Mechanisms of formation of adducts from reactions of glycidaldehyde with 2'-deoxyguanosine and/or guanosine

Convenient syntheses of rac-glycidaldehyde from rac-but-3-ene-1,2-diol and (R)-glycidaldehyde from D-mannitol are described. (R)-Glycidaldehyde (1) reacts with guanosine in water (pH 4-11, faster reaction at higher pH) to give initially 6(S)-hydroxy-7(S)-(hydroxymethyl)3-(beta-D-ribofuranosyl)-5 ,6,7-trihydroimidazo[1,2-a]purin-9(3H)-one (7a) and 6(S), 7(R)-dihydroxy-3-(beta-D-ribofuranosyl)-5,6,7,8-tetrahydropyrimidoll[1,2-a]purin-10(3H)-one (8a). The former decomposes to 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazol[1,2-a]purine (3a), 5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2-a]purine (5a, 1,N-2-ethenoguanosine), and formaldehyde, while the latter adduct is relatively stable. The position of the hydroxymethyl group on the imidazo ring of 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo-[1,2-a]purine was proved by C-13 NMR analysis of adducts derived from [1-N-15]guanosine and [amino-N-15]guanosine. At longer reaction times, the adduct 7,7'-methylenebis[5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2-a]purine[(4a) is formed from guanosine and glycidaldehyde. The structure analysis of this adduct was also aided by C-13 NMR analysis of the N-15-labeled adduct derived from [1-N-15]guanosine. Analogous adducts were obtained from the reaction between glycidaldehyde and deoxyguanosine. Mechanisms of formation of the adducts from glycidaldehyde and guanosine/deoxyguanosine are proposed and supported by model studies with simple amines. The formaldehyde produced in the reactions described reacts with guanosine to give the known adduct N-2-(hydroxymethyl)guanosine (9).