Organometallic Intermediates in the Synthesis of Nucleoside Analogs

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Abstract The common nucleosides, modified or derivatized in some way at the heterocyclic ring carbons, include examples of structures which a r e useful as biological probes and chemotherapeutic agents. Like previous authors, we will use the term “nucleoside analog” for structures related to one of the common naturally occurring nucleosides. Nucleosicle analogs can be derivatives which differ by such minor modification as replacement of hydrogen by a single atom or derivatives which are grossly modified at both the carbohydrate and the base. Examples of the former include 5-fluoro-2′-deoxyuridine, an inhibitor of thymidylate synthetase as its 5′-phosphate, and 5′-iodo-2′-deoxyuridine, a clinically useful antiviral agent. Larger groups have frequently been linked to nucleoside as probes for enzymatic processes. Side chains in “nonrestricted positions” may be used to carry spectroscopic or chemically reactive probes, or provide the means to attach a molecule to an affinity column. Ultimately with positions of bulk tolerance defined, it may be possible to design “active site directed irreversible enzyme inhibitors” as defined by B.R. Baker. Nucleoside structures in which a side chain is attached at a pyrimidine or purine carbon will undoubtedly, in some instances be the most appropriate structure. Yet, these have typically been more difficult to synthesize than analogs with side chains attached to heteroatoms.