Synthesis of 4-Diphosphocytidyl-2-C-methyl-d-erythritol and 2-C-Methyl-d-erythritol-4-phosphate

Abstract
2-C-Methyl-d-erythritol 4-phosphate (MEP, 2) and 4-diphosphocytidyl-2-C-methyl-d-erythritol (CDPME, 3) are metabolites in the MEP pathway for biosynthesis of isoprenoid compounds in bacteria, plant chloroplasts, and algae. The free phosphoacid of 2 was prepared from benzyloxyacetone in five steps with an overall yield of 27% and an enantiomeric ratio (er) of 75:25. Following titration to the corresponding tributylammonium salt, 2 was coupled to cytidine 5‘-monophosphate using a protocol originally developed for synthesis of base-sensitive nucleoside diphosphate sugars to give 3 in 40% yield, following purification by size exclusion chromatography.