Independent Generation of C5‘-Nucleosidyl Radicals in Thymidine and 2‘-Deoxyguanosine

The synthesis of the C5‘ tert-butyl ketone of thymidine 1a and 2‘-deoxyguanosine 2 is achieved by
reaction of 5‘-C-cyano derivatives with tert-butyl lithium followed by acid hydrolysis. The 5‘R configuration
is assigned by X-ray crystal structure determination of an opportunely protected derivative of 1a. The
(5‘S)-isomers of both nucleosides are not stable, and a complete decomposition occurs in the reaction
medium. The photochemistry of 1a and 2 effectively produced the thymidin-5‘-yl radical and the 2‘-deoxyguanosin-5‘-yl radical, respectively. In the thymidine system, the C5‘ radical is fully quenched in
the presence of a physiological concentration of thiols. In the 2‘-deoxyguanosine system, the C5‘ radical
undergoes intramolecular attack onto the C8−N7 double bond of guanine leading ultimately to the 5‘,8-cyclo-2‘-deoxyguanosine derivative. The cyclization of the 2‘-deoxyguanosin-5‘-yl radical occurs with a
rate constant of ca. 1 × 106 s-1 and is highly stereoselective affording only the (5‘S)-diastereomer.