Conformationally locked carbocyclic nucleosides built on a bicyclo[3.1.0]hexane template with a fixed Southern conformation. Synthesis and antiviral activity
作者:Abdallah Ezzitouni、Victor E. Marquez
DOI:10.1039/a604352f
日期:——
The construction of carbocyclic nucleosides with a fixed
3E ring pucker in the Southern hemisphere of the
pseudorotational cycle is achieved from a common precursor carbocyclic
amine,
(1S,3S,4R,5
S
)-3-benzyloxy-4-benzyloxymethyl-1-aminobicyclo[3.1.0]hexane 20. This
carbocyclic amine is efficiently assembled from optically pure
2-benzyloxymethylcyclopent-3-enol 11 in ten steps. The key
cyclopropanation step is performed on
(3R,4S
)-1-cyano-4-benzyloxy-3-(benzyloxymethyl)cyclopentane 15, and proceeds
regio- and stereo-selectively to give the critical cyanocarbocyclic
intermediate 17 from which the amine 20 is subsequently obtained.
Synthesis of the pyrimidine analogues 6–8 is accomplished
via the intermediate acyclic acryloylureas 21 and 22.
Preparation of purines 9 and 10 required prior
N-formylation of the corresponding
4,6-dichloro-5-aminopyrimidine and 4,6-dichloro-2,5-diaminopyrimidine
heterocyclic precursors for efficient coupling with amine 20. Except for
(S)-2′-deoxy-methanocarba-A
(9, the 2′-deoxyadenosine analogue), all Southern conformers
appear to be devoid of antiviral activity.
具有固定结构的碳环核苷的构建
3E 南半球环皱褶
伪旋转循环是由共同的前体碳环实现的
胺,
(1S,3S,4R,5
S
)-3-苄氧基-4-苄氧基甲基-1-氨基双环[3.1.0]己烷 20. 这个
碳环胺由光学纯高效组装而成
2-苄氧基甲基环戊-3-烯醇 11 十步反应。关键
环丙烷化步骤进行于
(3R,4S
)-1-氰基-4-苄氧基-3-(苄氧基甲基)环戊烷15,并进行
区域和立体选择性地给出关键的氰基碳环
中间体17,随后由其获得胺20。
嘧啶类似物 6-8 的合成完成
通过中间体无环丙烯酰脲21和22。
需要事先准备嘌呤 9 和 10
相应的N-甲酰化
4,6-二氯-5-氨基嘧啶和4,6-二氯-2,5-二氨基嘧啶
与胺20有效偶联的杂环前体。除了
(S)-2′-脱氧甲烷碳-A
(9,2′-脱氧腺苷类似物),所有南方构象异构体
似乎缺乏抗病毒活性。