Late-Stage Functionalization of Histidine in Unprotected Peptides
Late-Stage Functionalization of Histidine in Unprotected Peptides
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DOI：
10.1002/anie.201910888
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发表时间：
2019-11-07
影响因子：
16.6
通讯作者：
Gopalakrishnan, Ranganath
中科院分区：
文献类型：
--
作者：
Noisier, Anais F. M.;Johansson, Magnus J.;Gopalakrishnan, Ranganath
多肽的后期功能化(LSF)是设计有效的多肽药物的一种有价值的策略，它使化学多样性的快速探索成为可能，并为多肽偶联提供了新的机会。色氨酸(Trp)的C(sp(2))-H活化是已知的，自由基化学的重新兴起为其他芳香族侧链的C-H官能化开辟了新的途径。在这里，我们报告了第一个利用广泛的脂肪族亚硫酸盐作为自由基前体的组氨酸(His)C2位LSF的例子。在这项工作中，通过复杂的无保护多肽在水介质中的烷基化反应，证明了组氨酸功能化的良好选择性。最后，这一方法被扩展到一个酮柄的安装，为组氨酸上的酮肟/肼的选择性结合提供了一个前所未有的锚。
The late-stage functionalization (LSF) of peptides represents a valuable strategy for the design of potent peptide pharmaceuticals by enabling rapid exploration of chemical diversity and offering novel opportunities for peptide conjugation. While the C(sp(2))-H activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the C-H functionalization of other aromatic side-chains. Herein, we report the first example of LSF at C2 of histidine (His) utilizing a broad scope of aliphatic sulfinate salts as radical precursors. In this work, the exquisite selectivity for histidine functionalization was demonstrated through the alkylation of complex unprotected peptides in aqueous media. Finally, this methodology was extended for the installation of a ketone handle, providing an unprecedented anchor for selective oxime/hydrazone conjugation at histidine.