Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters Featuring a Quaternary Stereocenter

The development of new and efficient methods, reagents, and catalysts for the introduction of fluorine atoms or fluorinated moieties in molecular scaffolds has become a topic of paramount importance in organic synthesis. In this framework, the incorporation of the SCF3 group into organic molecule has often led to beneficial effects on the drug’s metabolic stability and bioavailability. Here we report our studies aimed to the stereoselective synthesis of chiral α-SCF3-β−ketoesters featuring a tetrasubstituted stereocenter. The use of a chiral auxiliary was crucial to synthesize enantiopure enamines that were reacted with N-trifluoromethylthio saccharin or phthalimide, to afford enantioenriched α-SCF3-tetrasubstitued β-keto esters. By using a readily available, inexpensive chiral diamine, such as trans-1,2-diaminocyclohexane, the fluorinated products could be obtained in modest to good yields, and, after the removal of the chiral auxiliary, α-substituted- α trifluoromethylthio-β−ketoesters were isolated with high enantioselectivity (up to 91% ee).


Introduction
Fluorine atoms or residues are essential constitutive elements in many pharmaceuticals, including very popular drugs such as Lipitor, Odanacatib, and Prozac, or fluorohydrocortisone acetate [1,2]. Enhanced lipophilicity, membrane permeability, receptorbinding selectively, and oxidative resistance are some of the attractive features that explain the increasing request of new fluorinated chemical entities, not only in medicinal chemistry ( Figure 1) but also in agrochemicals and material chemistry [3][4][5].

Introduction
Fluorine atoms or residues are essential constitutive elements in many pharmaceuticals, including very popular drugs such as Lipitor, Odanacatib, and Prozac, or fluoro-hydrocortisone acetate [1][2]. Enhanced lipophilicity, membrane permeability, receptor-binding selectively, and oxidative resistance are some of the attractive features that explain the increasing request of new fluorinated chemical entities, not only in medicinal chemistry ( Figure 1) but also in agrochemicals and material chemistry [3][4][5].  Modern organic chemists have, therefore, turned their attention to the development of new and efficient methods, reagents, and catalysts for the introduction of a fluorine atom or fluorinated moieties. In this context, the incorporation of the SCF3 group into organic molecules has led often to beneficial effects on the drug's stability and bioavail- Modern organic chemists have, therefore, turned their attention to the development of new and efficient methods, reagents, and catalysts for the introduction of a fluorine atom or fluorinated moieties. In this context, the incorporation of the SCF 3 group into organic molecules has led often to beneficial effects on the drug's stability and bioavailability. Being highly lipophilic (Hansch's hydrophobic parameter π = 1.44) and a strong electron withdrawing group (Hammett constant: σ m = 0.40 and σ p = 0.50), the SCF 3 group has been employed to tune lipophilicity and modify metabolic properties in new drugs [6,7].
Not surprisingly, many SCF 3 -containing molecules have been recently synthesized [8,9], and different synthetic methods have been developed to realize the trifluoromethylthiolation of organic compounds, exploiting electrophilic, nucleophilic, or radical trifluoromethylthiolating reagents [10][11][12]. Alternative strategies can be used to accomplish the stereoselective synthesis of chiral molecules featuring a trifluoromethylthio group: one possibility is to start from enantiopure, fluorine containing building blocks; alternatively, chiral reagents or chiral catalysts may be employed to accomplish the enantioselective synthesis of the target molecule [13][14][15].
Trifluoromethylthiolated carbonyl derivatives are particularly attractive for their application in medicinal chemistry and as starting building block for the synthesis of functionalized molecules. However, stereoselective strategies to synthetize enantioenriched α-SCF 3 -substituted carbonyl compounds are still very rare [16].
The first examples of a catalytic enantioselective approach were reported independently by Shen [17] and Rueping [18] in 2013. Both groups studied the trifluoromethylthiolation of indanone-derived β-keto esters catalyzed by Quinine; however, the methodology suffers from severe substrate limitations and work only with cyclic five-membered β−keto esters. Later, Shen published the first chiral trifluoromethylthiolating agent based on the commercially available (1S)-(-)-N-2,10-camphorsultam scaffold. Stereoselective αtrifluoromethylthiolation of β-keto esters, oxindoles, and benzofuranones was successfully achieved in the presence of potassium carbonate as a catalytic base. Excellent results in terms of yield and enantioselection were achieved, with the major disadvantage related to the use of a stoichiometric amount of enantiopure sulfenylating reagent [19]. In 2016, Wu and Sun described a reaction based on an enamine catalysis performed on dihydrocinnamaldehyde in the presence of Hayashi-Jorgensen's catalyst [20]. Unfortunately, although yields are excellent, the system presents low stereochemical efficiency. In 2018, Wan and co-workers published a diastereo and enantioselective Cu-catalyzed tandem 1,4-addition/trifluoromethylthiolation of acyclic enones [21].
The diastereoselective trifluoromethyltiolation represents a valuable, practical, and efficient alternative to catalytic enantioselective methods. Along these lines, Cahard and coworkers have recently reported the diastereoselective electrophilic trifluoro-methylthiolation of chiral oxazolidinones [22].
Following our interest in the development of novel synthetic strategies for the preparation of fluorinated carbonyl derivatives [16,23], we wish to present our studies aimed to the stereoselective synthesis of α-SCF 3 -β-ketoesters featuring a quaternary stereocenter.

Results and Discussion
In the attempt to develop a catalytic stereoselective α-trifluoromethylthiolation of carbonyl derivatives we decided to take advantage of recent progress in amino catalysis, by generating the enamine intermediate in situ starting from a β-keto ester and a catalytic amount of primary amine in the presence of a sub-stoichiometric quantity of acid. However, despite several catalytic systems being tested, no product formation was observed, or it was observed in very low yields only. Amino-Cinchona derivatives and several amino alcohols, in combination with benzoic acids, acetic, triflic, trifluoroacetic acids among others, were tested with no success. Therefore, we turned our attention on the use of the preformed enamine, in order to evaluate the feasibility of the approach and the reactivity of such intermediates with Ntrifluoromethylthio phthalimide (B) or saccharin (A) as sources of the electrophilic species SCF 3 + (Scheme 1). Different α-substituted β-keto esters 1A-F were reacted with n-hexylamine or 4-methoxyaniline to generate enamines 2 which were reacted with N-trifluoromethylthio phthalimide or saccharin. For the synthesis of achiral enamines 2a-i and their characterization see the Supporting Information. In preliminary tests on N-hexyl protected enamine of ethyl-2-methyl-3-oxobutanoate 2a as model compound, after a deep investigation of the reaction quench conditions, it was noticed that from the same reaction two different products could be obtained by simple changing the quench procedure (Scheme 2, eq A). When N-hexyl protected enamine was reacted with N-trifluoromethylthio phthalimide B, β-keto ester 4 was formed using a 5M aqueous solution of hydrochloric acid, while β-iminoester 3a instead could be obtained in 70% yield, when a saturated aqueous solution of NH4Cl was employed. However, when the reaction was performed in the presence of N-trifluoromethylthio saccharin (A), even with mild acidic work up, only the β-keto ester 4 was obtained, in higher yields (74%, Scheme 2, eq B). Scheme 1. Synthetic strategies for α-SCF 3 substituted β-imminoesters and β-ketoesters.
Different α-substituted β-keto esters 1A-F were reacted with n-hexylamine or 4methoxyaniline to generate enamines 2 which were reacted with N-trifluoromethylthio phthalimide or saccharin. For the synthesis of achiral enamines 2a-i and their characterization see the Supporting Information. In preliminary tests on N-hexyl protected enamine of ethyl-2-methyl-3-oxobutanoate 2a as model compound, after a deep investigation of the reaction quench conditions, it was noticed that from the same reaction two different products could be obtained by simple changing the quench procedure (Scheme 2, eq A). When N-hexyl protected enamine was reacted with N-trifluoromethylthio phthalimide B, β-keto ester 4 was formed using a 5M aqueous solution of hydrochloric acid, while β-iminoester 3a instead could be obtained in 70% yield, when a saturated aqueous solution of NH 4 Cl was employed. However, when the reaction was performed in the presence of N-trifluoromethylthio saccharin (A), even with mild acidic work up, only the β-keto ester 4 was obtained, in higher yields (74%, Scheme 2, eq B).
On the other hand, N-4-methoxyhenyl (PMP)-substituted iminoesters were found to be more stable, and only the reaction with cerium ammonium nitrate (CAN) was allowed to remove the aromatic ring to afford the expected β-keto ester. Since it was observed that reaction usually afforded better yields with N-trifluoromethylthio saccharin (A), that was selected as reagent of choice in the further studies.
In a typical experimental procedure, the enamine was dissolved in dry DCM (0.1 M) and the trifluorometyltiolation agent (1.2 eq.) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After the work up (see Experimental section), the crude was purified by filtration on an aluminum oxide basic column.
After a mild acidic work up, the reaction of N-PMP substituted enamines 2b-e afforded the trifluoromethylthio substituted β-iminoesters in good isolated yields; the methodology could also be applied to lactones (products 3b-e, Scheme 3, eq A). On the other hand, N-4-methoxyhenyl (PMP)-substituted iminoesters were found to be more stable, and only the reaction with cerium ammonium nitrate (CAN) was allowed to remove the aromatic ring to afford the expected β-keto ester. Since it was observed that reaction usually afforded better yields with N-trifluoromethylthio saccharin (A), that was selected as reagent of choice in the further studies.
In a typical experimental procedure, the enamine was dissolved in dry DCM (0.1 M) and the trifluorometyltiolation agent (1.2 eq.) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After the work up (see Experimental section), the crude was purified by filtration on an aluminum oxide basic column.
After a mild acidic work up, the reaction of N-PMP substituted enamines 2b-e afforded the trifluoromethylthio substituted β-iminoesters in good isolated yields; the methodology could also be applied to lactones (products 3b-e, Scheme 3, eq A).

