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New approaches for the synthesis of unusual amino acids

Fanning, Katherine Nora (2008) New approaches for the synthesis of unusual amino acids. PhD thesis, University of Glasgow.

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Abstract

The thermal and metal-catalysed aza-Claisen rearrangement of allylic trichlororacetimidates has found widespread application in the synthesis of nitrogen-containing molecules including alkaloids, antibiotics and unnatural amino acids. We have recently investigated the use of this reaction for the rearrangement of chiral molecules. This has led to the development of a highly diastereoselective, ether-directed palladium(II)-catalysed process which has been used for the synthesis of β-hydroxy-α-amino acids. To expand the scope and understanding of the rearrangement, a number of analogues of 1 have been synthesised and subjected to a palladium(II)-catalysed rearrangement. Gizzerosine ((S)-2-amino-9-(4-imidazolyl)-7-azanonanoic acid) is a potent agonist for the H2-receptor. It brings about gizzard erosion and ulceration in broiler chickens. This disease is colloquially known as ‘Black Vomit’ due to bleeding of lesions and subsequent regurgitation. Its biological profile suggests it could be a promising drug candidate for gastric achlorhydria and osteoporosis, although only small amounts can be isolated from fish meal for biological studies. A short and highly efficient synthesis has been developed in ten steps and 31% overall yield. Protein-protein inteactions are the key to organising cellular processes in space and time. Protein-protein interactions are involved in viral fusion and so are promising targets for anti-viral drugs. Photoactivatable amino acids have been used to identify these interactions. Activation by ultraviolet light induces covalent cross-linking (known as photo cross-linking) of the interacting proteins which can be detected with high specificity by simple western blotting. Significant progress has been made towards the development of a stereoselective synthesis of photoactivatable amino acids incorporating a diazirine ring, such as photo-leucine, which generate a reactive carbene after the light induced loss of nitrogen.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: thermal and metal-catalysed aza-Claisen rearrangement, unnatural amino acids, palladium(II)-catalysed , Gizzerosine, Protein-protein inteactions , Photoactivatable amino acids, diazirine
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Sutherland, Dr Andrew
Date of Award: 2008
Depositing User: Katherine N Fanning
Unique ID: glathesis:2008-210
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Jan 2009
Last Modified: 10 Dec 2012 13:16
URI: http://theses.gla.ac.uk/id/eprint/210

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