Anhydro linkage

Despite the fact that secondary hydroxyl groups of nucleosides also react with 23 (see later), selective iodination of only the primary hydroxyl group in some unprotected, pyrimidine nucleosides can also be achieved.82 Thus, brief treatment of thymidine with 1.1 mol-equivalents of 23 in N,N-dimethylformamide gave crystalline 5 -deoxy-5 -iodothymidine in 63% yield. It was even possible to effect some selective iodination of the 5 -hydroxyl group of 2,2 -anhydrouri-dine without excessive cleavage of the (quite labile) anhydro linkage. 

Recently various chemical modifications and derivatizations of polysaccharides have been developed to meet new needs. However, introduction of 3,6-anhydro-linkages to the polysaccharides appear to be limited to 3,6-anhydro-amylose (14). Our interest has been drawn to the introduction of 3,6-anhydro-linkages into a-(1 4)-linked D-glucose units of elsinan, whereby some alteration of the physical properties would be expected. 

Although our primary purpose to obtain somewhat agar-like physical property failed, better control of the reaction conditions and distribution of 3,6-anhydro-linkages, may yet provide a unique derivative of elsinan or other polysaccharides. 

Benzyl-2-deoxy-2-C-hydroxymethyl-D-glucose has beai prepared as a usefiil intermediate fiir the synthesis of the potent glucosidase inhibitor, isoti ondne by reaction of vin magneshim bromide on l,6 2,3-dianhydro-4-0-ben2 -p-4>-mannopyranoside followed by ozonolysis, l dride reduction and Iqrdrolysis of the anhydro linkage. ... 

Whilst direct displacement of the 2 -o-triflyl group in (26) could be effected, attempts to hydrolyse the anhydro-linkage resulted in formation of an unsaturated chloronucleoside (Scheme 8). ... 

The stability of these 2,5 -anhydro nucleoside derivatives (38-41) which displayed antiviral activity, as well as compound 42, were determined at pH 7.5 and 2.0 (Table 4).l This was performed to determine if the biological activity of this class of compounds was due to the anhydro compound itself, or whether hydrolysis of the 2,5 -anhydro linkage occurred in solution to yield the parent compound which, as previously shown, had antiviral activity. All of the compounds tested are stable at neutral pH, with half-life values ranging from 60.5 h for 2,5 -anhydro-3 -azido-5-bromo-2, 3 -dideoxyuridine (40) to >168 h for 3 -azido-2, 3 -dideoxy-5-methylisocytidine (42). At low pH, however, the compounds displayed shorter and more variable half-lives, ranging from 11.3 min for 2,5 -anhydro-3 -azido-2, 3 -dideoxyuridine (38) to 140 min for 3 -azido-2, 3 -dideoxy-5-methylisocytidine (42). Pyrimidine base formation was not detected from any of these compounds. Moreover, the compounds decomposed to yield 7.5% or less of the parent compound after one half-life at either neutral or acidic pH, except for 18% of 2,5 -anhydro-3 -azido-2, 3 -dideoxyuridine (38), which was recovered as AZDU (1). 

These data suggest that the basis for antiviral activity of the 2,5 -anhydro nucleoside analogues does not depend on a conversion of "inactive" (anhydro) prodrug to yield an active (parent) species, but rather the anhydro compounds appear to be active per se. However, an intracellular cleavage of the 2,5 -anhydro linkage or other metabolic conversions cannot be ruled out. 

Full details of a preliminary communication (S.J. Mantell et at., Vol. 26, p. 310) of the synthesis of epimeric 3-hydroxymuscarines from L-rhamnono-1,4- or 1,5-lactones have appeared. The synthesis of the anhydrothioalditol 13 as an analogue of deoxymannojirimycin has been reported. The anhydro linkage is introduced by treating the intermediate bromothioacetate derivative 14 with sodium methoxide to give bicyclic compound 15. Subsequent de-silylation, benzylation, acid hydrolysis, hydride reduction and catalytic hydrogenolysis furnished 13. 

The introduction of 3,6-anhydro linkages into (l->4)-a-D-glucans is mentioned in Chapter 4, and the synthesis of various 1,4-anhydropentitols as abasic derivatives of nucleosides in order to study relative strength of various guache and anomeric effects that affect the pseudorotational equilibrium of the pentofuranose moiety of nucleosides is covered in Chapter 21. 

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