NUCLEOSIDES .55. SYNTHESIS OF A SULFUR-BRIDGED THYMINE ANHYDRO NUCLEOSIDE AND DERIVATIVES

Treatment of 2-O-methyl-3′-O-mesylthymidine (13) in dimethylformamide with hydrogen sulfide afforded (S)-2,3′-anhydro-1-(2,3-dideoxy-β-D-three-pentofuranosyl)-2-thiothymine (3). Compound 3 was cleaved in alkali to yield the relatively stable mercapto derivative, 1-(2,3-dideoxy-3-mercapto-β-D-three-pentofuranosyl)- thymine (14). Acid-catalyzed treatment of 14 with acetone gave the oxathiolane derivative, 1-[2,3-dideoxy- 3,5(S,O)-isopropylidene-β-D-three-pentofuranosyl]thymine (15). Compound 14 was oxidized to the intermolecular disulfide, 17. The sulfur-bridged anhydro nucleoside (3) was also obtained by treatment of 2,5′- anhydro-3′-O-mesylthymidine (5) in dimethylformamide with hydrogen sulfide. From the latter reaction a second product was obtained and identified as the internal disulfide of 1-(trideoxy-3,5-dimercapto-β-D-three-pentofuranosyl) thymine (8). An alternate and preferred synthesis of 8 from di-O-mesylthymidine (11) is described. The ultraviolet absorption spectrum of the 3′-mercapto derivative (14) as a function of pH revealed the presence of two dissociations with apparent pKa values of 10.2 and ∼8.4. The higher of these is due to ionization of the N-3 proton. The ionization associated with pKa ∼ 8.4 is interpreted as a reflection of the rupture of a weak hydrogen bond between the 3′-mercapto group and the 2-carbonyl. © 1969, American Chemical Society. All rights reserved.