Synthesis and biological applications of non natural α-amino acids.

Abstract

In this PhD Thesis work, the synthesis and the biomedical application of non natural a-amino acids was accomplished in three different projects. A “one-pot” procedure for the synthesis of optically active and pure methyl N-acetamido acrylate starting from cheap and commercial sources was developed and fine-tuned, obtaining the target compound in good yields and identifying the major reaction by product. This acrylate was used as acceptor in Michael reaction conditions for the formation of new C-C and C-S bonds, evaluating the asymmetry induced by the (-)-menthol.Different nucleophiles were used and different bases were tested in order to obtain a full conversion. After that, reaction of the aforementioned molecule with opportune nucleophiles to synthesise five-membered tetrahydrothiophene rings and other intermediates with a bicyclo[3.1.0]hexane and bicyclo[ 4.1.0]heptane structure was investigated. The project was undertaken in order to find new synthetic ways obtain constrained glutamate analogues, which have been identified by Eli Lilly as potent, selective and active agonists of mGluR receptors. The second project, developed in the laboratory of Professor Matteo Zanda at the Univesity of Aberdeen, is focused on the synthesis of small arginine-containing peptides and arginine analogues. The small peptides are obtained by simple coupling of the amino acid residue with different picolyl amines, while analogues of the parent amino acid will contain a triple bond and a methyl or trifluoromethyl substituent on the a-carbon of the amino acid skeleton. Interest in these two type of compounds was risen because arginine is a substrate for Nitric Oxide Synthase, a class of enzymes involved in the regulation of muscular relax and blood pressure through nitric oxide synthesis starting from the aforementioned amino acid. The designed and synthesised substrates result being able to polarise their signal under specific NMR conditions in the presence of parahydrogen. In this way, a possibility towards the synthesis of of specific and target-focused tracers for Magnetic Resonance Imaging would be achieved, allowing for a simple and secure detection of illness via a simple and quick MRI scan. Indeed, some of the synthesised compounds polarise and are substrates for the Enzyme. On the last note, a method for the determination of the amount of trifluoroacetic counter-ion was developed. The third project is focused on the development of an alternative synthetic route for the cheap synthesis of 2,6-dimethyl-L-tyrosine, a potent amino acid analogue to tyrosine and employed in peptides which target opioid receptors. An analogue of Hagemann’s ester ’s was used as starting point for the entire process and it was used in two synthetic pathways. The first one is stereoselective in the fact that involves alkylation of the chiral synthon 2,5-diketopiperazine, while in the second one the key-step involves a Michael addition for the introduction of the amino acidic residue.