Department of Chemistry, University of California, Irvine, Irvine, California 92697, United States.
Department of Chemistry, University of Redlands, Redlands, California 92373, United States.
J Org Chem. 2024 Sep 6;89(17):12479-12484. doi: 10.1021/acs.joc.4c01414. Epub 2024 Aug 23.
Our laboratory reported the chemical synthesis and stereochemical assignment of the recently discovered peptide antibiotic clovibactin. The current paper reports an improved, gram-scale synthesis of the amino acid building block Fmoc-(2,3)-3-hydroxyasparagine-OH that enables structure-activity relationship studies of clovibactin. An alanine scan reveals that residues Phe, d-Leu, Ser, Leu, and Leu are important for antibiotic activity. The side-chain amide group of the rare d-Hyn residue is not essential to activity and can be replaced with a methyl group with a moderate loss of activity. An acyclic clovibactin analogue reveals that the macrolactone ring is essential to antibiotic activity. The enantiomer of clovibactin is active, albeit somewhat less so than clovibactin. A conformationally constrained clovibactin analogue retains moderate antibiotic activity, while a backbone -methylated analogue is almost completely inactive. X-ray crystallography of these two analogues reveals that the macrolactone ring adopts a crown-like conformation that binds anions.
我们的实验室报道了最近发现的肽类抗生素克洛维巴坦的化学合成和立体化学分配。本文报道了改进的、克级规模的 Fmoc-（2,3）-3-羟基天冬酰胺-OH 氨基酸构建块的合成方法，该方法可用于克洛维巴坦的结构-活性关系研究。丙氨酸扫描表明，残基 Phe、d-Leu、Ser、Leu 和 Leu 对抗生素活性很重要。罕见的 d-Hyn 残基的侧链酰胺基团对活性不是必需的，可以被一个甲基取代，活性略有降低。无环克洛维巴坦类似物表明大环内酯环对抗生素活性至关重要。克洛维巴坦的对映异构体是有活性的，尽管活性稍低。构象受限的克洛维巴坦类似物保留了中等的抗生素活性，而主链甲基化类似物几乎完全没有活性。这两种类似物的 X 射线晶体学揭示了大环内酯环采用了一种类似于冠状的构象，可与阴离子结合。
