Date of Award
Bachelor of Science
Timothy P. Curran
Maria L. Parr
Richard V. Prigodich
Previous research within the Curran group has demonstrated that ferrocene may be used as an organometallic constraint to induce the formation of α-helices in short peptides which traditionally possess undefined conformations. Through strategic placement of lysine residues at the i and i+3 positions within the peptide, such a constraint was accomplished via the crosslinking of the lysine side chains to ferrocene dicarboxylic acid chloride in solution phase synthesis. The aim of this work was to develop a method for solid phase peptide synthesis (SPPS) for the synthesis of these ferrocene-constrained helices. In particular, we seek to develop a method in which the nascent peptide can be cyclized while it is still anchored to the resin. For the synthesis, Fmoc-protected amino acids were utilized to afford the pentapeptide Ac-Lys(Aloc)-Ala-Val-Lys(Aloc)-Gly-NH2. For the synthesis, Fmoc-protected amino acids and Aloc side chain protecting groups were utilized due to the mild conditions under which they are removed. This allowed the use of a Rink Amide AM resin, which is cleaved under acidic conditions. In this study it was found that on resin Pd0 catalyzed Aloc removal required very specific conditions and work up for efficient deprotection. Additionally, Fmoc-protected amino acids were utilized in an analogous manner to afford the pentapeptide Ac-Lys(Z)-Ala-Val-Lys(Z)-Gly-NH2. The Z-protected pentapeptide was then removed from the resin, hydrogenated using Pd on C and subsequently cyclized with 1,1’-ferrocenedicarboxylic acid chloride. Results from on-resin cyclization indicate that a new approach must be developed in order to accomplish on-resin cyclization. Future work includes the use of different resins, different protecting groups, and different removal conditions for optimization. In solution phase, the ferrocene coupling, the data indicates that a peptide dimer with a single ferrocene was formed due to incomplete Z protecting group removal. Future work in solution phase includes hydrogenation and cyclization optimization.
McTeague, Thomas A., "Ferrocene Constrained Helical Peptides via On-Resin Cyclization". Senior Theses, Trinity College, Hartford, CT 2012.
Trinity College Digital Repository, http://digitalrepository.trincoll.edu/theses/241