Portal de Periódicos da CAPES

An Efficient Process for Synthesis of 2′- O -methyl and 3′- O -methyl Guanosine from 2-aminoadenosine Using Diazomethane and the Catalyst Stannous Chloride

2006; Taylor & Francis; Volume: 25; Issue: 3 Linguagem: Inglês

10.1080/15257770500544529

1532-2335

Anilkumar R. Kore, Gaurang Parmar, S. Ravinder Reddy,

HIV/AIDS drug development and treatment

An improved strategy for the selective synthesis of 2′-O-methyl and 3′-O-methyl guanosine from 2-aminoadenosine is reported by using the catalyst stannous chloride. The regioselectivity of the 2′ and 3′-O-alkylation was achieved by optimizing the addition, timing, and concentration of the catalysts and diazomethane during the methylation reaction. An efficient and selective alkylation at 2′-OH of 2-aminoadenosine was achieved by mixing a stoichiometric amount of stannous chloride at room temperature in DMF. The reaction mixture was stirred at 50°C for 1 min and immediately followed by addition of diazomethane. The resulting 2′-O-methyl 2-aminoadenosine was treated with the enzyme adenosine deaminase, which resulted in an efficient conversion to the desired 2′-O-methylguanosine (98% yield). The product was isolated by crystallization. In contrast, the methylation at 3′-OH of 2-aminoadenosine was achieved by mixing a stoichiometric amount of stannous chloride in DMF and stirring at 50°C for 15 min, followed by addition of diazomethane. The resulting mixture containing 3′-O-methyl-2-aminoadenosine in 90% yield and 2′-O-methyl-2-aminoadenosine in 10% yield was treated with the enzyme adenosine deaminase, which preferentially deaminated only 3′-O-methyl-2-aminoadenosine, resulting in the production of 3′-O-methylguanosine in 88% yield. Due to the extremely low solubility 3′-O-methylguanosine, the compound precipitated and was isolated by centrifugation. This synthetic route obviates the chromatographic purification. Selective monomethylation is achieved by using the unprotected ribonucleoside. As a result, the method described herein represents a significant improvement over the current synthetic approach by providing superior product yield and economy, a much more facile purification of 2′,3′-O-methylated isomers, and eliminating the need for protected ribonucleosides reagents. Keywords: Nucleoside AnaloguesAdenosine DeaminaseDiazomethaneCatalyst Acknowledgments The financial support from National Institute of Health (SBIR Phase II: R44GM070156-02) is gratefully acknowledged. We are thankful to Prof. Dr. Fritz Eckstein (Max-Planck Institut für Experimentelle Medizin, Göttingen, Germany) for commenting and critical reading of this manuscript. We also thank Zhongting Hu and Gary Latham for helpful discussion.