Biological importance of purine tautomerism

The tautomerisation of the purine bases adenine and guanine and of the pyrimidine bases thymine, cytosine, and uracil has important implications in molecular biology, and the occurrence of rare tautomeric forms of these bases has been suggested as a possible cause of spontaneous mutagenesis (Lowdin, 1965 Pullman and Pullman, 1971 Kwiatowski and Pullman, 1975). Three of the most likely tautomers for cytosine are shown in [87]—[89], together with the less likely imino forms [90] and [91] (Scanlan and Hillier,... 

The understanding of the tautomeric properties of the purine and pyrimidine bases of the nucleic acids and the determination of the electronic properties of the principal tautomers are of fundamental importance in molecular biology, in particular in connection with the theory of mutations (for general references see, e.g. refs. 1-6.) B. Pullman and A. Pullman have presented recently in these Advances3 a detailed review of the problem as it concerns the purine bases. The present paper... 

There are various forms of tautomerism which operate in the different purine species. (1) Prototropy which involves attachment of the proton to any one of the four ring nitrogen atoms (Scheme 5). Corresponding CH tautomers, for example (52), seem to be of little significance. (2) Amine-imine tautomerism which operates in the aminopurines such as adenine (Scheme 6). (3) Lactam-lactim tautomerism as in the hydroxypurines such as hypoxanthine (Scheme 7) and the related thioxo-thiol tautomerism (53) and (54) in the biologically important mercaptopurines (Scheme 8). The subject has recently been discussed in some detail (76AHC(S1)502>. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

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