Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of β-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for the next round of reaction without further purification.


Introduction
Fluorinated organic compounds have unique properties because fluorine forms a strong carbon-fluorine bond with a small covalent radius and high electronegativity.Other than fluorinated polymers in materials science, organofluorine compounds have gained increasing popularity in medical chemistry and agricultural chemistry.Introducing one or a few fluorine atoms to biologically interesting molecules can significantly change the physical, chemical and biological properties [1,2].The significant amount of publications on fluorinated small molecules, amino acids, carbohydrates, steroids and nucleosides indicates that organofluorine chemistry plays an important role in the life sciences [3,4].

Results and Discussion
Cinchona alkaloids and their derivatives have been wellexplored in asymmetric synthesis [28].We envisioned that the introduction of a fluorous tag could facilitate the recycling of cinchona alkaloids.The synthesis of fluorous quinine ester C-1 was accomplished by the reaction of quinine with a fluorous acid chloride (Scheme 1).This compound was easily purified by fluorous-solid phase extraction (F-SPE) with a cartridge charged with fluorous silica gels [29,30].It is stable in air and soluble in solvents such as CH 2 Cl 2 , CH 3 OH, and CH 3 CN.
With the fluorous quinine ester C-1 in hand, we explored the fluorination reaction using ethyl 2-methyl-3-oxo-3-phenylpropanoate (1a) as a model compound.Nonfluorous quinine esters, such as C-2 and C-3, cinchona alkaloids C-4 and C-5, and fluorous pyrrolidine ester C-6, were also evaluated (Figure 2).The results of the fluorination of β-ketoester 1a with Selectfluor and different promoters are listed in Table 1.It was found that using MeCN as a solvent with 1 equiv of C-1 gave fluorinated product 2a in 49% yield and 65% ee (Table 1, entry 1).Compared to other promoters (Table 1, entries 2-5), C-1 gave fluorinated products in a slightly low yield but better enantioselectivity.This may be attributed to the stereo and the electronic effect of the fluorous tag.Fluorous pyrrolidine C-6 (Table 1, entry 6) gave the lowest product yield and ee among all six promoters.Reducing the amount of C-1 from 1 equiv to 0.5 and 0.2 equiv significantly reduced the ee of the product (Table 1, entries 7 and 8).A control reaction without C-1 gave 2a in 35% yield as a racemic product (Table 1, entry 9).The results suggest that a stoichiometric amount of C-1 is required to minimize the formation of achiral fluorination product by direct fluorination.Solvent screening indicated that using 1:1 CH 3 CN/CH 2 Cl 2 gave product 2a in 51% yield and 70% ee (Table 1, entry 15), which is better than using CH 3 CN alone.Other single or binary solvent systems containing toluene, THF, H 2 O, and CF 3 C 6 H 5 did not afford better results (Table 1, entries [10][11][12][13][14].It was also found that lowering of the reaction temperature from 25 to 10 or 0 °C did not necessarily improve the enantioselectivity of the fluorination (Table 1, entries 16 and 17).[19,20].In the current work, upon completion of the fluorination reaction, a base such as aqueous NaOH or KOH was added to the reaction mixture to convert the cinchona alkaloid/ Selectfluor complex to free cinchona alkaloid.The organic phase was loaded onto a fluorous silica gel cartridge for F-SPE.Promoter C-1 was recovered in high yield (94%) and excellent purity (98%).It was used for five rounds without significant change of product yield and ee (Scheme 2).

Conclusion
A fluorous cinchona alkaloid-ester has been introduced as a promoter for Selectfluor-based asymmetric fluorination of β-ketoesters.The fluorous promoter has slightly lower reactivity but better enantioselectivity than the nonfluorous cinchona alkaloids.It can be easily recovered by simple fluorous solidphase extraction for reuse.

Experimental General
Chemicals and solvents were purchased from commercial suppliers and used as received. 1H and 13 C NMR spectra were recorded on a 300 MHz Varian NMR spectrometer.Chemical shifts were reported in parts per million (ppm), and the residual solvent peak was used as an internal reference, i.e., proton (chloroform δ 7.26), carbon (chloroform δ 77.0).Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublet), br s (broad singlet).Coupling constants were reported in hertz (Hz).LC-MS were performed on an Agilent 2100 system.A C18 column (5.0 μm, 6.0 × 50 mm) was used for the separation.The mobile phases were methanol and water, both containing 0.05% trifluoroacetic acid.A linear gradient was used to increase from 25:75 v/v methanol/water to 100% methanol over 7.0 min at a flow rate of 0.7 mL/min.UV detections were conducted at 210, 254 and 365 nm.Low-resolution mass spectra were recorded in APCI (atmospheric pressure chemical ionization).The highresolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer.Sorbent silica gel XHL TLC plates (130815) were used for the thin-layer chromatography (TLC).Flash chromatography separations were performed on YAMAZEN AI-580 flash column system with Agela silica gel columns (230-400 μm mesh).The enantiomeric excesses of products were determined by chiral phase HPLC analysis on an SHIMADZU LC-20AD system.
General procedure for recycling of C-1 The reaction mixture was loaded onto a fluorous silica-gel cartridge (5 g) and eluted by 80:20 MeOH/H 2 O to collect nonfluorous components, including the fluorinated product.The cartridge was eluted with MeOH to collect C-1.After concentration of the MeOH fraction and drying at 60 °C for 8 h, the recovered promoter was ready for the next round of reactions.