Synthetic studies of some pyrazine, indole and quinoline nucleosides. (1998)

A wide variety of heterocycles have been identified as aglycons in naturally occurring C-nucleosides and additional heterocycles have been incorporated into synthetic C-nucleosides. No examples of pyrazine (1,4-diazine) $2\sp\prime$-deoxy-C-nucleosides had appeared in the literature at the time we initiated research in this area. Our approach was based on a palladium-mediated coupling reaction between a substituted iodopyrazine and a protected glycal. The palladium-mediated coupling proceeded in good yields and led to the key pyrazine $3\sp\prime$-keto-$2\sp\prime$-deoxy-riboside intermediates. Subsequent transformations yielded the targeted 3-chloro-5-(2-deoxy-$\beta$- scD-ribofuranosyl)-2,6-diaminopyrazine. In the course of this study, we developed an efficient and convenient synthesis of methyl 3-aminopyrazine-2-carboxylate, using a Curtius rearrangement as the key step. The reactions were conveniently scaled up and a successful run of 500 g has been achieved. We also developed a facile and general synthesis of bis-silylated ribofuranoid glycals. Pyrido (2,3-b) pyrazines have been obtained from an unusual intramolecular rearrangement of pyrazine $3\sp\prime$-keto-C-nucleosides. The mechanism of the rearrangement was established by using $\sp1$H NMR spectroscopy. A pyrazine intermediate, methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, was found to exhibit strong cytotoxicity. A series of structurally related pyrazines have been synthesized and evaluated against L1210, HCMV, HSV, HFF and KB cell lines. 2,5,6-Trichloro-1-$(\beta$- scD-ribofuranosyl)benzimidazole (TCRB) and 2-bromo-5,6-dichloro-1-($\beta$- scD-ribofuranosyl)benzimidazole (BDCRB) are benzimidazole nucleosides that exhibit strong and selective anti-HCMV activity. Indole N- and C-nucleosides may be viewed as 3-deaza and 1-deaza analogs of these biologically active benzimidazole nucleosides. The indole N-nucleosides were prepared by using the sodium salt glycosylation method, i.e., coupling of an indole sodium salt with a ribofuranosyl halide. Some modifications of this method have been developed to achieve high yield and stereoselectivity for the specific 2-haloindole substrates. We have also developed an in situ protecting strategy for the synthesis of the related indole-3-carboxaldehyde, indole-3-carboxamide and indole 3-carbonitrile N-nucleosides. The indole C-nucleosides were initially prepared via the sodium salt glycosylation method, using the same starting materials as those used for the indole N-nucleoside. The indole C-nucleosides were later prepared via a Lewis acid-mediated glycosylation, which was more stereoselective. We have also synthesized 2-halo-6,7-dichloro-4-($\beta$- scD-ribofuranosyl)quinolines as 6+6 bicyclic analogs of TCRB. The synthesis used Wittig reactions in two key steps. The first Wittig reaction coupled a fully functionalized benzene with a ribofuranose derivative to provide a basic skeleton for the target compounds. The second Wittig reaction constructed a quinolin-2-one nucleoside from a 2-aminophenone nucleoside with a ketene ylide. In the process, we discovered that an electrophile-mediated intramolecular cyclization of an alkene intermediate afforded a nucleoside with an $\alpha$-configuration, which was contrary to the literature precedence. We established that a double-bond isomerization was the cause of the unexpected stereochemistry. This multistep synthesis provided 4-($\alpha$- scD-ribofuranosyl)-2,6,7-trichloroquinoline as the major product. The 2-aminophenone nucleoside intermediate was successfully anomerized to the $\beta$-anomer, which led to the synthesis of the targeted 2-halo-6,7-dichloro-4-($\beta$- scD-ribofuranosyl)quinolines.