2.NH-3.NH	w	w	w	w	w	w
	3.NH-4.NH	w	w	w	w	w	w
	4.NH-5.NH	w	w	w	w	w	w
	5.NH-NH2	o	o	o	o	o	o
	Ac-1.NH	o	o	o	o	o	o
	1.Hγ-2.NH	s	s	s	s	s	s
	2.Hγ-3.NH	s	s	s	s	s	s
	3.Hγ-4.NH	s	s	s	s	s	s
	4.Hγ-5.NH	s	s	s	s	s	s
	5.Hγ-NH2	s/s	s/s	s/s	s/s	s/s	s/s
	1.Hγ-2.Hγ	o	o	o	o	o	o
	2.Hγ-3.Hγ	w	w	w	o	o	o
	3.Hγ-4.Hγ	w	w	w	o	o	o
	4.Hγ-5.Hγ	w	w	w	o	o	o
	1.Hγ-2.Hτ	w+1	w+1	w+1	w+1	w+1	o
	2.Hγ-3.Hτ	w+1	w+1	w+1	w+1	w+1	o
	3.Hγ-4.Hτ	w+1	w+1	w+1	w+1	w+1	o
	4.Hγ-5.Hτ	w+1	w+1	w+1	w+1	w+1	o
	1.Hγ-2.Hδ	w+1	w+1	o	w+1	o	o
	2.Hγ-3.Hδ	w+1	w+1	o	w+1	o	o
	3.Hγ-4.Hδ	w+1	w+1	o	w+1	o	o
	4.Hγ-5.Hδ	w+1	w+1	o	w+1	o	o
	1.Hζ-2.Hτ	m+2	m+2	o	o	o	o
	2.Hζ-3.Hτ	o	o	o	o	o	o
	3.Hζ-4.Hτ	o	o	o	o	o	o
	4.Hζ-5.Hτ	m+2	m+2	o	o	o	o
	1.Hζ-1.Hτ	m+2	m+2	o	o	o	o
	2.Hζ-3.Hγ	o	w+1	o	o	o	o
	2.Hζ-4.Hζ	o	w+1	o	o	o	o
	3D-
	Structure
	RMSD (Å) a	0.818	0.653	0.959	0.823	0.765	1.040

a backbone without capping; w: weak = 5.0 Å; m: medium = 3.3 Å; s: strong = 2.7 Å; o: off = no restraint applied CHAPTER 5: STRUCTURE DETERMINATION AT THE ATOMIC LEVEL OF THE ATC-OLIGOMERS 151

Table 22 :

 22 Average values of dihedral angles found in the RX structures of CCDC 922304

Table 23

 23

	illustrates the information contained in the different file
	types.

Table 23 :

 23 Information contained in different files, Y means yes, and D means that it will be discarded when converted to force field files.

	Information	mol2	prepin	inpcrd	frcmod	pdb	prmtop
	Residue name	Y	Y			Y	Y
	Atom name	Y	Y			Y	Y
	Atom type	Y	Y		Y		Y
	Charges	Y	Y				Y
	Connectivity	Y	Y			Y	Y
	Coordinates	Y	D	Y		Y
	Atom mass				Y		Y
	Bonded parameters				Y		Y
	Non-bonded parameters				Y		Y

I developed a short script to generate the Amber model parameter file types '.prepin', '.inpcrd', '.frcmod', '.pdb' and '.prmtop'. The structures drawn with UCSF Chimera were saved as a

  en changeant la nature du groupement catalytique et/ou en modulant la topologie du squelette foldamérique et le microenvironnement autour du centre catalytique. C'est dans ce cadre que notre équipe s'est intéressée au développement d'architectures pseudopeptidiques capables d'adopter en solution des états conformationnels stables et prévisibles.

	Potentiellement, de tels catalyseurs peuvent
	présenter de nombreux avantages et pourraient être une solution originale pour répondre aux
	doubles enjeux économiques et environnementaux de la chimie de synthèse. Faciles à
	synthétiser et peu couteux à produire à grande échelle, ils peuvent, contrairement aux enzymes

dont ils s'inspirent, être utilisés dans de nombreux solvants organiques et dans une large gamme de températures ou de pressions. Par ailleurs, l'activité et la spécificité catalytique peuvent être modulées facilement

  cyclohexanone, 1.0 équiv. de β-trans-nitrostyrène et 10 mol% de catalyseur. Les résultats obtenus après 16 h de réaction sont rapportés dans le Tableau 1.

	A/ équiv. de Schéma 7: Réaction d'addition de Nitro-Michael
	Tableau 1 : Optimisation de la réaction de nitro Michael avec le catalyseur (46) ;
	B/ Entrée a	Solvant	T (°C)	Conversion b (%)	Syn/Anti b	Excès énantiomérique c (%)
	1	Toluène	30	54	95/5	27
	2	DMSO	30	82	87/13	29
	3	CHCl3	30	81	93/7	27
	4	THF	30	80	94/6	28
	5	CH3CN	30	80	92/8	22
	6	Hexane	30	88	94/6	31
	7	MeOH	30	18	95/5	nd
	8	EtOH	30	98	92/8	34
	9	iPrOH	30	92	96/4	41
	10	iPrOH	4	98	96/4	45

a Réalisé dans 400 µl de solvant ; b Déterminée par RP-HPLC à 214 nm; c Déterminé par HPLC chirale (Colonne IC; Hex/iPrOH 8:2 vv, d=1 ml/min, =214 nm). Sélectivité vers (2S)-2-[(1R)-2-Nitro-

1-phenylethyl]

Table S1 :

 S1

					SUPPORTING INFORMATION
	Res. 3	10.27	5.61	3.31	Ph 7.13 τ1 CH3 2.70
	NHiPr	8.85	-	-	CH 4.07 CH3 1.24
	1 H NMR in CD3OH at 288K
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 1.94
	Res. 1	8.94	5.31	3.08	Ph 6.74 τ1 CH3 2.68
	Res. 2	9.90	5.63	2.25-2.35	ε CH2 2.08 τ1 CH 5.08 τ2 CH2 2.15-2.29 τ3 CH2 2.07-2.21 τ4 CH2 3.42-3.48
					S51

Table S2 -

 S2 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in CD3OH at 298K.

	Residue	3 J(NH, γ CH)
	Res. 1	7.5
	Res. 2	6.5
	Res. 3	6.5
	NHiPr	7.5
	Table S3-Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in CD3OH at
	288K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).
	NOE correlations	Intensity
	1.NH-2.NH	nd
	2.NH-3.NH	nd
	3.NH-NHiPr	nd
	Ac-1.NH	m
	1.H-2.NH	s
	2.H-3.NH	s
	3.H-NHiPr	s
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-iPr	w
	1.H-2.H	w
	2.H-3.H	s
	1.H-2.H	nd
	2.H-3.H	nd
	1.Ph-2.H	w
	2.Ph-3.H	w
	nd: not detected

Table S5 -

 S5 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in CD3OH at 298K.

							SUPPORTING INFORMATION
				2.H-3.NH	s
			3.H-NHiPr	s
					1.H-2.H	nd
					2.H-3.H	nd
					3.H-iPr	nd
				1.H-2.H	nd
				2.H-3.H	w
					1.H-2.H	nd
					2.H-3.H	nd
	Table S4 -1 H NMR in CD3OH at 298K		3.H-iPr	nd
	Residue	HN	 CH 1.Ph-2.H  CH	m	Others
	Ac	-	-	-2.Ph-3.H	w	CH3 1.92
					nd: not detected
	Res. 1	8.76	5.45	3.08	Ph 6.84 τ1 CH3 2.71
	Res. 2	9.64	5.52	2.25-2.34	ε CH2 2.07 τ1 CH 5.01 τ2 CH2 2.57-2.29 τ3 CH2 2.07-2.22 τ4 CH2 3.42-3.51
	Res. 3	10.32	5.64	3.31	Ph 7.13 τ1 CH3 2.70
	NHiPr	8.79	-		-	CH 4.07 CH3 1.24
					Residue	3 J(NH, γ CH)
					Res. 1	7.5
					Res. 2	6.5
					Res. 3	6.5
					NHiPr	7.5
	Table S6 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in CD3OH at
	298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).
			NOE correlations	Intensity
			1.NH-2.NH	nd
			2.NH-3.NH	nd
			3.NH-NHiPr	nd
					Ac-1.NH	m
				1.H-2.NH	s
							S54

Table S8 -

 S8 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in in CD3OH at 293K.

					SUPPORTING INFORMATION
	NHiPr	9.07	-	-	CH 4.09 CH3 1.26-1.24
				Residue	3 J(NH, γ CH)
				Res. 1	7.1
	Table S7 -1 H NMR in CD3OH at 293K
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.06
	Res. 1	9.04	5.51	3.18	Ph 7.00-6.78 τ1 CH3 2.68
	Res. 2	10.65	5.41	3.29	Ph 7.03-6.76 τ1 CH3 2.74
	Res. 3	9.89	5.74	2.32	ε CH2 2.15 τ1 CH 5.20 τ2 CH2 2.38-2.20 τ3 CH2 2.07-2.14 τ4 CH2 3.41-3.49
	Res. 4	10.34	5.75	3.32	Ph 6.96-6.83 τ1 CH3 2.72
	Res. 5	10.14	5.50	3.36	Ph 7.19-7.15 τ1 CH3 2.76
					S56

Table S21 -

 S21

	Residue	C(O)	 C	 C	β C	α C	Others
	Ac	172.0	-	-	-	-	CH3 21.2
	Res. 1	171.5	49.5	38.8	136.6	153.5	Ph 127.3-125.6 τ1 C na
	Res. 2	162.0	50.6	38.6	136.5	153.7	Ph 127.5 τ1 C na
	Res. 3	162.2	50.7	39.0	136.8	153.8	Ph 127.7 τ1 C 17.0
	Res. 4	161.3	48.5	30.3	135.6	na	ε C na τ1 C 57.5 τ2 C na τ3 C 22.0 τ4 C na
	Res. 5	160.3	51.8	44.6	137.7	155.5	Ph 128.5-128.4 τ1 C na
					na: not assigned

Table S22 -

 S22 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

	Residue	Major (298 K)
	Res. 1	7.0
	Res. 2	5.6
	Res. 3	6.3
	Res. 4	7.3
	Res. 5	6.5
	o: overlap with the solvent signals; nd: not detected
	Table S23 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m)

