Design, Synthesis, and Evaluation of a Novel Class of Enantioselective Electrophilic Fluorinating Agents:  N-Fluoro Ammonium Salts of cinchona Alkaloids (F-CA-BF₄)

Abstract

The first enantiopure N-fluoro quaternary ammonium salts of cinchona alkaloids as enantioselective fluorinating agents are reported. A one-step transfer-fluorination on the naturally occurring cinchona alkaloids gave the fluorinating agents F-CA-BF(4). This new generation of fluorinating agents exhibited asymmetric induction up to 61% on fluorination of enolates and silyl enol ethers of 2-methyl-1-tetralone.

Recent Advances in Catalytic Enantioselective Fluorination Reactions

“…[41] Based on this finding, a catalytic version of this methodology was reported in 2006. Shibata and Toru noticed that Selectfluor shows low reactivity towards acyl enol ethers.…”

Selectfluor: Mechanistic Insight and Applications

“…Selectfluor was used to prepare the N-fluoroammonium derivatives 23 a-d of cinchona alkaloids by transfer fluorination (Figure 3, Scheme 26). [66][67][68] The fluorinated reagents 23 a-d were tested in the enantioselective fluorination of the sodium enolate of 2-methyl-1-tetralone, providing the product in up to 98 % yield and with up to 50 % ee (Table 8). Higher enantioselectivities (up to 94 % ee) were later observed with modified N-fluoro cinchona alkaloids.…”

Regio‐ and Enantioselective Synthesis of Allylic Fluorides by Electrophilic Fluorodesilylation of Allyl Silanes

“…[9] These preliminary results encouraged us to investigate the use of enantiopure N-fluorocinchona alkaloids in an enantioselective version of this new reaction. In recent work by Shibata et al [11] and Cahard and co-workers [12] on the fluorination of silyl enol ethers with N-fluorocinchona alkaloids, a-fluorocarbonyl compounds were prepared with ee values of up to 91 %. N-Fluorocinchona alkaloids have proved to be efficient reagents and are readily prepared from commercially available compounds.…”

“…Furthermore, we found the use of the fluorinated cinchona alkaloids as isolated reagents to be problematic, as the chemical yields observed were less satisfactory. [12,13] In subsequent studies we therefore used the protocol developed by Shibata et al for the preparation of these reagents in situ. [11] We next investigated the effectiveness of our system for the enantioselective fluorination of allyl silanes 1 c-h. [14] As can be seen from the results summarized in Table 2, the corresponding allylic fluorides could be formed with very high conversion (in all cases greater than 95 %) and with moderate to excellent ee values.…”

“…The levels of enantioselectivity observed in the reactions to form the allylic fluorides 2 a and 2 c-g compare favorably with the best ee values observed by Shibata et al, and Cahard and coworkers, for fluorinated ketones. [11,12] To assign the absolute configurations of the products, compounds 2 c, 2 e, and 2 f were prepared by an alternative asymmetric method. [14] We assume that the reactive conformation of the N-fluorocinchona alkaloids is similar to the one suggested by Shibata et al, as the reactions described herein were performed under similar conditions to those for the fluorination of analogous silyl enol ethers.…”