DAVID C. J WU, University of Rhode Island


Synthetic efforts aimed at preparing potential adenosine deaminase inhibitors are presented. The work includes attempts to prepare heterocyclic bases as well as modified nucleosides whose structures resemble those of the well studied inhibitors, deoxycoformycin (pentostatin) and (+) erythro-9-(2S-hydroxy-3R-nonyl) adenine ((+)-EHNA).^ An attractive synthesis of imidazole 4(5)-carboxaldehyde was discovered. This was based on an oxidative base catalyzed fragmentation of {5(4)-nitroimidazol-4(5)-yl}methyl nitrate. Structure proof of the aldehyde was derived from the preparation of suitable derivatives and from an X-ray crystallographic analysis of its precursor {4-nitro-1-(tetrahydropyran-2-yl)imidazol-5-yl}methyl nitrate.^ Attempts to prepare the aglycone of deoxycoformycin via a {2 + 3} cycloaddition reaction necessitated the development of a suitable synthesis of 2-deoxy-2-amino-D-threose. Starting with 5,6-O-isopropylidene-D-isoascorbic acid, methyl 3,4-O-isopropylidene-D-erythronate was prepared. While attempts to introduce an azido function at C-2 of this compound were not successful, the SN(,2) azide displacement of the tosylate group in 3,4-O-isopropylidene-2-p-toluenesulfonyl-D-erythritol-1-p-nitrobenzoate furnished the corresponding azide. Catalytic reduction of this compound followed by N-protection and subsequent oxidation of the alcohol gave an aldehyde as shown by ('1)H NMR.^ In an effort to develop a regiospecific glycosylation for certain imidazole ribosides, a reaction involving a condensation between D-glucosamine and 2,3,5-tri-O-benzoyl ribofuranosyl isothiocyanate was performed. The structure of the isolated product was derived from a detailed ('1)H NMR study of its triacetate and was shown to be 3-(2,3,5-tri-O-benzoyl-(beta)-D-ribofuranosyl)-5-(1R-1,2-dihydroxy-ethyl)-6R-6-hydroxytetrahydrofuro{4,5-b}-3(,a)S,6(,a)R-imidazolidine-2-thione. Significant features of this compound are: the potential to introduce desirable chiralities in the aglycone, and the specific ribosylation at N-3. Further modifications to convert the above imidazolidine-2-thione to an imidazoline-2-thione or to an imidazole are discussed. ^

Subject Area

Chemistry, Pharmaceutical

Recommended Citation

DAVID C. J WU, "SYNTHETIC APPROACHES TO POTENTIAL ADENOSINE DEAMINASE INHIBITORS" (1982). Dissertations and Master's Theses (Campus Access). Paper AAI8326501.