| Abstract | Pharmaceutical development maintains a disproportionate focus on the synthesis of small molecules. This emphasis is based on historical research about bioavailability of molecules and the position that small molecule synthesis is cheaper and more efficient than the synthesis of large molecules. Macrocycles challenge these beliefs vis-a-vis the viability of large molecule pharmaceuticals. With availability in a simple three step process, macrocycles demonstrate the potential to be bioavailable and maintain biologically useful conformations in solution, representing a new frontier in pharmaceutical development. The previous synthesis of the 26-atom G-G macrocycle indicates that these molecules can maintain a beta-sheet like structure which could be utilized in antagonizing protein-protein interactions like the formation of beta-amyloid plaques in Alzheimer's disease.1
The synthesis of the leucine 26-atom macrocycle in this project investigates how the addition of leucine, a bulky hydrophobic amino acid, affects the formation of the planar structure as adopted by the G-G macrocycle. The macrocycle is obtained through a three-step reaction pathway. BOC-hydrazine, leucine, and dimethylamine (DMA) are added sequentially to a triazine core in a one-pot reaction. This acid then has a four-carbon acetal group installed using conventional coupling reagents to create the monomer. Dimerization of monomer is induced using a 1:1 mixture of dichloromethane (DCM) and trifluoracetic acid (TFA). Upon evaporation of solvent, this reaction is found to be qualitative in its yield of macrocycle.
Both 13C and 1H NMR spectra are used to confirm the resulting macrocycle's formation. COSY and rOesy two-dimensional NMR are utilized to assign structure. Downfield shifts of critical resonances in the 1H NMR spectra confirm that the macrocycle adopts a beta-sheet conformation. |
