Stereoselective Synthesis of Chiral

S S symmetry

Article Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters FeaturingArticle a Quaternary Stereocenter Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters Monica Fiorenza Boselli, Chiara Faverio, Elisabetta Massolo, Laura Raimondi, Alessandra Puglisi andFeaturing Maurizio Benaglia a Quaternary * Stereocenter

Monica Fiorenza Boselli, ChiaraDipartimento Faverio, diElisabetta Chimica, UniversitMassolo,à Lauradegli Studi Raimondi, di Milano, Alessandra Via Golgi 19,Puglisi I-20133 and Milano, Maurizio Italy; Benaglia * monicafi[email protected] (M.F.B.); [email protected] (C.F.); [email protected] (E.M.); [email protected] (L.R.); [email protected] (A.P.) *DipartimentoCorrespondence: di Chimica, [email protected]; Università degli Studi di Milano, Tel.: Via +39-02-5031-4171; Golgi 19, I-20133 Milano, Fax: +39-02-5031-4159 Italy; [email protected] (M.F.B.); [email protected] (C.F.); [email protected] (E.M.); Abstract:[email protected] development (L.R.); of [email protected] new and efficient methods, (A.P.) reagents, and catalysts for the introduction * Correspondence: [email protected]; Tel.: +39-02-5031-4171; Fax: +39-02-5031-4159 of fluorine atoms or fluorinated moieties in molecular scaffolds has become a topic of paramount

importanceAbstract: The in development organic synthesis. of new and In thisefficient framework, methods, thereagents, incorporation and catalysts of thefor SCFthe introduc-3 group into organic moleculetion of fluorine has oftenatoms ledor fluorinated to beneficial moieties effects in molecular on the drug’s scaffolds metabolic has become stability a topic andof para- bioavailability. Heremount we importance report ourin organic studies synthesis. aimed In to th theis framework, stereoselective the incorporation synthesis of of the chiral SCF3 αgroup-SCF into3-β −ketoesters featuringorganic molecule a tetrasubstituted has often led stereocenter.to beneficial effects The useon the of drug’s a chiral metabolic auxiliary stability was crucial and bioavaila- to synthesize enan- tiopurebility. Here enamines we report that were our reactedstudies with aimedN-trifluoromethylthio to the stereoselective saccharin synthesis or phthalimide,of chiral to afford α-SCF3-β−ketoesters featuring a tetrasubstituted stereocenter. The use of a chiral auxiliary was enantioenriched α-SCF3-tetrasubstitued β-keto esters. By using a readily available, inexpensive chiral crucial to synthesize enantiopure enamines that were reacted with N-trifluoromethylthio saccharin diamine, such as trans-1,2-diaminocyclohexane, the fluorinated products could be obtained in modest or phthalimide, to afford enantioenriched α-SCF3-tetrasubstitued β-keto esters. By using a readily toavailable, good yields, inexpensive and, afterchiral the diamine, removal such of theas trans- chiral1,2-diaminocyclohexane, auxiliary, α-substituted- the αfluorinatedtrifluoromethylthio- βproducts−ketoesters could werebe obtained isolated in modest with high to good enantioselectivity yields, and, after (upthe removal to 91% of ee). the chiral auxiliary, α-substituted- α trifluoromethylthio-β−ketoesters were isolated with high enantioselectivity (up to

Citation: Boselli, M.F.; Faverio, C.; Keywords:91% ee). asymmetric synthesis; fluorinated compounds; chiral auxiliary; stereoselectivity; Massolo, E.; Raimondi, L.; Puglisi, trifluoromethylthio-substituted ketones A.; Benaglia, M. Stereoselective Keywords: asymmetric synthesis; fluorinated compounds; chiral auxiliary; stereoselectivity; tri- synthesis of chiral fluoromethylthio-substituted ketones Citation: Boselli, M.F.; Faverio, C.; α-SCF3-β-ketoesters featuring a Massolo, E.; Raimondi, L.; Puglisi, A.; quaternary stereocenter. Symmetry Benaglia,2020 M., 13 Stereoselective, x. Synthesis 1. Introduction of Chiralhttps://doi.org/10.3390/xxxxxα-SCF3-β-Ketoesters 1. IntroductionFluorine atoms or residues are essential constitutive elements in many pharmaceu- Featuring a Quaternary Stereocenter. ticals,Fluorine including atoms very or residues popular are drugs essential such constitutive as Lipitor, elements Odanacatib, in many andpharmaceu- Prozac, or fluoro- Received: 5 December 2020 Symmetry 2021, 13, 92. https:// ticals, including very popular drugs such as Lipitor, Odanacatib, and Prozac, or fluo- Accepted: 4 January 2021 hydrocortisone acetate [1,2]. Enhanced lipophilicity, membrane permeability, receptor- doi.org/10.3390/sym13010092 ro-hydrocortisone acetate [1–2]. Enhanced lipophilicity, membrane permeability, recep- Published: 7 January 2021 binding selectively, and oxidative resistance are some of the attractive features that explain thetor-binding increasing selectively, request and of new oxidative fluorinated resistance chemical are some entities, of the notattractive only infeatures medicinal that chemistry Received: 5 December 2020 explain the increasing request of new fluorinated chemical entities, not only in medicinal Publisher’s Note: MDPI stays neu- (Figure1) but also in agrochemicals and material chemistry [3–5]. Accepted:tral with 4 January regard to 2021 jurisdictional chemistry (Figure 1) but also in agrochemicals and material chemistry [3–5]. Published:claims 7 in January published 2021 maps and institutional affiliations. O O O Publisher’s Note: MDPI stays neu- F3CS H SCF3 O H tral with regard to jurisdictional clai- F CS H 3 ms in published maps and institutio- H H Copyright: © 2021 by the authors. O nal affiliations.Submitted for possible open access α α α publication under the terms and -SCF3-carvone -SCF3-santonin -SCF3-cholestenone conditions of the Creative Commons Figure 1. Trifluoromethylthio containing chiral drug candidates. Attribution (CC BY) license Figure 1. Trifluoromethylthio containing chiral drug candidates. Copyright:(http://creativecommons.org/licenses© 2021 by the authors. Li- Modern organic chemists have, therefore, turned their attention to the development censee/by/4.0/). MDPI, Basel, Switzerland. Modern organic chemists have, therefore, turned their attention to the development of newof new and and efficient efficient methods, methods, reagents, and and catalysts catalysts for for the the introduction introduction of a fluorine of a fluorine atom This article is an open access article atom or fluorinated moieties. In this context, the incorporation of the SCF3 group into distributed under the terms and con- ororganic fluorinated molecules moieties. has led often In this to beneficial context, theeffects incorporation on the drug’s ofstability the SCF and3 groupbioavail- into organic ditions of the Creative Commons At- molecules has led often to beneficial effects on the drug’s stability and bioavailability. tribution (CC BY) license (https:// Being highly lipophilic (Hansch’s hydrophobic parameter π = 1.44) and a strong electron creativecommons.org/licenses/by/ withdrawing group (Hammett constant: σm = 0.40 and σp = 0.50), the SCF3 group has been Symmetry 2021, 13, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/symmetry 4.0/). employed to tune lipophilicity and modify metabolic properties in new drugs [6,7].

Symmetry 2021, 13, 92. https://doi.org/10.3390/sym13010092 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, 92 2 of 16

Not surprisingly, many SCF3-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 [10–12]. Alternative strategies can be used to accomplish the stereoselective synthesis of chiral molecules featuring a trifluoromethylthio group: one pos- sibility 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 [13–15]. 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-SCF3-substituted carbonyl compounds are still very rare [16]. The first examples of a catalytic enantioselective approach were reported indepen- dently 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 α- trifluoromethylthiolation 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 re- lated 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 dihy- drocinnamaldehyde 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 cowork- ers 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-SCF3-β-ketoesters featuring a quaternary stereocenter.

