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Title
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Transition metalcatalyzed directed amide cleavages for use in peptidomimetic research
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Author
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Abstract
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| The amide bond is the key functional group in many biomolecules, such as peptides and proteins, and its selective formation was studied extensively, witnessed by a catalogue of so-called coupling reagents able to condense amines and carboxylic acids. Such direct acylations of an amine by an in situ activated carboxylic acid remain the commonly applied methods to form amides. Although rarely considered, the amide is herein presented as a carboxylic acid surrogate to overcome the inherent limitations associated with coupling reagents. In the framework of this PhD thesis, an in-house developed methodology involving the esterification of a primary amide through a Zn-catalyzed nicotinate-directed cleavage with alcohols was extended to transamidations. The activation mechanism can be regarded as ‘biomimetic’: the C3-ester substituent of the pyridine in the directing group contributes to the abundance of the trans amide bond conformer which is suitable for Zn chelation, allowing C=Oamide-Zn-Ndirecting group coordination. Additionally, the incoming nucleophile, a Zn-coordinated alcohol, is activated by hydrogen bonding with the ligand of the catalyst. A focus was placed on primary amide cleavage by amines to make and modify peptide substrates. Accordingly, the efficient introduction of the directing group was pursued via Pd-catalyzed amidation of the N-Boc-protected amino acid amides. The consecutive amide cleavage successfully allowed the desired transamidations with amino acid esters/amides as a method for diverse applications in peptide research, exemplified by segment condensations, macrocyclizations, and solid-phase synthesis. Additionally, the amide cleavage was pursued on products of the Ugi reaction through the development of suitable 3-substituted 2-isocyanopyridines. These enabled the cleavage of the C-terminal amide of the Ugi product with various O- and N-nucleophiles, which eventually led to the assembly of constrained dipeptide mimetics. |
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Language
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English
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Publication
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VUB, Faculty of Science and Bio-Engineering Sciences, Department of Chemistry
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2019
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Volume/pages
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380 p.
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Note
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:
Ballet, Steven [Supervisor]
:
Maes, Bert [Supervisor]
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Full text (publisher's version - intranet only)
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