Suzuki purine derivatives

Since the Suzuki coupling of purine derivatives was covered by recent reviews,1 we only present a selection lfom these reactions. Xanthine (3,6-dihydropurine-2,6-dione) derivatives were coupled with different boronic acids, including styrylboronic acid, in the presence of the conventional tetrakis(triphenylphosphino)palladium catalyst and tripotassium phosphate as a mild base (8.1.), to obtain the appropriate 8-substituted xanthines in acceptable yield.4 The advantage of the use of anhydrous tripotassium phosphate as base over the classical aqueous carbonate or hydroxide reagents might be attributed to the sensitivity of the 8-halopurine core towards nucleophilic attack. 

The Suzuki—Miyaura reaction of protected 6-chloropurine and 2-amino-6-chloropurine bases and nucleosides with substituted phenylboronic acids led to the corresponding protected 6-(substituted phenyl)purine derivatives 6—9. Their deprotection yielded a series of substituted 6-phenylpurine bases and nucleosides 10—13. Significant cytostatic activity (IC50 0.25—20 /tmol/ L) in CCRF-CEM, HeLa, and L1210 cell lines was found for several 6-(4-X-substituted phenyl-purine ribonucleosides 12 (X = H, F, Cl, and OR), while the 6-phenylpurine and 2-amino-6-phenylpurine bases 10 and 11, as well as 2-amino-6-phenylpurine ribosides 13, were entirely inactive against these cell lines. 

In conclusion, the application of the Suzuki—Miyaura reaction of 6-chloropurine derivatives with substituted phenylboronic acids is a facile and effective approach for the synthesis of a series of specifically substituted 6-phenylpurine bases and nucleosides. In comparison with the previously known methods25-30 using other types of organometallic reagents or photochemistry, this method is more effective and selective, and therefore, further applications in the synthesis of 6 C-substituted purine derivatives may be expected. 

In 2004, Liu and Robbins demonstrated that a Ni/SIPr [1 1] system allowed the synthesis of 6-arylpurine 2 -deoxynucleosides and nucleosides from 6-(imidazol-l-yl)- and 6-(l,2,4-triazol-4-yl)purine derivatives by a Suzuki coupling (Equation (10.17)). These reactions were not observed with classical pPd(PPh3)4] while [Ni(dppp)Cl2] (dppp = l,3-bis(diphenylphosphino)propane) only led to 30% of desired product. 

Many 6-alkylaminopurine nucleosides are important adenosine receptor antagonists, and acyclic nucleotide analogues derived from 6-dialkylaminopurines are strong antivirals, anti-neoplastic agents, and immunomodulators. Recently, several 6-(arylalkynyl)-, 6-(arylalkenyl)-, and 6-(arylalkyl)purines have been reported to exhibit cytokinine activity. Suzuki crosscoupling reactions of 9-benzyl-6-chloropurine with boronic acids have recently been reported to provide 6-substituted purines in moderate to excellent yields (Eq. (46)) [77]. 

Purine bases and their nucleosides constitute an important class of antineoplastic and antileukemic agents. Efforts to improve their efficiency in these roles have resulted in the introduction of various structural modifications in both the base and the sugar moiety. Recently, Suzuki reactions of the 6-chloropurine derivative 19 with phenylboronic acids was reported to afford 20 (Equation 45) [54]. 

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