2. 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 N- trifluoromethylthio phthalimide (B) or saccharin (A) as sources of the electrophilic species + SCF3 (Scheme1). Symmetry 2021, 13, 92 3 of 16 Symmetry 2021, 13, x FOR PEER REVIEW 3 of 16

SchemeScheme 1.1. Synthetic strategiesstrategies forfor αα-SCF-SCF33 substituted β-imminoesters and β-ketoesters.-ketoesters.

Different α-substituted ββ-keto-keto estersesters 1A1A––FF werewere reacted reacted with withn -hexylaminen-hexylamine or or 4- 4-methoxyanilinemethoxyaniline to to generate generate enamines enamines2 2which whichwere were reactedreacted withwith NN-trifluoromethylthio-trifluoromethylthio phthalimide oror saccharin.saccharin. ForFor thethe synthesissynthesis of achiral achiral enamines enamines 2a-i2a-i andand their their characterization characteriza- seetion the see Supporting the Supporting Information Information.. In preliminary In preliminary tests testson N on-hexylN-hexyl protected protected enamine enamine of ethyl-2-methyl-3-oxobutanoateof ethyl-2-methyl-3-oxobutanoate 2a as2a modelas model compound, compound, after after a deep a deep investigation investigation of the of reactionthe reaction quench quench conditions, conditions, it was it was noticed noticed that that from from the the same same reaction reaction two two different products could be obtained by simple changing the the quench quench procedure procedure (Scheme (Scheme 22,, eqeq A).A). When NN-hexyl-hexyl protected protected enamine enamine was was reacted reacted with with N-trifluoromethylthioN-trifluoromethylthio phthalimide phthalimide B, β βB-keto, -keto ester ester 4 was4 was formed formed using using a a5M 5M aqueous aqueous solution solution of of hydrochloric hydrochloric acid, while β β-iminoester-iminoester 3a insteadinstead couldcouldbe be obtained obtained in in 70% 70% yield, yield, when when a saturateda saturated aqueous aqueous solution solu- of NH4Cl was employed. However, when the reaction was performed in the presence of tion of NH4Cl was employed. However, when the reaction was performed in the pres- N-trifluoromethylthio saccharin (A), even with mild acidic work up, only the β-keto ester ence of N-trifluoromethylthio saccharin (A), even with mild acidic work up, only the 4 was obtained, in higher yields (74%, Scheme2, eq B). 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, Scheme3, eq A).

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n-Hex 1) DCM, rt, N O dark,18h OEt SCF n-Hex O 2) NH4Cl s.s. 3 NH O N SCF 3a; Yield 70% OEt 3 A) R 2 O O O 1) DCM, rt, dark,18h 2a OEt SCF 2) 5M HCl 3 4; Yield 68%

n-Hex O O O O NH O S 1) DCM, rt, N SCF dark,18h OEt OEt 3 B) SCF3 2) NH Cl s.s. O 4 2a 4; Yield 73% β SchemeScheme 2.2. NonNon stereoselectivestereoselective trifluoromethylthiolationtrifluoromethylthiolation ofofN- N-alkylalkyl β-iminoesters.-iminoesters. Operating with a different experimental procedure, after performing the trifluo- On the other hand, N-4-methoxyhenyl (PMP)-substituted iminoesters were found to romethylthiolation, the crude reaction mixture was reacted with Cerium ammonium be more stable, and only the reaction with cerium ammonium nitrate (CAN) was allowed nitrate (CAN) to afford directly the β-keto esters 4–9 in overall yields ranging from 43 to to remove the aromatic ring to afford the expected β-keto ester. Since it was observed that 77% (products 4–9, Scheme3, eq B). reaction usually afforded better yields with N-trifluoromethylthio saccharin (A), that was Having demonstrated the chemical efficiency of the methodology, we then investigated selected as reagent of choice in the further studies. the use of chiral amines to generate enantiopure enamines, in the attempt to develop a stereoselectiveIn a typical synthesis experimental of fluorinated procedure, products the enamine4–9, featuring was dissolved a quaternary in dry stereocenter, DCM (0.1 M) by andexploiting the trifluorometyltiolation the chiral auxiliary approach agent (1.2 (Scheme eq.) was4 ).added. In an exploratoryThe reaction test, was the stirred preformed at dark atenamine r.t. for 1018, obtainedh under static by the nitrogen reaction atmosp of (S)-1-phenylethanaminehere. After the work withup (see ethyl-2-methyl-3- Experimental section),oxobutanoate, the crude was was reacted purified in the by presence filtration of Non-trifluoromethylthio an aluminum oxide saccharin basic column. and afforded the desiredAfter a productmild acidic4 in work 60% up, yield the and reaction modest of enantiomericN-PMP substituted excess enamines (33% e.e.). 2b When–e af- fordedN-(trifluoromethylthio) the trifluoromethylthio phthalimide substituted was employed β-iminoesters as a trifluoromethylthiolating in good isolated yields; agent, the methodologyonly traces of thecould desired also be product applied were to lactones detectable (products by 19F NMR.3b–e, Scheme 3, eq A). 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 2,20-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 (Scheme4). 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 (Scheme5).

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SchemeScheme 3.3. Non stereoselective triﬂuoromethylthiolationtrifluoromethylthiolation ofof N-N-PMPPMP ββ-iminoesters.-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-3-oxobutanoate, was reacted in the presence of N-trifluoromethylthio saccharin and afforded the desired product 4 in 60% yield and modest enantiomeric ex-

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Symmetry 2021, 13, 92 6 of 16 cess (33% e.e.). When N-(trifluoromethylthio) phthalimide was employed as a trifluoromethylthiolating agent, only traces of the desired product were detectable by 19F NMR.

Scheme 4. Stereoselective trifluoromethylthiolation triﬂuoromethylthiolation of β-ketoesters: selection selection of of the the best performing chiral auxiliary.

UsingWhile ethyl-2-methyl-3-oxobutanoate the chiral enamine of β-ketoester as a1B mocoulddel substrate, not be isolated other chiral as clean amines product were investigated,and its reactivity including was not aminoesters, studied, the Cinchona reaction of derivatives, enamine 16 andderived symmetric from β 1,2-ketoester diamines,1C suchfeaturing as cyclohexane-1,2-diamine, a benzyl group in α position 1,2-diphenyl afforded the ethylendiamine, expected reaction and product 2,2′-binaphthyl6, although di- in amine.poor yields Different and with enantiopure very low enamines enantioselectivity 11–13 were (33% prepared, yield, 21% while e.e.). compounds The poor reactivity 14 and 15and were the obtained low enantioselection in very low yields may beand ascribed their reactivity to the stereoelectronic could not be investigated. hindrance ofWhen the enantiopurebenzyl moiety thatenamines would probably11–13 obstructwere reacted the approach at ofroom the trifluoromethyltiolation temperature with α Nagent.-trifluoromethylthio However, with othersaccharin, ketoesters, enamine featuring 11 afforded an alkyl the group product in inposition, 70% yield good but results only β 15%were e.e., obtained while and with stereoselectivities enamine 12, product higher formation than 80% was were not reached. observed. Indeed, The best-ketoesters results 7–9 were obtained with modest to fair yields but high enantioselectivities, ranging from 80 were obtained with the C2-symmetric enamine 13 derived from (1toS 91%,2S)- e.e.trans-1,2-diaminocyclohexane, that gave β-ketoester 4 in 45% yield and 91% enan- In conclusion, although the work represents only a preliminary exploration of the use tioselectivity (Scheme 4). A 24 h reaction time was found to be the best compromise to reach de- centof the yields chiral in a auxiliary reasonable approach time; shorter to synthetize times gave chiral very low fluorinated yields, while molecules for longer featuring reaction quater- times, decompositionnary stereocenters, of the it reagents was demonstrated led to the format that byion using of byproducts a readily available, and to a inexpensivenot significant chiral im- provementdiamine, such of the as yield.trans-1,2-diaminocyclohexane, We then decided to use the the same fluorinated chiral productsauxiliary couldto investigate be obtained the applicationin modest-to-good of the method yields, to and, other after substrates the removal (Scheme of 5). 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

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Symmetry 2021, 13, x FOR PEER REVIEWthe products and determine the absolute conﬁguration. Further studies are needed7 of to 16

clarify this point.

