Direct Catalytic Asymmetric Mannich-Type Reaction of α- and β‑Fluorinated Amides

The last two decades have witnessed the emergence of direct enolization protocols providing atom-economical and operationally simple methods to use enolates for stereoselective C–C bond-forming reactions, eliminating the inherent drawback of the preformation of enolates using stoichiometric amounts of reagents. In its infancy, direct enolization relied heavily on the intrinsic acidity of the latent enolates, and the reaction scope was limited to readily enolizable ketones and aldehydes. Recent advances in this field enabled the exploitation of carboxylic acid derivatives for direct enolization, offering expeditious access to synthetically versatile chiral building blocks. Despite the growing demand for enantioenriched fluorine-containing small molecules, α- and β-fluorinated carbonyl compounds have been neglected in direct enolization chemistry because of the competing and dominating defluorination pathway. Herein we present a comprehensive study on direct and highly stereoselective Mannich-type reactions of α- and β-fluorine-functionalized 7-azaindoline amides that rely on a soft Lewis acid/hard Brønsted base cooperative catalytic system to guarantee an efficient enolization while suppressing undesired defluorination. This protocol contributes to provide a series of fluorinated analogs of enantioenriched β-amino acids for medicinal chemistry.

近二十年来，直接烯醇化（direct enolization）策略应运而生，该策略为利用烯醇负离子进行立体选择性碳-碳键形成反应提供了原子经济性优异、操作简便的方法，同时规避了使用化学计量试剂预制备烯醇负离子这一固有弊端。在发展初期，直接烯醇化反应高度依赖潜在烯醇负离子的固有酸性，反应底物范围仅局限于易于烯醇化的酮类与醛类。近年来该领域的研究进展使得羧酸衍生物（carboxylic acid derivatives）也可应用于直接烯醇化反应，为便捷获取合成用途广泛的手性合成砌块（chiral building blocks）开辟了可行路径。尽管对映体富集的含氟小分子（fluorine-containing small molecules）的需求日益增长，但由于存在竞争性且占主导地位的脱氟（defluorination）路径，α-和β-氟化羰基化合物在直接烯醇化化学领域中一直被忽视。本研究针对α-和β-氟官能化的7-氮杂吲哚酰胺（7-azaindoline amides）展开系统性探究，该类底物的直接且高立体选择性曼尼希型（Mannich-type）反应依托软路易斯酸（soft Lewis acid）/硬布朗斯特碱（hard Brønsted base）协同催化体系，在保障高效烯醇化的同时抑制了不期望发生的脱氟副反应。本策略可为药物化学领域提供一系列对映体富集的氟化β-氨基酸类似物。