Synopsis The thesis entitled “Synthesis of Glyco-amino-acids, Glycosyl-amino-acids, and α-Amino γ-Lactams from Carbohydrate Derived Donor-Acceptor Cyclopropanes” is divided into five chapters. Chapter 1: Introduction and Background: Carbohydrate Derived Cyclopropanes and Glycoconjugates of Amino Acids and Peptides In this chapter, introduction and background on cyclopropanes, carbohydrate derived DA-cyclopropanes, glycopeptides and its mimetics is discussed Chapter 2: Efficient Synthesis of Glycosyl Esters of Amino Acids from Carbohydrate Derived Cyclopropanecarboxylates In this chapter, the N-iodosuccinimide (NIS) mediated ring opening of carbohydrate derived donor-acceptor (DA) cyclopropanes with carboxylic group of various N-protected amino acids is discussed. Under mild conditions, glucosyl esters of amino acids have been synthesized in moderate to good yields. This methodology has also been applied to galactose derived DA-cyclopropanes for the synthesis of galactosyl-amino-acid derivative. Among three N-protected valine derivatives (–Fmoc, –Boc, and –Cbz), the reaction of N-Fmoc protected valine derivative of glycosyl-amino-acid has not been successful due to the steric hindrance of bulky Fmoc group. Chapter 3: Synthesis of O–Linked Glycosyl-amino-acids & C–Linked Glyco-amino-acids. In this chapter, the synthesis of glycosyl-amino-acids and glyco-amino-acids by the NIS mediated ring opening of carbohydrate derived DA-cyclopropanes is reported. To synthesize the precursors of glycopeptides, deprotection of NHBoc has been performed with trifluoroacetic acid (TFA) and trimethylsilyl chloride (TMSCl). Trimethylsilyl chloride is found to be a better reagent than trifluoroacetic acid for this reaction. The synthesis of both O–linked glycosyl-amino acids and C–linked glycopeptides from single starting material using the orthogonal strategy at amine groups has been achieved. In these glycoconjugates of amino acids, the azide group (–N3) has been used as a masked amine (–NH2) which circumvents the protection and deprotection steps. Chapter 4: Synthesis of Carbohydrate Fused α-Amino γ-Lactams. In this chapter a flexible protocol for the synthesis of carbohydrate fused α-Amino γ-Lactams from carbohydrate derived cyclopropanecarboxylates has been disclosed. Also, the synthesis of carbohydrate fused γ-Lactams in a single-step from the iodo-azide by reductive cyclization has been reported. The formation of -lactam is achieved in low yield using both methods (A & B). The utility of the carbohydrate fused α-Amino γ-Lactams in the synthesis of Agl-bridged glycopeptide conjugates in a single-step with high efficiency has been demonstrated. Chapter 5: Studies on the Synthesis of Septanosides from Carbohydrate Derived DA-Cyclopropanes In carbohydrate derived DA 1,2-cyclopropanes, generally, the electron withdrawing group is attached at C-7 (type-I), C-2 (type-II), or C-3 (type-III). In this chapter, studies on the synthesis and use of carbohydrate derived DA-cyclopropanes of type-II & -III to form the the septanoside derivatives have been described. Attempts at the synthesis of 3,4,6-tri-O-methyl-D-glucal derived cyclopropanecarboxylates of type-II have not been successful. The failure of the cyclopropanation reactions might be due to presence of the carbmethoxy group at C-2 causing steric hindrance on the olefinic bond of 3,4,6-tri-O-tri-methyl-D-glucal methyl ester. It was then speculated that replacement of the of the carboxylate group in tri-O-methyl-glucal with hydroxymethyl group can promote the cyclopropanation reaction. Cyclopropanation of benzyl protected corresponding alcohol furnished the desired cyclopropane derivative in moderate yield (48%) as an inseparable mixture of diastereomers (1:1). Hence the synthesis of cyclopropanecarboxylates of type-II has not been achieved using this methodology. Glucose derived 3-oxo-1,2-cyclopropanes is synthesized from 3,4,6-tri-O-acetyl-D-glucal in good yield. This glucose derived cyclopropane of type-III did not furnish the septanoside derivative under different conditions. The synthesis of 3-oxo-1,2-cyclopropanated galactose derivative has been achieved in reasonably good yield from D-galactal with in three steps. When the galactose derived DA-cyclopropane is reacted with NIS and MeOH in the presence of catalytic amount of TMSOTf, it furnished the desired septanoside along with many side-products. The attempts at separation and identification of the septanoside in pure form have not been successful.

