Synthesis of 1-(3-azido-2,3-dideoxy-beta-D-allofuranosyl)thymine, 1-(2,3-dideoxy-beta-D-allofuranosyl)thymine, and 1-(2,3-dideoxy-beta-D-erythro-hex-2-enofuranosyl)thymine.
1-(2-O-Acetyl-3,5,6-tri-O-benzoyl-beta-D-glucofuranosyl)thymine (1) was converted into the 2,2'-anhydro derivative 4 by selective deacetylation, mesylation, and treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene. Cleavage of the 2,2'-anhydro ring in 4 with hydrogen bromide or hydrogen chloride led to the 2'-bromo (5) or 2'-chloro (6) derivative, respectively. Dehalogenation of 6 with tributylstannane and then debenzoylation gave 1-(2-deoxy-beta-D-arabino-hexofuranosyl)thymine (8). Isopropylidenation of 8 followed by mesylation, azide displacement, and deprotection gave 1-(3-azido-2,3-dideoxy-beta-D-ribo-hexofuranosyl)thymine (12). Oxidation of 12 with Dowex 1 (IO4-) resin followed by reduction with Dowex 1 (BH4-) resin gave 1-(3-azido-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (AZT). Catalytic hydrogenation of 5 afforded a mixture of 1-(5,6-di-O-benzoyl-2,3-dideoxy-beta-D-erythro-hexofuranosyl)thymi ne (13) and 1-(3,5,6-tri-O-benzoyl-2-deoxy-beta-D-arabino-hexofuranosyl)thymin e (7). Reaction of 5 with a Cu/Zn couple gave 1-(5,6-di-O-benzoyl-2,3-dideoxy-beta-D-erythro-hex-2-enofuranosyl) thymine (15). 1-(2,3-Dideoxy-beta-D-erythro-hexofuranosyl)thymine (14) and 1-(2,3-dideoxy-beta-D-erythro-hex-2-enofuranosyl)thymine (16) were obtained by debenzoylation.
Hrebabecký
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Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Sciences, Prague.
Holý
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D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D015394:Molecular Structure; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D015215:Zidovudine