| Abstract | The long-term motivation for exploring macrocycles molecules wherein at least 12 of the atoms are arranged in a ring is to be able to produce drugs that can interfere with specific protein-protein interactions within cells. Many diseases involve abnormal cellular protein-protein interactions that have the potential to be disrupted by macrocycles that would improve the physical manifestation of disease. The molecule described in this thesis incorporates the amino acid aspartic acid. Aspartic acid is particularly intriguing due to the ionizable carboxylic acid group on its side chain and its ability to hydrogen bond. This potential offers the possibility of previously unreported three- dimensional shapes and dynamic behavior for this family of molecules.
The macrocycle was synthesized in three steps. First, cyanuric chloride was substituted with BOC- hydrazine dropwise in THF under basic conditions while being carefully monitored by thin layer chromatography (TLC) to prevent excess substitution. In the same reaction vessel, Boc-protected aspartic acid was added under basic conditions and monitored by TLC. To complete the first step, dimethyl amine was subsequently added also to the same vessel. Following extraction and chromatography, the first intermediate was obtained. In the second step, this intermediate was reacted with an amino acetal to form the monomer. Again, an extraction was performed followed by chromatography. The third synthetic step was a reaction with acid to produce the dimeric macrocycle.
Characterization of the macrocycle was accomplished using various methods. Both one-dimensional and two-dimensional proton NMR spectroscopy confirmed the structures of the macrocycle and the intermediates. Clues to the three-dimensional structure were obtained using two-dimensional ROESY and variable temperature NMR experiments as well as and data from related molecules. |
