Milind Joshi (Vassar College)| Nicholas Dodge (Vassar College)
Efficient, scalable total synthesis of 4-Amino-N-(2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl) benzamide, a marine-sourced compound with antibacterial properties is introduced, highlighting the importance of nature and its selection process to produce effective antibacterial compounds, thus serving as a template in the development of new drugs. We proposed a one-pot process where 6-aminouracil was acylated using 4-N-Boc-aminobenzoyl chloride over an expansive range of solvents and temperatures. We also proposed a one-pot carbodiimide mediated carboxylic acid coupling with 6-aminouracil. Both processes were unsuccessful and the difficulty encountered in these approaches is likely due to the reduced nucleophilicity of the amino group of 6-aminouracil. Literature studies helped refocus our approach to exploit the pyrimidine character of the uracil as a workaround, employing a dialkoxy aminopyrimidine, which is a precursor to our specific uracil starting material. The 4-amino-2,6-dimethoxypyrimidine was extensively screened for the same two reactions using a variety of solvents and temperatures, with the key amide bond successfully being formed using benzoyl chloride in excess pyridine. The amide bond formation was further optimized, obtaining a purer, higher-yielding coupling product. Current work involves dealkylation of the pyrimidine to furnish the uracil moiety as the final step in a three-step total synthesis. The attempted acidic demethylation of a methoxypyrimidine substrate resulted in undesired amide bond cleavage. Future work involves attempting the demethylation of the methoxypyrimidine substrate using a variety of Lewis acids and if successful, testing the natural product's antibiotic properties. The pyrimidinyl benzamides themselves may have useful biological activities which would be worth investigating as well.
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