Department of Chemistry and Skaggs Institute for Chemical Biology , The Scripps Research Institute , 10550 North Torrey Pines Road , La Jolla , California 92037 , United States.
Department of Chemistry , Princeton University , Princeton , New Jersey 08544 , United States.
J Am Chem Soc. 2019 Oct 30;141(43):17361-17369. doi: 10.1021/jacs.9b09067. Epub 2019 Oct 17.
Streptide () is a peptide-derived macrocyclic natural product that has attracted considerable attention since its discovery in 2015. It contains an unprecedented post-translational modification that intramolecularly links the β-carbon (C3) of a residue 2 lysine with the C7 of a residue 6 tryptophan, thereby forming a 20-membered cyclic peptide. Herein, we report the first total synthesis of streptide that confirms the regiochemistry of the lysine-tryptophan cross-link and provides an unambiguous assignment of the stereochemistry (3 vs 3) of the lysine-2 C3 center. Both the 3 and the originally assigned 3 lysine diastereomers were independently prepared by total synthesis, and it is the former, not the latter, that was found to correlate with the natural product. The approach enlists a powerful Pd(0)-mediated indole annulation for the key macrocyclization of the complex core peptide, utilizes an underdeveloped class of hypervalent iodine(III) aryl substrates in a palladium-catalyzed C-H activation/β-arylation reaction conducted on a lysine derivative, and provides access to material with which the role of streptide and related natural products may be examined.
Streptide（）是一种肽衍生的大环天然产物，自 2015 年发现以来引起了广泛关注。它包含一种前所未有的翻译后修饰，即通过分子内连接残基 2 赖氨酸的β-碳（C3）与残基 6 色氨酸的 C7，从而形成一个 20 元环肽。本文报道了 streptide 的首次全合成，该合成证实了赖氨酸-色氨酸交联的区域化学，并对赖氨酸-2 C3 中心的立体化学（3 与 3）提供了明确的归属。通过全合成分别独立制备了 3 和最初分配的 3 赖氨酸非对映异构体，并且发现前者而不是后者与天然产物相关。该方法利用强大的 Pd(0)介导的吲哚环化反应进行复杂核心肽的关键大环化，利用在赖氨酸衍生物上进行的钯催化 C-H 活化/β-芳基化反应中未充分开发的一类高价碘(III)芳基底物，并提供了可用于研究 streptide 和相关天然产物作用的材料。
