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

从灰橙黄链霉菌的培养液中分离出灰胆酸A、B和C。这些核苷作为不可水解的环AMP模拟物，据报道是大鼠脑磷酸二酯酶的有效抑制剂。我们设计了新的双环糖腺苷，作为潜在的磷酸二酯酶抑制剂，它可以通过某些核苷二烯和亲二烯体如丙烯酸甲酯的Diels-Alder反应合成。当N^6-苯甲酸-9-（）腺嘌呤甲酯（1）.以腺苷为原料，在丙烯酸甲酯中于80 ℃加热57 h，得到β-endo（2）、β-exo（3）、α-endo（4）和α-exo（5）四种Diels-Alder产物，其比例为3：1：1：3，产率为79%。然而，由8，2 '-脱水-8-巯基腺苷制备的N，6-苯甲酰基-8，2'-脱水-8-巯基-9-（3，5，6-三脱氧-β-D-阿拉伯-庚-3，5-二烯呋喃糖苷酰）腺嘌呤（6）用丙烯酸甲酯在80 ℃下处理48小时，以58%的产率以7：4的比例获得α-内（7）和α-外（8）产物。为了提高面选择性，反应在高压条件下进行。1与丙烯酸甲酯在DMSO中在11 Kbar下的反应。反应的面选择性大大提高，得到2和4（1：1），产率91%。另外，在相同条件下，由6以79%的收率得到7。因此，用于这些反应的高压条件改善了面选择性，但没有改善内/外型选择性。这些双环糖核苷被脱保护，并测试对狗磷酸二酯酶III。然而，这些都没有表现出有效的抑制活性。

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.