Nucleophiles asymmetric fluorination

This section focuses on the preparation of fluorinated compounds through asymmetric hydrogenation/reduction reactions and nucleophilic additions by listing some examples. The first successful example of catalytic asymmetric hydrogenation of a fluoro-compound was reported by Konig et al.81... 

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

C. Lemaire, M. Guillaume, R. Cantineau, A. Plevenaux, L. Christiaans, An approach to the asymmetric synthesis of L-6-[ F]fluorodopa via NCA nucleophilic fluorination, Appl. Radiat. Isot. 42 (1991) 629-635. 

Basically, two different routes are conceivable for their asymmetric construction 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic a-trimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. 

The importance of fluorinated organic componnds both in medicinal chemistry and biochemistry has resulted in much recent attention towards efficient carbon fluorine bond formation [30]. The reactions developed include a very successful electrophilic asymmetric mono-fluormation of 1,3-dicarbonyl compounds [31]. A nucleophilic variant was also investigated. In this context, the groups of Togni and Mezzetti have established that ruthenium Lewis acids could efficiently catalyze fluorination reactions [32]. In the presence of [Ru(l,2-bis(diphenylphosphino)ethane)2Cl][PF6] (8) (10 mol%), fert-butyl iodide reacted at room temperature with TIF (1.1 equiv.) to yield fert-butyl fluoride (84% yield). This reaction was extended successfully to a range of organic halides (Entries 1-3, Scheme 10.19). The use of the chiral complex [Ru((lS,2S)-N,N bis[2-diphenylphos-phino)benzylidene]diaminocydohexane))Cl][PF6] (9) showed modest chiral induction at the outset of the reaction (Entry 4, Scheme 10.17). The near-racemic mixture obtained at completion points to an SNl-type process in this nucleophilic halide... 

Stelzer and co-workers reported a number of chiral water-soluble secondary phosphines [14], prepared by nucleophilic phosphination of primary phosphines with fluorinated aryl sulfonates in the superbasic medium DMSO/KOH. Further reaction with alkyl halides gives bidentate tertiary phosphines with P-chirality, but only racemic versions have been reported so far. Hanson et al. introduced so-called surface-active phosphines into asymmetric aqueous-phase catalysis. One of the main problems inherent to two-phase catalysis is the often very low miscibility of the substrates in the aqueous phase. Insertion of long alkyl chains between phosphorus atoms and phenyl groups in sulfonated phosphine ligands has been proven to increase reaction rates in the Rh-catalyzed hydroformylation of 1-octene [15], This concept was extended to a number of chiral ligands, i.e., the monoden-... 

Most recently, the Wang group and the Sun group described simultaneously the first NHC-catalyzed oxidative asymmetric a-fluorination of simple aliphatic aldehydes. NFSI serves both as an oxidant and as an F source. Under the optimized conditions, the desired a-fluorinated esters were obtained in up to 92% yield and 98% ee, while no competitive difluorination or nonfluorination occurred. A postulated mechanism of this reaction process is depicted via an NHC-bound enolate intermediate which behaves as a nucleophile to interact with the second NFSI to eventually form the a-flu-oro ester product. Furthermore, acyl fluoride was employed as the starting material under the optimized conditions. Pleasingly, with NFSI (only 1.1 equiv.), the expected a-fluoro ester was obtained in 90% yield and 96% ee, which supported the formation of an NHC-bound acyl azolium intermediate (Scheme 7.94). 

In Scheme 15.1, the initial steps of O Hagan s asymmetric route to a motif containing four syn vicinal fluorines are presented." Within this, three examples of introduction of nucleophilic fluoride are required to successfully complete the synthesis with two being shown in Scheme 15.1, and these serve to illustrate the scope of reagents available and some of the issues arising in this chemistry. 

Leckta has developed a catalytic asymmetric a-fluorination of acid chlorides utilising a dual activation strategy. " Treatment of an acid chloride with both quinidine and either a Ni(ii) or Pd(ii) source in the presence of NFSI and Hunig s base resulted in the formation of an unactivated, a-fluorinated carbonyl which could be subsequently captured by a range of nucleophiles resulting in the formation of densely functionalised products with excellent enantioselectivity (Scheme 15.40). 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

One of the most fascinating aspects of organofluorine chemistry is the asymmetric synthesis of fluorinated molecules [137]. Accordingly, there has been continuing interest in the development of PTC methods for the asymmetric electrophilic fluorination of p-ketoesters [52, 138] and nucleophilic trifluoromethylation of imines [45]. 

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