Pyrimidines, silyl derivatives

Replacement of heterocyclic rings in nucleosides by ring systems which do not occur in nature represents another approach to compounds which may have activity against viral and neoplastic diseases. One of the early successes in this category involves replacement of a pyrimidine ring by a triazine. The synthesis starts with a now classical glycosidation of a heterocycle as its silylated derivative (146) with a protected halosugar (145), in this case a derivative of arabinose... 

The thieno[3,2-d]pyrimidine-2,4-diones were prepared as shown in Scheme 237, and their silyl derivatives were coupled with various acetoxy-methyl ethers in the presence of stannic chloride to give diseco (type 2.1), triseco (type 3.1), and pentaseco benzyl derivatives of type 5.1 nucleosides (94JHC305). 

Unsubstituted thieno[2,3-d]pyrimidin-4(3//)-one 2a was converted into the trimethylsilyl derivative 137 by heating in hexamethyldisilazane. Silyl derivative 137 was alkylated at N-3 with l-0-acetyl-2,3,5-tri-O-benzoyl-/3-D-ribofuranose in the presence of stannic chloride in 1,2-dichloroethane or... 

Replacement of the chlorine by the purine or pyrimidine base is sometimes quite tricky and silver or silyl derivatives are often used. Lewis acid catalysis is necessary to help the chloride ion leave in this S l reaction. We shall avoid detailed technical discussion and simply draw the adenosine prod-... 

The mono-silylated or free acetamides, which are liberated during silylation with 22 a, can, furthermore, interfere with any subsequent reaction, e.g. with electrophiles. Thus in the one-pot/one-step silylation, Friedel-Crafts catalyzed, nucleoside synthesis starting from protected sugar derivatives and pyrimidine or purine bases, the mono- or bis-silylated amides such as 22 a can compete with less reactive silylated heterocycHc bases for the intermediate electrophilic sugar cation to form protected 1-acetylamino sugars in up to 49% yield [42, 47]. On silylation with trimethylsilylated urea 23 a the Hberated free urea is nearly insoluble in most solvents, for example CH2CI2, and thus rapidly precipitated [43]. 

Treatment of the allylic sulfoxide 1227 a with diisopropylethylamine (DIPEA) or of 1227 b with N-trimethylsilyldiethylamine 146 and TMSOTf 20 leads in ca. 90% yield to the quaternary amino derivatives 1228 and 1229 and HMDSO 7 [36] (Scheme 8.15). Tetramethylene sulfoxide 1230 reacts with silylated thymine 1231 in the presence of three equivalents of TMSOTf 20 to give the 4 -thio-nucleoside analogue 1232 and HMDSO 7 [37]. Other silylated pyrimidine, pyridine, and purine bases react analogously with cyclic sulfoxides to give 4 -thio-nucleoside analogues [37, 37a, 38]. 

Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl (3-enaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. 

Sulfoxides have also been used in the synthesis of nucleoside analogs (Scheme 3.2). Chanteloup and Beau reported the synthesis of ribofuranosyl sulfoxide 13 and its use in the glycosylation of a series of silylated pyrimidine and purine bases.7 Although 16 is not an anomeric sulfoxide, its reaction with cytosine derivative 17 is conceptually related.8... 

Trimethylsilylpyrimidinium triflate, derived from pyrimidine and trimethylsilyl triflate, adds silylated enol ethers to form 1,4-dihydropyrimidines. /V-Acylpyrimidinium tetrafluoroborates undergo analogous reactions (85H(23)207). 

Reactions of enamines with monoimines of o-quinones afford polycylic compounds 228 with an oxazine ring (86MI2).Trifluoroacetylation of enamines with trifluoroacetic acid takes place in the /3-position of the enamine. Ketones (229) thus formed in an acidic medium afford fused 1,3-oxazines (230) (82JOC3339). Treatment of amines with silyl isothiocyanate gives not only pyrimidine derivatives but also l,3-oxazine-4-thiones (231) (81CCC2696). 

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-... 