Table S33 -

 S33 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

					SUPPORTING INFORMATION
	Table S31 -1 H NMR in iPrOH-d7 at 293K minor conformer a (12%)
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 1.95
	Res. 1	8.97	5.46	3.10	Ph na τ1 CH3 na
	Res. 2	10.73	5.05	3.16-3.07	Ph na τ1 CH3 na
	Res. 3	9.42	5.80	3.24-2.99	τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 4	9.99	5.23	3.14-3.07	Ph na τ1 CH3 na
	Res. 5	9.75	5.42	3.40-3.05	Ph na τ1 CH3 na
	NH2	8.88-7.37	-	-	-
				na: not assigned
	Table S32 -1 H NMR in iPrOH-d7 at 293K minor conformer b (11%)
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.02
	Res. 1	8.95	4.83	2.97-2.77	Ph na τ1 CH3 na
	Res. 2	10.06	5.53	3.44-3.10	Ph na τ1 CH3 na
	Res. 3	10.33	5.93	3.06-2.82	τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 4	10.71	5.93	3.06-2.82	Ph na τ1 CH3 na
	Res. 5	10.17	5.53	3.22-3.32	Ph na τ1 CH3 na
	NH2	8.88-7.37	-	-	-
				na: not assigned
		Residue	Major (298 K) Minor a (298 K) Minor b (298 K)
		Res. 1		6.8	6.7	6.7
		Res. 2		6.2	6.6	7.4
		Res. 3		7.9	7.9	7.1
		Res. 4		6.1	6.8	6.3
		Res. 5		6.8	6.6	6.8
						S74

Table S34 -

 S34 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

		SUPPORTING INFORMATION
	NOE correlations	Intensity
	1.NH-2.NH	w
	2.NH-3.NH	w
	3.NH-4.NH	w
	4.NH-5.NH	o
	5.NH-NH2	nd
	5.NH-NH2	nd
	Ac-1.NH	m
	1.H-2.NH	s
	2.H-3.NH	m/s
	3.H-4.NH	m/s
	4.H-5.NH	s
	5.H-NH2	m/s
	5.H-NH2	w/m
	1.H-2.H	o
	2.H-3.H	w
	3.H-4.H	nd
	4.H-5.H	nd
	1.H-2.H	w
	2.H-3.H	nd
	3.H-4.H	w
	4.H-5.H	w
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	1.Ph-2.H	w
	4.Ph-5.H	w/m
	o: overlap with the solvent signals; nd: not detected
		S75

Table S37 -

 S37 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

	Residue	Major (298 K)
	Res. 1	7.0
	Res. 2	6.1
	Res. 3	4.7
	Res. 4	5.7
	Res. 5	6.4
	Table S38 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

Table S41 -

 S41 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

	Residue	Major (298 K)
	Res. 1	6.7
	Res. 2	6.3
	Res. 3	7.6
	Res. 4	5.6
	Res. 5	6.1
	Table S42 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

Table S45 -

 S45 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

	Residue	Major (298 K)
	Res. 1	6.8
	Res. 2	6.3
	Res. 3	7.4

Table S56 -

 S56 Coupling Constants 3 J(NH,

									SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION
		Res. 4	10.09	5.60	3.19-3.16 Ac-1.NH		s	Ph 6.82-6.72 τ1 CH3 2.57
		Res. 5	10.07	5.53 1.H-2.NH 3.32-3.23		Ph 7.10-6.99 τ1 CH3 2.62 nd
					2.H-3.NH			s
		NH2	8.71-7.29	-	-3.H-4.NH			s	-
					na: not assigned 4.H-5.NH	s
						5.H-NH2			s
	Table S55 -13 C NMR in iPrOH-d7 at 293K major conformer (84%) 5.H-NH2 nd
	Residue	C(O)	 C			 C 1.H-2.H	β C	α C	nd	Others
	Ac	171.2	-			-2.H-3.H	-	-	o	CH3 21.2
						3.H-4.H			o
	Res. 1	163.3	43.7		18.9 4.H-5.H	na	na	m	-
	Res. 2	161.7	na		45.5 1.H-2.H	na	na	nd	Ph na τ1 C 17.1
	Res. 3	160.2	48.4		28.6 2.H-3.H	na	na	s	ε C na τ1 C na τ2 C na τ3 C na τ4 C na
					3.H-4.H			w
	Res. 4	161.4	51.4		38.9 4.H-5.H	na	na	w	Ph 127.8 τ1 C 18.1
	Res. 5	na	50.9		39.5 1.H-2.H	na	na	nd	Ph 128.2-125.7 τ1 C 18.3
						2.H-3.H			nd
						na: not assigned
						3.H-4.H			w
						4.H-5.H			w
			o: overlap with the solvent signals; nd: not detected
						Residue		Major (298 K)
						Res. 1		6.7
						Res. 2		5.9
						Res. 3		7.8
						Res. 4		6.2
						Res. 5		7.8
	Table S54 -1 H NMR in iPrOH-d7 at 293K major conformer (84%)
	Table S57 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	Residue d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w). HN  CH  CH Others
		Ac	-	-NOE correlations -	Intensity	CH3 2.03
					1.NH-2.NH			w
		Res. 1	8.43	5.43 2.NH-3.NH 1.32		w	NH2
		Res. 2	10.33	5.23 3.NH-4.NH 3.11		Ph 6.93-6.57 τ1 CH3 1.84 w
		Res. 3	9.79	5.67 4.NH-5.NH 2.31-2.23 ε CH2 na τ1 CH 5.12 τ2 CH2 na τ3 CH2 na τ4 CH2 na o 5.NH-NH2 w
						5.NH-NH2			s
									S91 S92 S93

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S60 -

 S60 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

		SUPPORTING INFORMATION
	Residue	Major (298 K)
	Res. 1	6.6
	Res. 2	6.2
	Res. 3	7.7
	Res. 4	5.8
	Res. 5	6.8
	Table S61 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).
	NOE correlations	Intensity
	1.NH-2.NH	w
	2.NH-3.NH	nd
	3.NH-4.NH	w
	4.NH-5.NH	o
	5.NH-NH2	nd
	Ac-1.NH	s
	1.H-2.NH	s
	2.H-3.NH	s
	3.H-4.NH	s
	4.H-5.NH	s
	5.H-NH2	m
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	1.H-2.H	m
	2.H-3.H	nd
	3.H-4.H	m
	4.H-5.H	m
	1.H-2.H	w
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	o: overlap with the solvent signals, nd: not detected
		S96

Table S63 -

 S63 Coupling Constants 3 J(NH,

					SUPPORTING INFORMATION
	Table S62 -1 H NMR in iPrOH-d7 at 298K major conformer (95%)
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.03
	Res. 1	9.12	5.47	3.21-3.18 Ph 6.72 τ1 CH2 2.78 τ2 CH 2.11 τ3 CH3 0.99-0.97
	Res. 2	10.51	5.07	2.14-1.68	ε CH 1.08 ζ CH3 0.78-0.43 τ1 CH 2.75
	Res. 3	10.27	5.80	2.42-2.32	ε CH2 2.42-2.32 τ1 CH 5.27 τ2 CH2 2.50-2.26 τ3 CH2 2.18 τ4 CH2 3.50
	Res. 4	10.33	5.72	3.42-3.28	Ph 6.92 τ1 CH3 2.67
	Res. 5	10.10	5.63	3.38-3.30	Ph 7.15 τ1 CH3 2.69
	NH2	8.80-7.40	-	-	-
				na: not assigned
				Residue	Major (298 K)
				Res. 1	6.5
				Res. 2	6.0
				Res. 3	7.2
				Res. 4	5.5
				Res. 5	6.7
					S98

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S64 -

 S64 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

	NOE correlations	Intensity
	1.NH-2.NH	w
	2.NH-3.NH	w
	3.NH-4.NH	w
	4.NH-5.NH	w
	5.NH-NH2	nd
	Ac-1.NH	s
	1.H-2.NH	s
	2.H-3.NH	s
	3.H-4.NH	s
	4.H-5.NH	s
	5.H-NH2	s
	1.H-2.H	s
	2.H-3.H	nd
	3.H-4.H	w
	4.H-5.H	w
	1.H-2.H	w
	2.H-3.H	w
	3.H-4.H	w
	4.H-5.H	m
	1.H-2.H	m
	2.H-3.H	w
	3.H-4.H	w
	4.H-5.H	w
	4.H-5.H	m
	1.Ph-2.H	m
	4.Ph-5.H	m
	1.Ph-1.H	s
	1.Ph-1.H2	w
	1.Ph-1.H3	m
	2.H-Ph	w
	2.H-4.Ph	w
	2.H-3.H	nd
	2.H-3.H	w

o: overlap with the solvent signals, nd: not detected

Table S70 -

 S70 Coupling Constants 3 J(NH,

												SUPPORTING INFORMATION
	Res. 5		10.16	5.52	1.65			τ1 CH3 2.65
	NH2		8.81-7.48	-		-			-
									na: not assigned
	Table S69 -13 C NMR in iPrOH-d7 at 298K major conformer (88%)
	Residue		C(O)		 C		 C		β C	α C		Others
	Ac		171.8		-		-		-	-		CH3 21.8
	Res. 1		162.3		44.2		19.7		na	na	ε C na τ1 C na τ2 C na τ3 C na τ4 C na
	Table S65 -1 H NMR in iPrOH-d7 at 298K major conformer (86%) Res. 2 161.1 49.7 28.8 na na		τ1 C 18.6
	Residue Res. 3 162.3	HN	45.8	 CH 19.5	 CH	na	na	Others	τ1 C 18.6
	Res. 4	Ac	161.6	-	45.8	-	19.5	-	na	na	CH3 2.03	τ1 C 18.6
	Res. 1 Res. 5	na	8.96	45.8	5.38 19.5	2.23-2.15 na	ε CH2 1.90 τ1 CH2 na τ2 CH2 2.24 τ3 CH2 2.29 na τ1 C 18.6
	Res. 2		10.60	5.71	1.57 na: not assigned	τ1 CH3 2.65
	Res. 3		10.10	5.69	1.56			τ1 CH3 2.65
	Res. 4		10.18	5.71	1.59			τ1 CH3 2.65
								Residue		Major (298 K)
	Res. 5		10.20	5.52	1.65			τ1 CH3 2.65
									Res. 1		7.1
	NH2		8.81-7.48	-		-			-
									Res. 2		6.5
									na: not assigned
									Res. 3		6.1
	Table S66 -13 C NMR in iPrOH-d7 at 298K major conformer (86%) Res. 4 5.6
	Residue		C(O)		 C		 C	Res. 5	β C	α C 5.9		Others
	Ac		172.5		-		-		-	-		CH3 21.8
	Res. 1		161.4		49.1		29.0		na	na	ε C 31.2 τ1 C 51.8 τ2 C 52.0 τ3 C na τ4 C na
	Res. 2		162.4		45.7		19.5		na	na		τ1 C 18.7
	Res. 3		162.4		45.7		19.5		na	na		τ1 C 18.7
	Res. 4		161.6		45.7		19.5		na	na		τ1 C 18.7
	Res. 5			na		45.9		19.6		na	na		τ1 C 18.7
									na: not assigned
													S104

