Synthesis, chemical reactivity, and biological evaluation of pyrazinoic acid C-nucleosides.

Abstract

Many nucleosides bearing a carboxylic acid derivative meta- to the site of glycosylation have been shown to possess potent biological activity. Naturally occurring compounds such as bredinin, pyrazofurin, and clitidine, and synthetic analogs such as ribavirin and tiazofurin are all nucleoside carboxylic acid derivatives with potent biological activity. As part of our ongoing studies on the synthesis of nucleoside analogs, we became interested in synthesizing some heretofore unknown 6-glycosylated derivatives of pyrazinoic acid (1,4-diazine-2-carboxylic acid). Attempts at mediating C-glycosylation of various pyrazines using Lewis acids were largely unsuccessful. Cross-coupling of iodopyrazines with furanoid glycals yielded C-glycosylated products, but in moderate 25-38% yields. Using this method, we synthesized methyl 3-amino-6-(2-deoxy-$\beta$- scD-ribofuranosyl)pyrazine-2-carboxylate as an analog of clitidine. The use of organolithium chemistry to condense pyrazines with 2,3,5-tri-O-benzyl- scD-ribono-1,4-lactone proceeded in very good yields to give, following ionic hydrogenation, protected $\beta$-C-nucleosides exclusively. These adducts were subjected to a second lithiation and treated with various electrophiles to install a carboxylic acid derivative meta- to the site of ribosylation. From this sequence, a versatile intermediate, ethyl 3,5-dichloro-6-($\beta$- scD-ribofuranosyl)pyrazine-2-carboxylate, was synthesized in a 50% overall yield in 4 steps. This intermediate was then treated with various reagents to create a series of pyrazine C-riboside carboxylates and carboxamides. The structure of one of these carboxylates, ethyl 5-amino-3-chloro-6-($\beta$- scD-ribofuranosyl)pyrazine-2-carboxylate, was determined unequivocally via X-ray crystallographic studies. Biological evaluation of these compounds in antitumor and antiviral assays are tabulated in chapter IV of this thesis.