Le peptidomimétisme permet de synthétiser des composés ayant le potentiel de répliquer l’activité biologique des peptides naturels sans les propriétés non désirées telles que le métabolisme rapide. En stabilisant la conformation active et en modifiant les éléments clés de la structure d’un peptide, il est possible d’améliorer sa puissance et sa sélectivité, de favoriser son transport membranaire et d’augmenter sa stabilité métabolique. Les α-amino-γ-lactames (Agl) font partie d’une classe de mimes peptidiques qui permettent de rigidifier, par des liens covalents, le squelette peptidique. Les résidus Agl pourraient stabiliser la structure secondaire du peptide de type tour β. Ils pourraient favoriser une conformation qui augmente les interactions avec le récepteur. Il est possible d’ajouter des substituants à la position β des résidus Agl afin de mimer les chaines latérales d’un peptide avec un squelette possédant une conformation contrainte. Ce mémoire présente une revue des différentes méthodes de synthèses stéréosélectives des α-amino-γ-lactames β substitués. Au cours du projet, l’organocatalyse asymétrique de Mannich catalysée par la proline a été exploitée afin de préparer un dérivé d’acide aminé pour mimer la chaine latérale de la leucine. L’approche mettant de l’avant la synthèse des sulfamidates cycliques a été explorée ainsi que l’approche par l’amination réductrice qui permettra de synthétiser des α-amino-γ-lactames β substitués. Ce travail présente la possibilité d’insérer l’α-amino-γ-lactame β-isopropyle mimant la D-leucine dans le peptide biologiquement actif 101.10 reconnu comme un modulateur allostérique du récepteur de l’interleukine-1β (IL-1β). Le peptide 101.10 inhibe la cascade inflammatoire menant aux accouchements prématurés et limite les effets de la rétinopathie du prématuré. Ainsi, le peptide analogue synthétisé au laboratoire sera testé biologiquement in vitro en collaboration avec le Professeur Sylvain Chemtob de l’Hôpital Sainte-Justine, afin d’étudier les effets de l’insertion du Agl β-substitué sur l’activité biologique de celui-ci en tant que modulateur de l’interleukine-1. / Peptide mimicry enables the synthesis of surrogates of natural peptides that replicate activity without potentially undesired properties such as rapid metabolism. Peptide mimics can stabilize active conformations and alter key structural elements to enhance potency, selectivity, membrane permeability, and metabolic stability. α-Amino-γ-lactam (Agl) residues belong to a class of peptide mimics that rigidify the peptide backbone through covalent bonds. β-Turn peptide secondary structures can be stabilized by Agl residues. Locking the peptide into such conformations, Agl residues can enhance interactions with receptors. Substituents can be added to the β position of the Agl residue to mimic side chain functions projecting from a constrained backbone conformation. The thesis presents a review of various methods for the stereoselective synthesis of β-substituted α-amino-γ-lactams. In the context of the developed research, the organocatalyzed asymmetric Mannich reaction using proline was employed to prepare an amino acid derivative possessing a leucine side chain. Approaches featuring cyclic sulfamidates and reductive amination were explored to synthesize β-substituted α-amino-γ-lactams. A β-isopropyl α-amino-γ-lactam was synthesized with potential to mimic D-leucine and inserted into the biologically active peptide 101.10 which has shown to be a potent allosteric modulator of the interleukin-1β (IL-1β) receptor. The peptide 101.10 can inhibit the inflammatory cascade leading to preterm birth and mitigate the pathology of retinopathy of prematurity. The synthesised peptide mimic will be tested in vitro in collaboration with Professor Sylvain Chemtob from Sainte-Justine Hospital to study the effects of inserting the β-substituted Agl on biological activity as an interleukin-1 receptor modulator.