Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, UniteUSA.
J Org Chem. 2012 Apr 6;77(7):3099-114. doi: 10.1021/jo202105v. Epub 2012 Mar 13.
A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, and ortho-meta, were systematically explored through regiochemical variation of the aryl halide and aryl boronate coupling partners, allowing fine-tuning of the resultant macrocycle conformation. Suzuki-Miyaura macrocyclizations were successfully achieved both in solution and on solid phase for all three sizes of peptide. This approach constitutes a means of constraining peptide conformation via direct carbogenic fusion of side chains of naturally occurring amino acids such as phenylalanine and tyrosine, and so is complementary to strategies involving non-natural, for example, hydrocarbon, bridges.
已经开发出一种通过连接芳侧链来约束肽构象的通用方法。通过 Suzuki-Miyaura 交叉偶联，适当地官能化的三肽、四肽和五肽的环化已用于生成侧链到侧链、联芳基桥接的 14 到 21 元大环肽。通过芳基卤化物和芳基硼酸偶联物的区域化学变化系统地探索了具有三种不同构型（间-间、间-邻和邻-间）的联芳基桥，从而可以精细调整所得大环的构象。所有三种大小的肽都可以在溶液中和固相中成功地进行 Suzuki-Miyaura 环化。这种方法通过直接碳融合天然存在的氨基酸（如苯丙氨酸和酪氨酸）的侧链来约束肽构象，因此与涉及非天然的策略（例如烃桥）互补。
