Medicinal Chemistry, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.
Discovery Sciences, BioPharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.
Angew Chem Int Ed Engl. 2019 Dec 19;58(52):19096-19102. doi: 10.1002/anie.201910888. Epub 2019 Nov 7.
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 )-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.
晚期功能化（LSF）肽代表了通过使化学多样性快速探索和为肽缀合提供新机会来设计有效肽药物的有价值策略。虽然色氨酸（Trp）的 C（sp ）-H 活化已有很好的记载，但自由基化学的复兴为其他芳族侧链的 C-H 功能化开辟了新途径。在此，我们报告了首次利用广泛的脂肪族亚磺酸盐作为自由基前体在组氨酸（His）的 C2 上进行 LSF 的实例。在这项工作中，通过在水介质中对复杂的未保护肽进行烷基化，证明了组氨酸功能化的极好选择性。最后，该方法扩展到酮基的安装，为组氨酸的选择性肟/腙缀合提供了前所未有的连接点。
