I. D. Jenkins, J. Verheyden, J. G. Moffatt
May 26, 1976
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0
Influential Citations
77
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Journal
Journal of the American Chemical Society
Abstract
The addition of iodine fluoride to N6,N6-dibenzoyl-9-(5-deoxy-2,3-O-isopropy~idene-~-D-er~f~ro-pent-4-enofuranosyl)adenine (9) leads to the formation of the corresponding 5’-deoxy-4’-fluoro-5’-iodo nucleosides with the P-D-ribofuranosyl (10) and a-L-lyxofuranosyl (11) configurations. Nucleophilic displacement of the 5’-iodo functions was very difficult but could be accomplished with azide ion giving the 5’-azido-4’-fluoro nucleosides (18, Ma). Photolysis of the azides followed by mild hydrolysis and borohydride reduction gave the corresponding 4’-flUOrO nucleosides (20, 2Oa) which were converted to their sulfamoyl esters (22, 22a) by way of intermediate 5’-O-tributyltin (21, 21a, R = SnBuj ) derivatives. Following removal of protecting groups the nucleoside antibiotic nucleocidin (1) and its cu-L-lyxofuranosyl epimer la were isolated. Several alternative methods for conversion of the 5’-iodo function in 10 and 11 to the hydroxy counterparts (20,ZOa) were investigated and this could be accomplished by oxidation with silver(I1) oxide followed by borohydride reduction. A number of consistent rules were established for assignment of configuration to 4’-fluoro-2’,3’-O-isopropylidene nucleosides from their N M R spectra. A number of other reactions of the 4’-fluoro-5’-iodo nucleosides are also described and some comments concerning the facile cleavage of the pyrimidine ring in N6-acetyl-N3,5’-cycloadenosine derivatives are presented. The microorganism Streptomyces calvus, isolated from an Indian soil sample, was shown in 1957 to elaborate an antibiotic substance related to adenosine and referred to as nu~ l e o c i d i n . ~ This substance was shown to exhibit a rather broad antibacterial spectrum and to be particularly active against trypanosome^.^ Its practical use as either an antibiotic or antitrypanosomal agent is, however, seriously limited by its toxicity, the LD50 of nucleocidin in mice being 0.2 mg/kg via intramuscular or intraperitoneal admini~t ra t ion .~ Nucleocidin has been shown to be a highly potent inhibitor of protein biosynthesis, but its precise mechanism of action has not been clearly defined.5 Several partial and complete structures were proposed for nucleocidin,6 but not until 1969 was it realized that the empirical formula properly contained fluorine.’ With this realization it was possible, by use of N M R and mass spectrometry, to conclude that nucleocidin was correctly represented as 4’fluoro-5’-O-sulfamoyladenosine (1) or an isomer thereof.