Park So Ok, Kim Jonghoon, Koh Minseob, Park Seung Bum
Department of Chemistry, Seoul National University, Seoul 151-747, Korea.
J Comb Chem. 2009 Mar 9;11(2):315-26. doi: 10.1021/cc800197s.
In this study, the practical construction of a pilot library with benzopyranylpyrazole, a novel core skeleton synthesized through the recombination of privileged structures, benzopyran and pyrazole, was successfully conducted through the efficient utilization of solution-phase parallel synthesis using solid-phase reagents and solid-phase parallel synthesis. We have also developed a novel procedure for the synthesis of benzopyranylpyrazoles via regioselective condensation of substituted hydrazines with beta-keto aldehydes. The diversity of this core skeleton was expanded by the regioselective introduction of alkyl- and aryl-substituents at the R(1) diversity point on the pyrazole moiety and by the introduction of piperazine on the benzopyran substructure, which provide the R(2) diversity point. Lastly, the introduction of a nitro group on the benzopyran moiety was found to accelerate the nucleophilic aromatic substitution of piperazine and provide the R(3) diversity point at the aniline moiety through the reduction of the nitro group. In this pilot library, we only focused on the diversification at the R(1) position with either the R(2) or R(3) position, and thus maximized the diversity through the rational selection of building blocks using chemoinformatics. Overall, a 192-member benzopyranylpyrazole pilot library was constructed with an appending potential for further diversification. The average purity of the library is 87%.
在本研究中，通过高效利用使用固相试剂的溶液相平行合成和固相平行合成，成功地进行了具有苯并吡喃基吡唑的先导库的实际构建，苯并吡喃基吡唑是一种通过特权结构苯并吡喃和吡唑的重组合成的新型核心骨架。我们还开发了一种通过取代肼与β-酮醛的区域选择性缩合来合成苯并吡喃基吡唑的新方法。通过在吡唑部分的R(1)多样性位点区域选择性引入烷基和芳基取代基，以及在苯并吡喃亚结构上引入哌嗪（提供R(2)多样性位点），扩展了该核心骨架的多样性。最后，发现苯并吡喃部分上硝基的引入加速了哌嗪的亲核芳香取代，并通过硝基的还原在苯胺部分提供了R(3)多样性位点。在这个先导库中，我们仅关注R(1)位置与R(2)或R(3)位置之一的多样化，因此通过使用化学信息学合理选择构建模块来最大化多样性。总体而言，构建了一个由192个成员组成的苯并吡喃基吡唑先导库，并具有进一步多样化的潜力。该库的平均纯度为87%。
