Synthesis of Histidine Derivatives Present in Cardiac Muscle

Campbell, Jacqueline Ann (1991) Synthesis of Histidine Derivatives Present in Cardiac Muscle. PhD thesis, University of Glasgow.

Abstract

N-Acyl-L-histidine derivatives, a number of N-acyldipeptides containing L-histidine (A), and dipeptides containing 1-methyl-L-histidine (B) or 3-methyl-L-histidine (C) are thought to be present in cardiac muscle. These compounds are believed to play an important role in the healthy functioning of the heart. The work presented in this thesis investigates the synthesis of optically active forms of some of these L-histidine derivatives. The results obtained when these compounds were tested by the physiologists for their individual effects on cardiac muscle are presented. (A). N-Acyl-L-histidine Derivatives and N-Acyldipeptides Containing L-Histidine N-Acetyl-L-histidine and A-propionyl-L-histidine were successfully synthesised in good yield and high optical purity by the direct acylation of L-histidine with acetic or propionic anhydride. Two routes aimed at providing a range of N- acyldipeptides containing L-histidine in chemically and optically pure form were studied. A series of N-acylamino acids were coupled to L-histidine protected on the carboxyl function. The first route used the benzyl ester of L-histidine but a number of problems were encountered which made this route unattractive. The second route involved L-histidine protected as a metal salt. The mixed anhydride method of peptide coupling was employed to produce the compounds in chemically pure form. A number of methods were used in an attempt to determine the optical purities of the histidine derivatives synthesised. The most promising method involved the coupling of (R)-a-methylbenzylamine to the carboxyl function of the N-acyldipeptides. The diastereoisomeric mixtures formed were then analysed using reverse-phase high performance liquid chromatography (HPLC). The solvent mixture used to elute the column was adjusted to find a composition which would allow the separation of the diastereoisomers. The areas under the peaks were then used to estimate the optical purities of the compounds under investigation. The L-histidine derivatives were examined by physiologists at Glasgow University. They discovered, using HPLC techniques, that N-acetyl-L-histidine, N-acetyl-L-carnosine and N-acetyl-L-homocarnosine were present in cardiac muscle. The N-propionyl derivatives synthesised had an adverse effect on the Ca-sensitising apparatus of cardiac muscle. N-Acetyl-L-histidine, N-acetyl-L-alanyl-L-histidine and N-acetyl-D-alanyl-L-histidine were weak Ca-sensitisers. N-Acetylglycyl-L-histidine, N-acetyl-L-carnosine and N-acetyl-L-homocarnosine produced more positive action on the Ca-sensitising apparatus of the heart muscle. (B). 1-Methyl-L-histidine. 3-Methyl-L-histidine and Dipeptides Containing L-Histidine Methylated on the Imidazole Ring Because the imidazole function of L-histidine has two possible sites for N-alkylation to take place, routes were developed to obtain selectively the desired N-methylated histidine derivatives as pure isomers. A synthesis of 1-methyl-L-histidine, reported in the literature, was attempted. Problems were encountered in introducing the protecting group onto the 3-position of the imidazole ring. This could not be achieved in the manner described in the literature, thus an alternative route was studied. N(a),3-bis(t-Butoxycarbonyl)-L-histidine methyl ester was alkylated using methyl iodide. The residue obtained from the reaction was found to be a mixture of the desired 1-methyl compound and the 1,3-dimethyl compound. This mixture was successfully separated. The final stage was to remove the protecting groups. A number of different methods were used. Each procedure removed the protecting groups without any difficulties but each attempt yielded 1-methylhistidine which was not optically active. The synthesis of 3-methyl-L-histidine, reported in the literature, was attempted. The synthetic sequence was successful until the final deprotection stage which yielded 3-methylhistidine in chemically pure form, but contrary to the data published, the product was not optically active. An alternative route was investigated. N(a)-t-Butoxy carbonyl-1-benzoxy methyl-3-methyl- L-histidinium methyl ester iodide was synthesised. 3-Methyl-L-histidine should then be obtained upon removal of the protecting groups. The removal of the methyl ester resulted in a racemic product. Attempts to remove the benzoxymethyl group were consistently unsuccessful. 3-Methylhistidine could not be obtained in chemically or optically pure form from this route. A route to dipeptides containing 1-methylhistidine was established. 1-Methylglycylhistidine, 1-methylcarnosine and 1-methylhomocarnosine were synthesised in chemically pure form. The intermediates in this route all possessed some degree of optical purity but the hydrolysis of the methyl esters at the end of the route resulted in racemic products. The route established for the synthesis of dipeptides containing 3-methylglycylhistidine and 3-methylcarnosine produced these compounds as pure isomers. Problems in removing the methyl esters in the final stage resulted in the products being racemic.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1991
• Depositing User: Enlighten Team
• Unique ID: glathesis:1991-78338
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2020 15:32
• Last Modified: 30 Jan 2020 15:32
• URI: https://theses.gla.ac.uk/id/eprint/78338