2,6-Disubstituted purine

Scheme 3. Solid-phase synthesis of 2,6-disubstituted purines.

Preparation of 2,6-Disubstituted Purines (65) Using Pd-Mediated Reactions Involving Amines and Boronic Acids (Fig. 11)33... 

Table 2. ll NMR chemical shifts (ppm) of selected 2,6-disubstituted purines in DMSO-tZg... 

H.C. van der Plas and coworkers continue to publish papers on the action of amide ion in liquid ammonia on heterocyclic compounds. Two publications on the reaction with purines show that several processes can occur. For example, with the 2,6-disubstituted purine (282), potassium amide in liquid ammonia gives (283), (284), and (285). Compound (283) is formed first and is then converted to (285), which is the precursor of (284). Compound... 

A systematic study has been reported on the isomer distribution in condensations between 2-deoxy- 3,5-di-O-p-toluoyl -a-D-e/ythro-pentofuranosyl chloride (24) and the sodium salts of various 2-substitutcd and 2,6-disubstituted purines. Typically 9-p- and 7-P products were obtained in ratios of ca. 4 1, with smaller amounts of a-nucleosides, with 2-bromo-6-(methylthio)purine giving the highest amount of 9-P-linked product. 2,6-Dibromopurine, however, gave only N-9 linked products (p oc, 4 1). Other workers have reported that if the a-chloride 24 is allowed to stand in acetonitrile-THF for periods of 30-40 min, followed by the addition of the sodium salt of a purine, or of 2,4-bis-O-trisylthymine, then a-2 -deoxynucleosides can be obtained (a P ca. 3 1), a result which is attributed to epimerization of the glycosyl halide before coupling. 5... 

Robins MJ, Wilson JS, Made) D, Tyrrell DLJ, Gati WP, Lindmark RJ, Wnuk SF (2001) Nucleic acid related compounds. 114. Synthesis of 2,6-(disubstituted)purine 2, 3 -dideoxy-nucleosides and selected cytotoxic, anti-hepatitis B, and adenosine deaminase substrate activities. J Heterocycl Chem 38 1297-1306... 

Sequential cross-coupling reactions of 2,4-dichloropurine 69 have been conducted. 2,6-Disubstituted purine 69 was cross-coupled with MeZnBr to give monosubstituted purine 70, which underwent Suzuki cross-coupling with phenylboronic acid to furnish disubstituted purine 71. Recently, the synthesis of 6-(2-hydroxyethyl)purines was developed based on the Negishi palladium-catalyzed cross-coupling reactions of 6-chloropurines with the Reformatsky reagent followed by reduction by sodium borohydride and treatment with manganese(IV) oxide. ... 

Nugl997a Nugiel, D.A., Cornelius, L.A.M. and Corbett, J.W, Facile Preparation of 2,6-Disubstituted Purines Using Solid-Phase Chemistry, J. Org. Chem., 62 (1997) 201-203. 

Scheme 4 outlines an alternative synthesis of a library of disubstituted purines by a strategy similar to that shown in Scheme 315 except that... 

A highly regioselective and traceless solid-phase route to N(l)-N(7)-disubstituted purines 73 has been developed. The reaction involves coupling of 6-chloropurine 72 to the REM resin (Michael addition), oxidation, N(l)-alkylation, quatemization and product release through Hoffman elimination <05JCC734>. 

A highly enantioselective catalytic conjugate addition of iV-heterocycles including purines 76 to a,P-unsatured ketones and amides 77 has been developed to give 6,9-disubstituted purines 78 <05AG(E)2393>... 

Isomeric [l,5-u]-analogues of 291 can also be obtained by treatment of 1,2-diamino-7,8-disubstituted purine-6,8-diones 290 with carboxylic anhydrides. Compounds of this type are potential B-cell-selective activators and the 6-methyl-l-(2-piperidinoethyl)-3-/l-D-ribofuranosyl-derivate of 291 was shown to be an example (94JMC3561) (Scheme 83). 

Nickel catalysts have been used in several reactions forming C-C bonds. Several different Grignard reagents alkylate the sp carbon of N-l,4-disubstituted purines and A(l)-substituted benzimidazoles in the presence of an Ni(dppp)Cl2 catalyst and 1,2-dichloroethane in THF (tetrahydrofuran) at room temperature. Yields range from 47 to 91%. Benzthiazole also reacts, but the yield is significantly lower. A possible mechanism is given. 

Other pA a studies include those on 6-substituted 7-azaindoles and 7-azaindolines,377 benzoxazolines and benzoxazolthiones substituted in the 5-, 6-, and 7-positions,378 purines, for which the basic centre appears to be located in the pyrimidine nucleus,379 4,4 -, 5,5 -, 6,6 -, and 7,7 -disubstituted leucothioindigos,380 and dyes (54).381... 

With the same protocol, a heterocyclic dibenzoate 86 derived from furan in one step has been efficiently desymmetrized to provide facile entry to either D or L nucleosides (see Scheme 8E.10). As depicted in Scheme 8E.10, the catalyst derived from ligand 71 gave rise to high enantioselectivities in the alkylation with both a purine 83 and a pyrimidine 87 [62], Subsequent allylic alkylations with an achiral ligand introduced the tartronate and aminomalonate moieties to furnish enantiomerically pure Ci s-2,5-disubstituted-2,5-dihydrofurans 89 and 91, respectively. Only six steps from furan were required to synthesize the alio and talo isomers of the nucleoside skeleton of the polyoxin-nikkomycin complexes. It should be noted that the corresponding enzymatic desymmetrization of substrate 86 is impossible because the product is labile. 

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