Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Org Biomol Chem. 2014 Jan 28;12(4):566-73. doi: 10.1039/c3ob42168f.
Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously "scan" two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.
在这里，我们描述了一种基于半胱氨酸硫醇与新一代高反应性全氟芳族小分子接头之间的 SNAr 反应的未保护肽文库侧链大环化的通用合成平台。该策略使我们能够同时“扫描”多肽中 i、i + 1 到 i、i + 14 位两个半胱氨酸残基，用 7 个接头与 14 个肽反应产生 98 个大环产物。开发了一种互补的反向策略；首先用非桥连全氟芳基部分修饰多肽中的半胱氨酸残基，然后使用市售的二硫醇接头进行大环化。这两种策略具有高度收敛性、非依赖性和模块化性质，以及 SNAr 转化的独特化学选择性，允许快速进行基于多样性导向的混合大环肽文库的合成，具有不同的化学和结构复杂性。
