Purines, solid-phase synthesis

A general and efficient solid-phase synthesis of A-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase <06TL8897>. 

Austin, R.E., Okonya, J.F., Bond, D.R.S. and Al-Obeidi, F., Microwave-assisted solid-phase synthesis (MASS) of 2,6,9-trisubstituted purines, Tetrahedron Lett., 2002, 43, 6169-6171. 

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

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin-bound 6-thiopurines <02T7911>, and microwave assisted solid-phase synthesis of 2,6,9-trisubstituted purines <02TL6169> have been described. A resin-capture and release strategy toward combinatorial libraries of 2,6,9-trisubstituted purines has been reported <02JCO183>. Alkylated purines chlorinated at the 6,8- or 2,6,8-positions can be captured onto a solid support and further elaborated by aromatic substitution or via palladium catalyzed crosscoupling reactions <02JA1594>. 

A microwave assisted solid-phase synthesis of trisubstituted 2-(2,6-purin-9-yl)acetamides has been described <05TL2873>. New trisubstituted purin-8-ones 71 have been synthesized starting from cheap and readily available 5-bromouracil 70 <05S2227>. 

The phosphoramidate linkage in its aliphatic variant has been exploited by Gryaznov and Letsinger [252] for solid phase synthesis of oligonucleotide 3 -phosphates (Figure 19.9). After phosphate 2-cyanoethyl group removal by prior ammonolysis the phosphoramidate required milder conditions to break down (80% acetic acid, 4h at ambient temperature) that are tolerable for the purine... 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

Trisubstituted Purines. Schultz and Brun have reported a traceless resin capture and release strategy for the solid-phase synthesis of 2,6,9-trisubstituted purines... 

All these modified purine nucleosides have the advantage that they are readily converted to fluorescent building blocks for solid-phase DNA synthesis or to 5 -triphosphates for enzymatic DNA synthesis. Such compounds are useful for single DNA molecule detection in solution by laser-induced fluorescence as well as for single DNA molecule sequencing. 

Base modification at the 4-position of pyrimidines leads to loss of base-pairing properties. The thiol moiety in 91 was deprotected after ODN synthesis using 1 M DBU in acetonitrile. The modified oligothymidylate was then cleaved from the solid phase and reacted with N-(2-chloroethylthio)phthalimide to yield 92, which was subjected to further derivatization [264]. Purine base positions accessible for ligand attachment are C-8 of adenosine (93) [265] and C-2 of guanosine (94) [266]. 

Figure 2.11 Fluorescent purines. Two very useful non-invasive DNA (base fluorophores that can be included by solid phase DNA synthesis are 2-aminopurine (left) and 3-methyl-isoxanthopterin (right). The fluorescence quantum yield depends on the base stacking, and both bases are useful probes of conformational change/state in DNA.

Fused pyrimidine-2,4-diones are important heterocyclic pharmacophores examples include natural purine bases, alkaloids, and pteridines. Benzo derivatives in this series (quinazoline-2,4-diones) bear ample precedence as potent ligands and inhibitors of receptors and enzymes of pharmaceutical interest. Based on these precedents, Gordeev et al. reported a solid-phase protocol for the synthesis of fused pyrimidine-2,4-diones. 

Figure 8.3 Process of solid-phase phosphoramidite nucleotide synthesis. In the process, X = linker which is later incorporated into the polymer matrix DMTr = dimethoxy trityl protecting group which is removed by treatment with add to hberate the hydroxyl gronp for snbseqnent phosphitylation reaction. B s = protected purine and pyrimidine bases. Phosphite is oxidized with iodine in the presence of esterification agent to phosphotriester before the chain extension or it is oxidized at the completion of chain extension as shown...

Solid phase combinatorial synthesis is also applicable to purine nucleosides, as exemplified by the preparation of a library of more than five hundred 2,8-disubstituted guanosine analogues using SNAr displacement of the 2-fluoro group in the protected nucleoside 28, linked to the polystyrene resin with a methoxytrityl group through the ribose C-5 hydroxyl [54] (Scheme 12). The SnAt reactions were successful with primary or secondary alkylamines, but not with anilines or other arylamines. 

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