Hilbert-Johnson method

Heterocyclic bases, amination of, 1, 4 in nucleosides, 55, 1 Heterodienophiles, 53, 2 Hilbert-Johnson method, 55, 1 Hoesch reaction, 5, 9... 

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-... 

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). 

A-Glycosylimidazoles (related to nucleosides) are of interest in the preparation of novel chemotherapeutic agents, hence selective A -glycosylation techniques are of interest. The palladium-catalyzed addition of vinyl epoxides and allyl acetates to imidazoles provides one such route to imidazole nucleoside analogues <91JCS(Pi)2603, 9UOC4990>. The silyl-Hilbert-Johnson method is another in which the imidazole is silylated, then treated with a suitable peracetylated carbohydrate derivative in the presence of trimethylsilyl triflate catalyst. With 4-carbamoylimidazolium-5-olate, for example, the major product is the l-glycosyl-5-carbamoyl isomer with only low yields of the... 

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>. 

P-D-Rihofuranosyl derivatives of various 1,2.4-triazoles have been reported, along with P-D-arabinofurano l and 2 - and 5 -deo3 - analogues. Ribofuranosylation of 1.2,3-triazoIe (4) gave the 2- substituted nucleoside, while the l,4-thlazin-3-one nucleoside (5), and its S-oxide, a potential tetrahedral intermediate analogue for enzymes in pyrimidine nucleoside metabolism, have been prepared by silyl-Hilbert-Johnson methods, Also available by standard methods are P-D-ribofuranosyl derivatives of... 

The rearrangement of 2- or 4/6-alkoxypyrimidines, either by thermal means or by the Hilbert-Johnson reaction, also leads to iV-alkylpyrimidinones the former method is of little preparative value but the Hilbert-Johnson reactiop is quite important. The processes are outlined in Section 2.13.2.2.7/. 

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-... 

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),... 

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 products of the mercuri process in most cases possess a C-V-C-2 -trans system in accordance to the Baker trans rule61-64 and are sterically more uniform than the Hilbert-Johnson products. On the other hand, certain anomers inaccessible by the mercuri process may be obtained under certain conditions (solvent) by the Hilbert-Johnson reaction as a mixture with the other anomer chromatographic methods have been worked out to separate these mixtures almost quantitatively into the individual anomers (cf. Section X). The Hilbert-Johnson reaction intermediates may be converted into nucleosides of both types, of the uridine type as well as of the cytidine type (cf. Section V), whereas conversion of the mercuri process of the uridine type into the cytidine type is somewhat tedious. On the whole, the Hilbert-Johnson reaction represents a suitable complementary method to the mercuri process. 

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... 

Imbach et al. have reported syntheses of 4 -thiothymidine (104) and 4 -thiouridine (105) starting fromL-lyxose, following the dithiobenzyl acetal cyclization method and the Hilbert-Johnson silyl condensation reaction of 103 with silylated thymine (77% yield, a p 43 57) and uracil (74% yield, a 47 53),... 

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. 

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