Studies on nucleoside analogs: I. Total synthesis and properties of N(1)-(Beta-erythrofuranosyl-)-uracil and its 2'-3'-cyclic phosphate, a substrate analog for ribonuclease. II. Improvements in the determination of conformations of nucleosides by nmr spectroscopy



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The first synthesis of an N (1) - ((3-D-erythrofuranosyl) -pyrimidine nucleoside was carried out by two methods which unambiguously established the structure of the desired nucleoside analog and a number of side products. D-Erythrose triacetate (V) was synthesized according to the literature method from glucose in four steps. The nmr spectrum of V was completely interpretable by first order rules, and the interpretation was confirmed with the use of a paramagnetic shift reagent, Eu(DPM)g. Compound V is predominantly the 3-anomer. Reaction with hydrogen chloride in dichloromethane afforded a good yield of the unstable acylglycosyl chloride, VI, as an oil containing only the g-anomer. The mercuri and mercuric cyanide reactions failed to produce an isolable yield of a pyrimidine nucleoside from VI because of instability of the halogenose. The Hilbert-Johnson reaction of VI with 2,4-bis(trimethylsilyloxy)pyrimidine afforded predominantly the a-anomer(VII) of the N(1)-glycoside, and the desired gnucleoside analog was obtained in only fair yield. Reaction of the triacetate V with 2,4-bis(trimethylsilyloxy)pyrimidine in the presence of stannic chloride afforded a satisfactory yield of the desired N(l)-(2',3'-di-0-acetyl-g-D-erythrofuranosyl)-uracil(VIII), along with two O-nucleosides, and a bis(erythrofuranosyl)-uracil. Compound VIII was hydrolyzed to N(1)-(g-D-erythrofuranosyl)-uracil(X), which was found to be inactive against leukemia L1210 in mice. Reaction of X with trimethylphosphite in the presence of trifluoroacetic acid afforded the 2'(3')-monophosphite derivatives, which were oxidized with hexachloroacetone to give N(l)-(g-D-erythrofuranosyl)-uracil-21,31-cyclic monophosphate, XV. Compound XV will be studied as a substrate analog for ribonuclease. A computer program was developed for accurately calculating the dihedral angles for twist, intermediate, and envelope conformations of any degree of puckering for both cyclopentane and tetrahydrofuran rings. The most popular literature tables for determining conformations of nucleosides by nmr spectroscopy were shown to contain numerous large inaccuracies of up to 15[degrees]. Dihedral angles of hydrogen substituents of fourteen nucleosides were calculated from literature X-ray data, and it was determined that distortions of up to 26[degrees] (compared to ring dihedral angles) commonly occur. In light of all of the data described above and of our own and literature correlations of the Karplus equation to molecules of fixed conformation, a more reliable method of determining conformations of nucleosides in solution was developed. The conformations of VIII, X, and other molecules containing five-member rings are discussed.