Journal of the American Chemical Society
1554
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101:6
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March 14, 1979
Nucleoside 4’,5’-Enol Acetates. Synthesis and Chemistry of a Unique Uridine 02,4’-Anhydronucleoside1 Steven L. Cook and John A. Secrist III* Contribution from the Department of Chemistry, The Ohio State University, Columbus, Ohio 43210. Received August 3, 1978
Abstract: The synthesis of the uridine 4’,5’-enol acetate 2a and its conversion to the unique anhydronucleoside5a are described. The chemistry of 5a with regard to a variety of nucleophiles is examined. For example, treatment of 5a with methanol, ethanol, or ethylene glycol and AgN03 produced epimeric 4’-alkoxy substituted nucleosides, isolated as the 5’-hemiacetal (16a, 16d, 17a, 17d, 18).These hemiacetals were readily reduced with NaBH4 to the corresponding alcohols (16c, 16f, 16g, 17c, 17f, 17g). Selective removal of the cyclohexylidene protecting group in the presence of the newly generated ketal at Cq’ was possible under carefully controlled conditions utilizing aqueous trifluoroacetic acid.
T h e development of synthetic methods for substituent incorporation a t C4’ of nucleosides was prompted by the discovery and structure elucidation of the antibacterial agent nucleocidin ( l ) , which has a , fluorine attached to C4’.2-5 Strategies based on a 4’,5’-exo-methylene precursor have allowed introduction of fluorine6-s and m e t h ~ x y l , ~ though -’~ difficulties a r e sometimes encountered in the reintroduction of oxygen functionality a t C5’. A n aldol-Cannizzaro sequence on several nucleoside 5’-aldehydes led to the incorporation of a hydroxymethyl group a t C4’.l3-I5Our approach has been to utilize 4’,5’ unsaturation while maintaining oxygen functionality (or its equivalent) a t C5’. T h u s far, we have directed our efforts toward the synthesis of nucleoside 4’,5’-enol acetateslb and nucleoside 4’,5’-enamine~’~ and their utilization in the preparation of 4’-substituted nucleosides. W e have found that various nucleoside 4’,5‘-enol acetates (from uridine, adenosine, thymidine, and cytidine) a r e readily available from the corresponding nucleoside 5’-aldehydes and a r e generally stable, and we have reported one reaction leading to 4’-substituent incorporation.lb Also available in quantitative yield from the S’-aldehyde is l-(5-deoxy-5-pyrrolidino-2,3-O-cyclohexylidene-P-D-erythro-pent-4-enofuranosyl)uracil(2d).I6Alkyl-
Results and Discussion
T h e precursor to 2a is the known 2’,3’-O-cyclohexylideneuridine 5’-aldehyde monohydrate (3a), which is available from by suitable modification (see Experimental Section) of literature procedures in overall yields of ca. 60%. Literature procedures for the conversion of aldehydes to enol acetates generally involve treatment of the aldehyde with either isopropenyl acetate and a catalytic amount of p-toluenesulfonic acid20 or with acetic anhydride (reactant and solvent) and K O A C . ~ ’T h e former method gave a complex mixture of products with 3a, while the latter method afforded a 1:l mixture of enol acetate 2a and 5’-diacetate 3b. A study of various bases (KHCO3, K2CO3, pyridine) as substitutes for K O A c demonstrated K2CO3 to be the most effective a t reducing reaction times, and, if the reaction temperature was held a t 80 OC, the amount of 2a was maximized. Higher temperatures caused some decomposition as well a s the production of the N-acetylated enol acetate 2c. These optimized conditions afforded 85-90% isolated yields of 2a, still contaminated with minor amounts of 3b and 2c. If, however, the reaction is carried out in acetonitrile with 2.2 equiv of acetic anhydride and K 2 C 0 3 , only a trace of 3b is produced (
