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

Article abstract of DOI:10.1002/hlca.19960790210

The application of the improved phosphoramidite strategy for the synthesis of oligonucleotides using β-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 (6) 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]cordycepin (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 1H-tetrazole, to the corresponding nucleoside-phospholipid conjugates 26-38 in high yield. The deprotection was accomplished via β-elimination with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in aprotic solvents to give analytically pure nucleoside-phospholipid diesters 39-51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and ¹H-NMR spectra.