Synthesis of viridamine analogues for use in selective metal complexation studies

Abstract

M.Sc.The aim of this project was the synthesis of viridamine analogues, to be used for selective metal complexation. This, therefore, required the synthesis of diketopiperazines, containing an imidazole-type side chain. The imidazole functionality was introduced into the synthesis via peptide acid coupling reaction between histidine and another amino acid. Before any coupling reactions were possible it was necessary to protect the carboxylic acid functionality of one of the two amino acids being used and the amine functionality of the other. This was to prevent mixed products forming. Owing to the continued difficulty at achieving selective N-protection of histidine, it was decided to make use of the corresponding methyl ester instead. After some initial attempts, it was found that the methyl ester of histidine, which was bought as the dihydrochloride salt, could be readily coupled to a variety of Boc protected amino acids. The Boc protected amino acids could be prepared under various conditions using di-tertbutyl dicarbonate. A range of conditions was investigated for the coupling of the two amino acids, i.e. the histidine methyl ester dihydrochloride and a Boc protected amino acid. Successful coupling was finally achieved using tetrahydrofuran as solvent, N-hydroxy benzotriazole as reaction promoter, N-methyl morpholine as a base and dicyclohexylcarbodiimide as the coupling agent. After varying the reaction conditions the optimised reaction conditions gave yields in the region of 76%. Once coupling had been achieved, it remained to cyclise the dipeptide. Cyclisation was preceded by the removal of the Boc protecting group either in situ or in a two step process. In the absence of the imidazole functionality, removal of the Boc group was readily achieved using trifluoroacetic acid. However, attempted deprotection of dipeptides containing the imidazole functionality led to decomposition of the dipeptide under identical conditions. It was therefore necessary to find an alternative form of deprotection. This was found in the form of formic acid, which proved to be successful in removing the Boc group and in effecting cyclisation to the analogous diketopiperazine. This particular form of in situ cyclisation proved to be very low yielding. This problem was circumvented by following the formic acid treatment by a period of reflux in a toluene I 2-butanol mixture. Cyclisation was effected with pure products being obtained in high yield, after column chromatography. Complexation reactions were initiated with the synthesised diketopiperazines but unfortunately no X-Ray diffraction studies could be carried out, due to the formation of amorphous solids instead of crystalline materials