6-Diazo-5-oxo-L-norleucine (DON, 1) is a non-standard amino acid, which was originally isolated from Streptomyces bacteria found in Peruvian soil in 1956. DON is one of very few naturally occurring diazoketones and it was characterized by Dion. It has shown robust anticancer efficacy in preclinical and clinical studies, but development was halted by significant systemic toxicity. To enhance DON’s therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Several prodrugs were prepared and the most stable compound 2 was tested in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON.