Purines, silyl derivatives

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-... 

Silyl derivatives have proved valuable intermediates in purine glycosylation reactions. Thus the trimethylsilyl derivative of hypoxanthine (136) with 2,3,4,6-tetra-O-acetyl-a-D-glucosyl chloride produced, after deblocking, an anomeric mixture of the two 9-glucosylhypoxanthines, and similar reactions with trimethylsilylated W -benzoyladenine led to a mixture of 9-substituted anomers (B-68MI40901, p. 135). 

Silyl derivatives of purines are commonly used in the same way as in a synthesis of 9-(a, -D-glucopyranosyl)adenine from AT -benzoyl-9-bis(trimethylsilyl)adenine and 2,3,4,6-tetra-O-acetyl-a-D-glucosyl chloride at 150-160 °C over 4 hours to produce, after deblocking, a mixture of anomeric nucleosides (B-68MI40901,p. 135). The hypoxanthine nucleosides may be obtained in a similar fashion or by deamination of the adenine derivatives. 

Pentostatin 219 is clearly a modified deoxynucleoside with a seven-membered ring instead of the normal six-membered ring of a purine.25 It is simplest to remove the stereochemistry in the seven-membered ring by FGI of the alcohol to a ketone 220. We can then disconnect the sugar, expecting to use the sort of chemistry earlier in the chapter, maybe a silyl derivative of the purine analogue 221 and a derivative of the sugar 222, maybe with X = OAc. 

Alternative methods for A-alkylation include heating with trimethyl phosphate and the alkylation of 0-silylated derivatives, which is an important method for unambiguous A-alkylation especially ribosylation of uracils ribosylation is subject to the same stereochemical difficulties as in purine chemistry (for further discussion see section 24.2.1.2). 

Analogs with a sulfur instead of an oxygen atom in the side chain were also prepared. Thus, the starting synthon 332 was prepared from 265 via 331 in four steps. Alkylation of 332 with the silyl derivative of 2-amino-6-chloro-9//-purine gave a mixture of 334 and its N-7 isomer that could be... 

Ribosylation of uracils is usually carried out via bis-silyl derivatives and is subject to the same stereochemical difficulties as purine ribosylation (for further discussion see section 23.2.1.2). 3-Pyridazinones alkylate cleanly on N-2 under phase-transfer conditions but the regiochemistry of uracil alkylation is sometimes difficult to control. 

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]. 

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... 

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. 

The Lewis acid catalyst, such as trimcthylsilyl triflate, reacts simultaneously with the peracylated sugar bearing a 2-acyloxy group to generate in situ the electrophilic 1,2-acyloxoni-um ion D and with the silylated purine A to form in situ the trimcthylsilyl tr-complex at Nl, the center of highest electron density, B. The a-complex B can also exist in equilibrium with the Nl trimethylsilyl derivative C. Either of the silylated intermediates reacts with the acyloxonium cation to result in a 1-, 3-, 7-, and 9-ribosylation. Under optimum reaction conditions, the 1-, 3-, and 7-isomers rearrange to the thermodynamically most favored N9 isomer... 

The rest of the synthesis follows the methods already discussed. The purine analogue 221 was silylated and coupled with the sugar derivative 236 to give a mixture of stereoisomers at the anomeric position. Deprotection and not very stereoselective reduction gave pentostatin. 

Direct conversion of inosines into 6-amino derivatives, without the intermediacy of a halo-purine, can be achieved by heating with a mixture of phosphorus pentoxide and the amine hydrochloride or using the amine with p-toluenesulfonic acid and a silylating agent (HMDS), or the amine with iodine and triphenylphosphine. ... 

Nakashima, K. Inoue, K. Mayahara, K. Kuroda, N. Hamachi, Y Akiyama, S. Use of 3-(l,8-naphthal-imido)propyl-modified silyl silica gel as a stationary phase for the high-performance liquid chromatographic separation of purine derivatives. J.Chromatogr.A, 1996, 722, 107-113... 

Reviews on catalytic uses of DMAP and other 4-(dialkylamino)pyridines have appeared [9]. These bases are very efficient reagents for acylations, alkylations, silylations, phosphorylations, condensations, and transesterifications [ 10]. More recent applications of DMAP as a catalyst include a parallel synthesis of benzyl purine derivatives [11] and it has been employed as a base in the asymmetric synthesis of an amino acid via an auxiliary [12]. Uses of DMAP tethered to solid supports (of which one such example is commercially available) have been reviewed [10,13]. Such a system has recently been employed to synthesize multiple oligonucleotides linked end to end in tandem [14]. 

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