Formation of etheno adducts of adenosine and cytidine from 1-halooxiranes. Evidence for a mechanism involving initial reaction with the endocyclic nitrogen atoms

Article abstract of DOI:10.1021/ja00029a041

The etheno derivatives of nucleic acid bases contain an additional ring and are of interest because of their useful fluorescence properties and their potential as mutagenic lesions in DNA. The mechanism of formation from 2-haloacetaldehydes is known to involve initial Schiff base formation at an exocyclic nitrogen; however, mechanisms of formation from the more relevant 1-substituted oxiranes have not been established. The reaction of N⁶-methyladenosine (5) with 1-chlorooxirane yielded the stable carbinolamine 7,8-dihydro-8-hydroxy-9-methyl-3-β-D-ribofuranosylimidazo[2,1-i]purinium species (10), consistent with initial attack of the N¹ atom of adenine at the methylene of 1-chlorooxirane. No products indicative of initial reaction at the N⁶ atom of adenine were found. Reaction of 2,2-dibromoethanol with adenosine or cytidine at pH 9.2 yielded 1,N⁶-ethenoadenosine (1) or 3,N⁴-ethenocytidine (2), respectively, presumably via the base-catalyzed formation of 1-bromooxirane from the bromohydrin. When reactions were done with 2,2-dibromo[1-¹³C]ethanol, 1 contained label only at C-7 and 2 contained label only at C-3. A role for 2-bromoacetaldehyde in these reactions was ruled out by the lack of incorporation of deuterium from ²H₂O into 1 under conditions where the exchange of the methylene protons of 2-bromoacetaldehyde with the solvent was relatively rapid. The collective results are most consistent with a mechanism in which the basic endocyclic nitrogen (N¹ of adenine or N³ of cytosine) reacts with the methylene carbon of the 1-halooxirane, and, after ring opening and loss of the leaving group, the resulting aldehyde reacts with the exocyclic nitrogen to form the additional ring.