Approaches to unsaturated analogues of nucleosides comprising four- and six-membered rings

Article abstract of DOI:10.1021/jo000276p

Unsaturated nucleoside analogues 21, 22, 46, and 54, comprising four- and six-membered rings, were synthesized using two different approaches. The 2-benzyloxycycloalkanones 23a and 23b served as starting materials for both methods. Conversion to methylenecyclobutanes 29a and 29b was followed by addition of bromine via pyridinium perbromide to give vicinal dibromides 30a and 30b. Reaction of 29a with Br₂ gave a ring-contracted cyclopropane derivative 31. Alkylation - elimination of adenine with 30a gave bromoalkene 32 as the major product and adenine-containing unsaturated derivatives 33, 34, and 35 as minor components. Vicinal dibromide 30b gave the Zaitsev cyclohexene 45 as the only product. Epoxidation of 29a and 29b afforded oxiranes 36a and 36b which were used in alkylation of adenine to furnish hydroxy derivatives 37a, 37b, 38a, and 38b. β-Elimination via mesylates 39a and 40a using tBuOK/DMF gave Z- and E-methylenecyclobutanes 34 and 35. With an excess of base the E-bis-methylenecyclobutane 41 was obtained. Mesylation of cyclohexane derivatives 37b and 38b gave the Z- and E-N⁶-mesylated product 48. By contrast, the N⁶-benzoyl derivatives 49 and 50 afforded O-mesyl intermediates 51 and 52. β-Elimination gave both Hofmann and Zaitsev products 53 and 45. O-Debenzylation of 34 and 35, 45, and 53 afforded analogues 21, 22, 46, and 54. The E-isomer 22 was also obtained by hydroboration procedure from E-bis-methylenecyclobutane 41.