• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Chemistry: A European journal >Selectively N-Protected Enantiopure 2,5-Disubstituted Piperazines:Avoiding the Pitfalls in Solid-Phase FukuyamaCMitsunobu Cyclizations
【24h】

Selectively N-Protected Enantiopure 2,5-Disubstituted Piperazines:Avoiding the Pitfalls in Solid-Phase FukuyamaCMitsunobu Cyclizations

机译：选择性N保护的对映纯2,5-二取代哌嗪：避免固相FukuyamaCMitsoobu环化中的陷阱

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

An efficient solid-phase route to ring-substituted piperazines from O-linked resin-bound (S)-aziridine- 2-methanol is described. Regioselective microwave-assisted aminolysis followed by intramolecular FukuyamaC Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines and diazepanes were readily obtained without preceding N-protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5-disubstituted piperazines failed. Modifications encompassing Ncarbamoylation prior to ring-closure were therefore investigated. However, standard carbamoylating agents, for example, Fmoc-Cl and Alloc-Cl tended to give bis-protected by-products. Thus, novel microwave-assisted solid-phase N-protection procedures were developed for efficient introduction of Fmoc, Boc and Alloc groups. The subsequent cyclization proceeded in moderate to excellent yields depending on the bulk of the side chain and type of N-protecting group.This protocol readily provided novel cis- and trans-2,5-disubstituted piperazines displaying a variety of N-protecting group patterns after further on-resin manipulations.Also, unexpected by-products obtained during these optimization studies were identified and characterized. This includes nosylated ureas arising from an alternative cyclization pathway. Finally,post-cleavage oxidation gave access to the Fmoc/Boc-protected a-amino acid as well as the corresponding aldehyde.The chiral piperazines described in this work will enable construction of combinatorial libraries with a higher chemical diversity compared to those containing simple N,N-ifunctionalized piperazines,often present in drug-like compounds.
机译：描述了从O-连接的树脂结合的（S）-氮丙啶-2-甲醇制备环取代的哌嗪的有效固相途径。区域选择性微波辅助氨解，然后进行分子内FukuyamaC Mitsunobu环化，构成了方案的关键特征。在没有对无环中间体进行N-保护的情况下，可以轻松获得简单的哌嗪和二氮杂苯，而将该方案扩展至手性2,5-二取代哌嗪的尝试却失败了。因此，研究了在闭环之前包含氨基甲酰基化的修饰。但是，标准的氨基甲酸酯化剂，例如Fmoc-Cl和Alloc-Cl倾向于产生双保护的副产物。因此，为有效引入Fmoc，Boc和Alloc基团，开发了新颖的微波辅助固相N-保护程序。随后的环化反应以中等至极好的收率进行，具体取决于侧链的体积和N保护基的类型。该方案可轻松提供新颖的顺式和反式2,5-二取代哌嗪，显示出多种N保护基模式在进一步的树脂上操作之后。此外，还对这些优化研究过程中获得的意外副产物进行了鉴定和表征。这包括源于替代环化途径的Nosylated脲。最后，裂解后的氧化使Fmoc / Boc保护的α-氨基酸以及相应的醛得以进入。与仅含N的那些相比，本文描述的手性哌嗪将使化学文库的组合性更高。 ，N-功能化的哌嗪，常存在于类药物化合物中。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号