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S73 -

 S73 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

		SUPPORTING INFORMATION
	Residue	(298 K)
	Res. 1	6.8
	Res. 2	5.8
	Res. 3	5.8
	Res. 4	6.3
	Res. 5	6.3
	Table S74 -Inter-residue NOE correlations observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s) <
	2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).
	NOE correlations	Intensity
	1.NH-2.NH	w
	2.NH-3.NH	w
	3.NH-4.NH	o
	4.NH-5.NH	w
	5.NH-NH2	nd
	Ac-1.NH	s
	1.H-2.NH	s
	2.H-3.NH	s
	3.H-4.NH	s
	4.H-5.NH	s
	5.H-NH2	m
	1.H-2.H	w
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	1.H-2.H	w
	2.H-3.H	nd
	3.H-4.H	w
	4.H-5.H	w
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	4.H-5.H	nd
		S107

Table S80 -

 S80 Coupling Constants 3 J(NH,

													SUPPORTING INFORMATION
	Res. 4		10.32		5.39			1.59		ε CH2 na τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 5		10.14		5.56			2.45-2.31		τ1 CH3 2.66
		NH2	8.88-7.75	-			-			-
										na: not assigned
	Table S79 -13 C NMR in iPrOH-d7 at 298K major conformer (91%)
	Residue		C(O)		 C		 C			β C	α C	Others
	Ac		172.0		-		-			-	-	CH3 21.7
	Table S75 -1 H NMR in iPrOH-d7 at 298K Res. 1 162.3 44.5 19.5		na	na	τ1 C 18.9
	Residue Res. 2 162.3	HN	45.7	 CH	19.5	 CH	na	na	Others	τ1 C 18.9
	Res. 3	Ac	162.4	-	45.7	-	19.5	-	na	na	CH3 2.00	τ1 C 18.9
	Res. 1 Res. 4 162.1	8.81	45.8	5.51	19.5	1.46	na	na	τ1 CH3 2.65	τ1 C 18.9
	Res. 2 Res. 5	na	10.55	49.4	5.65	23.4	1.58	na	na	τ1 CH3 2.65 ε C 20.6 τ1 C na τ2 C na τ3 C na τ4 C na
	Res. 3		10.32		5.40			1.57 na: not assigned	τ1 CH3 2.65
	Res. 4		10.21		5.61			2.40-2.26 ε CH2 2.09 τ1 CH na τ2 CH2 na τ3 CH2 2.05 τ4 CH2 na
	Res. 5		10.26		5.59			1.65			τ1 CH3 2.65
	NH2		8.66-7.50	-			-			-
								na: not assigned Residue Major (298 K)
									Res. 1		6.7
	Table S76 -13 C NMR in iPrOH-d7 at 298K
	Residue		C(O)		 C		 C	Res. 2	β C	α C 5.5	Others
									Res. 3		5.7
	Ac		171.7		-		-			-	-	CH3 21.7
									Res. 4		4.4
	Res. 1		162.5		44.6		19.5		na	na	τ1 C 18.8
									Res. 5		6.8
	Res. 2		162.3		45.5		19.5		na	na	τ1 C 18.8
	Res. 3		162.1		45.4		19.5		na	na	ε C na τ1 C na τ2 C na τ3 C na τ4 C na
	Res. 4		160.8		50.0		31.5		na	na	τ1 C 18.8
	Res. 5			na		46.0		19.5		na	na	τ1 C 18.8
										na: not assigned
													S112

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S84 -

 S84 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

												SUPPORTING INFORMATION
		Res. 5		10.30		5.73	Res. 3 1.61		6.1	τ1 CH3 2.66
		Res. 6		10.09		5.72		1.59			τ1 CH3 2.68
		Res. 7		10.17		5.53		1.64			τ1 CH3 2.66
		NH2	8.81-7.48	NOE correlations --	Intensity	-
							1.NH-2.NH na: not assigned	w
							2.NH-3.NH			w
	3.NH-NH2 Table S86 -13 C NMR in iPrOH-d7 at 298K major conformer (95%) nd
								Ac-1.NH			s
	Residue	C(O)		 C	1.H-2.NH  C	β C	α C	m	Others
	Table S81 -1 H NMR in iPrOH-d7 at 298K major conformer (>95%) 2.H-3.NH s Ac 171.9 ----	CH3 21.7
	Residue Res. 1 167.8	HN	44.5	 CH	 CH 3.H-NH2 19.6	na	na	s	Others	τ1 C 18.9
	Res. 2	Ac	167.8	-	45.8	-	-1.H-2.H 2.H-3.H 19.5	na	nd nd na	CH3 1.99	τ1 C 18.9
	Res. 3	Res. 1 168.1	8.91	45.7	5.21 1.H-2.H 1.43 19.5	na	nd na	τ1 CH2 2.63	τ1 C 18.9
	Res. 4	Res. 2	na	10.48	50.1	5.62	30.9	2.39-2.29 na	3.51 ε CH2 na τ1 CH na τ2 CH2 2.24 τ3 CH2 2.09 τ4 CH2 na ε C 20.6 τ1 C na τ2 C na τ3 C na τ4 C na
	Res. 5		167.2		45.8		19.5		na	na	τ1 C 18.9
		Res. 3		10.23		5.56		1.64			τ1 CH3 2.66
	Res. 6		168.1		45.8		19.5		na	na	τ1 C 18.9
		NH2	8.66-7.47	-		-			-
	Res. 7			na		45.8		19.5		na	na	τ1 C 18.9
									na: not assigned
									na: not assigned
	Table S82 -13 C NMR in iPrOH-d7 at 298K major conformer (>95%)
	Residue	C(O)		 C		 C		β C	α C	Others
	Ac		171.7		-		-		-	-	CH3 21.7
	Res. 1		162.2		44.5		19.8		na	na	τ1 C 18.6
	Res. 2		160.8		49.8		na		na	na	ε C 52.1 τ1 C na τ2 C na τ3 C 45.3
	Res. 3					46.1		19.7		na	na	τ1 C 18.8
									na: not assigned
	Table S83 -Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.
								Residue		Major (298 K)
								Res. 1		7.1
								Res. 2		6.2
												S114

2.H-3.H m 1.H-2.H nd 2.H-3.H nd o: overlap with the solvent signals, nd: not detected Figure S49 -1 H NMR spectrum of M(16)-ATC3-2-NH2 in iPrOH-d7 at 298K

Table S87 -

 S87 Coupling Constants 3 J(NH,

		SUPPORTING INFORMATION
	Residue	Major (298 K)
	Res. 1	6.6
	Res. 2	5.3
	Res. 3	6.0
	Res. 4	6.0
	Res. 5	5.5
	Res. 6	5.6
	Res. 7	6.0
		S117

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S88 -

 S88 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

		SUPPORTING INFORMATION
	6.H-7.H	o
	1.H-2.H	o
	NOE correlations 2.H-3.H	Intensity o
	1.NH-2.NH 3.H-4.H	w nd
	2.NH-3.NH 4.H-5.H	w o
	3.NH-4.NH	w
	4.NH-5.NH 5.H-6.H	w o
	5.NH-6.NH 6.H-7.H	w o
	6.NH-7.NH	w
	7.NH-NH2	nd
	7.NH-NH2	nd
	Ac-1.NH	s
	1.H-2.NH	s
	2.H-3.NH	s
	3.H-4.NH	s
	4.H-5.NH	s
	5.H-6.NH	s
	6.H-7.NH	s
	7.H-NH2	s
	7.H-NH2	s
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-4.H	nd
	4.H-5.H	nd
	5.H-6.H	nd
	6.H-7.H	nd
	1.H-2.H	m
	2.H-3.H	s
	3.H-4.H	nd
	4.H-5.H	w
	5.H-6.H	m
	6.H-7.H	s
	1.H-2.H	o
	2.H-3.H	o
	3.H-4.H	o
	4.H-5.H	o
	5.H-6.H	o
		S118

o: overlap with the solvent signals, nd: not detected

Table S91 -

 S91 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

								SUPPORTING INFORMATION
	NH2	9.00-7.70	-	-			-
					na: not assigned
	Table S90 -13 C NMR in iPrOH-d7 at 298K major conformer (>95%)
	Residue	C(O)	 C		 C	β C	α C	Others
	Ac	172.1	-		-	-	-	CH3 21.8
	Res. 1	na	47.7		28.7	na	na	ε C 51.8 τ1 C na τ2 C na τ3 C 45.3
	Res. 2	na	48.9		30.4	161.3	na	ε C 52.1 τ1 C na τ2 C na τ3 C 45.3
	Res. 3	na	49.4		28.6	161.5	na	ε C 49.4 τ1 C na τ2 C na τ3 C 45.3
					na: not assigned
					Residue	Major (298 K)
					Res. 1		7.7
					Res. 2		5.9
					Res. 3		5.9
	Table S92 -Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-
	d7 at 298K. Strong (s) < 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).
				NOE correlations	Intensity
					1.NH-2.NH		w
					2.NH-3.NH		w
					3.NH-NH2		nd
					Ac-1.NH		s
					1.H-2.NH		s
					2.H-3.NH		s
	Table S89 -1 H NMR in iPrOH-d7 at 298K major conformer (>95%) 3.H-NH2 s
	Residue	HN	 CH	 CH 1.H-2.H	nd	Others
	Ac		-	-	-2.H-3.H		nd	CH3 2.00
	Res. 1	8.95	5.28	2.26-2.16 ε CH2 1.97 τ1 CH 5.09 τ2 CH2 na τ3 CH2 na τ4 CH2 na 1.H-2.H nd
					2.H-3.H		nd
	Res. 2	10.59	5.47	2.44-2.31 1.H-2.H	ε CH2 na τ1 CH 5.11 τ2 CH2 na τ3 CH2 na τ4 CH2 na s
	Res. 3	10.32	5.53	2.46-2.29 2.H-3.H	ε CH2 na τ1 CH 5.11 τ2 CH2 na τ3 CH2 na τ4 CH2 na s
								S120

o: overlap with the solvent signals, nd: not detected

Table S94 -

 S94 Coupling Constants 3 J(NH,

					SUPPORTING INFORMATION
	Table S93 -1 H NMR in iPrOH-d7 at 298K major conformer (>95%)
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.02
	Res. 1	8.97	5.27	2.19	ε CH2 1.96 τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 2	10.45	5.54	2.28	ε CH2 2.06 τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 3	10.41	5.46	2.43-2.26 ε CH2 na τ1 CH 5.17 τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 4	10.36	5.56	2.45-2.31 ε CH2 na τ1 CH 5.11 τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 5	10.20	5.51	2.43	ε CH2 na τ1 CH 5.15 τ2 CH2 na τ3 CH2 na τ4 CH2 na
	NH2	8.99-7.69	-	-	-
				na: not assigned
				Residue	Major (298 K)
				Res. 1	7.1
				Res. 2	6.1
				Res. 3	nd
				Res. 4	nd
				Res. 5	nd
				nd: not detected
					S123

 CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

Table S95 -

 S95 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m) < 3.3 Å, 3.3 Å < Weak (w).

