Heterocycles purine

Purines — These molecules have basic skeletons of purine heterocycles. Adenine and guanine, intrinsic components of nucleic acids, are also ubiquitous molecules. Related molecules are isoguanine, xanthine, and uric acid. 

As part of an investigation into new synthetic routes to the important acyclic nucleoside class of antiviral drugs, the cross metathesis of 9-allyl-6-chloropurine with 2,2-dimethyl-4-vinyl-l,3-dioxolane was attempted <2003TL9177>. The reaction was confounded by the coordination of the ruthenium metathesis catalyst with the purine heterocyclic nitrogens. This was overcome to some extent by using the /i-toluenesulfonic acid or hydrogen chloride salts of the... 

The well-known application of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine as a diene in inverse electron demand Diels-Alder cyclizations was adapted for the synthesis of purines <1999JA5833>. The unstable, electron-rich dienophile 5-amino-l-benzylimidazole was generated in situ by decarboxylation of 5-amino-l-benzyl-4-imidazolecarboxylic acid under mildly acidic conditions (Scheme 54). Collapse of the Diels-Alder adduct by retro-Diels-Alder reaction and elimination of ethyl cyanoformate, followed by aromatization by loss of ammonia, led to the purine products. The reactions proceeded at room temperature if left for sufficient periods (e.g., 25 °C, 7 days, 50% yield) but were generally more efficient at higher temperatures (80-100 °C, 2-24 h). The inverse electron demand Diels-Alder cyclization of unsubstituted 1,3,5-triazine was also successful. This synthesis had the advantage of constructing the simple purine heterocycle directly in the presence of both protected and unprotected furanose substituents (also see Volume 8). 

Since the -NH2 group in adenine is conjugated and therefore coplanar with the purine heterocycle, intramolecular hydrogen bonding with the proximal N(7) atom is invariably observed as the minor component of a three-center bond. These H- N interactions are in the distance range from 2.5 to 2.9 A, with... 

The four principal bases of the nucleic acids are uracil and cytosine, which are derivatives of pyrimidine, and adenine and guanine, which are derived from the purine heterocycle (Fig. 15.1). In the nucleic acids, ribose (in ribonucleic acid,... 

All these bases derived from pyrimidine and purine heterocycles are planar... 

Fig. 15.10. The intramolecular hydrogen bond in adenine is due to the coplanarity of amino group and purine heterocycle...

The bases found in RNA (ribonucleic acid) are the purine heterocyclics adenine (6-aminopurine) and guanine (2-amino-6-oxypurine) and their complementary pyrimidine bases uracil (2,4-dioxypyrimidine) and cytosine (2-oxy-4-aminopyrimidine), respectively (Section 1, Appendix). In RNA double-stranded duplexes adenine (A) base-pairs with uracil (U) via two hydrogen bonds (A=U) and guanine base-pairs with cytosine (C) via 3 hydrogen bonds (G=C). Adenine forms the nucleoside adenosine by an N-glycosidic link with the... 

The purine ring system represents a fusion of the two aromatic heterocycles pyrimidine and imidazole. As a logical consequence, appropriately substituted pyrimidines or imidazoles have been used as precursors followed by a cyclization reaction. The purine heterocycle can also be formed from simple acyclic precursors. The most widely used method to synthesize purine is the addition of an imidazole ring to a functionalized pyrimidine moiety (Traube synthesis). The alternative route for the formation of the purine system by the annulation of the pyrimidine ring to a substituted imidazole relates back to a method of Sarasin and Wegmann, and these synthetic protocols principally follow the biosynthetic pathway of purine synthesis. 

The reagents used for the completion of the purine heterocycle are essentially the same as those used for the Traubc synthesis. The purine ring is formed by condensation with derivatives of formic acid or other carboxylic acids. Alternatively, formylation of the amino group is accomplished by a mixture of formic acid and acetic anhydride followed by cyclization. Alkyl esters or trialkyl ortho esters are also versatile synthons for ring closure. Moreover, heating in formamide or cyclization with urea or thiourea provides a satisfactory route. Condensations with isothiocyanates show unusual versatility leading to 2-sulfanylpurin-6-ols. From carbonic acid derivatives, cyclization is reported with chlorocarbonic esters, diethyl carbonate or carbon disulfide. 

Nucleoside chemistry is traditionally labor intensive and the output of compoxmds is consequently relatively low. In order to overcome these limitations, several groups have implemented a parallel or combinatorial approach to speed up the synthesis process this chapter will only discuss the use of solid support for the synthesis of nucleoside libraries, not for the piupose of oligonucleotide synthesis. Chang <05BMC4760> attached a purine diehloride to a Merrifield 3,4-dihydropyran resin, followed by sequential displacement of the two ehloro atoms by various amines. The purine heterocyclic bases were then condensed with Dd.-ribofuranosides following a classical Vorbruggen method to yield nucleosides of general formula 171. 

Gunic <04NNNA495> and Koh <04NNNA501> condensed nucleosides 172, 173 and 174 with a Merrifield 4-methoxytrityl chloride resin. These three nucleosides were already bearing one or two reactive groups ready for fiirther chemical modifications. To prevent side reactions on the highly activated 2- and 6-positions of the purine heterocycle, the only acceptable non-nucleophilic base that could be used for the eondensation of the nucleoside with the resin was... 

Previously constructed recombinant strain E. coli BM-D6 produced homologous purine nucleoside phosphorylase (PurNPase) acting (like PyrNPase) as a key catalyst transforming pyrimidine nucleosides into modified purine nucleosides via enz5miatic transglycosylation reaction [7]. PurNPase catalyzes stereoselective reaction of intermediate a-D-pentofuranose-1-phosphate (product of pyrimidine nucleoside phosphorolysis mediated by PyrNPase) condensation with purine heterocyclic base leading to formation of modified purine nucleoside. 

Derivatives of bicyclic pefloxacin 13 and 14 represent an interesting type of hybrid molecules, in which N-butylfluoroquinolone fragments are linked with the pyrimidine and purine heterocyclic bases (Scheme 7) [40]. 

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