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Please use this identifier to cite or link to this item: http://hdl.handle.net/10277/108

Authors: Delatouche, Régis
Title: Design, synthesis and structural evaluation of peptidomimetics with a defined secondary structure.
Abstract: The efficient synthesis of a g-butyrolactone based d-amino acid was realised starting from furan methyl ester. Its enantioselecive cyclopropanation by copper triflate and a chiral bis-oxazoline led to the formation of an enantiopure cyclopropanated furan product which could be subjected to ozonolysis affording a cyclopropane aldehyde having three chiral centers. A Sakurai allylation was performed efficiently in high d.r. The lactonisation of the allylated cyclopropane alcohol could be realised with barium hydroxide. This reaction could be scaled up using triethylamine in the same conditions. The reductive amination of the resulting lactonaldehyde could be realised in good yields in mild conditions. The Boc protection of the secondary amine and the PMB cleavage were performed affording the lactone with a protected primary amine. The allylic double bond could be oxidised by ruthenium chloride and sodium periodate affording the d-amino acid 199 in good yields. Modification of the lactone by a-substitution was investigated to obtain a better NMR dispersion. The a-methylation with LDA and methyl iodide led to poor diastereoselectivities (d.r. 3/1). The a-fluorination was not diastereoselective as well (d.r. 2/1) and yields were poor. The a-dimethylation of the lactone could be performed in good yields and the resulting d-amino acid showed an excellent NMR dispersion for further foldamers studies. The liquid-phase synthesis of the desired tetramer of dimethylated d-amino acid could not be performed, even by using efficient coupling reagents. The synthesis of mixed a-d-peptides with the non-methylated building block was realised. First, an alternated a-d-pentapeptide containing L-Phe and the lactone building block was efficiently synthesised and its secondary structure analysed by various techniques. Despite overlapping of some protons in NMR spectroscopy, some NOE contacts could be observed and allowed computational studies using NOE constraints. The calculations predicted an extended loop conformation of the pentapeptide and other analyses such as IR in solution or CD spectroscopy are in favour of intramolecular hydrogen bonding. CD spectra refences missing for that type of alternated peptide, no comparison could be done with similar peptides. The secondary structure could not be determined with certainty and attemps to crystallise the peptide in a stable form failed. Secondly, a heptapeptide containing only one d-amino acid was synthesised in order to know whether this building block could induce hairpin secondary structures. IR in solution revealed the presence of intramolecular hydrogen bonding and CD spectroscopy showed interesting features suggesting the presence of a stable secondary structure although its CD spectrum looked a little disorganised. Its 2D-NMR analysis revealed interstrand contacts and showed that this heptapeptide was forming, among other things, a 13-membered hydrogen-bonded ring. As a consequence, we came to the conclusion that it did not adopt a hairpin conformation but a disorganised helicoidal structure. For the second part of this project, the ability of cis-DKP in b-bend ribbon structure was investigated. The trimer of DKP could be synthesised and fully characterised and revealed a partial b-bend ribbon conformation. The tetramer, on the other hand, could not be fully characterised by 2D-NMR, but its CD spectrum showed the presence of a stable secondary structure and comparison with other b-bend ribbon CD spectra in the literature showed a similar behaviour in terms of shapes and intensities. The CD data collected, in addition to proton-deuterium exchange analysis are in favour of a stable b-bend ribbon secondary structure. A short cyclic peptide based on a trans-DKP scaffold was successfully synthesised and fully characterised by 2D NMR spectroscopy. The presence of a g-turn in the peptide was detected and confirmed preliminary computational studies realised on a similar peptide. It is very probable that a pentapeptide containing a RGD sequence and the trans-DKP scaffold would as well induce a g-turn, whose presence is primordial for its activity against integrins avb3. Finally, two potential tripeptidic organocatalysts were synthesised, each of them containing a cis-DKP and being linked by an amide or an ester bond to a proline. Their investigation in organocatalysed aldol reaction and Michael addition is now in progress.
Issue Date: 2008
Doctoral course: Scienze Chimiche
Publisher: Università degli Studi dell'Insubria
Other university: Universität Regensburg
Citation: Delatouche, R.Design, synthesis and structural evaluation of peptidomimetics with a defined secondary structure. (Doctoral Thesis, Università degli Studi dell'Insubria, 2008).

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