Cinchona alkaloids, fluorination

Fluorination of cinchona alkaloids has also been investigated. For instance, fluorination of quinine acetate under similar superacidic conditions (HF—SbFs/CHCls) affords a mixture of difluorocompounds in the 10 position that are ephners in 3 (60% yield, 1 1 ratio). This reaction involves a mechanism similar to the one described earlier (protonation, isomerization of carbenium ions, and Cl— F exchange). Curiously, when the reaction is performed on quinine itself, fluorination does not occur and an unprecedented rearrangement takes place (Figure 4.51). ... 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

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. 

A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. 

The direct enantioselective organocatalytic a-fluorination can also be performed with cinchona alkaloid derivatives as catalyst under phase-transfer reaction conditions [25]. The fluorination reaction by NFSI of / -ketoesters 21, readily enolizable substrates, generated a stereogenic quaternary C-F bond in high yields and with enantioselectivities up to 69% ee for the optically active products 26 (Eq. 6). 

A variety of highly enantioselective chiral N-F fluorinating reagents derived from Cinchona alkaloids were developed for the direct enantioselective fluorination of C—H acidic substrates (for details, see Chapter 6). Simultaneously, metal-catalyzed... 

Table 4.8 Cinchona alkaloids and their derivatives promoted the enantioselective fluorination of 2-oxo-cyclopentanecarboxylic acid tert-butyl ester.

Stereoselective a-fluorination of a-nitro esters 107 was performed using Selectfluor as a fluorinating agent and cinchona alkaloid catalyst 109 by Togni and coworkers (Scheme 6.32) [60]. Under the basic condition (NaH inTHFat —40 °C) were obtained the a-fluorinated products 99 in high yield (up to 91%) with relatively low enantios-electivities (up to 31%). 

Shibata and coworkers extended their enantioselective a-fluorination works [53, 54] to catalytic version using cinchona alkaloids-Selectfluor combination (Scheme 6.33) [61]. Acyl enol esters 110 were employed as substrates in the presence of 112 with Selectfluor and sodium acetate in CH2C12 to afford a-fluoroketones 111 (up to 53% ee). 

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... 

Whereas closely related catalysts allowed the Friedel-Crafts-type additions to be expanded to other carbonyl acceptors, such as isatins, the same reactions depicted in Schemes 14.17 and 14.18 have also been achieved in an environmentally more benign solvent, namely Solkane 365 mfc, a liquid hydrofluorocarbon (CF3CH2CF2CH3) that is nontoxic with no impact on the ozone layer, and is used as an insulating and blowing agent for polyurethane foams. To achieve useful yields and enantioselectivities in this fluorinated reaction medium, perfluorinated CPN and CPD Cinchona alkaloid derivatives, able to dissolve in it, were designed and synthesised by Shibata and coworkers (Figure 14.4). 

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. 

SCHEME 13.3. Cinchona alkaloid-mediated transfer fluorination. 

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 s Cinchona alkaloid-mediated asymmetric fluorination of oxindoles was used in the first enantioselective synthesis of BMS-204352 (MaxiPost), a potent opener of maxi-K channels developed by Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of acute ischemic stroke [7]. The Togni group [8] developed a similar method for the asymmetric fluorination of another class of substrates with activated methylene groups, a-nitroesters however, usefiil levels of enantioinduction were not obtained. 

Finally, the Tu group reported a novel transfer fluorination/semipinacol rearrangement of allylic alcohols that generated enantioenriched fluorinated products containing a chiral quaternary carbon center (Scheme 13.4) [12]. Quinine was identified as the optimal Cinchona alkaloid for this transformation. While the majority of substrates examined contained cyclohexenes, resembling the one shown in Scheme 13.4, substrates containing a cycloheptene and an acyclic allylic alcohol were also suitable for this transformation. 

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]. 

Gouverneur and co-workers [18] have described an organocatalytic enantioselective fluorocyclization (Scheme 13.7). In most cases, enantiomeric excesses were slightly improved when stoichiometric quantities of (DH(5)2PHAL were used. Preliminary mechanistic studies suggest that when stoichiometric quantities of Cinchona alkaloid are employed, the reaction proceeds via a transfer fluorination process, whereas another mechanism may be operative when catalytic quantities of Cinchona alkaloid are used. 

An enamine-catalyzed asymmetric a-fluorination of ketones, which are notoriously challenging substrates for this reaction, was reported by MacMillan and coworkers in 2011 [27]. After exhaustive automated screening of over 250 organo-catalysts, a Cinchona alkaloid-derived primary amine organocatalyst was identified as the optimal catalyst for this transformation (Scheme 13.11). Only cyclic ketones provided fluorinated products in high yields and enantiomeric excesses. 

The Tu group [43] reported a chlorination/semipinacol rearrangement of aUyHc alcohols (Scheme 13.18). In this transformation a Cinchona alkaloid-derived catalyst was used in catalytic quantities, in contrast to the related fluorination/semipinacol rearrangement also developed by this group (Scheme 13.4). A chlorinated hydan-toin (l,3-dichloro-5,5-dimethylhydantoin DCDMH) was used as the electrophilic chlorine source, and a chiral acid cocatalyst (/V-Boc-L-phenylglycine NBLP) was also employed. 

The first highly enantio-selective a-fluorination of ketones using organocatalysis has been accomplished. " The optimal catalytic system, a primary amine-functionalized cinchona alkaloid (24), allows the direct and asymmetric a-fluorination of a variety of carbo- and hetero-cyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemo-selective catalyst control in fluorinations involving complex carbonyl systems (up to 98 2 dr, 99% ee, and >99 1 regiocontrol). 

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... 

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. 

Baudequin, C. Loubassou, J.-F. Plaquevent, J.-C. Cahard, D. Enantioselective Electrophilic Fluorination A Study of the Fluorine-Transfer from Achiral N-F Reagents to Cinchona Alkaloids. J. Fluorine Chem. 2003, 122,189-193. 

Oxindoles are fluorinated by NFSi with excellent enantioselec-tivity in the presence of bis-cinchona alkaloid, (DHQD)2AQN, to furnish (5)-fluorinated oxindole in 87% yield with 87% ee. In the presence of (DHQ)2 AQN, (/ )-fluorinated oxindole was obtained in 85% yield with 89% ee (eq 22). This enantioselective... 

Enantioselective a-fluorination of cyclic ketones can be achieved with excellent enantioselectivity by the use of NFSi in the presence of a primary amine functionalized cinchona alkaloid catalyst (eq 29). ... 

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