Highly Stereoselective Synthesis of Bicyclic-sugar Adenosine Derivatives via Diels-Alder Reaction.

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Griseolic acid A,B,and C have been isolated from the cultured broth of S.griseoaurantiaus. These nucleosides act as nonhydrolyzable cyclic AMP mimetics and are reported to be potent inhibitors of rat brain phosphodiesterase. We designed new bicyclic-sugar adenosines, as potential phosphodiesterase inhibitors, which can be synthesized via Diels-Alder reactions of certain nucleoside-dienes and dienophiles such as methyl acrylate. When N^6-benzoic-9- () adenine methyl ester (1). Which was prepared from adenosine, was heated in methyl acrylate at 80ﾟC for 57h, beta-endo (2), beta-exo (3), alpha-endo (4), and alpha-exo (5) Diels-Alder products were obtained in a ratio of 3 : 1 : 1 : 3 in 79% yield. However, N^6-benzoyl-8,2'-anhydro-8-mercapto-9- (3,5,6-trideoxy-beta-D-arabino-hept-3,5-dienofuranosiduronyl) adenine (6), prepared from 8,2'-anhydro-8-mercaptoadenosine, was treated with methyl acrylate at 80ﾟC for 48 h, alpha-endo (7) and alpha-exo (8) products were obtained in a ratio of 7 : 4 in 58% yield. To improve facial selectivity, the reaction was carried out under high-pressure conditions. The reaction of 1 with methyl acrylate in DMSO under 11 Kbar. The facial selectivity of the reaction was improved greatly to give 2 and 4 (1 : 1 ratio) in 91% yields. Additionally, under the same condition, 7 was obtained from 6 in 79% yield. Therefore, the high-pressure conditions used for these reactions improved the facial selectivity but not the endo/exo selectivity. These bicyclic-sugar nucleosides were deprotected and tested against dog phosphodiesterase III.However, none of these showed potent inhibitory activity.