Sander Leon, Müller Jonas M, Stark Christian B W
Fachbereich Chemie, Institut für Organische Chemie, University of Hamburg, Martin-Luther-King-Platz 6, Hamburg 20146, Germany.
J Am Chem Soc. 2025 Jul 30;147(30):26506-26517. doi: 10.1021/jacs.5c06364. Epub 2025 Jul 17.
Prenylated indole alkaloids from bacteria, fungi, plants, and animals comprise a large structural diversity with a broad range of biological activities. A subclass of this alkaloid family are the 3a-reverse prenylated hexahydropyrrolo[2,3-]indole (HPI) natural products that are in principle synthetically accessible via a metal-catalyzed allylic substitution. Here we report the first catalytic enantioselective reverse prenylation of achiral 3-substituted indoles that furnishes hexahydropyrrolo[2,3-]indoles in a single step. The developed catalytic system utilizes a novel iridium-NHC-phosphoramidite catalyst and provides the 3-prenylated products with high yields and enantioselectivities as well as complete branched selectivity. This elaborate methodology closes a systematic gap in asymmetric allylic substitution chemistry and offers a convenient strategy for the synthesis of tryptamine-derived alkaloids as demonstrated in a short biomimetic total synthesis of (-)-flustramine A, a prototypical member of this class of natural products. Mechanistic investigations elucidate the catalyst's structure and reveal a chloride-induced allyl complex isomerization, which is dependent on the hemilabile phosphoramidite-olefin Carreira-type ligand.
来自细菌、真菌、植物和动物的异戊烯基化吲哚生物碱结构多样，具有广泛的生物活性。该生物碱家族的一个亚类是3a-反式异戊烯基化六氢吡咯并[2,3-b]吲哚（HPI）天然产物，原则上可通过金属催化的烯丙基取代进行合成。在此，我们报道了首例非手性3-取代吲哚的催化对映选择性反式异戊烯基化反应，该反应可一步生成六氢吡咯并[2,3-b]吲哚。所开发的催化体系使用了一种新型铱-N-杂环卡宾-亚磷酰胺催化剂，能以高收率、高对映选择性以及完全的支链选择性得到3-异戊烯基化产物。这一精细的方法填补了不对称烯丙基取代化学中的一个系统空白，并为色胺衍生生物碱的合成提供了一种便捷策略，如在（-）-flustramine A的短仿生全合成中所展示的那样，（-）-flustramine A是这类天然产物的一个典型成员。机理研究阐明了催化剂的结构，并揭示了氯离子诱导的烯丙基配合物异构化，这取决于半不稳定的亚磷酰胺-烯烃卡雷拉型配体。
