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

通过 Diels-Alder 反应高度立体选择性合成双环糖腺苷衍生物。

• 批准号: 06453184
• 负责人: MATSUDA Akira
• 金额: $ 4.22万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06453184/
• 关键词: griseolic acid; phosphodiesterase; Diels-Alder reaction; high-pressure; adenosine; facial selectivity; methyl acrylate; 面選択性; 位置選択性; グリゼオール酸

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.

从金黄色葡萄球菌培养的肉汤中分离出灰松酸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。我们设计了新的双糖腺苷，作为潜在的磷酸二酯酶抑制剂，可以通过某些核苷-二烯和二烯试剂（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，在丙烯酸甲酯中以80℃的温度加热57h，得到β -endo(2)、β -exo(3)、α -endo(4)、α -exo(5)以3:1:1:3的比例的Diels-Alder产物，产率79%。以8,2'-无水-8-巯基腺苷为原料，用丙烯酸甲酯在80℃条件下处理48 h，得到α -endo(7)和α -exo(8)，收率为58%，比例为7:4。为提高表面选择性，在高压条件下进行反应。1与丙烯酸甲酯在DMSO中11kbar的反应。该反应的表面选择性大大提高，2和4的比例为1:1，收率为91%。在相同条件下，6产7，收率79%。因此，高压条件下这些反应提高了表面选择性，但没有提高内/外选择性。这些双环糖核苷被去保护，并对犬磷酸二酯酶III进行了测试。然而，这些都没有表现出有效的抑制活性。