OEt O O

NH O * OEt SCF3 NH O Yield 45% OEt ee 91% 13 4

Bn OEt O O * NH O OEt Bn SCF3

NH O Yield: 33% ee 21% OEt 16 Bn 6

O Ph O O Ph NH O * O F3CS

NH O Yield: 45% ee 80% Ph O 7 17

OEt O O NH O * OEt SCF3

NH O Yield: 42% ee 86% OEt

18 8

OEt O O NH O * OEt SCF3 NH O Yield: 53% OEt ee 91%

9 19 SchemeScheme 5. 5.Stereoselective Stereoselective triﬂuoromethylthiolation trifluoromethylthiolation of ofβ β-ketoesters.-ketoesters.

3. ExperimentalWhile the chiral enamine of β-ketoester 1B could not be isolated as clean product andNMR its reactivity spectra: was1H-NMR, not studied,19F-NMR the reaction and 13 ofC-NMR enamine spectra 16 derived were from recorded β-ketoester with in- 1C strumentsfeaturing a at benzyl 300 MHz group (Bruker in α position Fourier afforded 300 or AMX the expected 300 (Bruker, reaction Billerica, product MA, 6, although USA)). Protonin poor chemical yields and shifts with are very reported low inenantioselec ppm (δ) withtivity the (33% solvent yield, reference 21% e.e.). relative The topoor tetram- reac- 13 ethylsilanetivity and the (TMS) low employed enantioselection as the internalmay be standardascribed to (CDCl the stereoelectronic3 δ = 7.26 ppm). hindranceC NMR of spectrathe benzyl were moiety recorded that operating would probably at 75 MHz, obstru withct the complete approach proton of the decoupling. trifluoromethyltio- Carbon chemicallation agent. shifts However, are reported with in other ppm ke (δtoesters,) relative featuring to TMS an with alkyl the group respective in α position, solvent reso- good 19 nanceresults as were the internal obtained standard and stereoselectivities (CDCl3, δ = 77.0 higher ppm). thanF NMR 80% spectrawere reached. were recorded Indeed, operatingβ-ketoesters at 282 7–9 MHz. wereFluorine obtained chemical with modest shifts to are fair reported yields inbut ppm high (δ )enantioselectivities, relative to CF3Cl. 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-

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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 ge- ometry) 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 thin- layer chromatography (TLC) using silica gel 60 F254 pre-coated glass plates (0.25 mm thickness) and visualized using UV light, vanillin, or KMnO4. 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, Brock- mann I 50–200 µm 60A previously deactivated with 6% of H2O.

3.1. Materials Dry solvents were purchased and stored under nitrogen over molecular sieves (bottles with crown caps). Commercial grade reagents and solvents were used without further purifications. Ethyl 2-methylacetoacetate (CAS 609-14-3), Ethyl 2-acetyl-3-phenylpropionate (CAS 620- 79-1), Ethyl 2-oxocyclopentanecarboxylate (CAS 611-10-9), and Ethyl cyclohexanone-2- carboxylate (CAS 1655-07-8) were purchased by Sigma Aldrich and they were used without further purifications. AgSCF3 (CAS 811-68-7) was purchased by TCI and it was used without further purifications.

3.2. 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 Symmetry 2021, 13, x FOR PEER REVIEWevaporated and the crude was purified by filtration on a silica gel flash column deactivated9 of 16

with trimethylamine (Figure2).

R' '' R OR

O O O DACH, pTsOH NH R OR'' toluene, reflux, 24 h ' NH R Dean-Stark O R OR'' R' FigureFigure 2.2. SynthesisSynthesis ofof chiralchiral enamines.enamines.

3.2.1. Diethyl 3,3′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-methylbut-2-enoate) 13

Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hex-EtOAc 9:1+ 2% di NEt3) to afford the desired product as a pale-yellow oil in 58% yield.

1H-NMR (300 MHz, CDCl3): δ 9.35 (d, J = 8.2 Hz, 2H), 4.09 (q, J = 7.1 Hz, 4H), 3.19 (m, 2H), 2.03–1.87 (m, 2H), 1.85 (s, 6H), 1.76 (m, 2H), 1.72 (s, 6H), 1.44–1.31 (m, 2H), 1.26 (t, J = 7.1 Hz, 6H), 1.20 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ 171.19, 159.50, 86.75, 58.64, 58.11, 33.40, 24.69, 15.36, 14.67, 12.51 ppm. MS (ESI+) C20H34N2O4: 366.252830 (Calc. Mass 366.251858). 3.2.2. Diethyl 3,3′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-benzylbut-2-enoate) 16

Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hex-EtOAc 8:2+ 2% di NEt3) to afford the desired product as a pale-yellow oil in 37% yield.

1H-NMR (300 MHz, CDCl3): δ 9.68 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 7.1 Hz, 4H), 7.17–7.09 (m, 6H), 4.05 (q, J = 7.1 Hz, 4H), 3.60 (dd, J = 57.8, 16.9 Hz, 4H), 3.32–3.15 (m, 2H), 2.02 (d, J = 12.8 Hz, 2H), 1.89 (s, 6H), 1.79 (d, J = 8.1 Hz, 2H), 1.51–1.25 (m, 4H), 1.17 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 171.22, 160.79, 143.07, 127.98, 127.65, 125.14, 90.51, 58.64, 58.03, 33.59, 32.67, 24.71, 15.37, 14.46 ppm. MS (ESI+) C32H42N2O4: 518.314640 (Calc. Mass 518.314458). 3.2.3. (3Z,3′Z)-3,3′-(((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(phenylmethanylylidene))bis(dihy drofuran-2(3H)-one) 17

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R' '' R OR

O O O DACH, pTsOH NH R OR'' toluene, reflux, 24 h R' NH R Dean-Stark O R OR'' Symmetry 2021, 13, 92 R' 9 of 16 Figure 2. Synthesis of chiral enamines.

3.2.1.3.2.1Diethyl. Diethyl 3,3 3,30-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-methylbut-2-enoate)′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-methylbut-2-enoate)13 13

PreparedPrepared according according to theto the general general procedure. procedure. The The crude crude mixture mixture was was puriﬁed purified by by columncolumn chromatography chromatography on on silica silica gel gel (Hex-EtOAc (Hex-EtOAc 9:1+ 9:1+ 2% 2% di NEtdi NEt3) to3) affordto afford the the desired desired productproduct as aas pale-yellow a pale-yellow oil oil in 58%in 58% yield. yield. 1 1 δ H-NMRH-NMR(300 (300 MHz, MHz, CDCl CDCl3):3): δ9.35 9.35 (d, (d,J J= = 8.2 Hz, 2H), 4.09 4.09 (q, (q, J J== 7.1 7.1 Hz, Hz, 4H), 4H), 3.19 3.19 (m, (m, 2H), 2H),2.03–1.87 2.03–1.87 (m, (m, 2H), 2H), 1.85 1.85 (s, (s,6H), 6H), 1.76 1.76 (m, (m, 2H), 2H), 1.72 1.72 (s, 6H), (s, 6H), 1.44–1.31 1.44–1.31 (m, (m,2H), 2H), 1.26 1.26(t, J (t,= 7.1 13 δ J =Hz, 7.1 Hz,6H), 6H) 1.20, 1.20 (m, (m,2H) 2H) ppm. ppm. 13C NMRC NMR (75 (75MHz, MHz, CDCl CDCl3): δ3 ):171.19,171.19, 159.50, 159.50, 86.75, 86.75, 58.64, MS (ESI+) 58.64,58.11, 58.11, 33.40, 33.40, 24.69, 24.69, 15.36, 15.36, 14.67, 14.67, 12.51 12.51 ppm. ppm. MS (ESI+) C20CH2034HN342ON42: O366.2528304: 366.252830 (Calc. (Calc. Mass Mass366.251858). 366.251858). 3.2.2.3.2.2.Diethyl Diethyl 3,3 3,30-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-benzylbut-2-enoate)′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(2-benzylbut-2-enoate)16 16

