A General Method for the Synthesis of the N2- and N6- Carcinogenic Amine Adducts of 2‘-Deoxyguanosine and 2‘-Deoxyadenosine1

A number of simple arylamino compounds (Figure 1) are well-established as pro-carcinogenic agents. Metabolic activation leads to a series of unstable N-hydroxy derivatives that on solvolysis, give nitrenium ions. The latter, which are regarded as the primary mutagenic/carcinogenic agents attack DNA to give a variety of adducts. Principal among these are the C-8 arylamination products of 2‘-deoxyguanosine (dG) and the N 2 - and N 6 -(2-acetylamino)arylation adducts of dG and 2‘-deoxyadenosine (dA), respectively. The latter types of adducts have received little biological attention because synthetic methods for their preparation have been lacking. We now describe a general high-yield method for the synthesis of both of these types of N -arylated 2‘-deoxynucleosides. The key step is a Buchwald−Hartwig coupling reaction between an appropriately protected derivative of dG or dA ( 1 and 7, respectively) and an o -nitroaryl bromide or triflate ( 2a − e ). Subsequent reduction, acetylation, and deprotection of the N 2 -adducts ( 3b − e ) of dG and of the N 6 -adduct ( 8c ) of dA then gives the desired adducts 6b − e (overall yield 70−88%) and 11 (overall yield 43%), respectively.