Wang Zi-Xuan, Xu Yameng, Gilmour Ryan
Institute for Organic Chemistry, University of Münster, Corrensstraße 36, 48149, Münster, Germany.
Nat Commun. 2024 Jul 9;15(1):5770. doi: 10.1038/s41467-024-50227-x.
The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, we describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes. It is envisaged that the transformation will find application in molecular design and accelerate the exploration of organofluorine chemical space.
炔丙基氟化物在药物化学中的突出地位和多功能性，再加上F/H和F/OH生物电子等排体的效力，为开发促进其构建的有效方法提供了强大动力。鉴于炔丙醇向丙二烯的成熟转化，一种基于有机催化、操作简单的策略，将这些丰富的不饱和前体转化为炔丙基氟化物将具有高度可行性：这将巩固连接炔丙醇和氟化物的生物电子等排关系。在此，我们描述了一种在廉价HF源存在下基于I(I)/I(III)催化的未活化丙二烯的高度区域选择性氟化反应，该HF源兼具亲核试剂和布朗斯特酸活化剂的双重作用。该策略能够制备多种仲和叔炔丙基氟化物：这些结构单元在生物活性小分子谱中普遍存在。本文还公开了产物的简便衍生化、多邻位氟化产物的简洁合成以及对映选择性催化的初步验证。通过丙二烯的高度区域选择性有机催化氧化、氯化和芳基化反应，也证明了该平台的广阔潜力。预计该转化反应将在分子设计中得到应用，并加速有机氟化学空间的探索。