PreparedPrepared according according to theto the general general procedure. procedure. The The crude crude mixture mixture was was puriﬁed purified by by column chromatography on silica gel (Hex-EtOAc 8:2+ 2% di NEt ) to afford the desired column chromatography on silica gel (Hex-EtOAc 8:2+ 2% di NEt3 3) to afford the desired productproduct as aas pale-yellow a pale-yellow oil oil in 37%in 37% yield. yield. 1 H-NMR1 (300 MHz, CDCl3): δ 9.68 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 7.1 Hz, 4H), 7.17– H-NMR (300 MHz, CDCl3): δ 9.68 (d, J = 9.0 Hz, 2H), 7.22 (d, J = 7.1 Hz, 4H), 7.17–7.09 (m, 7.09 (m, 6H), 4.05 (q, J = 7.1 Hz, 4H), 3.60 (dd, J = 57.8, 16.9 Hz, 4H), 3.32–3.15 (m, 2H), 6H), 4.05 (q, J = 7.1 Hz, 4H), 3.60 (dd, J = 57.8, 16.9 Hz, 4H), 3.32–3.15 (m, 2H), 2.02 (d, J = 2.02 (d, J = 12.8 Hz, 2H), 1.89 (s, 6H), 1.79 (d, J = 8.1 Hz, 2H), 1.51–1.25 (m, 4H), 1.17 (t, 12.8 Hz, 2H), 1.89 (s,13 6H), 1.79 (d, J = 8.1 Hz, 2H), 1.51–1.25 (m, 4H), 1.17 (t, J = 7.1 Hz, 6H) J = 7.1 Hz, 6H) ppm. C NMR (75 MHz, CDCl3): δ 171.22, 160.79, 143.07, 127.98, 127.65, ppm. 13C NMR (75 MHz, CDCl3): δ 171.22, 160.79, 143.07, 127.98, 127.65, 125.14, 90.51, 125.14, 90.51, 58.64, 58.03, 33.59, 32.67, 24.71, 15.37, 14.46 ppm. MS (ESI+) C32H42N2O4: 58.64, 58.03, 33.59, 32.67, 24.71, 15.37, 14.46 ppm. MS (ESI+) C32H42N2O4: 518.314640 (Calc. 518.314640 (Calc. Mass 518.314458). Mass 518.314458). Symmetry 2021, 13, x FOR PEER REVIEWMass 518.314458). 10 of 16 0 0 3.2.3.3.2.3.(3Z,3 Z)-3,3 -(((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(phenylmethanylylidene)) bis(dihydrofuran-2(3H)-one) (3Z,3′Z)-3,3′-(((1S,2S)-Cyclohexane-1,2-d17 iylbis(azanediyl))bis(phenylmethanylylidene))bis(dihy drofuran-2(3H)-one) 17

PreparedPrepared according according to theto the general general procedure. procedure. The The crude crude mixture mixture was was puriﬁed purified by by column chromatography on silica gel (Hex-EtOAc 8:2+ 2% di NEt ) to afford the desired column chromatography on silica gel (Hex-EtOAc 8:2+ 2% di NEt3 3) to afford the desired productproduct as aas yellow a yellow solid solid in 16%in 16% yield. yield. 1H-NMR (300 MHz, CDCl ): δ 7.96 (d, J = 9.3 Hz, 2H), 7.56–7.38 (m, 8H), 7.34 (bs, 2H), 1H-NMR (300 MHz, CDCl3 3): δ 7.96 (d, J = 9.3 Hz, 2H), 7.56–7.38 (m, 8H), 7.34 (bs, 2H), 4.22 4.22 (t, J = 8.0 Hz, 4H), 2.91–2.72 (m, 2H), 2.56 (td, J = 7.6, 2.5 Hz, 4H), 1.76 (d, J = 13.6 Hz, (t, J = 8.0 Hz, 4H), 2.91–2.72 (m, 2H), 2.56 (td, J = 7.6, 2.5 Hz,13 4H), 1.76 (d, J = 13.6 Hz, 2H), 2H), 1.49 (d, J = 9.4 Hz, 2H), 1.15 (m, 4H), 0.90 (m, 4H) ppm. C NMR (75 MHz, CDCl3): 1.49 (d, J = 9.4 Hz, 2H), 1.15 (m, 4H), 0.90 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): δ 174.27, 159.38, 134.52, 129.16, 127.74, 87.39, 65.72, 58.07, 34.46, 26.92, 24.31 ppm. MS (EI+) C28H30N2O4Na: 481.2109 (Calc. 481.2103). 3.2.4. Diethyl 2,2′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(cyclopent-1-enecarboxylate) 18

1H-NMR (300 MHz, CDCl3): δ 7.39 (d, J = 5.9 Hz, 2H), 4.18–3.97 (m, 4H), 2.87 (bs, 2H), 2.52 (dt, J = 15.3, 7.5 Hz, 2H), 2.42–2.26 (m, 6H), 2.05–1.93 (m, 2H), 1.80–1.53 (m, 6H), 1.26 (d, J = 1.5 Hz, 4H), 1.22 (td, J = 7.1, 2.7 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 168.76, 164.79, 92.77, 60.43, 58.32, 33.36, 32.37, 28.82, 24.85, 21.14, 14.75 ppm. MS (ESI+) C22H34N2O4Na: 413.2414 (Calc. 413.2416). 3.2.5. Diethyl 2,2′-(((1S,2S)-Cyclohexane-1,2-diyl)bis(azanediyl))bis(cyclohex-1-ene-1-carboxylate) 19

Prepared according to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hex-EtOAc 97:3+ 2% di NEt3) to afford the desired product as a pale yellow oil in 88% yield.

1H-NMR (300 MHz, CDCl3): δ 8.99 (d, J = 9.4 Hz, 2H), 4.05 (qq, J = 10.7, 7.1 Hz, 4H), 3.07 (m, 2H), 2.38–1.62 (m, 16H), 1.53–1.38 (m, 6H), 1.31 (m 4H), 1.20 (t, J = 7.1 Hz, 6H) ppm. 13C NMR (75 MHz, CDCl3): δ 171.07, 159.62, 89.24, 58.49, 57.34, 33.58, 26.55, 25.04, 23.92, 22.49, 22.32, 14.67 ppm. MS (ESI+) C24H38N2O4Na: 441.2731 (Calc. 441.2729).