	NOE correlations	Intensity
	1.NH-2.NH	w
	2.NH-3.NH	o
	3.NH-4.NH	o
	4.NH-5.NH	o
	5.NH-NH2	nd
	Ac-1.NH	s
	1.H-2.NH	m
	2.H-3.NH	m
	3.H-4.NH	m
	4.H-5.NH	m
	5.H-NH2	m
	1.H-2.H	w
	2.H-3.H	w
	3.H-4.H	nd
	4.H-5.H	nd
	1.H-2.H	nd
	2.H-3.H	nd
	3.H-4.H	w
	4.H-5.H	nd
	1.H-2.H	nd
	2.H-3.H	m
	3.H-4.H	m
	4.H-5.H	m

o: overlap with the solvent signals, nd: not detected

Table S97 -

 S97 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

					SUPPORTING INFORMATION
	Table S96 -1 H NMR in iPrOH-d7 at 298K major conformer (89%)
	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.05
	Res. 1	8.91	5.45	2.25-2.13 ε CH2 1.97 τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 2	10.66	5.57	3.31-3.20	Ph 6.86 τ1 CH 2.65
	Res. 3	9.67	5.73	2.34-2.16	ε CH2 na τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 4	10.42	5.34	3.28-3.18	Ph 6.77 τ1 CH3 2.67
	Res. 5	9.68	5.67	2.34	ε CH2 na τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	NH2	8.74-7.70	-	-	-
				na: not assigned
				Residue	Major (298 K)
				Res. 1	7.1
				Res. 2	6.2
				Res. 3	7.2
				Res. 4	5.8
				Res. 5	7.2
					S126

Table S98 -

 S98 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m)

Table S99 -

 S99

	Residue	HN	 CH	 CH	Others
	Ac	-	-	-	CH3 2.00
	Res. 1	9.05	5.35	3.13	Ph 6.72 τ1 CH3 2.54
	Res. 2	10.22	5.73	2.39-2.29 ε CH2 2.09 τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 3	10.38	5.40	3.28-3.16	Ph 6.82 τ1 CH3 2.58
	Res. 4	9.70	5.74	2.36-2.27 ε CH2 2.11 τ1 CH na τ2 CH2 na τ3 CH2 na τ4 CH2 na
	Res. 5	10.16	5.80	3.34	Ph 7.24 τ1 CH3 2.80
	NH2	8.50-7.36	-	-	-
				na: not assigned

Table S100 -

 S100 Coupling Constants 3 J(NH,  CH) (in Hz). Values were measured in i-PrOH-d6 at 298K.

		SUPPORTING INFORMATION
	Residue	Major (298 K)
	Res. 1	7.2
	Res. 2	6.9
	Res. 3	6.0
	Res. 4	7.2
	Res. 5	7.1
		S129

Table S101 -

 S101 Inter-residue NOE correlations in the major conformer observed in the ROESY spectrum in i-PrOH-d7 at 298K. Strong (s)< 2.7 Å, 2.7 Å < Medium (m)

