Liu Lei, Liu Yan-Hua, Shi Bing-Feng
Department of Chemistry , Zhejiang University , Hangzhou 310027 , China . Email:
Chem Sci. 2019 Nov 11;11(1):290-294. doi: 10.1039/c9sc04482e. eCollection 2020 Jan 7.
Amino acids and peptides with bulky side chains are of significant importance in organic synthesis and modern medicinal chemistry. The efficient synthesis of these molecules with full enantiocontrol and high diversity remains challenging. Herein we report a Pd-catalyzed ligand-enabled γ-C(sp)-H arylation of -leucine and its derived peptides without using an external directing group (DG) a less favored six-membered palladacycle. Structurally diverse bulky side chain amino acids and peptides were accessed in a step-economic fashion and the reaction could be conducted on a gram scale with retention of chirality. The resulting amino acids can be used as chiral ligands in Co(iii)-catalyzed enantioselective C(sp)-H amidation. It is worth noting that the weakly coordinating carboxylate DG outcompetes the strongly coordinating bidentate DG of the peptide backbone, providing the products of γ-C(sp)-H arylation of Tle residue exclusively. This protocol represents the first example of late stage C(sp)-H functionalization of peptides using a weakly coordinating directing group.
带有庞大侧链的氨基酸和肽在有机合成和现代药物化学中具有重要意义。以完全对映体控制和高多样性高效合成这些分子仍然具有挑战性。在此，我们报道了一种钯催化的、无需使用外部导向基团（DG）的亮氨酸及其衍生肽的配体导向γ-C(sp)-H芳基化反应，这是一种不太常见的六元钯环。以步骤经济的方式获得了结构多样的带有庞大侧链的氨基酸和肽，并且该反应可以在克级规模上进行，同时保持手性。所得氨基酸可作为手性配体用于钴（III）催化的对映选择性C(sp)-H酰胺化反应。值得注意的是，弱配位的羧酸盐导向基团比肽主链上强配位的双齿导向基团更具竞争力，仅提供叔亮氨酸（Tle）残基的γ-C(sp)-H芳基化产物。该方法代表了使用弱配位导向基团对肽进行后期C(sp)-H官能化的首个实例。
