复杂环肽分子的合成研究

Cyclic peptides, endowed with the ability to establish a broad number of non-covalent interactions with protein, carbonhydrate and lipid fragment, are able to act as miniproteins to regulate many “undrugable” biological processes. In nonribsomal cyclic peptides, additional cyclization chemistries beyond amide bond, such as crosslinkage between two amino acid side chains to form C-C bond or C-O bond are widespread. However, the synthesis of these type of new linking patterns has not been well studied, new pratical methodologies are urgently needed to modify or staple the side chains of peptide backbone. In this proposal, new protocol will be developed to synthesize the challenging architecture of cyclic peptides acicultin and streptide via metal catalyzed C-H functionalization reactions. Further more, a versatile strategy will be developed to construct cyclic peptide from their linear precursor by stapling the side chains of aromatic amino acid residues. This project will promote the development of new C-H activation methodologies and their applications in total synthesis of complex natural products, offering an easy accesss to conformational constrained cyclic pepetides with well defined three dimensional structures.

天然环肽骨架中存在大量氨基酸侧链通过交叉偶联形成的碳-碳键和碳-杂键链接结构。这些特殊链接对其母体骨架的构象、空间三维结构和生物活性有着重要的影响，是生物活性分子中的“优势骨架”。如何高效地构建此类构象限定的环肽骨架并深入理解其结构活性关系是有机合成化学需要解决的重要课题之一。我们选择以天然环肽Aciculitin和Streptide的特异环骨架作为模板，发展新的高实用性碳氢键官能团化方法构建其核心结构，实现其母体骨架的多样性合成。同时受到自然界构建此类碳-碳键和碳-杂键链接合成复杂环肽的启发，我们希望能发展出一种基于分子内碳氢键官能团化的通用关环策略构建环肽骨架，实现直链多肽的环化修饰和人工设计环肽的高效合成。

天然环肽骨架中存在大量氨基酸侧链通过交叉偶联形成的碳-碳键和碳-杂键链接结构。这些特殊链接对其母体骨架的构象、空间三维结构和生物活性有着重要的影响，是生物活性分子中的“优势骨架”。如何高效地构建此类构象限定的环肽骨架并深入理解其结构活性关系是有机合成化学需要解决的重要课题之一。本项目以天然环肽的特异环骨架作为模板，成功开发了一系列基于分子内碳氢键官能团化的通用关环策略来构建含有“环苯支架”的环肽骨架，实现直链多肽的环化修饰和人工设计环肽的高效合成。其中基于钯催化分子内烷基C-H芳基化反应构建环肽的系列工作收到国内国际同行广泛关注。发表相关论文34篇，其中含Nat. Chem. (1篇)，Nat. Catal.（1篇），JACS（5篇）。相关工作多次受到Synfact, X-mol 等专业和科普媒体专题介绍。