31. Restrained electrostatic potential (RESP) atomic partial charges calculated for ATC fragments

						SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION SUPPORTING INFORMATION
		NB HA HC H CT S CT HC CC HC	2.761054 14.266961 -6.356936 1.965822 7.738311 2.975954 5.158954 6.474409 7.546387 4.454495	-4.197451 0.01924 -2.859528 -1.735258 4.677512 4.041695 2.877297 1.589098 2.474882 1.140348	-0.425067 -1.580082 -1.141523 0.078046 -0.554899 -0.851004 -0.995139 3.760354 1.584925 -3.641834	-0.578315 0.144427 0.129441 0.404825 -0.144901 0.0619 0.019877 0.133769 0.422438 0.124626
		CA CA HC H1 HC C* H1 HC NB CT	1.466495 14.230915 -6.224395 0.953224 7.500263 4.260051 5.022019 5.344792 7.911215 4.049696	-4.292372 0.876585 -2.420363 0.89412 4.8746 5.189692 3.754063 2.768302 1.215313 4.365363	-0.608991 0.39664 0.460978 -0.267188 -1.601212 -0.618966 -1.634958 4.096121 1.433975 -4.264623	0.395849 -0.177488 0.168494 0.193121 0.109714 -0.57005 0.092756 0.133769 -0.588345 -0.512069
		CT HA HC HC HC C CT H1 CR HC	0.70455 15.292194 -4.396799 0.708062 7.830273 4.117077 4.998923 5.817472 9.079083 4.976129	-5.583182 0.717505 0.294868 0.058885 3.602653 6.627992 3.226367 4.077252 1.118283 4.561427	-0.552002 0.5697 -1.179958 -2.559914 -0.398947 -1.020027 0.494151 2.159462 0.844047 -4.340658	-0.397407 0.146176 0.151202 0.145672 0.109714 0.884374 0.006117 0.109557 0.672521 0.124626
		HC CA HC HC CT O HC CC N2 HC	1.392482 13.445678 -5.840151 1.100015 9.054575 3.582239 5.921625 7.438214 9.680014 3.565616	-6.401147 1.473805 -0.523012 -1.585592 5.357585 7.026924 3.601208 2.823303 -0.038689 4.87248	-0.338035 1.382924 -1.824701 -2.002625 -0.197792 -2.049751 0.942012 1.584569 0.571059 -4.905715	0.130255 -0.128028 0.134048 0.151599 -0.256671 -0.590998 0.028032 0.499553 -1.094466 0.124626
		HC HC HA CA Atome type HC HC HC HC NB H HC N CA HC HC Atome type CT CA H H1	-0.048653 0.216735 13.894596 12.08366 -5.707517 -2.433324 8.974612 4.222691 7.910288 10.580759 3.749704 Atom coordinates -5.52615 -5.759085 -1.509612 0.235217 1.778751 2.324757 1.677859 1.160903 -0.083705 -0.222241 -3.947857 -0.379062 6.29353 -0.332752 3.991656 0.598178 1.59797 1.44054 -0.043719 0.114186 4.589351 -3.392594 1.371865 -0.593624 1.319873 3.679327 -0.024648 -1.263318 -3.673872 -3.237018 0.681181 9.26255 5.186547 0.712204 Atom coordinates 4.51201 1.900747 1.074991 9.082486 1.597922 0.853451 9.234783 -0.910074 0.821174 2.024247 3.983392 -2.835954	0.130255 0.130255 0.144427 -0.265183 Partial 0.172169 0.1444 0.091258 0.028032 -0.587123 0.476863 0.124626 charges -0.603664 -0.233557 0.127295 0.091258 Partial charges -0.121271 0.413556 0.476863 0.153924
		Atome type S HA CT HA HC C N HC CT S CC C* CC CC CA CT O H HC HC C* NB	0.653558 11.471815 0.931178 3.231322 -3.843157 10.167219 6.962591 5.351372 9.869626 9.824353 0.398198 Atom coordinates -2.796342 2.142773 -0.052906 0.954718 -3.12378 4.809756 4.954331 1.201411 0.355596 2.625667 2.612644 2.194916 -2.001231 7.92964 2.381414 -0.561283 0.097428 2.866669 -1.141883 2.750382 -0.209766 10.934141 3.939764 7.66762 4.231249 4.035019 2.002771 9.315423 -0.517643 8.440383 3.427809 -0.006723 1.356988	-0.931974 1.929714 0.037278 -1.407957 -1.087177 -1.083502 1.717126 1.17404 0.553388 0.424935 -2.893934 -0.804951 0.674045 0.044242 -1.071584 -1.94642 -0.647536 1.764121 2.051994 0.897498 1.104961 -2.935961	Partial 0.070661 0.153065 -0.344671 0.162077 0.128951 0.750221 0.06154 -0.405055 0.012384 0.62371 -0.520275 charges -0.642903 0.960844 0.783152 0.313652 0.657874 -0.546277 0.348015 0.06154 0.131221 -0.593574 -0.582099
		N H C O NB CA CT CA CA HA HC CT OH HO CT H1 Atome type CT HC C CA H1 HC O CT	5.098439 5.607378 2.336944 1.758124 7.124661 5.882224 1.334438 -1.239878 3.441766 2.808662 3.050652 3.52689 10.311261 9.717003 6.643564 6.55162 3.540003 10.034598 8.323427 -1.311077 Atom coordinates -3.195375 -4.048365 -0.518493 0.152366 1.339198 1.706362 -0.987564 1.271964 -2.399113 -3.269626 -0.433701 -1.023596 5.253771 5.928142 5.217403 6.292263 1.419779 0.280596 4.924137 1.264997 3.399007 0.335052 10.830341 0.401542 9.238438 5.703067 -2.062977 -0.03174	0.916633 0.733633 -0.981915 -1.830705 0.572038 0.364951 -1.064472 -0.267181 -0.886176 -0.736557 -2.818531 -0.91754 -2.291446 -2.628614 0.316907 0.16095 0.000002 -0.521441 1.122973 -2.816932 0.017989 1.066238 1.375968 -2.827973	-0.684057 0.377414 0.931836 -0.598206 -0.677862 -0.024641 -0.434138 -0.741008 -0.286891 0.162805 -0.083238 -0.615309 -0.627825 0.466483 -0.26161 0.169001 0.188672 0.131221 0.887974 0.395784 Partial charges 0.019034 0.131221 -0.593955 -0.411713
		CT CT C CA CT CC CT N H1 S HC	4.633614 4.709389 -0.681573 4.829527 2.97902 5.348972 7.738311 10.068303 2.55889 9.696661 -1.361989	-2.637496 0.721567 2.606143 -2.539024 1.276497 4.548678 4.677512 4.222476 1.886875 3.161155 -0.857761	-0.34998 0.20297 -0.665164 -0.892683 -1.696414 -0.034999 -0.554899 -1.29704 0.143018 0.426388 -2.947994	-0.193615 0.646208 0.963897 -0.122726 -0.572303 0.513576 -0.144901 -0.706307 0.019034 0.061374 0.13352
		H1 H1 O HA HC NB HC H NT C* HC	4.777723 4.873355 -1.140541 5.277573 3.904733 5.194099 7.500263 9.180502 4.144853 8.247176 -2.6029	-1.557076 0.146589 3.333804 -3.518535 1.471829 3.260553 4.8746 4.692401 1.848642 3.846169 -0.146737	-0.344975 -0.533994 -1.540665 -0.748441 -1.772416 0.21307 -1.601212 -1.166083 -1.286644 1.100621 -1.888101	0.158161 -0.075898 -0.607009 0.144949 0.131293 -0.598719 0.109714 0.323289 -0.707477 -0.592112 0.13352
		CT CT S CA HC CA HC CT H C HC	5.41675 3.540003 -2.951392 5.642274 2.679399 4.007984 7.830273 10.104257 3.423918 8.003237 -2.771929	-3.240645 1.419779 0.998009 -1.421691 1.500062 2.836567 3.602653 2.780113 2.255639 5.326167 -0.033696	-1.478213 0.000002 -0.132246 -1.084369 -0.824 -0.153961 -0.398947 -1.117012 -1.875593 1.110617 -3.655912	-0.322849 0.090184 0.111959 -0.164289 0.168827 0.429002 0.109714 0.016837 0.361749 0.87973 0.13352
		HC HC CC HA HC CT CT H1 S O S	5.070717 3.741107 -2.592878 6.723501 2.495128 3.540003 9.054575 10.853233 6.723609 8.847517 -2.144998	-2.824549 2.49208 -0.635644 -1.530759 1.783134 1.419779 5.357585 2.390108 0.735742 6.182399 2.773928	-2.424376 0.002995 0.320447 -1.089334 -2.336592 0.000002 -0.197792 -1.810972 -1.921915 1.359701 -2.640893	0.144883 -0.08611 0.331687 0.144453 0.135658 -0.366738 -0.256671 0.118897 0.100809 -0.588065 0.064489
		HC CA Atome type HC CT NB CT CA HA HC HC HC HC HC HC CT HC C* C Atome type C* C	5.273753 6.911296 3.097086 2.660854 -1.316914 -3.693848 5.067071 5.700245 3.226926 3.384249 4.331047 Atom coordinates -4.321213 -2.922811 1.129851 1.088745 -0.937555 -1.605224 -0.164553 0.706022 -0.799324 -1.948927 0.823712 2.656209 1.396817 8.974612 6.29353 9.26255 5.186547 10.54133 2.405965 11.458076 2.959767 8.439428 0.978638 9.307308 -0.168291 -0.601542 3.568438 Atom coordinates -1.483213 -1.294271 -0.952818 1.058179 0.363821 0.6328 -1.269603 -1.41886 -0.045474 -1.07301 0.455035 0.635849 -0.332752 0.712204 0.310399 0.533369 -1.937878 -2.33084 -2.736958 -0.474492 5.060739 -2.653915	0.144883 0.237704 Partial charges -0.08611 0.109299 -0.624959 -0.352737 -0.127605 0.144488 0.194292 0.130384 0.122311 0.122311 0.091258 0.091258 -0.052525 0.083635 -0.590114 0.863355 -0.643104 Partial charges 0.921537
	CA HA CA HA CA HA CA HA CA HA N H CT H1 CT HC HC CA CA HA HC HC CT H1 H1 NT H S C* C H N HC HC C HC O N O H1 HC HC HC HC CT CT CC CT CA C O Atome type S C* C O O OH CT HC Atome type H Example of a .gjf file CT # M062X/6-311++g(d) geom=connectivity 7.842259 7.512295 9.197753 9.92273 9.620757 10.676221 8.69001 9.020038 7.336396 6.610648 9.573142 9.788023 9.393195 9.88044 10.004135 9.870225 9.518206 11.507786 12.292702 11.843657 1.754581 2.404812 3.319929 3.411922 2.768667 4.566338 4.673349 5.621261 7.326657 7.953735 1.570492 1.533758 4.452752 3.293886 10.167219 9.774047 9.006137 2.605057 -1.22755 1.393687 1.005491 0.871926 -3.263544 -4.280712 -4.594286 0.789723 -0.673405 1.263494 -1.673041 -1.545998 -2.298796 Atom coordinates -3.381845 -2.226269 -3.964721 -3.081123 -3.092809 -2.059205 -3.450836 -2.784202 -2.344886 -0.960249 -2.119837 -0.830180 -1.885966 -0.029477 -1.302989 0.826554 -2.174801 -0.195432 -1.816878 0.530342 1.298542 2.075876 0.363977 1.762036 2.16144 0.911991 3.120837 1.092077 1.509486 -0.292878 2.154212 -1.161497 0.551673 -0.472847 1.284484 -0.047916 0.688514 -1.033798 0.381489 -1.974895 0.63064 0.662062 1.98801 1.620359 0.198574 1.876313 0.615522 2.879205 -0.740811 1.918328 -0.018542 1.348141 -0.999925 1.130062 3.41749 0.279937 3.629488 0.546025 4.99057 0.611044 -1.577911 1.210956 -0.947673 0.539746 -0.828963 -0.993558 1.009601 -0.979427 4.809756 -1.083502 2.728098 1.023647 -1.318736 -1.986724 2.141749 -2.029169 5.867835 -3.191952 0.920679 -0.124693 -0.583856 -2.022057 -1.961192 -0.90241 -2.572078 0.893542 -1.230659 1.471753 -1.762083 -0.587199 -0.16862 -0.445708 -0.476606 -0.32534 -0.522783 -1.824174 0.478966 -0.168424 1.971288 -0.084965 2.777791 -0.623007 2.975954 4.041695 -0.851004 4.260051 5.189692 -0.618966 4.117077 6.627992 -1.020027 3.582239 7.026924 -2.049751 10.934141 3.939764 -0.647536 10.311261 5.253771 -2.291446 10.806235 0.913107 0.443375 9.898111 0.314087 0.302328 3.037172 1.354483 -2.491325 Atom coordinates 1.861248 2.920612 -3.014928 HO 9.717003 5.928142 -2.628614 HC 11.519232 0.576085 -0.320599 N 5.166287 2.056028 1.570994 CT 2.334126 2.566704 -4.392656 Pop=MK iop(6/33=2) iop(6/42=6) iop(6/50=1) CC 5.348972 4.548678 -0.034999 NB 5.194099 3.260553 0.21307 C 11.377359 0.540948 1.781776 O 11.59041 1.306037 2.69995 Atome type H 4.915367 1.254362 2.131771 HC 1.77922 3.148662 -5.128526 Ac-[ATC-pyr(d)-1]-NHMe 0 1 Atom coordinates CT 6.235275 2.789955 2.241975 HC 2.17112 1.50393 -4.571655 S -1.93170000 -1.57420000 -0.80170000 N -1.57800000 0.95090000 -0.53170000 CA 4.007984 2.836567 -0.153961 OH 11.640207 -0.773650 1.861734 N 5.102519 2.201464 1.569542 CT 6.289239 2.386998 3.68479 CT 3.820673 2.879557 -4.514631 C -0.32110000 0.38980000 -0.57730000 C -2.50890000 0.04870000 -0.65160000 CT -5.196468 -0.410123 -0.952373 CT -5.713431 -2.747054 -0.269063 HC -4.007712 -2.137021 -1.425896 S -3.215992 -0.316314 -0.071614 CC -2.381612 -1.824611 -0.24807 NB -1.078313 -1.733035 -0.366978 N 6.962591 4.954331 1.717126 H 7.66762 4.231249 1.764121 CT 6.643564 5.217403 0.316907 CT 3.540003 1.419779 0.000002 HO 12.007232 -0.95972 2.747852 H 4.920461 1.384366 2.134614 HC 7.087261 2.934955 4.185793 HC 4.121581 2.655618 -5.387446 C -0.30810000 -0.97090000 -0.73570000 C -3.98880000 0.33480000 -0.65910000 HC 4.331047 0.823712 0.455035 CC 8.741365 2.215217 -1.434024 CT 6.103412 3.028322 2.237464 HC 6.483241 1.316755 3.755811 CT 4.59757 2.065598 -3.48678 ……... C 3.10350000 -2.51150000 -1.37780000 HC 2.656209 1.396817 0.635849 NB 7.647352 2.967079 -1.063118 CT 6.189373 2.638346 3.68333 HC 5.458811 2.586143 4.100999 HC 5.523227 2.2605 -3.562766 H 1.93750000 -0.80790000 -1.96300000 H 2.92390000 -3.38920000 -1.96280000 H 3.93770000 -1.97760000 -1.78280000	-0.222312 0.144091 -0.143762 0.146288 -0.158384 0.142681 -0.143762 0.146288 -0.222312 0.144091 -0.641985 0.366648 -0.292761 0.182286 -0.471724 0.174598 0.174598 0.349685 -0.265183 0.153065 -0.023257 -0.023257 0.037965 0.019479 0.019479 -0.642954 0.284005 0.227223 -0.790349 0.885041 -0.718778 0.130437 0.122311 0.083635 -0.564065 -0.662169 -0.597714 0.750221 0.369519 0.202868 0.164141 0.178847 0.124168 0.104182 -0.331268 0.766725 -0.485129 -0.743098 1.010532 -0.614702 0.0619 -0.57005 0.884374 -0.590998 -0.546277 -0.170879 0.097791 0.371139 Partial charges -0.193046 -0.627825 0.097791 -0.424388 -0.694829 0.466483 0.513576 -0.598719 0.729613 -0.583185 0.13185 0.36509 Partial charges 0.13185 0.059926 Partial charges 0.429002 -0.680775 -0.683301 0.546334 -0.392918 0.522678 -0.613224 -0.568486 -0.036749 0.07686 0.393032 -0.592437 -0.520275 0.348015 -0.26161 0.474049 0.364863 0.125288 -0.065167 -0.366738 0.435808 0.051622 0.125288 -0.512069 0.122311 -0.513845 -0.420711 0.125288 0.124626 0.122311
	H	CC CA O HC CT H1 HC CA HC H1 HC 3.31680000 -2.79350000 -0.36790000 3.177946 -2.947346 13.654719 0.484462 7.676737 5.934703 -5.28355 -3.714061 -3.134346 -3.121936 6.55162 6.292263 3.293886 1.009601 6.534704 2.327339 6.936128 3.256097 6.040322 3.85996 4.297632 2.290555	-0.528937 -0.811773 -0.122042 -0.007855 -0.259149 0.16095 -0.979427 -1.27607 4.182169 2.169989 -2.613893	0.601545 -0.128028 -0.602566 0.110748 -0.412166 0.169001 0.122311 0.313043 0.133769 0.113575 0.124626
						S132 S133 S134 S135 S136 S137 S138 S139 S140 S141 S142 S143