Scheme 2. Non stereoselective trifluoromethylthiolation of N-alkyl β-iminoesters.
Operating with a different experimental procedure, after performing the trifluoromethylthiolation, the crude reaction mixture was reacted with Cerium ammonium nitrate (CAN) to afford directly the β-keto esters 4-9 in overall yields ranging from 43 to 77% (products 4-9, Scheme 3, eq B).
Having demonstrated the chemical efficiency of the methodology, we then investigated the use of chiral amines to generate enantiopure enamines, in the attempt to develop a stereoselective synthesis of fluorinated products 4-9, featuring a quaternary stereocenter, by exploiting the chiral auxiliary approach (Scheme 4). In an exploratory test, the preformed enamine 10, obtained by the reaction of (S)-1-phenylethanamine with ethyl-2-methyl-3oxobutanoate, was reacted in the presence of N-trifluoromethylthio saccharin and afforded the desired product 4 in 60% yield and modest enantiomeric excess (33% e.e.). When N-(trifluoromethylthio) phthalimide was employed as a trifluoromethylthiolating agent, only traces of the desired product were detectable by 19 F NMR.
Using ethyl-2-methyl-3-oxobutanoate as a model substrate, other chiral amines were investigated, including aminoesters, Cinchona derivatives, and symmetric 1,2 diamines, such as cyclohexane-1,2-diamine, 1,2-diphenyl ethylendiamine, and 2,2 -binaphthyl diamine. Different enantiopure enamines 11-13 were prepared, while compounds 14 and 15 were obtained in very low yields and their reactivity could not be investigated. When enantiopure enamines 11-13 were reacted at room temperature with N-trifluoromethylthio saccharin, enamine 11 afforded the product in 70% yield but only 15% e.e., while with enamine 12, product formation was not observed. The best results were obtained with the C 2 -symmetric enamine 13 derived from (1S,2S)-trans-1,2-diaminocyclohexane, that gave β-ketoester 4 in 45% yield and 91% enantioselectivity (Scheme 4). A 24 h reaction time was found to be the best compromise to reach decent yields in a reasonable time; shorter times gave very low yields, while for longer reaction times, decomposition of the reagents led to the formation of byproducts and to a not significant improvement of the yield. We then decided to use the same chiral auxiliary to investigate the application of the method to other substrates (Scheme 5). Operating with a different experimental procedure, after performing the trifluoromethylthiolation, the crude reaction mixture was reacted with Cerium ammonium nitrate (CAN) to afford directly the β-keto esters 4-9 in overall yields ranging from 43 to 77% (products 4-9, Scheme 3, eq B).
Having demonstrated the chemical efficiency of the methodology, we then investigated the use of chiral amines to generate enantiopure enamines, in the attempt to develop a stereoselective synthesis of fluorinated products 4-9, featuring a quaternary stereocenter, by exploiting the chiral auxiliary approach (Scheme 4). In an exploratory test, the preformed enamine 10, obtained by the reaction of (S)-1-phenylethanamine with ethyl-2-methyl-3-oxobutanoate, was reacted in the presence of N-trifluoromethylthio saccharin and afforded the desired product 4 in 60% yield and modest enantiomeric ex-  cess (33% e.e.). When N-(trifluoromethylthio) phthalimide was employed as a trifluoromethylthiolating agent, only traces of the desired product were detectable by 19 F NMR.
Using ethyl-2-methyl-3-oxobutanoate as a model substrate, other chiral amines were investigated, including aminoesters, Cinchona derivatives, and symmetric 1,2 diamines, such as cyclohexane-1,2-diamine, 1,2-diphenyl ethylendiamine, and 2,2′-binaphthyl diamine. Different enantiopure enamines 11-13 were prepared, while compounds 14 and 15 were obtained in very low yields and their reactivity could not be investigated. When enantiopure enamines 11-13 were reacted at room temperature with N-trifluoromethylthio saccharin, enamine 11 afforded the product in 70% yield but only 15% e.e., while with enamine 12, product formation was not observed. The best results were obtained with the C2-symmetric enamine 13 derived from (1S,2S)-trans-1,2-diaminocyclohexane, that gave β-ketoester 4 in 45% yield and 91% enantioselectivity (Scheme 4). A 24 h reaction time was found to be the best compromise to reach decent yields in a reasonable time; shorter times gave very low yields, while for longer reaction times, decomposition of the reagents led to the formation of byproducts and to a not significant improvement of the yield. We then decided to use the same chiral auxiliary to investigate the application of the method to other substrates (Scheme 5). While the chiral enamine of β-ketoester 1B could not be isolated as clean product and its reactivity was not studied, the reaction of enamine 16 derived from β-ketoester 1C featuring a benzyl group in α position afforded the expected reaction product 6, although in poor yields and with very low enantioselectivity (33% yield, 21% e.e.). The poor reactivity and the low enantioselection may be ascribed to the stereoelectronic hindrance of the benzyl moiety that would probably obstruct the approach of the trifluoromethyltiolation agent. However, with other ketoesters, featuring an alkyl group in α position, good results were obtained and stereoselectivities higher than 80% were reached. Indeed, β-ketoesters 7-9 were obtained with modest to fair yields but high enantioselectivities, ranging from 80 to 91% e.e.
In conclusion, although the work represents only a preliminary exploration of the use of the chiral auxiliary approach to synthetize chiral fluorinated molecules featuring quaternary stereocenters, it was demonstrated that by using a readily available, inexpensive chiral diamine, such as trans-1,2-diaminocyclohexane, the fluorinated products could be obtained in modest-to-good yields, and, after the removal of the chiral auxiliary, α-substituted-α trifluoromethylthio-β−ketoesters were isolated with up to 91% enantioselectivity. The determination of the absolute configuration was attempted, but it was not possible to obtain solid products for X-ray determination. N-alkyl -imino esters produced in the reactions with the saccharin-based reagent cannot be purified; therefore it was not possible to isolate While the chiral enamine of β-ketoester 1B could not be isolated as clean product and its reactivity was not studied, the reaction of enamine 16 derived from β-ketoester 1C featuring a benzyl group in α position afforded the expected reaction product 6, although in poor yields and with very low enantioselectivity (33% yield, 21% e.e.). The poor reactivity and the low enantioselection may be ascribed to the stereoelectronic hindrance of the benzyl moiety that would probably obstruct the approach of the trifluoromethyltiolation agent. However, with other ketoesters, featuring an alkyl group in α position, good results were obtained and stereoselectivities higher than 80% were reached. Indeed, β-ketoesters 7-9 were obtained with modest to fair yields but high enantioselectivities, ranging from 80 to 91% e.e.
In conclusion, although the work represents only a preliminary exploration of the use of the chiral auxiliary approach to synthetize chiral fluorinated molecules featuring quaternary stereocenters, it was demonstrated that by using a readily available, inex-Scheme 5. Stereoselective trifluoromethylthiolation of β-ketoesters.

