Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA.
Angew Chem Int Ed Engl. 2022 Aug 1;61(31):e202207153. doi: 10.1002/anie.202207153. Epub 2022 Jun 23.
Non-proteogenic amino acids and functionalized peptides are important motifs in modern drug discovery. Here we report that Ala can serve as universal building blocks in the synthesis of a diverse collection of modified amino acids, peptides, and proteins. First, we develop the synthesis of Ala from redox-active esters of aspartic acid resulting in a series of β-boronoalanine derivatives. Next, we show that Ala can be integrated into automated oligopeptide solid-phase synthesis. Ala is compatible with common transformations used in preparative peptide chemistry such as native chemical ligation and radical desulfurization as showcased by total synthesis of Ala -containing ubiquitin. Furthermore, Ala reagents participate in Pd-catalyzed reactions, including C-C cross-couplings and macrocyclizations. Taken together, Ala synthons are practical reagents to access modified peptides, proteins, and in the synthesis of cyclic/stapled peptides.
非天然氨基酸和功能化肽是现代药物发现中的重要结构单元。在这里，我们报告说丙氨酸可以作为通用构建块，用于合成各种修饰的氨基酸、肽和蛋白质。首先，我们开发了一种从天冬氨酸的氧化还原活性酯合成丙氨酸的方法，得到了一系列β-硼代丙氨酸衍生物。接下来，我们表明丙氨酸可以整合到自动寡肽固相合成中。丙氨酸与制备肽化学中常用的转化方法（如天然化学连接和自由基脱硫）兼容，这一点在含有丙氨酸的泛素的全合成中得到了展示。此外，丙氨酸试剂还参与钯催化反应，包括 C-C 交叉偶联和大环化反应。总之，丙氨酸合成子是一种实用的试剂，可以用来合成修饰的肽、蛋白质，以及环状/订书钉肽的合成。
