Doctor of Philosophy
School of Chemistry
Jennepalli, Sreenu, Synthesis of fullerenyl amino acid derivatives for medicinal chemistry and material science applications, Doctor of Philosophy thesis, School of Chemistry, University of Wollongong, 2015. http://ro.uow.edu.au/theses/4381
Chapter 1 reviews the synthesis and applications of fullerene amino acids and peptides, in material science and biological activities reported so far. We segregated the type of fullerene amino acids based on their connectivity, such as, fullerenyl substituents directly substituted to the amino acid α-carbon, fullerenyl N-capped peptides and amino acids, fullerenyl C-capped peptides and amino acids and fullerenyl amino acids that could potentially be incorporated within peptide chains.
Chapter 2 demonstrated the synthesis of the novel fullerene monopeptide 201 and dipeptide 204. Fullerenoproline acid 198 was coupled to lysine amine 200 to yield the monopeptide 201 in 62% yield, which was separately deprotected to its amine salt 202 using TFA and to its acid derivative 203 with Sn(CH3)3OH. An amide coupling reaction of the amine 202 and the acid 203 resulted in the dipeptide 204 (57%). Attempts to synthesise the tetrapeptide 207 using the same approach were not successful because of its poor solubility. Monopeptide 201 and the dipeptide 204 have been studied experimentally using spectroelectrochemical measurements by Prof. Timothy Clark and Prof. Dirk M. Guldi at the University of Erlangen-Nuremberg, Germany. The bis-fullerene-substituted peptide 204 provided experimental support for density-functional theory (DFT) calculations which indicate that van der Waals fullerene dimers can form between adjacent fullerenes in semiconductor layers resulting in interstitial electron traps.
An alternative synthesis of the tetrapeptide 207 was examined. The lysine tetrapeptide 216 (70% yield) and its tetramine 217 (100%) were successfully synthesised. Attempts to couple 217 with fullerenoproline acid 198 to produce the tetrapeptide 207 were also unsuccessful, possibly due to steric hindrance problems because of the sterically demanding fullerene groups. Accordingly, we thought that the cyclic peptide tetrapeptide 220 might help to solve these steric hindrance problems. Tetrapeptide 216 was successfully converted to the novel cyclic peptide 220 in three synthetic steps. However we did not pursue this route any further because of the poor chemical yields and the difficulties in purifying 220.
Chapter 3 reported an extension of fullerenyl oligomers with the incorporation of spacers between the fullerenyl groups. Two types of amino acid spacers (L-lysine and L-phenylalanine) were introduced in to the oligomers (hexapeptide 227 and hexapeptide 238). The synthesis of tripeptides with L-lysine spacers 224 in 62%, and L-phenylalanine spacers 235 (in 60%) were achieved by coupling the acid 203 with the amine 213 and the amine 202 with the acid 234, respectively. The previously used ester and N-Boc cleavage reaction conditions were adopted to synthesise the corresponding acids (225 and 236) and amines (226 and 237) of 224 and 235. Their amide coupling reaction provided the hexapeptides of 227 (44%) and 238 (40%) respectively. Currently, these molecules are under studies to form supramolecular complexes between these fullerene peptides and porphyrin and photoinduced charge separation in Prof. Fukuzumi’s laboratory at Osaka University, Japan.
Chapter 4 reported the synthesis and antibacterial screening of mono substituted fullerenyl peptides (243, 245, 247, 272-279) and bis-fullerenyl peptide (285). A range of tri, tetra and pentapeptides having an oxazole or isopentyl ester terminal group were synthesised. These peptides were then deprotected to form their HCl and TFA salts 247, 276-279. Antibacterial screening of these peptides (243, 245, 247, 272-279 and 285) was performed at the University of Western Australia in Prof. Thomas Riley’s laboratory; unfortunately, none of these compounds showed significant activity.