Experimental
NMR spectra: 1 H-NMR, 19 F-NMR and 13 C-NMR spectra were recorded with instruments at 300 MHz (Bruker Fourier 300 or AMX 300 (Bruker, Billerica, MA, USA)). Proton chemical shifts are reported in ppm (δ) with the solvent reference relative to tetramethylsilane (TMS) employed as the internal standard (CDCl 3 δ = 7.26 ppm). 13 C NMR spectra were recorded operating at 75 MHz, with complete proton decoupling. Carbon chemical shifts are reported in ppm (δ) relative to TMS with the respective solvent resonance as the internal standard (CDCl 3 , δ = 77.0 ppm). 19 F NMR spectra were recorded operating at 282 MHz. Fluorine chemical shifts are reported in ppm (δ) relative to CF 3 Cl. HPLC: For HPLC analyses on chiral stationary phase, to determine enantiomeric excesses, it was used an Agilent Instrument Series 1100 (Agilent, Santa Clara, CA, USA). The specific operative conditions for each product are reported from time to time.
Mass spectra: Mass spectra and accurate mass analysis were carried out on a VG AUTOSPEC-M246 spectrometer (double-focusing magnetic sector instrument with EBE geometry) equipped with EI source or with LCQ Fleet ion trap mass spectrometer, ESI source, with acquisition in positive ionization mode in the mass range 50-2000 m/z. TLC: Reactions and chromatographic purifications were monitored by analytical thinlayer chromatography (TLC) using silica gel 60 F 254 pre-coated glass plates (0.25 mm thickness) and visualized using UV light, vanillin, or KMnO 4 .
Chromatographic purification: Purification of the products was performed by column chromatography with flash technique (according to the Still method) using as stationary phase silica gel 230-400 mesh (SIGMA ALDRICH) or Aluminium oxide, neutral, Brockmann I 50-200 µm 60A previously deactivated with 6% of H 2 O.

