Synthetic Studies of Imidazole C-nucleosides aimed at Novel Histomine Ligands

我们最近报道了C-4连接的咪唑核苷的β-立体选择性合成，在已有的基础上，我们开始有兴趣合成咪唑C-核苷(ICN)类似物的四个可能的立体异构体，其中咪唑和氨基被限制在四氢呋喃环上。首次提出了一条合成新型2‘，3’-二脱氧咪唑C-核苷衍生物四种可能的立体异构体的路线，该路线是通过利用L-谷氨酸中的PHSE基团来实现的。以较高的产率将关键中间体硒内酯相继衍生为5-芳基-2‘，3’-二脱氧-ICN衍生物，它们的对映体通过D-戊二酸的核苷以相同的方法提供。5‘-氨基-2’，3‘-二氢-2’，3‘-二脱氧-ICN的四个异构体也是通过氧化消除中间体的C2’-苯基亚硒基而合成的。以D-核糖为起始原料，合成了4(5)-(5-氨基甲基呋喃-2-基)-1H-咪唑(5)。特别值得注意的是，只有名为咪呋拉明的(+)-4(5)-{(2R，5R)-5-(aminomethyl)-tetrahydrofuran-2-yl}imidazole被活体脑微透析鉴定为H3激动剂。

We recently reported the beta-stereoselective synthesis of C-4 linked imidazole nucleosides, On the basis of what we have now, we became interested in the synthesis of the four possible stereoisomerers of a novel imidazole C-nucleoside (ICN) analogues in which the imidazole and amino groups were restricted across a tetrahydrofuran ring. A synthetic route to the four possible stereoisomers of a novel 2' 3' dideoxyimidazole C-nucleoside derivative was at first developed via the efficient use of PhSe group from L-glutamic acid. The key intermediates selenolactols were successively derived to the respective 5 arnino-2', 3' -dideoxy-ICN derivatives in excellent yields Their enantiomers were provided via nucleosides from D-glutarnic acid by the same methodology. The four isomers of 5' Amino-2', 3' didehydro-2' 3' dideoxy-ICN were also synthesized via oxidative elimination the C2'-phenylselenyl group of the intermediates. Further, 4(5)-(5-aminomethylfuran-2-yl)-1H-imidazole (5) was synthesized starting from D-ribose. Of particular interest, only (+)-4(5)-{(2R,5R)-5-(aminomethyl)-tetrahydrofuran-2-yl}imidazole named imifuramine, was identified as a H_3 agonist by in vivo brain microdialysis.