Symmetry 2021, 13, x FOR PEER REVIEW 10 of 16 Symmetry 2021, 13, x FOR PEER REVIEW 10 of 16

Prepared according to the general procedure. The crude mixture was purified by columnPrepared chromatography according toon thesilica general gel (Hex-EtOAc procedure. 8:2+ The 2% crude di NEt mixture3) to afford was purifiedthe desired by columnproduct chromatographyas a yellow solid onin 16%silica yield. gel (Hex-EtOAc 8:2+ 2% di NEt3) to afford the desired product as a yellow solid in 16% yield. 1H-NMR (300 MHz, CDCl3): δ 7.96 (d, J = 9.3 Hz, 2H), 7.56–7.38 (m, 8H), 7.34 (bs, 2H), 4.22 Symmetry 2021, 13, 92 1(t,H-NMR J = 8.0 Hz,(300 4H), MHz, 2.91–2.72 CDCl3): (m, δ 7.96 2H), (d, 2.56 J = 9.3(td, Hz, J = 2H),7.6, 2.5 7.56–7.38 Hz, 4H), (m, 1.76 8H), (d, 7.34 J = 13.6(bs, 102H),Hz, of 16 2H),4.22 (t,1.49 J = (d, 8.0 J Hz, = 9.4 4H), Hz, 2.91–2.72 2H), 1.15 (m, (m, 2H), 4H), 2.56 0.90 (td, (m, J = 4H)7.6, 2.5ppm. Hz, 13 4H),C NMR 1.76 (75(d, JMHz, = 13.6 CDCl Hz, 2H),3): δ 1.49174.27, (d, 159.38,J = 9.4 134.52,Hz, 2H), 129.16, 1.15 127.74,(m, 4H), 87.39, 0.90 65.72,(m, 4H) 58.07, ppm. 34.46, 13C 26.92,NMR 24.31(75 MHz, ppm. CDCl MS (EI+)3): δ 174.27,C28H30N 159.38,2O4Na: 134.52, 481.2109 129.16, (Calc. 127.74, 481.2103). 87.39, 65.72, 58.07, 34.46, 26.92, 24.31 ppm. MS (EI+) δ 174.27, 159.38, 134.52, 129.16, 127.74, 87.39, 65.72, 58.07, 34.46, 26.92, 24.31 ppm. MS (EI+) C28H30N2O4Na: 481.2109 (Calc. 481.2103). C283.2.4.H30N 2DiethylO4Na: 481.21092,2′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(cyclopent-1-enecarboxylate) (Calc. 481.2103). 3.2.4.18 Diethyl 2,2′-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(cyclopent-1-enecarboxylate) 3.2.4.18 Diethyl 2,20-((1S,2S)-Cyclohexane-1,2-diylbis(azanediyl))bis(cyclopent-1-enecarboxylate) 18

Prepared according to the general procedure. The crude mixture was purified by Prepared according to the general procedure. The crude mixture was puriﬁed by columnPrepared chromatography according toon thesilica general gel (Hex-EtOAc procedure. 9:1+ The 2% crude di NEt mixture3) to afford was purifiedthe desired by columncolumnproduct chromatography chromatographyas a pale yellow on oilon silica insilica 53% gel gel (Hex-EtOAcyield. (Hex-EtOAc 9:1+ 9:1+ 2% 2% di NEtdi NEt3) to3) to afford afford the the desired desired productproduct as aas pale a pale yellow yellow oil oil in 53%in 53% yield. yield. 1 1 H-NMR (300 MHz, CDCl3): δ 7.39 (d, J = 5.9 Hz, 2H), 4.18–3.97 (m, 4H), 2.87 (bs, 2H), 2.52 H-NMR1 (300 MHz, CDCl ): δ 7.39 (d, J = 5.9 Hz, 2H), 4.18–3.97 (m, 4H), 2.87 (bs, 2H), (dt,H-NMR J = 15.3, (300 7.5 MHz, Hz, 2H), CDCl 2.42–2.263 3): δ 7.39 (m, (d, 6H),J = 5.9 2.05–1.93 Hz, 2H), (m, 4.18–3.97 2H), 1.80–1.53 (m, 4H), (m, 2.87 6H), (bs, 1.26 2H), (d, 2.52 J = 2.52(dt, (dt, J = J15.3,= 15.3 7.5, Hz, 7.5 Hz,2H), 2H),2.42–2.26 2.42–2.26 (m, 6H), (m, 2.05–1.93 6H),13 2.05–1.93 (m, 2H), (m, 1.80–1.53 2H), 1.80–1.53 (m, 6H), (m, 1.26 6H), (d, J = 1.5 Hz, 4H), 1.22 (td, J = 7.1, 2.7 Hz, 6H) ppm. C NMR (7513 MHz, CDCl3): δ 168.76, 164.79, 1.26 (d, J = 1.5 Hz, 4H), 1.22 (td, J = 7.1, 2.7 Hz,13 6H) ppm. C NMR (75 MHz, CDCl3): 1.592.77, Hz, 60.43, 4H), 1.2258.32, (td, 33.36, J = 7.1, 32.37, 2.7 Hz, 28.82, 6H) 24.85, ppm. 21.14,C NMR 14.75 (75 ppm. MHz, MS CDCl (ESI+)3): δ C168.76,22H34N 164.79,2O4Na: δ 168.76, 164.79, 92.77, 60.43, 58.32, 33.36, 32.37, 28.82, 24.85, 21.14, 14.75 ppm. MS (ESI+) 92.77,413.2414 60.43, (Calc. 58.32, 413.2416). 33.36, 32.37, 28.82, 24.85, 21.14, 14.75 ppm. MS (ESI+) C22H34N2O4Na: C22413.2414H34N2O (Calc.4Na: 413.2414 413.2416). (Calc. 413.2416). 3.2.5. Diethyl 0 3.2.5.3.2.5.2,2Diethyl′-(((1S,2S)-Cyclohexane-1,2-diyl)bis(azanediyl))bis(cyclohex-1-ene-1-carboxylate) 2,2 -(((1S,2S)-Cyclohexane-1,2-diyl)bis(azanediyl))bis(cyclohex-1-ene-1-carboxylate) 19 Diethyl19 2,2′-(((1S,2S)-Cyclohexane-1,2-diyl)bis(azanediyl))bis(cyclohex-1-ene-1-carboxylate) 19

PreparedPrepared according according to theto the general general procedure. procedure. The The crude crude mixture mixture was was puriﬁed purified by by column chromatography on silica gel (Hex-EtOAc 97:3+ 2% di NEt ) to afford the desired columnPrepared chromatography according toon thesilica general gel (Hex-EtOAc procedure. 97:3+ The 2%crude di NEt 3mixture3) to afford was purifiedthe desired by productcolumnproduct as chromatography aas pale a pale yellow yellow oil oil inon 88% insilica 88% yield. gel yield. (Hex-EtOAc 97:3+ 2% di NEt3) to afford the desired 1H-NMRproduct(300 as a MHz, pale yellow CDCl ):oilδ in8.99 88% (d, yield.J = 9.4 Hz, 2H), 4.05 (qq, J = 10.7, 7.1 Hz, 4H), 3.07 1H-NMR (300 MHz, CDCl3 3): δ 8.99 (d, J = 9.4 Hz, 2H), 4.05 (qq, J = 10.7, 7.1 Hz, 4H), 3.07 (m,1H-NMR 2H), 2.38–1.62 (300 MHz, (m, 16H),CDCl 1.53–1.383): δ 8.99 (d, (m, J 6H),= 9.4 1.31Hz, (m2H), 4H), 4.05 1.20 (qq, (t, J =J =10.7, 7.1 7.1 Hz, Hz, 6H) 4H), ppm. 3.07 13 (m, 2H), 2.38–1.62 (m, 16H), 1.53–1.38 (m, 6H), 1.31 (m 4H), 1.20 (t, J = 7.1 Hz, 6H) ppm. C NMR (75 MHz, CDCl3): δ 171.07, 159.62, 89.24, 58.49, 57.34, 33.58, 26.55, 25.04, 23.92, (m,13C NMR2H), 2.38–1.62 (75 MHz, (m, CDCl 16H),3): δ1.53–1.38 171.07, 159.62,(m, 6H), 89.24, 1.31 58.49,(m 4H), 57.34, 1.20 33.58, (t, J = 26.55,7.1 Hz, 25.04, 6H) 23.92,ppm. 22.49,13 22.32, 14.67 ppm. MS (ESI+) C24H38N2O4Na: 441.2731 (Calc. 441.2729). 22.49,C NMR 22.32, (75 14.67 MHz, ppm. CDCl MS3): (ESI+)δ 171.07, C24 159.62,H38N2O 89.24,4Na: 441.2731 58.49, 57.34, (Calc. 33.58, 441.2729). 26.55, 25.04, 23.92, 22.49, 22.32, 14.67 ppm. MS (ESI+) C24H38N2O4Na: 441.2731 (Calc. 441.2729). 3.3. 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 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 58Å, Figure3). Symmetry 2021, 13, x FOR PEER REVIEW 11 of 16

