NUCLEOTIDES .46. THE SYNTHESIS OF PHOSPHOLIPID CONJUGATES OF ANTIVIRALLY ACTIVE NUCLEOSIDES BY THE IMPROVED PHOSPHORAMIDITE METHODOLOGY

The application of the improved phosphoramidite strategy for the synth esis of oligonucleotides using beta-eliminating protecting groups to p hospholipid chemistry offers the possibility to synthesize phospholipi d conjugates of AZT (6) and cordycepin. The synthesis of 3'-azido-3'-d eoxythymidine (6) was achieved by a new isolation procedure without ch romatographic purification steps in an overall yield of 50%. Protected cordycepin (= 3'-deoxyadenosine) derivatives, the ,2'-bis[2-(4-nitrop henyl)ethoxycarbonyl]cordycepin (12) and the ,5'-bis[2-(4-nitrophenyl) ethoxycarbonyl]cordycepin (13) were prepared by known methods and dire ct acylation of N-6-[2-(4-nitrophenyl)ethoxycarbonyl]cordycepin (9), r espectively. These protected nucleosides and the 3'-azido-3'-deoxythym idine (6) reacted with newly synthesized and properly characterized li pid-phosphoramidites 21-25, catalyzed by 1H-tetrazole, to the correspo nding nucleoside-phospholipid conjugates 26-38 in high yield. The depr otection was accomplished via beta-elimination with 1,8-diazabicyclo[5 .4.0]undec-7-ene (DBU) in aprotic solvents to give analytically pure n ucleoside-phospholipid diesters 39-51 as triethylammonium or sodium sa lts. The newly synthesized compounds were characterized by elemental a nalyses and UV and H-1-NMR spectra.