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

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-P^v-1,3,2-dioxaphosphole (or 1,2-dimethylethenylene phosphorochloridate), and 4,5-dimethyl-2-(1-imidazolyl)-2-oxo-P^v-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. 1. Introduction - Scope of the Review 2. Strategies for Phosphodiester Synthesis 3. The Double Phosphorylation Strategy 4. Double Phosphorylation with Cyclic Enediol Phosphoryl (CEP) Derivatives 5. Preparation of Methyl Acetoin Enediol Cyclophosphate, CEP-OCH₃ 6. Preparation of CEP-X Reagents 7. General Reactions of CEP-X Reagents 8. Synthesis of Simple Phosphodiesters 9. Synthesis of Phospholipids and Phospholipid Analogs 10. Synthesis of Oligonucleotides 11. Conclusions