Symmetry 2021, 13, x FOR PEER REVIEW 11 of 16 Symmetry 2021, 13, x FOR PEER REVIEW 11 of 16 3.3. 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 CH2Cl2 (0.1 M) 3.3. General Procedure for of α-SCF3 Substituted β-Imino Esters 3.3.and General the trifluorometyltiolation Procedure for of α-SCF3 agent Substituted (0.16 mmol, β-Imino 1.2 Esters eq) was added. The reaction was stirredThe at achiraldark at enamine r.t. for 18 (0.14 h under mmol, static 1 eq) nitrogen was dissolved atmosphere. in 1.4 mLAfter of thisdry CHtime,2Cl the2 (0.1 reac- M) The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) tionand themixture trifluorometyltiolation was quenched with agent 2 mL (0.16 × 2mmol, of NH 1.24Cl eq)and was extracted added. withThe reaction2 mL × 2was of and the trifluorometyltiolation agent (0.16 mmol, 1.2 eq) was added. The reaction was CHstirred2Cl2 :at the dark combined at r.t. for organic 18 h under layers static were nitrogen dried over atmosphere. Na2SO4 andAfter concentrated this time, the under reac- stirred at dark at r.t. for 18 h under static nitrogen atmosphere. After this time, the reac- vacuum.tion mixture The wascrude quenched was purified with by2 mLfiltration × 2 of on NH a 4basicCl and aluminum extracted oxide with flash2 mL column × 2 of tion mixture was quenched with 2 mL × 2 of NH4Cl and extracted with 2 mL × 2 of (BrockmannCH2Cl2: the combinedI 50–200 μ morganic 58+, Figure layers 3). were dried over Na2SO4 and concentrated under Symmetry 2021, 13, 92 CHvacuum.2Cl2: the The combined crude was organic purified layers by filtrationwere dried on overa basic Na aluminum2SO4 and concentratedoxide flash column 11under of 16 vacuum. The crude was purified+ O by filtration on a basic aluminum oxide flash column (BrockmannR' I 50–200 μm 58 , Figure 3). R' (BrockmannNH O I 50–200 μm 58+X, Figure 3). N O CH2Cl2, r.t. R' ON SCF3 R1 OR3 RR' OR R' NH O XO 1 N O 3 CH2darkCl2, r.t. R' R SCF NHR2O X N2 O 3 ON SCF3 CH2Cl2, r.t. R1 OR3 N SCF3 R1 OR3 R1 OR3 A: X= S=O dark R2 R1 R2 SCFOR3 3 B: X=O C dark R SCF R2 O 2 3 A: X= S=O Figure 3. Synthesis of iminoA: esters.X= S=O B: X= C B: X= C 3.3.1.Figure Ethyl 3. Synthesis 3-((4-Methoxyphenyl)imino)-2-methyl of imino esters. -2-((trifluoromethyl)thio)butanoate 3b Figure 3. Synthesis of imino esters. 3.3.1. Ethyl 3-((4-Methoxyphenyl)imino)-2-methyl-2-((trifluoromethyl)thio)butanoate 3b 3.3.1. Ethyl 3-((4-Methoxyphenyl)imino)-2-methyl-2-((triﬂuoromethyl)thio)butanoate3-((4-Methoxyphenyl)imino)-2-methyl-2-((trifluoromethyl)thio)butanoate 3b3b

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)Prepared Prepared(Pentane-CH accordingaccording2Cl2 7:3) toto to the theafford generalgeneral the desired procedure.procedure. product TheThe as crudecrude a colorless mixturemixture oil was wasin 65% puriﬁedpurified yield. byby columncolumnPrepared chromatographychromatography according atoa basic bathesic general aluminumaluminum procedure. oxideoxide ﬂashflash The columnco crudelumn (Brockmannmixture(Brockmann was IIpurified 50–20050–200µ μbymm column1H NMR chromatography (300 MHz, CDCl a3 )ba δ sic6.88 aluminum (d, J = 8.8 Hz,oxide 2H), flash 6.67 co (d,lumn J = 8.8(Brockmann Hz, 2H), 4.30 I 50–200 (q, J = μ 7.1m 58Å)58Å) (Pentane-CH(Pentane-CH22Cl22 7:3) to afford the desired product as a colorlesscolorless oiloil inin 65%65% yield.yield. Hz, 2H), 3.80 (s, 3H), 2.01 (s, 3H), 1.87 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, 158Å) (Pentane-CH2Cl2 7:3) to afford the desired product as a colorless oil in 65% yield. 1H NMR (300 MHz, CDCl ) δ 6.88 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.30 (q, CDClH NMR3) δ 170.18,(300 MHz, 166.14, CDCl 156.69,3)3 δ 6.88 142.50, (d, J =130.61 8.8 Hz, (q, 2H), J = 309.2 6.67 (d,Hz), J = 120.40, 8.8 Hz, 114.48, 2H), 4.30 64.57, (q, 63.01,J = 7.1 1H NMR (300 MHz, CDCl3) δ 6.88 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.3013 (q, J = 7.1 J55.62,Hz,= 7.1 2H), 23.51, Hz, 3.80 2H), 16.08, (s, 3.803H), 14.04 (s, 2.01 3H), ppm. (s, 2.013H), 19F (s,1.87 NMR 3H), (s, 1.873H),(282 (s,1.32MHz, 3H), (t, CDCl3):J 1.32 = 7.1 (t, Hz, Jδ= 3H).− 7.137.28 Hz,13 Cppm. NMR 3H). MS (75C NMR(ESI+) MHz, (75Hz, MHz,2H), 3.80 CDCl (s, )3H),δ 170.18, 2.01 (s, 166.14, 3H), 1.87 156.69, (s, 3H), 142.50, 1.32 130.61 (t, J = (q,7.1 JHz,= 309.2 3H). Hz),13C NMR 120.40, (75 114.48, MHz, CDCl15 183) δ 170.18,3 3 3 166.14, 156.69, 142.50, 130.61 (q, J = 309.2 Hz), 120.40, 114.48, 64.57, 63.01, C H NO F S: 349.096590 (Calc. Mass 349.095950).19 3 δ 64.57,CDCl55.62, 63.01,)23.51, δ 170.18, 55.62,16.08, 166.14, 23.51,14.04 156.69, 16.08,ppm. 142.50, 14.0419F NMR ppm. 130.61 (282 F(q, NMRMHz, J = 309.2 (282CDCl3): Hz), MHz, 120.40,δ CDCl3):−37.28 114.48, ppm.− 64.57, 37.28MS (ESI+)63.01, ppm. MS55.62, (ESI+) 23.51,C 16.08,H NO 14.04F S:ppm. 349.096590 19F NMR (Calc. (282 Mass MHz, 349.095950). CDCl3): δ −37.28 ppm. MS (ESI+) 3.3.2.C15H18 NO3F315S: 349.09659018 3 3 (Calc. Mass 349.095950). Methyl 15 18 3 3 C3-((4-Methoxyphenyl)imino)-2-methyl-3-phH NO F S: 349.096590 (Calc. Mass 349.095950).enyl-2-((trifluoromethyl)thio)propanoate 3c 3.3.2. Methyl 3-((4-Methoxyphenyl)imino)-2-methyl-3-phenyl-2-((trifluoromethyl)thio)propanoate 3c 3.3.2. Methyl 3.3.2.3-((4-Methoxyphenyl)imino)-2-methyl-3-ph enyl-2-((trifluoromethyl)thio)propanoate 3c Methyl 3-((4-Methoxyphenyl)imino)-2-methyl-3-phenyl-2-((trifluoromethyl)thio)propanoate 3c

