Hilbert-Johnson procedure

By use of the Hilbert-Johnson procedure,139,140 a synthesis186 of cytidine (II) was effected this involved condensation of crude tri-O-acetyl-D-ribo-furanosyl bromide with a 2,4-dialkoxypyrimidine, followed by treatment of the crude reaction mixture with alcoholic ammonia. Although the yields were low, this achievement marked the first synthesis of a naturally occurring nucleoside. 

Aside from the successful synthesis of cytidine,185 attempts made thus far to apply the Hilbert reaction to the preparation of 1 -glycofuranosyl-pyrimidines have yielded anomalous results. Although the syntheses of 5 -methyluridine (I, R = CH3) and 5 -methylcytidine (II, R = CH3) by the condensation of sirupy tri-O-acetyl-D-ribofuranosyl bromide with 2,4-diethoxypyrimidine have been reported,192 the properties of these nucleosides differ from those of the verified substances synthesized by other routes.68 62 Other aspects of the Hilbert-Johnson procedure are discussed below. 

Vorbruggen s strategy, involving a Friedel-Crafts catalyzed silyl Hilbert-Johnson procedure, offered an alternative approach to the synthesis of 5-azacytidines.23 Utilizing these conditions, a related analog, 1-O-acetyl-2,3,5-tri-O-benzoyl-p-D-ribofuranose (14) was reacted with 2,4-bis(trimethylsilyloxy)-6-azauracil (15) and SnCl4 in 1,2-dichloroethane on a 10-kg scale. After hydrolysis of the reactive intermediate, 93% of recrystallized 6-azauridine-2,3, 5 -tri-(9-benzoate(16) was obtained. 

The synthesis of corresponding pyrimidine nucleosides was not possible by the mercuric chloride method. The syntheses succeeded, however, on application of the Hilbert—Johnson procedure. Tetra-O-acetyl-4-thio-D-ribofuranose was transformed with ethereal hydrogen chloride into the glycosyl chloride derivative 254, and this was directly heated for five days with 2,4-diethoxy-5-methylpyrimidine. The anomeric forms of 4-ethoxy-5-methyl-l-(2,3,5-tri-0-acetyl-4-thio-D-ribofuranosyl)-2(lH)-pyrimidinone obtained could be separated... 

The pyrimidine bases cytosine, uracil, and thymine cannot be directly alkylated by halo sugars. The nucleophilicity of the pyridone-type ring nitrogens is much reduced relative to the pyridine-type nitrogens present in the purine bases. The dialkoxypyrimidines are reactive, and dealkylation occurs at the alkylated nitrogen. This is known as the Hilbert-Johnson procedure A recent modification employs... 

Initial studies58 had indicated that 1-glycopyranosyl nucleosides prepared by the mercuri procedure are identical with those prepared by the Hilbert-Johnson method, when similar poly-O-acylglycosyl halides are employed. The applicability of the mercuri procedure to the synthesis of 1-aldopento-furanosyl nucleosides was demonstrated by the preparation of 5 -methyl-uridine (LIV). Condensation of dithyminylmercury (LI) with tri-O-benzoyl-... 

It is evident that the anhydronucleoside route, in contrast to the Hilbert-Johnson,139 the mercuri,68 and, probably, the glycosylamine229 230,288 procedures, offers the possibility of synthesizing Cl-C2-cfs-/3-D nucleosides of pyrimidines, from pre-formed Cl-C2-(rans-/3-D-aldofuranosyl derivatives of pyrimidines. In this regard, the total syntheses described previously and the anhydronucleoside-conversion method may be viewed as complementary processes. The preparation of spongothymidine from l-/3-u-ribo-furanosylthymine is an example of this complementary relationship. An-... 

In addition to the Hilbert-Johnson reaction, the so-called mercuri process,37 and, less frequently, the cyclization procedure of Shaw et a/.,53 64 have been used for the synthesis of nucleosides and their derivatives. l-Peracylglycosyl-4-alkoxy-2(l//)-pyrimidinones, the intermediates of the Hilbert-Johnson reaction, can be, in principle, prepared 56,56 also by the mercuri process, namely by reaction of 4-ethoxy-2(lZ/)-pyrimidinone chloromercuri salt with the corresponding halogenoses, but this method is of less importance because of the contamination of iV-l-glycosyl derivatives with the 0-2 isomers, namely, with 2-peracylglycosyloxy-4-alkoxypyrimidines. The advantageous features of the mercuri process in comparison with the Hilbert-Johnson reaction might be formulated as follows. 

The Anomeric Ratio op Products op the Hilbert-Johnson Reaction op Dimethoxyfyrimidines (54 and 55) with Halogenoses (56, 57, and 58) in Acetonitrile (Procedure A) and in Benzene (Procedure B)... 

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