Stapled Peptides by Late-Stage C(sp3)-H Activation
Stapled Peptides by Late-Stage C(sp3)-H Activation
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DOI：
10.1002/anie.201608648
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发表时间：
2017-01-02
影响因子：
16.6
通讯作者：
Albericio, Fernando
中科院分区：
文献类型：
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作者：
Noisier, Anais F. M.;Garcia, Jesus;Albericio, Fernando
尽管短链多肽在药物开发中具有重要意义，但目前制备交联肽的实际过程很少，因此目前可用的短链基序的结构多样性是有限的。同时，C-H活化已成为实现复杂分子功能化的有效途径。虽然有许多关于氨基酸C-H功能化的报道，但合成后的多肽C-H修饰的例子很少，几乎只有C(sp(2))-H激活。在这里，我们报道了一种钯催化的晚期C(sp(3))-H活化方法用于多肽的装订，提供了前所未有的碳氢交联物。该方法首次被用于制备溶液中的装订多肽文库。考察了其与各种氨基酸的配伍性，以及长度和尺寸(I，I+3和I，I+4)的影响。最后，还建立了一套简单的固相程序。
Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross-linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C-H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C-H functionalization of amino acids, examples of post-synthetic peptide C-H modification are rare and comprise almost only C(sp(2))-H activation. Herein, we report the development of a palladium-catalyzed late-stage C(sp(3))-H activation method for peptide stapling, affording an unprecedented hydrocarbon cross-link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i,i+3 and i, i+4) and length of the staple were investigated. Finally, a simple solid-phase procedure was also established.