A general approach to the synthesis of 5-S-functionalized pyrimidine nucleosides and their analogues

Abstract

A general and efficient approach was developed for the introduction of S-functionality at the C-5 position of cytosine and uracil nucleosides and their analogues. The key step is a palladium-catalyzed C-S coupling of the corresponding 5-bromo nucleoside derivative and alkyl thiol. The butyl 3-mercaptopropionate coupling products were further converted to the corresponding disulphides, the stable precursors of 5-mercaptopyrimidine nucleosides.

Crystal structure of racemic 2-[(β-arabinopyranosyl)sulfanyl]-4,6-diphenylpyridine-3-carbonitrile

“…In recent years, nucleoside analogues of pyrimidines and purines have been shown to be effective as chemical therapeutic agents against cancer cells (Yoshimura et al, 2000;Elgemeie et al, 2016Elgemeie et al, , 2017a. Recently, heterocyclic thioglycosides have been used as antimetabolic agents in medicinal chemistry (Dinkelaar et al, 2006;Kananovich et al, 2014;Elgemeie & Abu-Zaied, 2017). We and others have designed new syntheses for pyridine thioglycosides, which have shown strong cytotoxicity against various human cancer cell lines and block proliferation of various cancer cell lines (Komor et al, 2012;Elgemeie et al, 2015).…”

Copper-mediated arylsulfanylations and arylselanylations of pyrimidine or 7-deazapurine nucleosides and nucleotides

“…Synthesis Previously, 5-(alkylsulfanyl)pyrimidine bases or nucleosides were prepared by alkylation of 5-mercaptouracil, 23 reactions of toxic 5-(chloromercuri)pyrimidines with disulfides, 24 or more recently by Pd-catalyzed coupling of 5-bromopyrimidine derivatives with thiols, 25 whereas 7-arylsulfanyl-7-deazapurines were prepared by Cu-mediated S-H sulfenylations. 18 The 5-selenylated pyrimidines were prepared by Mn-mediated C-H selenylations 20 or electrophilic aromatic selenylation.…”

Transition-Metal-Catalyzed C–S, C–Se, and C–Te Bond Formations via Cross-Coupling and Atom-Economic Addition Reactions. Achievements and Challenges

“…175 Cross-coupling with C−S bond formation was used in a Pdcatalyzed reaction for the synthesis of 5-mercapto-functionalized pyrimidine nucleosides and their analogues (Scheme 15, C). 176 The natural amino acid cysteine and a water-soluble palladium complex were used to build aryl linkers in peptides and proteins (Scheme 16). 177 The recyclable palladium−prolinate complex Pd(L-Pro) 2 was proposed for the cross-coupling reaction between aryl iodide and various thiols (Scheme 17, A).…”

“…Cross-coupling with C–S bond formation was used in a Pd-catalyzed reaction for the synthesis of 5-mercapto-functionalized pyrimidine nucleosides and their analogues (Scheme , C) …”