4'-SUBSTITUTED NUCLEOSIDES .5. HYDROXYMETHYLATION OF NUCLEOSIDE 5'-ALDEHYDES

Crossed aldol condensations between variously substituted nucleoside 5'-aldehydes and formaldehyde in the presence of aqueous sodium hydroxide lead, following rate-limiting Cannizzaro reduction, to the corresponding 4'-hydroxymethyl nucleoside derivatives. The speed and overall efficiency of the above reactions are improved by incorporating a borohydride reduction of the initial aldol product rather than relying upon the normal Cannizzaro reduction. Such reactions conducted with 2', 3'-unsubstituted nucleoside S'-aldehydes give mixtures of 4'-hydroxymethyl nucleosides epimeric at C3- presumably via a reverse aldol cleavage followed by recyclization. Hence, the use of base stable 2', 3'-0 protecting groups is recommended for these reactions. In the case of 2', 3'-0-isopropylidene derivatives of N6-benzoyladenosine and N4-benzoylcytidine 5'-aldehydes, some exchange of the acetonide by a methylene group is observed and a mechanism is proposed. For extension to the 2'-deoxynucleoside series, the corresponding hydroxymethylation of 3'-0-benzylthymidine 5'-aldehyde followed by catalytic hydrogenolysis leads to 4'-(hydroxymethyl)thymidine. Syntheses of a number of new, variously protected nucleoside 5'-aldehydes are described. © 1979, American Chemical Society. All rights reserved.