Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Haifa 3200008, Israel.
J Am Chem Soc. 2022 Mar 23;144(11):4966-4976. doi: 10.1021/jacs.1c12906. Epub 2022 Mar 8.
In fundamental research and drug discovery, there is still a need for effective and straightforward chemical approaches for generating cyclic peptides. The divergent synthesis of cyclic peptides remains a challenge, in particular when cyclization is carried out in the presence of unprotected side chains and a nonpeptidic component within the cycle is needed. Herein, we describe a novel and efficient strategy based on Au(I)-mediated cyclization of unprotected peptides through rapid (30-60 min) amine addition on a propargyl group to generate an imine linkage. Mechanistic insights reveal that the reaction proceeds via regioselective Markovnikov's addition of the amine on the Au(I)-activated propargyl. This strategy was successfully applied to prepare efficiently (56-94%) over 35 diverse cyclic peptides having different sequences and lengths. We have also achieved stereoselective reduction of cyclic imines employing chiral ligands. The practicality of our method was extended for the synthesis of cyclic peptides that bind Lys48-linked di-ubiquitin chains with high affinity, leading to apoptosis of cancer cells.
在基础研究和药物发现中，仍然需要有效的、直接的化学方法来生成环肽。环肽的发散合成仍然是一个挑战，特别是当需要在未保护的侧链存在下进行环化并且环内需要非肽成分时。在此，我们描述了一种基于 Au(I)介导的未保护肽的环化的新的、有效的策略，该策略通过在炔丙基上快速（30-60 分钟）胺加成生成亚胺键来实现。机理研究表明，该反应通过胺在 Au(I)活化的炔丙基上的区域选择性 Markovnikov 加成进行。该策略已成功应用于制备 35 种具有不同序列和长度的不同环肽（产率为 56-94%）。我们还利用手性配体实现了环亚胺的立体选择性还原。我们的方法的实用性已扩展到与赖氨酸 48 连接的二泛素链具有高亲和力的环肽的合成，从而导致癌细胞凋亡。
