Jiong J. Chen

Studies Designed to Increase the Stability and Antiviral Activity (HCMV) of the Active Benzimidazole Nucleoside, TCRB

The potent activity of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) against Human Cytomegalovirus with the concomitant low cellular toxicity at concentrations that inhibit viral growth prompted considerable interest in this research area. This interest was moderated by the pharmacokinetic studies of TCRB in rats and monkeys that revealed the instability of TCRB in vivo. These studies suggested that the instability was due to a cleavage of the glycosidic bond in vivo which released the heterocycle (2,5,6-trichlorobenzimidazole) into the bloodstream. This prompted us to initiate synthetic studies designed to increase the stability of the glycosidic bond of TCRB and BDCRB. Several synthetic approaches to address this and other problems are presented.

Synthesis of pyrazine C-ribosides via direct metalation

Abstract A direct metalation method has been developed for the synthesis of novel pyrazine C-nucleosides. The regiochemistry was controlled by selecting different substituents on the pyrazine ring and excellent stereoselectivity was achieved via a hydride delivery strategy. The scope and limitations of this method were studied. The uniquely designed 4b is a versatile synthon for the preparation of other pyrazine C-nucleosides.

An efficient and stereospecific synthesis of novel pyrazine cnucleosides

Abstract A novel 2′deoxyβDribofuranosyl pyrazine Cnucleoside ( 6 ) was synthesized via a Stereospecific palladium(0)mediated crosscoupling reaction. The βconfiguration of this nucleoside was established by NOE analysis and the formation of a 5,5′anhydro nucleoside 5 . The compound 4a , obtained via the crosscoupling reaction and selective deprotection, is a versatile intermediate for the preparation of other pyrazine Cnucleoside analogues

Design, Synthesis, and Antiviral Evaluation of Some Polyhalogenated Indole C-nucleosides

2,5,6-Trichloro-1-(β-D-ribofuranosyl)benzimidazole (TCRB), 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (BDCRB) and 2-benzylthio-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole (BTDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. Polyhalogenated indole C-nucleosides were prepared as 1-deaza analogs of the benzimidazole nucleosides TCRB and BDCRB. A mild Knoevenagel coupling reaction between an indol-2-thione and a ribofuranose derivative was developed for the synthesis of 2-benzylthio-5,6-dichloro-3-(β-D-ribofuranosyl)indole (12). 3-(β-D-ribofuranosyl)-2,5,6-trichloroindole (16) was prepared from 12 in 4 steps. A Lewis acid-mediated glycosylation method was then developed to prepare the targeted 2-haloindole C-nucleoside 16 stereoselectively in four steps from the corresponding 2-haloindole aglycons. Only 12 was active against HCMV but it also was somewhat cytotoxic.

Novel 2′-Deoxy Pyrazine C-Nucleosides Synthesized VIA Palladium-Catalyzed Cross-Couplings

Abstract The palladium-catalyzed cross-couplings of 2-chloro-3,5-diamino-6-iodopyrazine (1a) and methyl 3-amino-6-iodopyrazine-2-carboxylate (1b) with 1,4-anhydro-3,5-O-bis[(tert-butyl)dimethylsilyl]-2-deoxy-D-erythro-pent-1-enitol (2) followed by desilylation and stereospecific reduction of the 2′-deoxy-3′-keto adduct leads to the formation of 2-chloro-6-(2-deoxy-s-D-ribofuranosyl)-3,5-diaminopyrazine (4a) and methyl 3-amino-6-(2-deoxy-s-D-ribofuranosyl)pyrazine-2-carboxylate (4b) in 58% yield and 21% yield, respectively. These are the first syntheses of the heretofore unknown 2′-deoxy pyrazine C-nucleosides and demonstrate the utility of a convergent approach for the synthesis of pyrazine C-nucleosides.

Application of the Curtius Rearrangement in a Convenient Preparation of 3-Aminopyrazinecarboxylic Acid, Methyl Ester

Abstract An efficient and convenient synthesis of 3-aminopyrazinecarboxylic acid, methyl ester (7) has been achieved through the use of a Curtius rearrangement.