In 1970, 1 was prepared by direct glycosylation of the silylated 5-azacytosine with acylated 1-halo sugars, but the yields were very low.20 In this procedure, 1,3,5-tri-O-acetyl-2-deoxy-D-ribofuranose (9) was converted into 3,5-di-0-acetyl-2-deoxy-D-ribofuranosyl chloride (10).21 The trimethylsilyl derivative of 5-azacytosine (11),22 prepared from 4-amino-6-pyrimidine by treatment with hexamethyldisilazane, was then allowed to react with intermediate 10 in acetonitrile over 7 days to give a mixture of anomers of l-(3,5-di-(9-acetyl-2-deoxy-D-ribofuranosyl)-5-azacytosine (12) in 10% overall yield. The anomeric mixture was treated with ethanolic ammonia to remove the acetyl groups. The resulting a and p anomers were separated by a combination of fractional crystallization and preparative layer chromatography on silica gel to give pure decitabine (1) and its a-anomer 13 in 7% and 52% yield, respectively. 

BSA was effective for the derivatization of purine and pyrimidine bases [456] and nucleosides [457]. Bases were silylated by heating at 150°C with BSA—acetonitrile (1 3) for 45 min. It was stated that under these conditions the TMS derivative of guanine can be prepared reproducibly, but both cytosine and 5-methylcytosine provided two peaks. Silylation of nucleosides, including pseudouridine, was carried out by heating at 120°C with a 100-fold excess of BSA for 2 h. With the use of OV-17 as the stationary phase, this procedure was adopted for the determination of the composition of ribonucleic acids. 

As already mentioned in Section IV,A, 2-methyl-4-hydroxypyrido-[3,4-i/]pyrimidine (48) on silylation-amination with benzylamine, affords 97% of the corresponding N-benzyl derivative 50, whereas the conventional two-step procedure via the 4-chloro compound 49 gives 50 (86ABC495) in only 40% yield. 

Pyrimidine reacts with trimethylsilyl cyanide and benzoyl chloride with aluminum chloride as catalyst, to give the Reissert-type compound (366) <81JHC443>. The intermediate acylpyrimidinium cation (367) adds a soft nucleophile such as the silyl ether of acetophenone, and the adduct rapidly undergoes a second A-quaternization to (368) with a subsequent nucleophilic attack to form (369) (Scheme 61). The reactive intermediate can also be trapped by reactions with heteronucleophiles <88JCS(P1)725>. Intramolecular nucleophilic addition is shown in the formation of the spiran derivative (370) <92JOC2526>. 

When 180 was subjected to acetolysis it gave an acyclic derivative, which when submitted to nucleosidation gave the acyclic nucleoside 181 (90-JOC3772). However, reaction of methyl-2-3,S-tri-O-benzoyl-a-o-arabino-side with silylated pyrimidines in the presence of TMS triflate gave the acyclic nucleoside 183 in addition to 182 (92S1299). 

Direct transformation [21] of p-lactams into the corresponding imino-p-lac-tams 19 has been effected with N-chlorosulphonylisocyanate (CSI) (Scheme 6). The reaction probably involves a [2 + 2] cycloaddition-cycloreversion sequence. The same experimental conditions applied to penam or cephem derivatives gave ring-enlarged products only [22]. Silylation of trichloroethyl 6p-phenoxyacetamido-penicillinate followed by reaction with CSI and reduction with metabisulphite yielded the bicyclic pyrimidine-2,4-dione 20a (1 1 mixture of epimers). The carboxylic acid 20b is devoid of antibiotic activity (Scheme 7). 

In the area of 2, 3 -didehydro-2, 3 -dideoxynucleosides, a new route to compounds of this type in the pyrimidine series is outlined in Scheme 4. The thioglycoside 54 was produced directly from deoxyribose and thiophenol in acidic conditions, and the condensations to form the nucleoside derivatives were P-selective by about 2 l/ A full account has been given of the formation of 2, 3 -didehydro-2, 3 -dideoxy systems from 2, 3 -dimesylates, protected at 0-5, by treatment with telluride anion (see Vol. 27, p. 247)7 Treatment of the furanoid glycal 55, made by cyclization of an acetylenic alcohol (Chapter 13), with silylated thymine in the presence of iodine, followed by sodium methoxide, provides a new route to d4T (56)7 A new synthesis of d4T (56) from 5-methyluridine has also been described, as has a route to d4T labelled with at C-1, which starts from [l- C]-ribose and proceeds via [r- C]-5-methyluridine, convertible in very high yield to [l - C]-d4T. ... 

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