Foldamers in Medicinal Chemistry

International audienc

A post-elongation strategy for the introduction of guanidinium units in the main chain of helical oligourea foldamers

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Synthèse asymétrique de diamines cyclopentaniques polyfonctionnelles (des outils pour l'étude d'interactions avec l'ARN)

Il a été établi au laboratoire que les diamines 1,3 cyclopentaniques fonctionnalisées pouvaient mimer le motif central des aminoglycosides et permettre ainsi d accéder à de nouvelles molécules capables de se lier aux ARN. Ces diamines peuvent être facilement obtenues après fonctionnalisation d hydrazines bicycliques, par coupure de la liaison N-N. Différentes voies de synthèse ont été développées pour introduire un atome de fluor de façon régio-, diastéréo- et dans certains cas énantiosélective sur ces composés polyazotés. Les diamines fluorées obtenues ont ensuite permis de mettre en évidence un phénomène de reconnaissance chirale supramoléculaire en présence d ARN, qui se traduit par un dédoublement caractéristique en RMN 19F. Ces petites molécules peuvent donc constituer d intéressantes sondes structurales pour l étude d interactions ligands-ARN. La désymétrisation des diamines 1,3 cyclopentaniques meso par substitution allylique a également été étudiée. La catalyse à l iridium n a pas permis de différencier les deux amines, seule la stéréochimie de la position allylique ayant pu être contrôlée efficacement. En revanche, le produit de monoallylation linéaire a pu être obtenu avec un excès énantiomérique allant jusqu à 61 % en présence d une catalyse au palladium.In the laboratory, functionalized 1,3-cyclopentanic diamines have been developped to design new RNA ligands by mimicking the central framework of aminoglycosides. These diamines are easily obtained after functionalization of bicyclic hydrazines and cleavage of the N-N bond. Different synthetic routes has been explored to allow a regio-, diastereo- and in some cases enantioselective introduction of a fluorine atom on these polynitrogenated compounds. Binding experiments using 19F NMR highlighted a supramolecular chiral recognition phenomenon between the fluorinated diamines and RNA. This led to a split of the signal correlated with the location of the fluorine nucleus and the structure of the RNA. Fluorinated diaminocyclopentanes could then serve as useful probes for the study of ligand-RNA interactions. The desymmetrisation of meso 1,3- cyclopentanic diamines using allylic substitution reactions has been studied as well. With the use of iridium catalysis, the efficiency of the resolution of the two amines proved to be very low, and only stereochemistry of the allylic position has been fully controlled. However, the linear monoallylated product could been obtained with an enantiomeric exces up to 61 % using palladium catalysisPARIS-BIUP (751062107) / SudocSudocFranceF

Straightforward Entry toward Highly Substituted 2,3-Dihydrobenz[b]oxepines by Ring Expansion of Benzopyryliums with Donor-Acceptor Diazo Compounds

International audienceYlide-type reactivity of diazo compounds is exploited in a new way to prepare benzo[b]oxepines thanks to the formation of three chemical bonds and two contiguous and highly substituted stereocenters in a single pot. This cationic reaction cascade first involves addition of a donor–acceptor-substituted diazo compound to a benzopyrylium. Selective 1,2 migration of the endocyclic C–C bond then results in a ring-expansion and generates a second oxocarbenium that is trapped by a nucleophile added sequentially

Regio- and stereoselective carbometallation reactions of N-alkynylamides and sulfonamides

The carbocupration reactions of heterosubstituted alkynes allow the regio- and stereoselective formation of vinyl organometallic species. N-Alkynylamides (ynamides) are particularly useful substrates for the highly regioselective carbocupration reaction, as they lead to the stereodefined formation of vinylcopper species geminated to the amide moiety. The latter species are involved in numerous synthetically useful transformations leading to valuable building blocks in organic synthesis. Here we describe in full the results of our studies related to the carbometallation reactions of N-alkynylamides

Stereoselective Synthesis of Fluorinated 1,3- cis -Diaminocyclopentanes

International audienceSeveral fluorinated 1,3-diaminocyclopentanes, previously reported to be useful RNA structural probes, can be prepared in a diastereoselective manner from a single bicyclic hydrazine precursor, in 3 to 9 steps

Methods Enzymol

N,N'-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features-such as synthetic accessibility, sequence modularity, and folding fidelity-that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties. Here we provide detailed protocols for the preparation of requested monomers and for the synthesis and purification of homo-oligoureas and peptide-oligourea hybrids.Hélices chimériques aux propriétés innovantes pour l'inhibition des interactions protéine-protéineMimétisme et ingénierie d'enzymes artificielles à l'aide de foldamère

Fluorinated diaminocyclopentanes as chiral sensitive NMR probes of RNA structure.

International audienceThe supramolecular chiral recognition between rac-2a and several structured RNA leads to a distinct (19)F NMR signal splitting. The (19)F NMR analysis of the diastereomeric pairs formed upon binding of this racemic probe delivers a topological footprint of the RNA. This phenomenon can be exploited to investigate dynamic events involving structural equilibria, as demonstrated in a melting experiment. This work provides a proof of concept that small fluorinated moderate binders can act as external probes of RNA structures

Fused Bis-lactams to Spirolactams: A New Member of the Family of Ring- Contraction Reaction

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Postelongation Strategy for the Introduction of Guanidinium Units in the Main Chain of Helical Oligourea Foldamers

The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo­(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural γ-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group