Synthesis of Phosphodiesters: The Cyclic Enediol Phosphoryl (CEP) Method

Abstract

Strategies to convert two different alcohols, R1OH and R2OH, into an unsymmetrical phosphodiester, (R1O)(R2O)P(O)OH, are outlined. One of these strategies utilizes a cyclic enediol phosphoryl derivative (CEP-X) as the only reagent for the establishment of the two P-O bonds of the diester without the need for additional activating reagents. Three CEP-reagents have been extensively utilized for the preparation of Simple cyclic and acyclic phosphodiesters and for phospholipids, oligonucleotides and phosphatidyloligonucleotides. These CEP-X reagents are: bis[2-butene-2,3-diyl] pyrophosphate (or bis[1,2-dimethylethenylene] pyrophosphate), 2-chloro-4,5-dimethyl-2-oxo-Pv-1,3,2-dioxaphosphole (or 1,2-dimethylethenylene phosphorochloridate), and 4,5-dimethyl-2-(1-imidazolyl)-2-oxo-Pv-1,3,2-dioxaphosphole [or N-(4,5-dimethylethenylenedioxyphosphoryl)-imidazole]. The review also includes other methods for the synthesis of phosphodiesters, including phospholipids, which have been published since the previous review1. The chemical synthesis of oligonucleotides has been described in recent reviews and is only mentioned briefly in this article.