Materials
Dry solvents were purchased and stored under nitrogen over molecular sieves (bottles with crown caps).

Preparation of Chiral Enamines
The β-keto ester (2.8 mmol, 2.2 eq) was dissolved in 12 mL of toluene (0.24 M) and (1S,2S)-1,2-trans-diaminocyclohexane (1.3 mmol, 1 eq) and p-toluensulfonic acid (0.13 mmol, 0.1 eq) were added. The reaction mixture was stirred at reflux (110 • C) with Dean-Stark apparatus equipped with molecular sieves for 48 h. After this time, the reaction mixture was filtered over a plug of celite and washed with AcOEt, then the solvent was evaporated and the crude was purified by filtration on a silica gel flash column deactivated with trimethylamine ( Figure 2).

General Procedure for of α-SCF3 Substituted β-Imino Esters
The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH 2 Cl 2 (0.1 M) and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of NH 4 Cl and extracted with 2 mL × 2 of CH 2 Cl 2 : the combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The crude was purified by filtration on a basic aluminum oxide flash column (Brockmann I 50-200 µm 58Å, Figure 3).
The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of NH4Cl and extracted with 2 mL × 2 of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on a basic aluminum oxide flash column (Brockmann I 50-200 μm 58+, Figure 3).  Figure 3. Synthesis of imino esters.

General Non Enantioselective Procedure for α-SCF3 SUBSTITUTED β-Ketoesters
The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reac-Prepared according to the general procedure. The crude mixture was purified by column chromatography a basic aluminum oxide flash column (Brockmann I 50-200 µm 58Å) (Hexane-CH 2 Cl 2 8:2) to afford the desired product as a colorless oil in 86% yield.

General Non Enantioselective Procedure for α-SCF3 SUBSTITUTED β-Ketoesters
The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reac-Prepared according to the general procedure using the N-SCF 3 phthalimide as trifluorometyltiolation agent. The crude mixture was purified by column chromatography a basic aluminum oxide flash column (Brockmann I 50-200 µm 58Å) (Pentane-CH 2 Cl 2 8:2) to afford the desired product as a colorless oil in 70% yield.

