HILBERT-JOHNSON Nucleoside Synthesis

HILBERT JOHNSON Nucleoside Synthesis Nucleoside synthesis front brontosugars and methoxypyiimidines (see Vorbrueggen). 

HILBERT - JOHNSON Nucleoside Synthesis Nucleoside synthesis from bromosugars and methoxypyrimidines (see Vorbrue ). 

Irreversible lactim-lactam tautomerization was recognized a long time ago and is generally achieved by either heat or catalysts. One of the synthetic applications was reported by Knorr as early as 1897. Later, this reaction was first applied to the synthesis of pyrimidine nucleoside by Johnson and Hilbert, thus being called the Hilbert-Johnson reaction (HJR). The reaction has been employed as one of protocols for the preparation of pyrimidine nucleosides. The biological and medicinal interest in pyrimidine affords further impetus to prepare new types of derivatives. Because of the synthetic utility of the HJR for synthesis of pyrimidine nucleosides, a more sophisticated version of the HJR has been developed by Vorbriiggen (the silyl HJR VHJR) employ-... 

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. 

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-... 

The synthesis of pteridine nucleosides from pteridones can be considered as an electrophilic attack on a ring N-atom forming an 0,iV-acetal. A large number of N-l, N-3, and N-8 substituted ribo-, 2 -deoxyribo, arabino, xylo-, and gluconucleosides have been synthesized and described silyl-method based on the Hilbert-Johnson-Birkofer reaction. Lumazine (3) reacts with hexamethyldisilazane to 2,4-bis-trimethylsilyloxypteridine (85), which condenses with l-0-acetyl-2,3,5-tri-0-benzoyl-/ -i>ribo-furanose (86) under SnCl4, BF3 or trimethylsilyl triflate catalysis to a mixture of A(-l)-mono (87),... 

N-Alkylation in the azine ring is demonstrated by the preparation of 2-substituted 6-(jS-D-ribofuranosyl)oxazolo[5,4-rf]pyrimidin-7(6/T)-ones (181). In this case the silyl ether variant of the Hilbert-Johnson method for the synthesis of pyrimidine nucleosides has been used the pyrimidinone (180) is converted into its silyl ether using HMDS and the ether reacted with 2,3,5-tri-O-acetyl-D-ribofuranosyl bromide under Hg(II) catalysis. Deacetylation using methanolic ammonia gives the nucleoside with a /3-anomeric configuration (74JMC1282). 

The Hilbert-Johnson reaction of a protected 2-amino-2-deoxy-D-glucopyranosyl chloride (14) has been used in the synthesis of amino sugar nucleosides.13... 

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 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 silyl-Hilbert-Johnson method of nucleoside synthesis, using trimethylsilyltriflate as catalyst, is useful for the preparation of N-3 nucleosides (e.g., from 4-carbamoylimidazolium-5-olate) <84JHC529>, and a similar silyl displacement method has been used to make 1-alkylthio- and 1-phenylthio-l-trimethylsilyloxyalkanes and -cycloalkanes. This latter process uses 1-trimethyl-silylimidazole (177) and trimethylsilyltriflate as catalyst <84CHE662, 90S104>. The use of two equivalents of the thiol prevents the formation of imidazole adducts (Scheme 116) <90S104>. 

The use of trimethylsilyloxy derivatives, instead of other bases in the Hilbert-Johnson synthesis of nucleosides has resulted in better yields. Niedballa and Vorbriiggen have reported on the scope and limitations of this modified Hilbert-Johnson reaction. Thus, in the example shown in Scheme 120, stannic chloride in 1,2-dichloroethane was used to effect a... 

The second step of new nucleoside preparation was the modification at the pyrrole nitrogen, using standard techniques of nucleoside synthesis such as the silyl-Hilbert-Johnson (or Vorbriiggen) reaction [17a, c, 18], alkylation under basic conditions [17d, 19] or Mitsunobu reaction [17f, 20], By means of methods mentioned, a series of nucleosides 44-46 was prepared in moderate to good yields. 

The first synthesis of pyrimidine nucleosides had been reported earlier [G. Hilbert and T. B. Johnson, J. Am. Chem. Soc., 62,4489 (1930)] by means of a condensation of 2,4-diethoxypyrimidine with tetra-O-acetyl-n-glucopyranosyl bromide, but the yields were poor and the scope of the reaction was limited. 

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