Synthesis of 5′-functionalized nucleosides:: S-Adenosylhomocysteine analogues with the carbon-5′ and sulfur atoms replaced by a vinyl or halovinyl unit

Adenosine and uridine analogues functionalized with alkenyl or. uoroalkenyl chain at C5' were prepared employing cross-metathesis, Negishi couplings, and Wittig reactions. Metathesis of the protected 5'-deoxy-5'- methyleneadenosine or uridine analogues with six-carbon amino acids (homoallylglycines) in the presence of Grubbs catalysts gave nucleoside analogues with the C5'-C6' double bond. Alternatively, the Pd-catalyzed cross-coupling between the protected 5'-deoxy-5'-(iodomethylene) nucleosides and suitable alkylzinc bromides also provided analogues with alkenyl unit. Stereoselective Pd-catalyzed monoalkylation of 5'-(bromofluoromethylene)-5'-deoxyadenosine with alkylzinc bromides afforded adenosylhomocysteine analogues with a 6'-(fluoro) vinyl motif. The vinylic adenine nucleosides produced time-dependent inactivation of the S-adenosyl-L-homocysteine hydrolases. (C) 2008 Elsevier Ltd. All rights reserved.