Radical Cyclization Approach to Cyclonucleosides

Efficient methodologies based on consecutive radical reactions for the preparation of cyclonucleosides 5 and 13 are reported. The reactions were performed on modified thymidine and 2?-deoxyadenosine substrates using (TMS)3SiH as the reducing agent. The protected 5?-carbaldehyde 3 afforded the cyclonucleoside 4 in 85 % yield and in a diastereoisomeric ratio 4a/4b = 3:7. The mono-desilylation at the 5?-O position of these cyclonucleosides has been successfully achieved by UV irradiation affording quantitatively derivatives 5a and 5b. The protected 5?-carbaldehyde 10 afforded the cyclonucleoside 12 in 70-75 % yield as a single diastereoisomer (5?R) either in deoxygenated solution, followed by in situ oxidation of the reaction mixture by chloranil, or in aerobic conditions. The photochemical 5?-O-desilylation of 12 has been obtained in 56 % yield affording the cyclopurine 13. The reaction mechanisms have been studied in some detail using a variant of the radical clock methodology. The C5? radical 6 or 15, generated by addition of the (TMS)3Si· radical to the corresponding aldehyde, undergoes a 6-exo-trig cyclization on the base moiety prior to termination. The rate constants for both 6-exo-trig radical cyclizations have been estimated to be close to 105 s-1 at 86 °C, the cyclization on the purine moiety being 4-5 times faster than that on the pyrimidine group.