PreparedPrepared accordingaccording to to the the general general procedure. procedure. The The crude crude mixture mixture was was purified purified by col- by umn chromatography a basic aluminum oxide flash column (Brockmann I 50–200 µm 58Å;) column chromatography a basic aluminum oxide flash column (Brockmann I 50–200 μm (Hexane-CH2Cl2-Et2O 80:15:5) afford the desired product as a colorless oil in 78% yield. 58+) Prepared(Hexane-CH according2Cl2-Et2 Oto 80:15:5) the general afford procedure. the desired The product crude mixtureas a colorless was purified oil in 78% by 1 Prepared according to the general procedure. The crude mixture was purified by yield.columnH NMR chromatography(300 MHz, CDCl a3 ba) δsic7.43–7.19 aluminum (m, oxide 2H), 7.09–6.95flash column (m, (Brockmann 2H), 6.65 (d, I J50–200= 1.4 Hz,μm column+ chromatography a basic aluminum oxide flash13 column (Brockmann I 50–200 μm 5H),58 ) 3.81(Hexane-CH (s, 3H), 3.712Cl2-Et (s,2O 3H), 80:15:5) 2.00 (s,afford 3H) the ppm. desiredC NMRproduct(75 as MHz, a colorless CDCl3 )oilδ 170.42,in 78% 1H+ NMR (300 MHz, CDCl3) δ 7.43–7.19 (m, 2H), 7.09–6.95 (m, 2H), 6.65 (d, J = 1.4 Hz, 5H), 58yield.) (Hexane-CH 2Cl2-Et2O 80:15:5) afford the desired product as a colorless oil in 78% 166.10, 156.97, 141.01, 133.82, 130.73 (q, J = 309.813 Hz), 129.34, 128.64, 128.35, 122.89, 113.82, yield.3.81 (s, 3H), 3.71 (s, 3H), 2.00 (s,19 3H) ppm. C NMR (75 MHz, CDCl3) δ 170.42, 166.10, 64.55, 55.40, 53.55, 23.91 ppm. F NMR (282 MHz, CDCl3) δ −37.68 ppm. MS (ESI+) 156.97,1H NMR 141.01, (300 MHz,133.82, CDCl 130.733) δ (q, 7.43–7.19 J = 309.8 (m, Hz), 2H), 129.34, 7.09–6.95 128.64, (m, 128.35, 2H), 6.65 122.89, (d, J =113.82, 1.4 Hz, 64.55, 5H), Symmetry 2021, 13, x FOR PEER REVIEW1 12 of 16 CH19 NMRH18NO (3003F3 S:MHz, 397.095520 CDCl3) (Calc.δ 7.43–7.19 Mass (m, 397.095950). 2H),13 7.09–6.95 (m, 2H), 6.65 (d, J = 1.4 Hz, 5H), 55.40,3.81 (s, 53.55, 3H), 3.7123.91 (s, ppm.3H), 2.00 19F (s,NMR 3H) ppm.(282 MHz,C NMR CDCl (753 )MHz, δ −37.68 CDCl 3ppm.) δ 170.42, MS 166.10,(ESI+) 3.81 (s, 3H), 3.71 (s, 3H), 2.00 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 170.42, 166.10, C156.97,19H18NO 141.01,3F3S: 397.095520133.82, 130.73 (Calc. (q, MassJ = 309.8 397.095950). Hz), 129.34, 128.64, 128.35, 122.89, 113.82, 64.55, 3.3.3.156.97,Ethyl 141.01, 2-Benzyl-3-((4-methoxyphenyl)imino)-2-((trifluoromethyl)thio)butanoate 133.82, 130.73 (q, J = 309.8 Hz), 129.34, 128.64, 128.35, 122.89, 113.82,3d 64.55, 55.40, 53.55, 23.91 ppm. 19F NMR (282 MHz, CDCl3) δ −37.68 ppm. MS (ESI+) 55.40, 53.55, 23.91 ppm. 19F NMR (282 MHz, CDCl3) δ −37.68 ppm. MS (ESI+) 3.3.3.C19H18 EthylNO3 F2-Benzyl-3-((4-methoxyphenyl)imino)3S: 397.095520 (Calc. Mass 397.095950).-2-((trifluoromethyl)thio)butanoate 3d C19H18NO3F3S: 397.095520 (Calc. Mass 397.095950). 3.3.3. Ethyl 2-Benzyl-3-((4-methoxyphenyl)imino)-2-((trifluoromethyl)thio)butanoate 3d 3.3.3. Ethyl 2-Benzyl-3-((4-methoxyphenyl)imino)-2-((trifluoromethyl)thio)butanoate 3d

PreparedPrepared accordingaccording toto thethe generalgeneral procedure.procedure. TheThe crudecrude mixturemixture waswas puriﬁedpurified byby columncolumn chromatographychromatography aa basicbasic aluminumaluminum oxideoxide ﬂashflash columncolumn (Brockmann(Brockmann II 50–20050–200µ μmm 58Å) (Hexane-CH Cl 8:2) to afford the desired product as a colorless oil in 61% yield. 58+) (Hexane-CH2Cl22 8:2) to afford the desired product as a colorless oil in 61% yield. 1H NMR (300 MHz, CDCl ) δ 7.41–7.14 (m, 5H), 6.84 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 1H NMR (300 MHz, CDCl3 3) δ 7.41–7.14 (m, 5H), 6.84 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 4.27 (q, J = 7.2 Hz, 2H), 3,79 (s, 3H), 3.79 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 15.1 Hz, 1H), 1.89 2H), 4.27 (q, J = 7.2 Hz, 2H), 3,79 (s, 3H),13 3.79 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 15.1 Hz, 1H), (s, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm. C NMR (75 MHz, CDCl3) δ 169.24, 165.04, 156.54, 1.89 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 169.24, 165.04, 142.46, 135.17, 130.91, 130.44 (q, J = 309.6 Hz) 128.18, 127.47, 120.09, 114.40, 69.55, 63.06, 156.54, 142.46, 135.17, 130.91, 130.44 (q, J = 309.6 Hz) 128.18, 127.47, 120.09, 114.40, 69.55, 63.06, 55.57, 39.88, 17.38, 13.97 ppm. 19F NMR (282 MHz, CDCl3) δ −37.04 ppm. MS (ESI+) C21H22NO3F3S: 425.126790 (Calc. Mass 425.127250). 3.3.4. (E)-3-(((4-Methoxyphenyl)imino)(phenyl)methyl)-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-o ne 3e

PMP N O Ph O F3CS

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-CH2Cl2 8:2) to afford the desired product as a colorless oil in 86% yield.

1H NMR (300 MHz, CDCl3) δ = 7.30 (m, 3H), 7.13 (m, 2H), 6.62 (m, 4H), 4.48 (td, 1H, J = 8.9Hz, J = 3.3Hz), 4.21 (m, 1H), 3.70 (s, 3H), 3.50 (m, 1H), 3.00 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ = 172.30, 162.59, 157.00, 140.87, 133.24, 131.03 (q, J = 309.6 Hz), 129.43, 128.72, 128.50, 122.75, 113.76, 66.88, 63.03, 55.28, 34.71 ppm. 19F NMR (282 MHz, CDCl3) δ = −36.87 (s, 3F) ppm. MS (ESI+) C19H16NO3F3SH: 396.0877 (Calc. Mass 396.0881). 3.3.5. Ethyl 3-(Hexylimino)-2-methyl-2-((trifluoromethyl)thio)butanoate 3a

Prepared according to the general procedure using the N-SCF3 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-CH2Cl2 8:2) to afford the desired product as a colorless oil in 70% yield.

