Radical Cyclization Approach to Cyclonucleosides

• Published in: European Journal of Organic Chemistry 2005-11, Vol.2005 (21), p.4640-4648
• Main Authors: Navacchia, Maria Luisa, Manetto, Antonio, Montevecchi, Pier Carlo, Chatgilialoglu, Chryssostomos
• Format: Article
• Language: English
• Subjects: Cyclization; Kinetics; Nucleosides; Organosilanes; Radical reactions
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.200500398

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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)