Synthesis of 5-fluoroalkylated pyrimidine nucleosides via Negishi cross-coupling.
5-Fluoroalkylated pyrimidine nucleosides (1) have potential as therapeutic agents and molecular imaging agents targeting HSV1-tk suicide gene therapy. Thus, straightforward preparation of 5-fluoroalkylated nucleoside derivatives has been developed. Reported herein are the first examples of Pd-catalyzed Negishi cross-coupling of 3-N-benzoyl-3',5'-di-O-benzoyl-5-iodo-2'-deoxyuridine (2a) and 3-N-benzoyl-3',5'-di-O-benzoyl-5-iodo-2'-deoxy-2'-fluoroarabinouridine (2b) with unactivated Csp(3) fluoroalkylzinc bromides. This paper demonstrates the first synthesis of six 5-fluoroalkyl-2'-deoxypyrimidine nucleoside derivatives with three to five methylene chain lengths (5). Furthermore, this methodology has been extended to create a series of 13 5-alkyl-substituted nucleosides, including the target nucleosides 5 and 5-silyloxypropyl and 5-cyanobutyl derivatives.
Department of Pharmacology, University of Pennsylvania, 3700 Market Street, Suite 305, Philadelphia, Pennsylvania 19104, USA.
Ann-Marie
AM
Chacko
Wenchao
W
Qu
Hank F
HF
Kung
D020650:Combinatorial Chemistry Techniques; D005461:Fluorine / Q000737:chemistry*; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis*
D011741:Pyrimidine Nucleosides; D005461:Fluorine