title: An efficient process for synthesis of 2'-O-methyl and 3'-O-methyl guanosine from 2-aminoadenosine using diazomethane and the catalyst stannous chloride.
abstract: 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 DME The reaction mixture was stirred at 50 degrees 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 degrees 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.
authors.affiliation: Ambion, Inc., Bioorganic Chemistry Division, Austin, Texas 78744, USA. akore@ambion.com
authors.forename: Anilkumar R
authors.initials: AR
authors.lastname: Kore
authors.forename: Gaurang
authors.initials: G
authors.lastname: Parmar
authors.forename: Srinu
authors.initials: S
authors.lastname: Reddy
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D003978:Diazomethane; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D017971:Tin Compounds
chemical_list: D017971:Tin Compounds; C037626:3'-O-methylguanosine; D006151:Guanosine; C023599:stannous chloride; C033854:2-aminoadenosine; D003978:Diazomethane; D000241:Adenosine; C024900:2'-O-methylguanosine