General Non Enantioselective Procedure for α-SCF3 SUBSTITUTED β-Ketoesters
The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH 2 Cl 2 (0.1 M) and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of H 2 O and extracted with 2 mL × 2 of CH 2 Cl 2 : the combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The crude was dissolved in 5.4 mL of acetonitrile (0.025 M), a solution of CAN (4.2 mmol, 3 eq) in 1.5 mL of H2O was added at 0 • C, and the stirring was continued at 0 • C for 4 h. Then, after this time, the reaction mixture was quenched with 5 mL of H 2 O and extracted with 5 mL of CH 2 Cl 2 : the combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column (Figure 4). the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was dissolved in 5.4 mL of acetonitrile (0.025 M), a solution of CAN (4.2 mmol, 3 eq) in 1.5 mL of H2O was added at 0 °C, and the stirring was continued at 0 °C for 4 h. Then, after this time, the reaction mixture was quenched with 5 mL of H2O and extracted with 5 mL of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 4

General Enantioselective Procedure for Chiral α-SCF3 Substituted β-Ketoesters
The chiral enamine (0.14 mmol, 1 eq), was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and N-trifluoromethylthio saccharin (0.16 mmol, 1.2 eq) was added. The reaction mixture was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of H2O and extracted with 2 mL × 2 of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 5).

General Enantioselective Procedure for Chiral α-SCF3 Substituted β-Ketoesters
The chiral enamine (0.14 mmol, 1 eq), was dissolved in 1.4 mL of dry CH 2 Cl 2 (0.1 M) and N-trifluoromethylthio saccharin (0.16 mmol, 1.2 eq) was added. The reaction mixture was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of H 2 O and extracted with 2 mL × 2 of CH 2 Cl 2 : the combined organic layers were dried over Na 2 SO 4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 5).
The crude was dissolved in 5.4 mL of acetonitrile (0.025 M), a solution of CAN (4.2 mmol, 3 eq) in 1.5 mL of H2O was added at 0 °C, and the stirring was continued at 0 °C for 4 h. Then, after this time, the reaction mixture was quenched with 5 mL of H2O and extracted with 5 mL of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 4

General Enantioselective Procedure for Chiral α-SCF3 Substituted β-Ketoesters
The chiral enamine (0.14 mmol, 1 eq), was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and N-trifluoromethylthio saccharin (0.16 mmol, 1.2 eq) was added. The reaction mixture was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of H2O and extracted with 2 mL × 2 of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 5).

Ethyl 2-Methyl-3-oxo-2-((trifluoromethyl)thio)butanoate 4
Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product as a colorless oil in 68% yield. The crude was dissolved in 5.4 mL of acetonitrile (0.025 M), a solution of CAN (4.2 mmol, 3 eq) in 1.5 mL of H2O was added at 0 °C, and the stirring was continued at 0 °C for 4 h. Then, after this time, the reaction mixture was quenched with 5 mL of H2O and extracted with 5 mL of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 4

General Enantioselective Procedure for Chiral α-SCF3 Substituted β-Ketoesters
The chiral enamine (0.14 mmol, 1 eq), was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and N-trifluoromethylthio saccharin (0.16 mmol, 1.2 eq) was added. The reaction mixture was stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reaction mixture was quenched with 2 mL × 2 of H2O and extracted with 2 mL × 2 of CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude was purified by filtration on silica gel flash column ( Figure 5). Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product as a colorless oil in 68% yield.

Ethyl 2-Oxo-1-((trifluoromethyl)thio)cyclopentanecarboxylate 8
Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hexane-AcOEt 9:1-> 8:2) to afford the desired product as a colorless oil in 45% yield. Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Pentane-CH2Cl2 6:4) to afford the desired product as a pale-yellow oil in 39% yield. All analytical data are in agreement with the [24].  The enantiomeric excess was determined by HPLC on chiral stationary phase with Daicel Chiralpack OD-H 10μm column, eluent Hexane/iPrOH 98-2, flow rate 0.8 mL/min, pressure: 32 bar λ = 210 nm, τminor: 7.431 min, τmajor: 8.781 min.