Diphthamide is a post-translationally modified histidine residue that is conserved from archaea to humans but is not found in eubacteria. It is located in the enzyme eukaryotic elongation factor 2, which is involved in protein synthesis in cells. Diphthamide is the target of a potent toxin known as exotoxin A which catalyzes the ADP-ribosylation of diphthamide, rending eEF2 completely inactive. This inactivation halts protein synthesis resulting in cell death. ETA is secreted from an opportunistic pathogen known as ' Pseudomonas aeruginosa', and is very prevalent in individuals suffering from cystic fibrosis. The biological role of diphthamide is still not fully understood and it has yet to be determined as to how the ADP-ribosylation of diphthamide causes the inactivation of eEF2. This report is an investigation of the synthesis of the post-translationally modified histidine residue, diphthamide. The complete synthesis of diphthamide has not been reported and providing a stereochemically pure species would allow for its manipulation in understanding its role in protein synthesis and the mechanism of ETA. An outline of the multi-step synthesis of diphthamide utilized L-histidine and L-glutamic acid as the principle building blocks and the development of an orthogonal protection strategy. Through this, the selective C-2 functionalization of L-histidine and the Barton decarboxylative iodination of L-glutamic acid were successfully carried out. However, failure to undergo the desired Negishi cross-coupling. between these functionalized backbone species resulted in the incomplete synthesis of diphthamide, Minimal success was observed during coupling with simplified derivatives, which through further investigation may eventually provide the framework for the more complex cross-coupling to be carried out, and the synthesis of diphthamide complete.