Hypervalent Iodine: New Reagents and Functionalization of Peptides

Alkynes are found in a multitude of natural or synthetic bioactive compounds. In addition to the capacity of these chemical motifs to impact the physicochemical properties of a molecule of interest, the well-established reactivity of alkynes makes them ideal building blocks to access complex compounds. They have found applications in a variety of applied fields, including biochemistry and material sciences. The development of new alkynylation strategies is therefore of high interest.    The growing importance of peptide therapeutics led to a surge of interest for research focusing on their functionalization. In that regard, chemoselective late-stage chemical modifications of peptides are particularly attractive. Owing to their high functional group tolerance and biocompatibility, hypervalent iodine reagents have recently emerged as powerful tools for the functionalization of biomolecules.    The first objective of this Thesis was to develop new N-heterocyclic alkynyl hypervalent iodine reagents. The targeted scaffolds were based on amidine, benzylamine and sulfoximine with the initial goal of developing atom economical reactions. Their respective reactivities were compared to already established reagents and rationalized through the study of their X-ray structures and electronic density distributions. In particular, the new reagents exhibited valuable alkyne transfer properties towards strong nucleophiles. However, their efficiencies in metal-catalyzed or radical reactions were more limited. Their bioactivities for the inhibition of thiol-mediated uptake were assessed and showed either low activity or early onset of toxicity.     The second goal of this Thesis was to investigate the alkynylation of hydrazides with hypervalent iodine reagents in order to access functionalized azadipeptide derivatives. Using copper-catalysis we could access non-symmetrical ynehydrazides in moderate to excellent yields. Most functional groups naturally present in amino acids were tolerated in the reaction conditions and silyl, alkyl and aryl substituted alkynes were efficiently transferred to hydrazide nucleophiles. Benefiting from the rich chemistry of alkynes, we could further derivatize the obtained alkynylated azadipeptides.    Finally, we explored the decarboxylative functionalization of the C-Terminus of small peptides promoted by hypervalent iodine reagents. In a first project, we used photoredox-catalysis to access a variety of N,O-acetals from native small peptides up to tetramer. These reactive intermediates could be used for the diversification of peptide C-terminus through Friedel-Crafts reactions with phenols and indoles. Employing proteinogenic nucleophiles we could synthesize peptide derivatives bearing non-natural cross-links. Building upon a side-reaction observed in this project, we could develop a decarboxylative cyclization reaction leading to aminal heterocycles from readily available dipeptide derivatives and commercially available hypervalent iodine reagent PIDA. A broad variety of fused ring sizes could be obtained and several functional groups were tolerated.

Alkynes are found in a multitude of natural or synthetic bioactive compounds. In addition to the capacity of these chemical motifs to impact the physicochemical properties of a molecule of interest, the well-established reactivity of alkynes makes them ideal building blocks to access complex compounds. They have found applications in a variety of applied fields, including biochemistry and material sciences. The development of new alkynylation strategies is therefore of high interest. The growing importance of peptide therapeutics led to a surge of interest for research focusing on their functionalization. In that regard, chemoselective late-stage chemical modifications of peptides are particularly attractive. Owing to their high functional group tolerance and biocompatibility, hypervalent iodine reagents have recently emerged as powerful tools for the functionalization of biomolecules. The first objective of this Thesis was to develop new N-heterocyclic alkynyl hypervalent iodine reagents. The targeted scaffolds were based on amidine, benzylamine and sulfoximine with the initial goal of developing atom economical reactions. Their respective reactivities were compared to already established reagents and rationalized through the study of their X-ray structures and electronic density distributions. In particular, the new reagents exhibited valuable alkyne transfer properties towards strong nucleophiles. However, their efficiencies in metal-catalyzed or radical reactions were more limited. Their bioactivities for the inhibition of thiol-mediated uptake were assessed and showed either low activity or early onset of toxicity. The second goal of this Thesis was to investigate the alkynylation of hydrazides with hypervalent iodine reagents in order to access functionalized azadipeptide derivatives. Using copper-catalysis we could access non-symmetrical ynehydrazides in moderate to excellent yields. Most functional groups naturally present in amino acids were tolerated in the reaction conditions and silyl, alkyl and aryl substituted alkynes were efficiently transferred to hydrazide nucleophiles. Benefiting from the rich chemistry of alkynes, we could further derivatize the obtained alkynylated azadipeptides. Finally, we explored the decarboxylative functionalization of the C-Terminus of small peptides promoted by hypervalent iodine reagents. In a first project, we used photoredox-catalysis to access a variety of N,O-acetals from native small peptides up to tetramer. These reactive intermediates could be used for the diversification of peptide C-terminus through Friedel-Crafts reactions with phenols and indoles. Employing proteinogenic nucleophiles we could synthesize peptide derivatives bearing non-natural cross-links. Building upon a side-reaction observed in this project, we could develop a decarboxylative cyclization reaction leading to aminal heterocycles from readily available dipeptide derivatives and commercially available hypervalent iodine reagent PIDA. A broad variety of fused ring sizes could be obtained and several functional groups were tolerated.