Silyl enol ethers enantioselective fluorination

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

Cahard and coworkers prepared polystyrene-bound cinchona alkaloids (PS-CA, 119), and successfully applied to enantioselective a-fluorination of silyl enol ether 117. Soluble-phase PS-CA along with Selectfluor gave both good chemical and optical yields. Facile recovery of the PS-CA by solid/liquid separation allowed an... 

Scheme 2.93 Enantioselective electrophilic fluorination of silyl enol ethers by N-fluorodihydro-quinine 4-chlorobenzoate. The enantioselective fluorination reagent is generated in situ from F-TEDA-BF4 (Selectfluor) and dihydroquinine 4-chlorobenzoate [206].

In 2008, Shibata et al. disclosed the first successful catalytic enantioselective fluorination based on the use of cinchona alkaloids. Therefore, it was demonstrated that allyl silanes and silyl enol ethers underwent efficient enantioselective fluorodesilylation with NFSI and a catalytic amount of a bis-cinchona alkaloid in the presence of an excess of base to provide the corresponding fluorinated compounds with an F-substituted quaternary carbon centre with enantioselectivities of up to 95% ee (Scheme 5.3). Furthermore, the authors showed that this catalytic system could be applied to the catalytic... 

The Behenna-Stoltz protocol was soon applied to a-fluoroketones. As shown in Scheme 5.26, the silyl enol ethers 80 of 2-fluoro-indanone, tetralone-, and ben-zosuberone can be reacted with allyl or methallyl carbonate to give the tertiary a-fluorinated ketones 81 in 83-95% ee [43]. The procedure that was also applied to an allylation of 4,4-dimethyl-6-fluorocyclohexenone offers an alternative to the enantioselective fluorination of enolates on the one hand and the decarboxylative allylation of fluorinated P-keto esters on the other hand vide infra). 

SCHEME 44.14. Catalytic enantioselective fluorination of silyl enol ethers and oxindoles. 

The ease of preparation and generality of fluorination make the [N-F] class of reagents an excellent choice for enantioselective electrophilic fluorination. Advantageously, enantioselective electrophilic fluorination was also achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of bis-cinchona alkaloids and NFSI in the presence of excess base (Scheme 44.14). Applications of these [N-F] reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (Scheme 44.15), a potent opener of maxi-K channels (BMS-204352, MaxiPost Xi an Unique Electronics Chemical Co., Ltd, Xi an, P.R. China), and 20-deoxy-20-fluorocamptothecin (see section 3). 

SCHEME 44.13. Enantioselective fluorination of silyl enol ethers by means of [N-F] ammonium salts of cinchona alkaloids. 

Ishimaru T, Shibata N, Horikawa T, Yasuda N, Nakamura S, Tom T, Shiro M. Cinchona alkaloid catalyzed enantioselective fluorination of allyl silanes, silyl enol ethers, and oxindoles. Awgew. Chem. Int. Ed. 2008 47 4157-4161. 

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