Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States.
J Org Chem. 2024 Oct 18;89(20):14665-14672. doi: 10.1021/acs.joc.4c01203. Epub 2024 Sep 22.
We have developed a high yielding synthesis of indolizine and directly elaborated the molecule into three optically active indolizinylalanine regioisomers. The protocols exploit metal catalyzed coupling of indolizinyl-halides with organozinc reagents derived from carbamoylated iodoalanine esters. The scalable protocols provide products in a form amenable to solid-phase peptide synthesis (SPPS). When incorporated into peptides, the indolizine heterocycle is more basic and markedly less nucleophilic than tryptophan. Its protonated vinylpyridinium form is deeply colored in solution while the neutral heterocycle is highly fluorescent. The fluorescence quantum yield of indolizine exceeds that of indole and aza-indoles in water, suggesting that indolizinylalanines could be powerful optical probes of protein structure and dynamics, functioning as true tryptophan isosteres.
我们开发了一种高产率的吲哚嗪合成方法，并直接将该分子衍生为三种具有光学活性的吲哚嗪基丙氨酸区域异构体。该方案利用金属催化吲哚嗪卤化物与氨基甲酰化碘代丙氨酸酯衍生的有机锌试剂的偶联反应。可规模化的方案提供了适用于固相肽合成 (SPPS) 的产物形式。当整合到肽中时，吲哚嗪杂环比色氨酸更碱性且明显亲核性更低。其质子化的乙烯基吡啶鎓形式在溶液中呈深颜色，而中性杂环则具有高度荧光。吲哚嗪的荧光量子产率超过了水中吲哚和氮杂吲哚，这表明吲哚嗪基丙氨酸可能是蛋白质结构和动力学的强大光学探针，可作为真正的色氨酸类似物。
