From Bifunctional to Trifunctional (Tricomponent Nucleophile–Transition Metal–Lewis Acid) Catalysis: The Catalytic, Enantioselective α-Fluorination of Acid Chlorides

• Published in: Journal of the American Chemical Society Vol. 133; no. 19; pp. 7536 - 7546
• Main Authors: Erb, Jeremy, Paull, Daniel H, Dudding, Travis, Belding, Lee, Lectka, Thomas
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18-05-2011
• Subjects: Carboxylic Acids - chemistry; Catalysis; Chlorides - chemistry; Halogenation; Lewis Acids - chemistry; Metals, Alkali - chemistry; Stereoisomerism; Transition Elements - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja2014345

We report in full detail our studies on the catalytic, asymmetric α-fluorination of acid chlorides, a practical method that produces an array of α-fluorocarboxylic acid derivatives in which improved yield and virtually complete enantioselectivity are controlled through electrophilic fluorination of a ketene enolate intermediate. We discovered, for the first time, that a third catalyst, a Lewis acidic lithium salt, could be introduced into a dually activated system to amplify yields of aliphatic products, primarily through activation of the fluorinating agent. Through our mechanistic studies (based on kinetic data, isotopic labeling, spectroscopic measurements, and theoretical calculations) we were able to utilize our understanding of this “trifunctional” reaction to optimize the conditions and obtain new products in good yield and excellent enantioselectivity.