UBC Theses and Dissertations

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UBC Theses and Dissertations

The synthesis of isomeric nucleoside polyphosphates Ward, David C.


The complete lack of experimental evidence concerning the chemical and biological properties of nucleoside-2' and -3' polyphosphates led to the synthesis and characterization of some of these compounds, as reported in this thesis. Since the deoxyribonucleoside-3' polyphosphates were chemically analogous to their 5'-isomers,, the synthesis of deoxycytidine-3' di-, tri- and tetraphosphates and thymidine-3' di-, tri- and tetraphosphates were readily achieved in good yields. The isomeric 2'- and 3'-ribonucleoside polyphosphates were, on the other hand, expected to be much more labile than the corresponding ribonucleoside-5' polyphosphates because of the presence of a cis vicinal hydroxyl group, which facilitates the formation of nucleoside-2',-3' cyclic phosphates. Attempts to synthesize adenosine-3' polyphosphates by way of diacetylated or dipyranylated nucleotide intermediates were without success for the conditions required to remove the protecting groups resulted in concomitant degradation of the pyrophosphate linkages. Investigation of the reaction of adenosine-(2'),3' monophosphate with phosphoramidic acid, as an approach to the synthesis- of adenosine-(2'),3'-polyphosphates, surprisingly revealed that phosphoramidic acid, under certain conditions, not only formed pyrophosphate bonds, as expected, but also esterified free hydroxyl groups. The maximal rate of ester formation occurred in a neutral or mildly alkaline media, with preferential esterification of secondary hydroxyl functions. Attempts to extend this phosphorylation reaction to the synthesis of phospho-diesters were without success as mono- or dialkylated phosphoramidates did not exhibit phosphorylative properties. Although the 2'-and 3'-isomers of adenosine di- and triphosphates were identified as products of the reaction of adenosine-(2'),3' monophosphate with phosphoramidic acid, only adenosine-2' -diphosphate was fully characterized. The latter compound when treated with strong alkali underwent a rearrangement reaction which was unique in the field of nucleotide chemistry. If this alkaline rearrangement is found to be characteristic of all isomeric 2'- and 3'-nucleoside polyphosphates, it will be of considerable practical synthetic value.

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