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 fluoroalkenyl 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.
Wnuk
Stanislaw F
SF
Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA. wnuk@fiu.edu
Sacasa
Pablo R
PR
Lewandowska
Elzbieta
E
Andrei
Daniela
D
Cai
Sumin
S
Borchardt
Ronald T
RT
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D000478:Alkylation; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010165:Palladium / Q000737:chemistry; D012435:S-Adenosylhomocysteine / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013455:Sulfur / Q000737:chemistry*; D014753:Vinyl Compounds / Q000737:chemistry*
D009705:Nucleosides; D014753:Vinyl Compounds; D010165:Palladium; D013455:Sulfur; D002244:Carbon; D012435:S-Adenosylhomocysteine; D043383:Adenosylhomocysteinase