  1/ Create .mol2 files of ATC-monomers using Chimera and save them in ./Bureau/Julie/ATC/init 2/ Open terminal : cd Bureau/Julie/ATC 3/ Launch the following script by replacing "name_of_residue" with the appropriate three-letter Creation of the parameters and coordinates files from a .mol2 file (Chimera) antechamber -i ./init/name_of_residue.mol2 -fi mol2 -o ./prep/name_of_residue.prepin -fo prepi -c bcc -s 2 > ./prep/antechamber.out parmchk -i ./prep/name_of_residue.prepin -f prepi -o ./prep/name_of_residue.frcmod We identify the atoms to remove and the one that will be used as connectors for the creation of sequences. -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/name_of_sequence2.frcmod parmchk -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/name_of_sequence3.frcmod parmchk -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/AGJ2180.frcmod parmchk -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/AGJ2053.frcmod parmchk -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/AGJ2167.frcmod #Association of residues from the ATC-library without capping then minimisation of the obtained structure ATC/Librairie_ATC_sans_cap/ACE_1.frcmod loadamberparams ./ATC/Librairie_ATC_sans_cap/NHE_1.frcmod #change the name of the sequence and the order and name of the specified residues #As many sequences as we want can be created at the same time, it is just needed to add new lines and double the following command lines to save the new sequences files Sequences/prep/name_of_sequence1.prmtop -c ./Sequences/prep/name_of_sequence1.rst > ./Sequences/prep/name_of_sequence1.pdb sander -O -i min.in -o ./Sequences/prep/name_of_sequence2.out -c ./Sequences/prep/name_of_sequence2.inpcrd -p ./Sequences/prep/name_of_sequence2.prmtop -r ./Sequences/prep/name_of_sequence2.rst ambpdb -aatm -p ./Sequences/prep/name_of_sequence2.prmtop -c ./Sequences/prep/name_of_sequence2.rst > ./Sequences/prep/name_of_sequence2.pdb sander -O -i min.in -o ./Sequences/prep/name_of_sequence3.out -c ./Sequences/prep/name_of_sequence3.inpcrd -p ./Sequences/prep/name_of_sequence3.prmtop -r ./Sequences/prep/name_of_sequence3.rst ambpdb -aatm -p ./Sequences/prep/name_of_sequence3.prmtop -c ./Sequences/prep/name_of_sequence3.rst > ./Sequences/prep/name_of_sequence3.pdb

	SUPPORTING INFORMATION SUPPORTING INFORMATION
	cat > leap.in <<EOF source leaprc.gaff source leaprc.ff99SBnmr loadamberprep ./prep/name_of_residue.prepin loadamberparams ./prep/name_of_residue.frcmod loadamberparams ./name_of_sequence1 = sequence { ACE LF1 LF1 LE2 LF1 LF1 NHE } #remove name_of_residue name_of_residue.1.HH31 cat > leap.in <<EOF name_of_sequence2 = sequence { ACE LF1 LF1 LF1 LE2 LF1 NHE }
	remove name_of_residue name_of_residue.1.HH32 source leaprc.gaff name_of_sequence3 = sequence { ACE LF1 LF1 LF1 LF1 LE2 NHE }
	remove name_of_residue name_of_residue.1.HH33 source leaprc.ff99SBnmr saveamberprep name_of_sequence1 ./Sequences/prep/name_of_sequence1.prepin
	remove name_of_residue name_of_residue.1.CX2 #load all the prepin and frcmod files needed (every useful residue) saveamberprep name_of_sequence2 ./Sequences/prep/name_of_sequence2.prepin
	remove name_of_residue name_of_residue.1.CX #as well as the ACE and NHE extremities modified to match the same nomenclature as ours (ACE_1 and saveamberprep name_of_sequence3 ./Sequences/prep/name_of_sequence3.prepin
	NHE_1) saveamberparm name_of_sequence1 ./Sequences/prep/name_of_sequence1.prmtop remove name_of_residue name_of_residue.1.OX ./Sequences/prep/name_of_sequence1.inpcrd loadamberprep ./ATC/Librairie_ATC_sans_cap/LF1.prepin remove name_of_residue name_of_residue.1.NX remove name_of_residue name_of_residue.1.HNX saveamberparm name_of_sequence2 ./Sequences/prep/name_of_sequence2.prmtop loadamberprep ./ATC/Librairie_ATC_sans_cap/LF2.prepin ./Sequences/prep/name_of_sequence2.inpcrd
	code: loadamberprep ./ATC/Librairie_ATC_sans_cap/LF3.prepin saveamberparm name_of_sequence3 ./Sequences/prep/name_of_sequence3.prmtop remove name_of_residue name_of_residue.1.CX3 ./Sequences/prep/name_of_sequence3.inpcrd loadamberprep ./ATC/Librairie_ATC_sans_cap/LF4.prepin remove name_of_residue name_of_residue.1.HH34 quit loadamberprep ./ATC/Librairie_ATC_sans_cap/LF5.prepin remove name_of_residue name_of_residue.1.HH35 EOF loadamberprep ./ATC/Librairie_ATC_sans_cap/LA1.prepin remove name_of_residue name_of_residue.1.HH36 tleap -f leap.in > ./Sequences/prep/leap.out loadamberprep ./ATC/Librairie_ATC_sans_cap/LA6.prepin set name_of_residue head name_of_residue.1.N #Minimisation of the structure loadamberprep ./ATC/Librairie_ATC_sans_cap/LL1.prepin set name_of_residue tail name_of_residue.1.C set name_of_residue.1 connect0 name_of_residue.1.N sander -O -i min.in -o ./Sequences/prep/name_of_sequence1.out -c loadamberprep ./ATC/Librairie_ATC_sans_cap/LE1.prepin ./Sequences/prep/name_of_sequence1.inpcrd -p ./Sequences/prep/name_of_sequence1.prmtop -r
	#Antechamber for 1 ATC-monomer set name_of_residue.1 connect1 name_of_residue.1.C loadamberprep ./ATC/Librairie_ATC_sans_cap/LE2.prepin ./Sequences/prep/name_of_sequence1.rst
	./Librairie_ATC_sans_cap/name_of_residue.inpcrd loadamberparams ./ATC/Librairie_ATC_sans_cap/LF3.frcmod source leaprc.gaff #corresponding .prepin/.prmtop/.inpcrd files name_of_residue = sequence { name_of_residue } saveamberprep name_of_residue ./Librairie_ATC_sans_cap/name_of_residue.prepin saveamberparm name_of_residue ./Librairie_ATC_sans_cap/name_of_residue.prmtop loadamberprep ./ATC/Librairie_ATC_sans_cap/ACE_1.prepin loadamberprep ./ATC/Librairie_ATC_sans_cap/NHE_1.prepin loadamberparams ./ATC/Librairie_ATC_sans_cap/LF1.frcmod loadamberparams ./ATC/Librairie_ATC_sans_cap/LF2.frcmod #cat > leap.in <<EOF #We now create a sequence containing only the residue (ATC-monomer) without its extremities to save the loadamberprep ./ATC/Librairie_ATC_sans_cap/LD2.prepin ambpdb -aatm -p ./
	source leaprc.ff99SBnmr quit loadamberparams ./ATC/Librairie_ATC_sans_cap/LF4.frcmod
	loadamberprep ./prep/name_of_residue.prepin EOF loadamberparams ./ATC/Librairie_ATC_sans_cap/LF5.frcmod
	loadamberparams ./prep/name_of_residue.frcmod tleap -f leap.in > ./prep/leap.out loadamberparams ./ATC/Librairie_ATC_sans_cap/LA1.frcmod
	saveamberparm name_of_residue ./prep/name_of_residue.prmtop ./prep/name_of_residue.inpcrd parmchk -i ./prep/name_of_residue.prepin -f prepi -o ./Librairie_ATC_sans_cap/name_of_residue.frcmod loadamberparams ./ATC/Librairie_ATC_sans_cap/LA6.frcmod
	quit loadamberparams ./ATC/Librairie_ATC_sans_cap/LL1.frcmod 4/ In the terminal: cd .. EOF loadamberparams ./ATC/Librairie_ATC_sans_cap/LE1.frcmod
	tleap -f leap.in > ./prep/leap.out loadamberparams ./ATC/Librairie_ATC_sans_cap/LE2.frcmod
	ambpdb -aatm -p ./prep/name_of_residue.prmtop < ./prep/name_of_residue.inpcrd > ./prep/name_of_residue.pdb loadamberparams ./ATC/Librairie_ATC_sans_cap/LD2.frcmod
	S145 S147

#We must be in terminal ./Bureau/Julie/ #Replace "name_of_sequence" by the appropriate same parmchk -i ./ATC/prep/lambda.prepin -f prepi -o ./Sequences/prep/name_of_sequence1.frcmod SUPPORTING INFORMATION S146 parmchk

  Create a "NOE restraints" text file named "contraintes.txt" (example of this file will be given at the end of this procedure) 7/ Open "prep" folder and copy-paste the 7 previously obtained files(.frcmod, .inpcrd, .out, .pdb, .prepin, .prmtop, .rst) for the desired sequence (they are located in Here we can modify the potential r4 strong between Hgamma(i) and NH(i+1) from 3.20 a 3.50 #edit the sa.in file by changing at the bottom of the page DISTANG="name.dist" by DISTANG="name_of_sequence".dist # Simulated annealing under NMR refinement (at least twice, until stabilisation of energies and gradients) In this file, we chose the 20 structures of lowest energy without violation greater than 0.3 Å 10/ Creation in folder sa2 of a list with these 20 structures called file_best.nam, containing

