James Thomas, Maclellan Paul, Burslem George M, Simpson Iain, Grant J Andrew, Warriner Stuart, Sridharan Visuvanathar, Nelson Adam
School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
Org Biomol Chem. 2014 Apr 28;12(16):2584-91. doi: 10.1039/c3ob42512f.
Piperazines are found widely in commercially-available compounds and bioactive molecules (including many drugs). However, in the vast majority of these molecules, the piperazine ring is isolated (i.e. not fused to another ring) and is not substituted on any of its carbon atoms. A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazines and related 1,4-diazepine and 1,5-diazocane scaffolds. By variation of the combinations of building blocks used, it was possible to vary the ring size, substitution and configuration of the resulting heterocyclic scaffolds. The approach was exemplified in the synthesis of a range of heterocyclic scaffolds that, on decoration, would target lead-like chemical space. It was demonstrated that lead-like small molecules based on these scaffolds would likely complement those found in large compound collections.
哌嗪广泛存在于市售化合物和生物活性分子（包括许多药物）中。然而，在这些分子中的绝大多数中，哌嗪环是孤立的（即不与另一个环稠合），并且其任何碳原子上都没有取代基。本文描述了一种模块化合成方法，其中环状氨基磺酸酯和羟基磺酰胺构建块的组合可以转化为哌嗪以及相关的1,4 - 二氮杂卓和1,5 - 二氮杂环辛烷骨架。通过改变所用构建块的组合，可以改变所得杂环骨架的环大小、取代基和构型。该方法在一系列杂环骨架的合成中得到了例证，这些骨架经修饰后将靶向类先导化学空间。结果表明，基于这些骨架的类先导小分子可能会补充大型化合物库中的那些分子。
