Purine library synthesis

In another purine library synthesis, Schultz and co-workers attached a 6-aminomethylaniline side chain to the PAL linker1718 via reductive amina-tion (Scheme 5). Alkylation at the 9-position was achieved using Mitsunobu conditions and an SwAr reaction was used to functionalize the 2-position with amines. The final cleavage of the aniline was achieved using 90%... 

R. Sarohia, M. Leost, L. Meijer, P. G. Schultz, Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors, Chem. Biol. 1999, 6, 361-375. 

One-pot synthesis of 6-mercaptopurines from 4,5-diamino-6-chloropurine, an aldehyde and elemental sulfur has been reported. The key advantage of this procedure is that H2S was generated in situ <04TL2321>. An efficient conversion of 6-cyanopurines into 6-alkoxyformimidoylpurines has been developed <040BC1019>. Synthesis of diverse purine libraries has been optimized by a microwave assisted method using minivials <04JCO171>. 

Combs P, Takvorian AG (2004) Microwave-assisted organic synthesis using minivials to optimize and expedite the synthesis of diverse purine libraries. J Comb Chem 6 171-174... 

Schultz and co-workers have described a crown-based synthesis of 406 purines varying at the C-2 and C-6 positions.14 This library was targeted for... 

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

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>. 

F.I. Raynaud, P.M. Fischer, B.P. Nutley, P.M. Goddard, D.P. Lane and P. Workman, Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis, Mol. Cancer Then, 2004, 3, 353. 

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. 

Parallel synthesis of libraries of 2,6,8,9-tetrasubstituted purines have been reported, one proceeding via a sulfur intermediate <05JCC627> and another through the 2,8,9-trisubstituted 6-chloropurine core <05JCA474>. 

Monocyclic and Bicyclic aromatic heterocycles such as imidazoles, thiazoles, thiadiazoles, oxazoles, oxadiazoles quinazolines, indoles, benzimidazoles, purines pyrido[43-d]pyri-midines, thiazolo[5,4-d]pyrimidines, thiazolo[4,5-d]pyrimidines, oxazolo[5,4-d]pyrimi-dines and thieno[2,3-d]pyrimidines are renowned pharmacophores in drug discovery. These special structures are well explained and exemplified in chemical compound libraries. In this chapter, several types of thiazole based heterocyclic scaffolds such as mono-cyclic or bicyclic systems synthesis and their biological activities studies are presented, which are not frequently present in books and reviews. We mention the first importance of synthetic route of various thiazole based compounds and their applications in medicinal chemistry in this chapter. 

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. 

Koh Y, Landesman MB, Amador R, Rong F, An H, Hong Z, Giraidet JL (2(X)4) Synthesis of nucleoside libraries on solid support. II. 2,6,8-Trisubstituted purine nucleosides using 6-bromoguanosine as precursor. Nucleosides Nucleotides Nucleic Acids 23 501-507... 

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