Nucleotides. Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology

Abstract

The application of the improved phosphoramidite strategy for the synthesis of oligonucleotides using p-eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT (6) and cordycepin. The synthesis of 3'-azido-3'-deoxythymidine (61 was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin ( = 3'-deoxyadenosine) derivatives, the N6,2'-bis[2-(4-nitrophenyl)ethoxycarbonyl]co~dycepin (12) and the N6,5'-bis[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (13) were prepared by known methods and direct acylation of N6-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (9), respectively. These protected nucleosides and the 3'-azido-3'-deoxythymidine (6) reacted with newly synthesized and properly characterized lipid-phosphoramidites 21-25, catalyzed by IH-tetrazole, to the corresponding nucleoside-phospholipid conjugates 26-38 in high yield. The deprotection was accomplished via 8-elimination with 1,8-diazabicyclo[5.4.O]undec-7-ene (DBU) in aprotic solvents to give analytically pure nucleoside-phospholipid diesters 39-51 as trie1:hylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and 1JV and 'H-NMR spectra.

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…P(III) chemistry has also been used by Sigmund et al 113 for the synthesis of AZT and 3′-deoxyadenosine phospholipid conjugates. 2-(4-Nitrophenyl)ethoxy-protected (NPE) alkoxyalkyl phosphoramidites 274 were first obtained by reacting alkoxyalkyl alcohols 273 and diisopropy1amino[2-(4-nitrophenyl)ethoxy] chloro phosphate.…”

Nucleolipids: Natural Occurrence, Synthesis, Molecular Recognition, and Supramolecular Assemblies as Potential Precursors of Life and Bioorganic Materials

“…In the mid 90s Sigmund and Pfleiderer published the first synthesis of phospholipid conjugates of the antivirally active nucleosides 3'-azido-3'-deoxythymidine (AZT; 118), the drug of choice for the treatment of HIV, and 3'-deoxyadenosine (cordycepin; 119) by an improved phosphoramidite methodology [50].…”