Synthesis of a bicyclic analogue of AZT restricted in an unusual O4'-endo conformation.
The [3.2.0]bicyclic beta-nucleoside analogue 5 has been designed as a conformationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its alpha-anomer 29 is hereby described. The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereoselectively incorporating the azide moiety as well as a methyl ester function. When the tert-butyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5 and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally restricted in an unusual O4'-endo (East) conformation, which is an intermediate between the North- and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.
Sørensen
M H
MH
Department of Chemistry, University of Southern Denmark, Odense University, DK-5230 Odense, Denmark.
Nielsen
C
C
Nielsen
P
P
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis; D002236:Carbohydrate Conformation; D003855:Deoxyribose / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015215:Zidovudine; D003855:Deoxyribose