Abstract
The first syntheses of 3-methyladenosine (3a) and 3-methyl-2'-deoxyadenosine (3b), both in the form of the p-toluenesulfonate salt, have been achieved through two parallel 6-step routes starting from adenosine (5a) and 2'-deoxyadenosine (5b), which are based on the "fission and reclosure" technology for modification of the adenine ring. These 3-methyladenine nucleosides (3a, b·TsOH) were very unstable under not only acidic but also alkaline conditions. At pH 1 and 25°C, 3a·TsOH (half-life 17 min) underwent glycosidic hydrolysis (depurinylation) some thousand times faster than did adenosine (5a) itself. At pH 3.34 and 25°C, the 2-deoxyribosyl analogue 3b·TsOH (half-life 2.7 min) was depurinylated 370 times more rapidly than the ribosyl analogue 3a·TsOH (half-life 1010 min). The glycosidic bond of the imidazole 2-deoxyriboside 11b, an intermediate for the present synthesis of 3b·TsOH, was also hydrolyzed easily at pH 1 and room temperature. In H2O at pH 8.32 and 25°C, 3a·TsOH readily underwent ring opening in the pyrimidine moiety and came to equilibrium with the (N-methylformamido)imidazole derivative 10a, which was further deformylated under more alkaline conditions. The ring opening was ca. 30 times as fast as that of 1-methyladenosine (17). In H2O at pH 8.98 and 25°C, the 2-deoxyribosyl analogue 3b·TsOH underwent not only similar ring opening but also glycosidic hydrolysis competitively. The possible factors responsible for the high reactivity of 3a·TsOH are discussed on the basis of its X-ray crystal structure.