	SUPPORTING INFORMATION SUPPORTING INFORMATION
	done #Conversion from .rst to .pdb for x in `seq 1 100` do ambpdb -aatm -p ./prep/name_of_sequence.prmtop -c ./sa2/name_of_sequence_$x.rst > 6/ Bureau/Julie/Sequences/prep) ./sa2/name_of_sequence_$x.pdb
	done
	#PART 1
	#MD at 1200K to generate initial structures 8/ Go to the terminal:
	sander -O -i cook_heat.in -o ./init/cook_heat.out -p ./prep/name_of_sequence.prmtop -c cd sa2/out
	./prep/name_of_sequence.rst -x ./init/name_of_sequence.mdcrd sviol *out>viol.out
	cat > trajin <<EOF gedit viol.out
	trajin ./init/name_of_sequence.mdcrd
	trajout ./init/name_of_sequence.rst restart EOF cpptraj ./prep/name_of_sequence.prmtop < trajin 9/ name_of_sequence_XX.pdb
	#Minimisation of the initial structures
	for x in `seq 1 100` 11/ In the terminal:
	cd ..
	dist -map
	map.C71
	#PART 2
	#for x in `seq 1 100`
	do
	sander -O -i sa.in -o ./sa1/out/name_of_sequence_$x.out -c ./min/name_of_sequence_$x.rst -p
	./prep/name_of_sequence.prmtop -r ./sa1/name_of_sequence_$x.rst -x ./sa1/traj/name_of_sequence_$x.traj
	done
	for x in `seq 1 100`
	S148 S149

do sander -O -i min.in -o ./min/out/name_of_sequence_$x.out -c ./init/name_of_sequence.rst.$x -p ./prep/name_of_sequence.prmtop -r ./min/name_of_sequence_$x.rst done #Preparation of the distance file makeDIST_RST -upb contraintes.txt -pdb ./prep/name_of_sequence.pdb -rst name_of_sequence.do sander -O -i sa.in -o ./sa2/out/name_of_sequence_$x.out -c ./sa1/name_of_sequence_$x.rst -p ./prep/name_of_sequence.prmtop -r ./sa2/name_of_sequence_$x.rst -x ./sa2/traj/name_of_sequence_$x.traj

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Scheme 10: A/Hantzsch cyclisation in two steps. B/Synthesized ATC-monomers via cyclisation then aromatisation, yields are calculated from both bromination and Hantzsch cyclisation steps

Bonnel, C., Thesis, Oligopeptides Construits autour du γ-Aminoacide ATC : Syntheses, Analyses Structurales et Evaluation Biologique (2016).

Byler, D. M. et al., Biopolymers, 25, 469-87 (1986).

Haris, P. I. et al., Biopolymers, 37, 251-63 (1995).

Surewicz, W. K. et al., Biochim. Biophys. Acta, 952, 115-30 (1988).

Vass, E. et al., Chem. Rev., 103, 1917-54 (2003).

Braiman, M. S. et al., Annu. Rev. Biophys. Biophys. Chem., 17, 541-70 (1988).

Aguesseau-Kondrotas, J. et al., Chem. -Eur. J., 25, 7396-7401 (2019).

H NMR indicators

Roux, S. et al., J. Pept. Sci., 14, 354-59 (2008).

Tsui, V. et al., Biopolymers, 56, 275-91 (2000).

Koradi, R. et al., J. Mol. Graph., 14, 51-55 (1996).

C NMR (CD3OH, 100 MHz) C18-RP HPLC analysis

ACKNOWLEDGEMENTS

Premièrement, j'aimerai remercier mon directeur de thèse, Docteur Ludovic Maillard et ma coencadrante, Docteur Renata Marcia De Figueiredo. Ludovic, tu as su être à mon écoute, me guider lorsqu'il le fallait, m'écouter et me faire confiance lorsque je souhaitais voler de mes

GENERAL EXPERIMENTAL CONDITIONS

Commercially available reagents and solvents were used without any further purification.

Reactions were monitored by HPLC using an analytical Chromolith® Speed Rod RP-C18 185 Pm column (50 x 4.6 mm, 5 µm) using a flow rate of 5.0 ml/min, and gradients from 100/0 to 0/100 eluents A/B over 3 min, in which eluents A = H2O / TFA 0.1% and B = CH3CN / TFA 0.1%. Detection was done at 214 nm and 254 nm using a Photodiode Array Detector. Retention times were reported as follows: LC: rt = (min). LC-MS spectra (ESI) were recorded on an HPLC using an analytical Chromolith Speed Rod RP-C18 185 Pm column (50 x 4.6 mm, 5 µm) using a flow rate of 3.0 mL/min, and gradients of 100/0 to 0/100 eluents A/B over 2.5 min, in which eluent solvent A = H2O / HCOOH 0.1% and solvent B = CH3CN/HCOOH 0.1%. High-Resolution Mass Spectrometric analyses were performed with a time-of-flight (TOF) mass spectrometer fitted with an Electrospray Ionization Source (ESI). All measurements were performed in the positive ion mode. Melting points (mp) are uncorrected and were recorded on a capillary melting point apparatus. Enantiomeric excesses were determined by Chiral HPLC analysis using a Chiralpak® IC column (250 x 4.6 mm) with n-hexane/isopropanol (80/20) as eluent or Chiralpak® IA column (250 x 4.6 mm) with n-hexane/isopropanol (90/10) as eluent and a flow rate of 1 ml/min. [START_REF] Nanda | Designing Artificial Enzymes by Intuition and Computation[END_REF] H and [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR spectra were recorded at room temperature in deuterated solvents. Chemical shifts (δ) are given, in this document, in parts per million, relative to TMS or relative to the solvent [ 1 H: δ (CDCl3) = 7.24 ppm; [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C: δ (CDCl3) = 77.2 ppm]. The following abbreviations are used to designate the signal multiplicities: s (singlet), d (doublet), dd (doublet doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Circular dichroism (CD) experiments were performed using a Jasco J815 spectropolarimeter.

The spectra were recorded at 50 µM compounds dissolved in iPrOH using a 1 mm path length CD cuvette at 4°C, over a wavelength range of 190-300 nm. Continuous scanning mode was used, with a response of 1.0 s with 0.5 nm steps and a bandwidth of 1 nm. The signal to noise ratio was improved by acquiring each spectrum over an average of three scans. Baseline was corrected by subtracting the background from the sample spectrum.

Middle-infrared experiments (400-5000 cm -1 ) were recorded in the transmission mode. The measurements were conducted on a Bruker Tensor 27 spectrometer equipped with a deuterated (L)-alanine doped triglycene sulphate (DLATGS) pyroelectric detector, a Globar source, and potassium bromide (KBr) beam splitter. The spectral resolution was 4 cm -1 , and 128 scans were SUPPORTING INFORMATION S5 co-added for each spectrum. The compounds were dissolved at 2 mM concentration in iPrOH transferred in a liquid cell equipped with CaF2 windows separated by a teflon spacer (thickness: 50 μM). A spacer thickness of 50 μM provide exploitable signal in term of signal-to-noise ratio S/N (S/N (Peak to peak = 4x10 -5 ), S/N (quadratic mean (RMS) = 1x10 -5 between 2000 and 2100 cm -1 ). Bellow this value, significant compensation problems between solvent spectral bands used as reference and sample spectrum appear. The FT-IR spectra were not smoothed. Linear baseline substraction and deconvolution were performed using IGOR Pro 7.0 software (WaveMetrics).

II. SYNTHESIS OF ATC-MONOMERS

Catalysts (46), ( 47 1. General procedure for the synthesis of β-keto-ester (42) Imidazolide formation: In a 250 mL two-neck flask under a nitrogen atmosphere was dissolved the Fmoc-AA-OH (1.0 equiv., 27.14mmol) in dry THF. Then CDI (1.1 equiv., 29.85mmol, 4.84g) was added in three turns. A catalytic amount of DMAP (3mol%, 0.8142mmol, 99mg) was added 2-3 min after and the solution was stirred for 1h at room temperature.

Enolate formation: Under a nitrogen atmosphere, a 500 mL three-neck flask was loaded with LiHMDS (22equiv, 597.6mmol, 100mL, 1M solution in THF) followed by dry THF (100mL).

After cooling at -78°C 2-methylbut-3-en-2-yl (4.0 equiv, 108.6mmol, 13.91g) was added dropwise over 10 min. The solution was stirred at -78°C for 10 min, then at r.t. for 10 min and finally at -78°C for 20 min. 47.3; 48.0; 60.9; 67.1; 82.8; 113.5; 120.1 (2C); 125. 2984; 1738; 1713; 1692; 1534; 1323; 1254; 1124; 1031; 929; 836; 755; 741; 703. ( Hz, 2H). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 17.4; 26.4 (2C); 47.0; 47.3; 56.0; 67.1; 82.8; 113.6; 120.1 (2C); 125. Hz, 2H) ppm. [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 26. 1, 26.4, 26.5, 28.2 (3C), 31.2, 47.4 (2C), 59.7, 67.1, 81.1, 82.8, 113.5, 120.2 (2C), 125.2 (2C), 127.2 (2C), 127.9 (2C), 141. 5, 141.9 (2C), 143.8, 143.9, 156.2, 165.6, 172.3, 201.7 = 6.6 Hz, 1H), 4.38-4.43 (m, 1H), 4.46-4.48 (m, 1H), 4.55-4.57 (m, 1 H), 5.06 (d, J = 10.7 Hz, 1H), 5.15 (d, J = 17.6 Hz, 1H), 5.87 (d, J = 9.6 Hz, 1H), 6.08 (dd, J = 10.7, 16.9 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.74 (d, J = 7.6 Hz, 2H) ppm. [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 26.4 (2C), 28.2 (3C), 36.7, 47.4, 56.9, 67.3, 82.2, 113.4, 120.2 (2C), 125.2 (2C), 127.2 (2C), 127.9 (2C), 141. 5, 142.0, 143.8, 156.3, 165.8, 201.7

Condensation

General procedure for ATC-monomer synthesis

(45a) to (45g) were synthesized following Scheme S1. [189] Scheme S1

Synthesis of bromo-β-ketoesters (43):

To a solution of the β-ketoester (42) (1.0 equiv., 17.5mmol) in acetonitrile (100mL) was added magnesium perchlorate (0.33 equiv., 5.77mmol, 1.29g). The solution was stirred at -45°C for 10 min. A solution of NBS (1.05 equiv., 18.36mmol, 3.27g,) in acetonitrile (160mL) was then added dropwise over 20 min. The reaction was completed after few minutes stirring at -45°C (HPLC monitoring). The mixture was diluted with Et2O (150mL), washed with water (2×100mL) and brine (3×100mL). The organic layer was dried on MgSO4, filtered and the solvent was removed under vacuum to give the crude product which was used in the next step without further purification.

