Synthesis of 1-(3-azido-2,3-dideoxy-β-D-allofuranosyl)thymine, 1-(2,3-dideoxy-β-D-allofuranosyl)thymine, and 1-(2,3-dideoxy-β-D-erythro-hex-2-enofuranosyl)thymine

Article abstract of DOI:10.1016/0008-6215(92)84160-T

1-(2-O-Acetyl-3,5,6-tri-O-benzoyl-β-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-β-D-arabino-hexofuranosyl)thymine (8). Isopropylidenation of 8 followed by mesylation, azide displacement, and deprotection gave 1-(3-azido-2,3-dideoxy-β-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-β-D-erythro-pentofuranosyl)thymine (AZT). Catalytic hydrogenation of 5 afforded a mixture of 1-(5,6-di-O-benzoyl-2,3-dideoxy-β-D-erythro-hexofuranosyl)thymine (13) and 1-(3,5,6-tri-O-benzoyl-2-deoxy-β-D-arabino-hexofuranosyl)thymine (7). Reaction of 5 with a Cu/Zn couple gave (1-(5,6-di-O-benzoyl-2,3-dideoxy-β-D-erythro-hex-2-enofuranosyl)thym idine (15). 1-(2,3-Dideoxy-β-D-erythro-hexofuranosyl)thymine (14) and 1-(2,3-dideoxy-β-D-erythro-hex-2-enofuranosyl)thymine (16) were obtained by debenzoylation. 1-(2-O-Acetyl-3,5,6-tri-O- benzoyl-β-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-β- D-arabino-hexofuranosyl)thymine (8). Isopropylidenation of 8 followed by mesylation, azide displacement, and deprotection gave 1-(3-azido-2,3-dideoxy-β- 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-β- D-erythro-pentofuranosyl)thymine (AZT). Catalytic hydrogenation of 5 afforded a mixture of 1 -(5,6-di-O-benzoyl-2,3-dideoxy- β-D-erythro-hexofuranosyl)thymine (13) and 1 -(3,5,6-tri-O-benzoyl-2-deoxy- β-D-arabino-hexofuranosyl)thymine (7). Reaction of 5 with a Cu/Zn couple gave 1-(5,6-di-O-benzoyl-2,3-dideoxy-β-D-erythro-hex-2 -2-enofuranosyl)thymine (15). 1-(2,3-Dideoxy-β- D-erythro-hexofuranosyl)thymine (14) and 1-(2,3-dideoxy-β-D-erythro- hex-2-enofuranosyl)thymine (16) were obtained by debenzoylation.