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) 3 SiH 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) 3 Si · 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 10 5 s –1 at 86 °C, the cyclization on the purine moiety being 4–5 times faster than that on the pyrimidine group. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)