Hantzsch cyclization to access (44):

To a solution of α-mono-brominated β-ketoester (43) (1.0 equiv, 15.6mmol) in absolute ethanol was added a solution of the thioamide (3 equiv., 46.7mmol) dissolved in absolute ethanol. The solution was heated for 2 h at 35°C until completion of the reaction (HPLC and TLC monitoring). EtOH was evaporated and the yellowish solid was partitioned between EtOAc (50mL) and water (50mL). The organic layer was washed with water (3×50 mL) and brine (1×50mL). The combined organic layers were dried on magnesium sulfate, filtered and evaporated under vacuum to yield the crude product.

Purification by column chromatography on silica gel afforded ATC (44).

SUPPORTING INFORMATION S17

Removal of the dimethylallylester: Under an argon atmosphere, Ac-ATC-O-dimethylallylester (44) (0.68 mmol) was dissolved in dry THF (10 mL). Tetrakis (triphenylphosphine)palladium (0) (3 mol %) was then added to the solution and the orange mixture was stirred for 5 min at r.t.. Hz,1 H), 5.75 (m, 1H), 7.28 (m, 2H), 7.37 (q, J = 7.9 Hz, 2H), 7.54 (m, 2H), 7.73 (dd, J = 3.2 and 7.9 Hz, 2H), 8.58 (s, 1H), 11.55 ppm (s, 1H). [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (CDCl3, 100 MHz): δ = 24.3, 30.5 (2C), 32.8, 45.7, 47.4, 49.7, 53.0, 59.5, 68.1, 120.2 (2C)

Synthesis of (47)

Compound (47) was prepared following Scheme S3.

Scheme S3

Synthesis of A: IBCF (4.04 mmol, 1.2 equiv.) and N-methylmorpholine (4.04 mmol, 1.2 equiv.)

were added to a solution of (45i) (3.37 mmol, 1 equiv.) in 15 ml anhydrous THF at 0°C. The suspension was stirred for 15 min at 0°C. iPrNH2 (1.3 equiv.) was then added to the mixture

then the solution was stirred 10 min at room temperature (TLC monitoring: alumina, 100 % DCM). The solution was diluted using 10 ml DCM then washed twice with 1M aq KHSO4 and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure.

The crude was purified on silica (eluent: DCM

Hz, 14H), 1.7-2.4 (m, 11H), 3.3-3.6 (m, 2H), 3.9-4.0 (m, 1H), 4.8-5.1 (m, 2H) ppm. [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (DMSO-d6, 100 MHz): δ = 22.5 (3C), 23.81, 23.83 (3C), 28.18 (3C), 29.08, 31.42, 33.02, 41.90, 47.19, 47.96, 59.19, 79.86, 80.19, 131.15, 153.17, 153.78, 159.74, 171.30 (2C), 176. ), 9.8-9.9 (br, 1H) ppm. [START_REF] Fodje | Occurrence, conformational features and amino acid propensities for the π-helix[END_REF] C NMR (DMSO-d6, 100 MHz): δ = 22.00 (2C) 23.02, 29.92, 30.44, 30.7, 30.98, 45.20, 47.59, 47.96, 58.9, 133.21, 153.15, 158.62, 164.96, 170.89, 173.52

Synthesis of ATC3-2-NHiPr:

ATC3-2-NHiPr was prepared in solution following Scheme S4.

Scheme S4

Synthesis of C: IBCF (130 µl, 0.98 mmol, 1.2 equiv.) and N-methylmorpholine (110 µl, 0.98 mmol, 1.2 eq) were added to a solution of (45a) (400 mg, 0.82 mmol, 1.0 equiv.) in 2 ml anhydrous THF at 0°C. The suspension was stirred for 15 min at 0°C. iPrNH2 (84µl, 1.2 equiv.)

was then added to the mixture then the solution was stirred for 10 min at room temperature (TLC monitoring: alumina, 100 % DCM). The solution was diluted using 10 ml DCM then washed twice with 1M aq KHSO4 and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. White solid. Yield: 86%. LC-MS: (ESI+): m/z 526.2 ([M+H] + ) 100%. The resulting material was then stirred for 1 hour at RT in 5 ml Et2NH / DMF (2:8 vv). The solvent was removed under reduced pressure yielding C that was used without any purification.

Synthesis of D:

To a solution of C (206 mg, 0.68 mmol, 1.0 equiv.) and (45i) (460 mg, 0.68 mmol, 1.0 equiv.) in 5 ml anhydrous DCM was added EDCI, HCl (143 mg, 1.1 equiv), HOBt (100 mg, 1.1 equiv.) and NMM (82 µl, 1.1 equiv.). The solution was stirred for 3 hours at RT to completion (HPLC monitoring). The solvent was removed under reduced pressure then the Synthesis of E: D (431 mg, 0.625 mmol, 1.0 equiv.) was stirred for 1 hour at RT in 5 ml Et2NH / DMF (2:8 vv). The solvent was removed under reduced pressure. The crude was diluted in 5 ml anhydrous DCM containing (45a) (303 mg, 0.625 mmol, 1.0 equiv.), EDCI, HCl (132 mg, 1.1 equiv), HOBt (93 mg, 1.1 equiv.) and NMM (76 µl, 1.1 equiv.). The solution was stirred 3h at rt to completion (HPLC monitoring). The solvent was removed under reduced pressure then the crude was purified by flash chromatography on silica gel (DCM / AcOEt from 100/0 to 6/4).

Yield: 50%. LC-MS: (ESI+): m/z 1207. 9-127.1-127.8-128.5-128.6-128.7-128.8-129.0 (14C); 132.1; 132.2; 134.8; 136.3; 137.4; 141.3 (2C); 143.5; 143.7; 154.2; 154.2-154.6 (3C) 9; 138.6; 154.5; 156.0; 158.5; 158.9; 159.9; 161.3; 161.5; 166.9; 168.4; 171.5; 171.6; 176.7.

Synthesis of ATC3

Synthesis of ATC5-3-NHiPr

ATC5-3-NHiPr was prepared in solution following Scheme S5.

Scheme S5

General procedure for Fmoc removal: The Fmoc-protected compound was stirred for 1 hour at RT in Et2NH / DMF (2:8 vv). The solvent was removed under reduced pressure and the resulting product was used without any other purification.

General procedure for removal of dimethylallyl protecting groups: Under an argon atmosphere, the dimethylallylester (1 equiv.) was dissolved in dry THF (10 mL for 0.7 mmol).

Tetrakis (triphenylphosphine)palladium(0) (3 mol %) was then added to the solution and the orange mixture was stirred for 5 min at RT. Then PhSiH3 (1.2 eq) was added in one portion and the solution was stirred for 30 min (HPLC monitoring). The solvent was then evaporated under vacuum and the resulting product was used without any other purification.

General procedure for peptide coupling:

To a solution of acid (1.0 equiv.) and amine (1.0 equiv.) in anhydrous DCM (5 ml for 0.7 mmol) was added EDCI, HCl (1.1 equiv), HOBt (1.1 equiv.) and NMM (1.1 equiv.). The solution was stirred for 3 hours at RT to completion (HPLC monitoring). The solvent was removed under reduced pressure then the crude was purified by flash chromatography on silica gel.

SUPPORTING INFORMATION S24

Solid phase peptide synthesis:

All reagents and solvents were obtained from commercial sources and used without further purification. Solid-phase synthesis was performed with a ChemMatrix® Rink Amide resin loaded at 0.49 mmol/g using Fmoc/t-Bu chemistry. Resin (0.5 mmol) was swollen in Nmethylpyrrolidone (NMP) for 10 minutes and filtered. Fmoc-ATC-OH (2 equiv.), DIC (2 equiv.), Oxyma Pure (2 equiv.) and NMP (30 ml/g) were added in this order for each peptide coupling (overnight at r.t.). Resin was washed using the following procedure: The catalyst ATC5-3-NH2 (0.0037 mmol, 4.9 mg, 0.1 equiv.) was dissolved in 150µL of a solution of NMM/iPrOH (11 µL in 4mL). The nitrostyrene (0.037 mmol, 1.0 equiv.) and the cyclohexanone (38.5 µL, 0.37 mmol, 10.0 equiv.) were then added and the reaction mixture was stirred at 4°C for 16 hours.

Monitoring was done by diluting 5µL of the reaction mixture in 400µL MeOH.

NMR analyses of M(12)-ATC5-2-NH2

NMR analyses of M(15)-ATC5-5-NH2

NMR analyses of M(17)-ATC7-4-NH2

Structure parameters

Table S102 -Average values (°) of the backbone torsion angles

Compound

Residue φ θ ζ ψ

ATC5-2-NH2

Res. 1 -67.7 ± 49.5 114.2 ± 22.0 -3.6 ± 3.2 -18.6 ± 24.6 Res. 2 -92.0 ± 65.8 98.3 ± 17.5 -4.6 ± 1.6 -29.7 ± 7.9 Res. 3 -67.0 ± 18.7 122.9 ± 7.9 -4. VII. CIRCULAR DICHROISM Circular dichroism (CD) experiments were carried out using a Jasco J815 spectropolarimeter.

The spectra were recorded at 50 µM compounds dissolved in iPrOH using a 1 mm path length CD cuvette at 4°C, over a wavelength range of 190-300 nm. Continuous scanning mode was used, with a response of 1.0 s with 0.5 nm steps and a bandwidth of 1 nm. The signal to noise ratio was improved by acquiring each spectrum over an average of three scans. Baseline was corrected by subtracting the background from the sample spectrum.

Name of sequence mre max λmax (nm) mre min λmin (nm) Crystal evaluation and data collection were performed on the XRD1 beamline of the Elettra synchrotron (Trieste, Italy) on a Huber 4-circles kappa goniometer and a Pilatus 2M detector.

The incident wavelength was set at 0.7000 Å. The XDS-program 3 was used for frame integration using default parameters, for the empirical absorption correction using spherical harmonics employing symmetry-equivalent and redundant data, and for the correction for Lorentz and polarization effects. The crystal structure was solved using the ab-initio iterative charge flipping method with parameters described by Van der Lee 4 using the Superflip program 5 and it was refined using full-matrix least-squares procedures as implemented in CRYSTALS 6 on all reflections with I > 2(I).

The H atoms were partially located in a difference map and partially positioned geometrically, and all were repositioned geometrically. They were initially refined with soft restraints on the bond lengths and angles to regularize their geometry (C---H in the range 0.93-0.98 Å) and Keywords: Foldamers, constrained γ-amino acids, organocatalysis, peptides, structural studies