Synthesis of polynucleotide analogs: Linear hydrophilic polymers containing optically active nucleic acid base derivatives.

Abstract

Polynucleotide analogs with linear hydrophilic polymer backbones and optically active nucleic acid base derivatives as pendants were prepared. Poly($N$-benzoyliminotrimethylene) was obtained by ring-opening polymerization of 2-phenyl-5,6-dihydro-4$H$-1,3-oxazine. Subsequent hydrolysis of the polymer in aqueous acid gave a linear polytrimethylenimine. The optically pure ($R$)-2-(adenin-9-yl)propanoic acid, ($R$)-2-(5-bromouracil-l-yl)propanoic acid, and ($R$)-2-(thymin-l-yl)propanoic acid were prepared from the corresponding nucleic acid bases and ($S$)-ethyl lactate utilizing a diethyl azodicarboxylate-triphenylphosphine method with subsequent hydrolysis in aqueous acid. The optically pure ($R$)-ethyl 2-(cytosin-1-yl)propanoate was obtained by reaction of sodium cytosine with ($S$)-ethyl 2-((methylsulfonyl)oxy) propanoate. The ester was hydrolyzed in aqueous acid to give the ($R$)-cytosinylpropanoic acid with 66% enantiomeric excess. The optically pure ($R$)-2-(hypoxanthin-9-yl)propanoic acid was converted from ($R$)-2-(adenin-9-yl)propanoic acid by reaction with nitrous acid. The pendant groups were grafted onto polytrimethylenimine by using the active ester method. The resulting polymers showed a wide range of percent grafting from 60% to 100%. The grafting reaction of the polymer with the ($R$) or the ($S$)-thyminylpropanoic acid yielded the chiral polymer. The reaction with other optically active pendant groups was accompanied by the racemization reaction. Poly(vinyl alcohol) underwent reaction with the (R)-bromouracilylpropanoic acid or the ($R$)-adeninylpropanoic acid in the presence of dicyclohexylcarbodiimide and a catalytic amount of 4-pyrrolidinopyridine. The resulting polymers were optically active and percents grafting were almost quantitative.