Electrophiles asymmetric fluorination

A -Fluoro-dihydrobenzo[l,2-i isothiazole is an efficient agent for electrophilic asymmetric fluorination of enolates <1999JOG5708>. A -Fluoro-2,10-camphorsulfonamide 237 (see Section 4.05.6.4.2) is a good asymmetric reagent for a-fluorination of ketones <1998JOG9604>. 

Although efficient organocatalytic methods for the electrophilic a-fluorination of aldehydes and ketones have recently been developed [7], high enantiomeric excesses can only be reached with aldehydes so far. The asymmetric inductions in the case of ketone fluorinations have remained low ee < 36%) [7a]. Thus, the a-silyl ketone-controlled stoichiometric asymmetric synthesis of a-fluoroketones 10 (Scheme 1.1.1) still constitutes a practical method. 

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... 

The asymmetric electrophilic a-fluorination of aldehydes with 2,5-disub-stituted pyrrolidines was tested independently by Jorgensen and Barbas III, but in these reactions MacMillan s imidazolidinones (Chapter 18) or diatylprolinol silyl ethers (Chapter 8) afforded much better yields and higher enantioselectivities. 

ASYMMETRIC FLUORINATION METHODS APPLICATION IN THE STEREOSELECTIVE SYNTHESIS OF FLUORINATED DRUGS Electrophilic fluorination by means of chiral [N-F] reagents... 

Combination of the Hantzsch ester mediated transfer hydrogenation together with chlorine (116) or fluorine (117) electrophiles allows for the formal addition of HCl or HF aaoss a double bond in a catalytic asymmetric manner (Scheme 48) [178], Within this paper the reactions were further refined by the use of two cycle-specific secondary amines which effectively operated independently within the same reaction mixture. Impressively, this allowed access to either diastereoisomer of the product depending upon the absolute configuration of the catalyst used in the second step of the sequence. 

Asymmetric electrophilic fluorination has already found application in medicinal chemistry. For example, the enantioselective synthesis of a fluorooxindole, Maxipost (BMS-204352), has been reported. This compound is an effector for opening calcium channels and is currently in development for the treatment of cerebral ischemia (Figure 2.5). ... 

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. 

Scheme 2.95 Asymmetric electrophilic fluorination of j8-ketoesters, catalyzed by chiral titanium TADDOL complexes (Np = 1-naphthyl, R = Et, R = 2,4,6-(/Pr)3C6H2-CH2) pH].

Houk, Rovis, and their co-workers later extended the scope of the asymmetric intermolecular Stetter reaction of p-nitrostyrenes to unactivated aliphatic aldehydes, which have rarely been utilized in this reaction due to their relatively lower electrophilicity compared with aryl aldehydes. Comparing to known scaffolds, tert-leucine derived trans-fluorinated catalyst leads to improved reactivity and enantioselectivity in this transformation. Computational studies show that the optimized catalyst is the most stereoselective one because the Re-face attack is stabilized by favorable electrostatic interactions between the phenyl group and the fluorine on the catalyst backbone (Scheme 7.31). 

Zhao reported the organocatalytic asymmetric synthesis of fluorinated flavanone derivatives by a tandem intramolecular oxa-Michael addition/ electrophilic fluorination and among various Cinchona alkaloid catalysts screened, the best results were obtained using cupreidine substituted with (4-CF3)-benzyl at the 9-0 position. ... 

The hrst organocatalytic asymmetric C-F bond-forming reactions occurred via transfer fluorination. This method utilized an achiral electrophilic source of fluorine, usually Selectfluor or A-fluorosulfonimide, in conjunction with a stoichiometric amount of a chiral amine, in all cases a Cinchona alkaloid. The fluorine was thus initially transferred from the achiral amine source to the chiral amine, resulting in the in situ generation of a new, chiral electrophilic source of fluorine. Upon subsequent addition of an achiral substrate, the fluorine was transferred from the chiral amine to the substrate. 

Shibata et al. [2,6] further extended this Cinchona alkaloid-mediated asymmetric transfer fluorination reaction to substrates with activated methylene groups, including acyclic (3-cyanoesters, cyclic (3-ketoesters, and oxindole substrates. Representative products, along with the optimal Cinchona alkaloids for these reactions, are shown in Scheme 13.3. Reaction conditions for the acyclic (3-cyanoesters and the cyclic (3-ketoesters used both (a) Selectfluor as the achiral electrophilic fluorine source in MeCN/CHaCla (3 4) at — 80 C and (b) dihydroquinidine acetate (DHQDA) in stoichiometric quantities. The oxindole substrates required the use of stoichiometric bis-Cinchona alkaloids, (DHQlaAQN or (DHQDlaPYR, to obtain useful yields and selectivities. Reactions of these substrates were run in MeCN at 0°C and also employed Selectfluor as the achiral electrophilic fluorine source. 

Shibata successfully adapted the asymmetric transfer fluorination to cyclic silyl enol ethers, cyclic allyl silanes and oxindoles, illustrated in Schemes 13.1-13.3, as a catalytic method (Scheme 13.6) [16]. Similar reaction conditions were identified for all three substrates, including the use of stoichiometric NFSI as the electrophilic fluorine source and a stoichiometric inorganic base additive. It was observed that bis-Cinchona alkaloid (DHQ)2PHAL was best for cyclic silyl enol ethers (X = 0), (DHQ)2PYR (Scheme 13.2) was best for cyclic allyl silanes (X = CH2), while (DHQD)2AQN was best for oxindoles. A similar method was applied to cyclic enol ethers, providing products in modest ee s [17]. 

Lam, Y.-H. Houk, K. N. How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones. /. Am. Chem. Soc. 2014,136,9556-9559. 

---