Synthesis of certain imidazo [4, 5-b] pyridine (1-deazapurine) and v-triazolo [4,5-b] pyridine (1-deaza-8-azapurine) nucleosides related to guanosine
Creators: name: Cline, Barry Lee
Publisher: name: University of Utah
Year: 2012

description: The synthesis of 1-deazaguanosine has been realized by two, separate synthetic routes.  Condensation of 5-acetamido-7-benzyloxyimidazo[4,5-b]-pyridine with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide in toluene in the presence of mercuric cyanide provided the isomeric nucleosides 5-acetamido-7-benzyloxy-3-(2,3,5-tri-O-benzoyl-?-D-ribofuranosyl)imidazole,5-b]pyridine (77%) and 5-acetamido-7-benzyloxy-l-(p-D-ribofuranosyl)-imidazo[4,5-b]pyridine (1%).  Deacetylation of 5-acetamido-7-benzyloxy-3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridine followed by hydrogenolysis gave 5-amino-3-(?-D-ribofuranosyl)imidazo[4,5-b]pyridin-7-one (1-Deaza-guanosine) in high overall yield.  A second approach to the synthesis of 1-deazaguanosine was initiated by the condensation of either 5-acetamido-7-chloroimidazo[4,5-b]pyridine or ethyl 7-chloroimidazo[4,5-b]pyridine-5-carbamate with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide in benzene in the presence of mercuric cyanide to afford 5-acetamido-7-chloro-3-(2,3,5-tri-O-benzoyl-3-D-ribofuranosyl)imidazo[4,5-b1pyridine (80%) and ethyl 7-chloro-3-(2,3,5-tri-O-benzoyl-?-D-ribofuranosyl)imidazo[4,5-b]pyridine-5-carbamate (80%), respectively.  Complete deacylation of either of these blocked nucleosides provided 5-amino-7-chloro-3-(3-D-ribofuranosyl)-imidazo[4,5-b]pyridine which was converted in a Sandmeyer reaction to 5,7-dichloro-3-(ft-D-ribofuranosyl)imidazo[4,5-b]pyridine.  Catalytic reduction of the 5,7-dichloro compound to the known, fully-characterized nucleoside 3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridine provided an unequivocal proof of structure for all the nucleosides in this series.  Reaction of ethyl 7-chloro-3-([3-D-ribofuranosyl)imidazo[4,5-b]pyridine-5-carbamate (or the similar 5-acetamido derivative) with sodium benzylate in benzyl alcohol for extended periods (48 hours) provided 5-benzylamino-7-benzyloxy-3-(?-D-ribofuranosyl)imidazo[4,5-b]pyridine which, upon hydrogenolysis, gave 1-deazaguanosine.  Shorter reaction times (6 hours) with sodium benzylate gave a chromatographically inseparable mixture of 5-amino-7-benzyloxy-3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridine and 5-amino~7-chloro-3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridine.  Catalytic hydrogenation of the mixture provided the desired 1-deazaguanosine. Attempts to prepare the 1-deaza analog of the chemotherapeutically important agent 6-thioguanosine by the thiation of ethyl 7-chloro-3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridine-5-carbamate using sodium hydrosulfide in dimethylformamide-provided only bis(5-amino-3-(3-D-ribofuranosylimidazo[4, 5-b~|pyrid-7-yl)disulf ide.  The desired 5-amino-3-(3-D-ribofuranosyl)imidazo[4,5-b]pyridin-7-thione was generated In situ by reduction of the disulfide compound with dithiothreitol; however, attempts to obtain the thione compound as a solid by crystallization or column chromatography resulted only in reoxidation to the disulfide. The synthesis of certain v-triazolo[4,5-b]pyridines (l-deaza-8-azapurines), related to guanine, guanosine, 6-thioguanine and 6-thioguanosine, has been realized.  Condensation of ethyl 7-chloro-v-triazolo-[4,5-b]pyridine-5-carbamate with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide in benzene in the presence of mercuric cyanide provided the isomeric nucleosides ethyl 7-chloro-3-(2,3,5-tri-O-benzoyl-3-D-ribofuranosyl)-v-triazolo[4,5-b]pyridine-5-carbamate (81%) and ethyl 7-chloro-2-(2,3,5-tri-O-benzoyl-p-D-ribofuranosyl)-v-triazolo[4,5-b]-pyridine-5-carbamate (1%). Reaction of ethyl 7-chloro-3-(?-D-ribofuran-osyl)-v-triazolo[4,5-b]pyridine-5-carbamate with sodium benzylate in benzyl alcohol afforded 5-amino-7-benzyloxy-3- (?-D-ribofuranosyl)-v-triazolo[4,5-b]pyridine which, upon hydrogenolysis, gave 5-amino-3-(?-D-ribofuranosyl)-v-triazolo[4,5-b]pyridin-7-one (l-Deaza-8-aza-guanosine).  Similarly, treatment of ethyl 7-chloro-3-(?-D-ribofuran-osyl)-v-triazolo[4, 5-b]pyridine-5-carbamate with the appropriate nucleophile provided 5-amino-7-ethoxy-3- (?-D-ribofuranosyl)-v-triazolo[4, 5-b]-pyridine and 5-amino-7-methylthio-3-(?-D-ribofuranosyl)-v-triazolo-[4,5-b]pyridine.  Nitrosative ring-closure of 4-benzyloxy-2,3,6-triamino-pyridine gave 5-amino-7-benzyloxy-v-triazolo[4,5-b]pyridine which, upon hydrogenolysis, provided 5-amino-v-triazolo[4,5-b]pyridin-7-one (1-Deaza-8-azaguanine).  Thiation of ethyl 7-chloro-3-(?-D-ribofuranosyl)-v-triazolo[4,5-b]pyridine-5-carbamate with sodium hydrosulfide in dimethyl-formamide gave 5-amino-3-(?-D-ribofuranosyl)-v-triazolo[4,5-b]pyridin-7-thione (1-Deaza-8-aza-6-thioguanosine).  This nucleoside was shown to undergo the well-known v-triazole/l,2,3-thiadiazole rearrangement. Thiation of ethyl 7-chloro-v-triazolo[4,5-b]pyridine-5-carbamate using sodium hydrosulfide in dimethylformamide gave 5-amino-v-triazolo[4,5-b]-pyridin-7-thione (1-Deaza-8-aza-6-thioguanine).  The site of ribosylation of the synthetic nucleosides discussed in this dissertation was established by a 13-C nuclear magnetic resonance spectral study based on the effect of N-ribosylation on the 13-C chemical shifts of the neighboring carbon atoms.  In addition, a study of the long-range (two- and three-bond) 13-C-1-H spin-spin couplings not only facilitated the unambiguous assignment of the 13-C resonance peaks, but also provided another method for establishing the site of ribosylation. The three-bond spin-spin coupling between the anomeric proton of the ribosyl moiety and the carbon atom adjacent to the site of substitution provided a means of unequivocally establishing the site of ribosylation of all the nucleosides in the study.