1H NMR (300 MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2H), 3.30 (td, J = 7.4, 2.1 Hz, 2H), 1.86 (s, 3H), 1.82 (s, 3H), 1.70–1.53 (m, 2H), 1.41–1.21 (m, 9H), 0.94–0.83 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 170.68, 163.34, 130.91 (q, J = 309.1 Hz), 65.06, 62.65, 51.61, 31.76, 30.14, 29.84, 27.16, 23.28, 22.75, 14.18, 13.98 ppm. 19F NMR (282 MHz, CDCl3) δ −37.77 ppm. MS (ESI+) C12H19NOF3S: 282.113910 (Calc. Mass 282.113946).

3.4. 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-

Symmetry 2021, 13, x FOR PEER REVIEW 12 of 16 Symmetry 2021, 13, x FOR PEER REVIEW 12 of 16

PreparedPrepared accordingaccording toto thethe generalgeneral procedure.procedure. TheThe crudecrude mixturemixture waswas purifiedpurified byby columncolumn chromatographychromatography aa babasicsic aluminumaluminum oxideoxide flashflash cocolumnlumn (Brockmann(Brockmann II 50–20050–200 μμmm 58+) (Hexane-CH2Cl2 8:2) to afford the desired product as a colorless oil in 61% yield. 58+) (Hexane-CH2Cl2 8:2) to afford the desired product as a colorless oil in 61% yield. 1H NMR (300 MHz, CDCl3) δ 7.41–7.14 (m, 5H), 6.84 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 1H NMR (300 MHz, CDCl3) δ 7.41–7.14 (m, 5H), 6.84 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3,79 (s, 3H), 3.79 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 15.1 Hz, 1H), Symmetry 2021, 13, 92 2H), 4.27 (q, J = 7.2 Hz, 2H), 3,79 (s, 3H), 3.79 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 15.1 Hz,12 1H), of 16 1.89 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 169.24, 165.04, 1.89 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 169.24, 165.04, 156.54,156.54, 142.46,142.46, 135.17,135.17, 130.91,130.91, 130.44130.44 (q,(q, JJ == 309.6309.6 Hz)Hz) 128.18,128.18, 127.47,127.47, 120.09,120.09, 114.40,114.40, 69.55,69.55, 63.06, 55.57, 39.88, 17.38, 13.97 ppm. 19F NMR (282 MHz, CDCl3) δ −37.04 ppm. MS (ESI+) 19 3 63.06, 55.57, 39.88, 17.38, 13.97 ppm.19 F NMR (282 MHz, CDCl ) δ −37.04 ppm. MS (ESI+) 55.57,C21H22 39.88,NO3F3S: 17.38, 425.126790 13.97 ppm. (Calc. MassF NMR 425.127250).(282 MHz, CDCl3) δ −37.04 ppm. MS (ESI+) C21H22NO3F3S: 425.126790 (Calc. Mass 425.127250). C21H22NO3F3S: 425.126790 (Calc. Mass 425.127250). 3.3.4.3.3.4. (E)-3-(((4-Methoxyphenyl)imino)(phenyl)methyl)-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-o3.3.4.(E)-3-(((4-Methoxyphenyl)imino)(phenyl)methyl)-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-o(E)-3-(((4-Methoxyphenyl)imino)(phenyl)methyl)-3-((triﬂuoromethyl)thio)dihydrofuran- ne2(3H)-onene 3e 3e 3e PMP PMP N O N O Ph Ph O F3CS O F3CS

PreparedPrepared according according to to thethe generalgeneral procedure.procedure. The TheThe crude crude mixture mixture was was purifiedpurifiedpurified byby columncolumn chromatographychromatography aa babasicbasicsic aluminumaluminum oxideoxide flashflashflash cocolumncolumnlumn (Brockmann(Brockmann II 50–20050–200 µ μμmm 58Å) (Hexane-CH2Cl2 8:2) to afford the desired product as a colorless oil in 86% yield. 5858Å)Å) (Hexane-CH 22ClCl22 8:2)8:2) to to afford afford the the desired desired produc productt as as a a colorless colorless oil oil in in 86% 86% yield. yield. 11H NMR (300 MHz, CDCl3) δ = 7.30 (m, 3H), 7.13 (m, 2H), 6.62 (m, 4H), 4.48 (td, 1H, J = 1HH NMR NMR (300(300 MHz, MHz, CDCl CDCl3)3 )δ δ= =7.30 7.30 (m, (m, 3H), 3H), 7.13 7.13 (m, (m, 2H), 2H), 6.62 6.62 (m, (m, 4H), 4H), 4.48 4.48 (td,(td, 1H,1H, J = 8.9Hz, J = 3.3Hz), 4.21 (m, 1H), 3.70 (s, 3H), 3.50 (m, 1H), 3.00 (m, 1H) ppm. 13C13 NMR (75 8.9Hz,J = 8.9Hz J =, 3.3Hz),J = 3.3Hz), 4.21 4.21 (m, (m,1H), 1H), 3.70 3.70 (s, 3H), (s, 3H), 3.50 3.50 (m, (m,1H), 1H), 3.00 3.00 (m,(m, 1H) 1H) ppm. ppm. 13C NMRC NMR (75 MHz, CDCl3) δ =δ 172.30, 162.59, 157.00, 140.87, 133.24, 131.03 (q, J = 309.6 Hz), 129.43, MHz,(75 MHz, CDCl CDCl3) δ3 =) 172.30,= 172.30, 162.59, 162.59, 157.00, 157.00, 140.87, 140.87, 133.24, 133.24, 131.03 131.03 (q, (q, J J== 309.6 309.6 Hz), Hz), 129.43, 128.72, 128.50, 122.75, 113.76, 66.88, 63.03, 55.28, 34.71 ppm.19 19F NMR (282 MHz, CDCl3)δ δ 128.72, 128.50, 122.75, 113.76,113.76, 66.88,66.88, 63.03,63.03, 55.28,55.28, 34.7134.71 ppm.ppm. 19F NMR (282 MHz,MHz, CDClCDCl33) δ = −36.87 (s, 3F) ppm. MS (ESI+) C19H16NO3F3SH: 396.0877 (Calc. Mass 396.0881). = −36.8736.87 (s, (s, 3F) 3F) ppm. ppm. MSMS (ESI+) (ESI+) CC19H19H16NO16NO3F33SH:F3SH: 396.0877 396.0877 (Calc. (Calc. Mass Mass 396.0881). 396.0881). 3.3.5. Ethyl 3-(Hexylimino)-2-methyl-2-((trifluoromethyl)thio)butanoate 3a 3.3.5. EthylEthyl 3-(Hexylimino)-2-methyl-2-(( 3-(Hexylimino)-2-methyl-2-((trifluoromethyl)thio)butanoatetrifluoromethyl)thio)butanoate 3a

Prepared according to the general procedure using the N-SCF3 phthalimide as triflu- Prepared according to the general procedure using the N-SCF3 phthalimide as tri- orometyltiolationPrepared according agent. to The the crude general mixture procedure was purified using the by columnN-SCF3 phthalimide chromatography as tri- a fluorometyltiolation agent. The crude mixture was purified by column chromatography fluorometyltiolationbasic aluminum oxide agent. flash The column crude (Brockmann mixture was I 50–200 purifiedµm by 58Å) column (Pentane-CH chromatography2Cl2 8:2) a basic aluminum oxide flash column (Brockmann I 50–200 μm 58Å) (Pentane-CH2Cl2 8:2) ato basic afford aluminum the desired oxide product flash ascolumn a colorless (Brockmann oil in 70% I 50–200 yield. μm 58Å) (Pentane-CH2Cl2 8:2) toto afford afford the the desired desired product product as as a a colorless colorless oil oil in in 70% 70% yield. yield. 1H NMR (300 MHz, CDCl ) δ 4.24 (q, J = 7.1 Hz, 2H), 3.30 (td, J = 7.4, 2.1 Hz, 2H), 1.86 (s, 1 3 H NMR (300 MHz, CDCl3) δ 4.24 (q, J = 7.1 Hz, 2H), 3.30 (td, J = 7.4, 2.1 Hz, 2H),13 1.86 (s, 13H),H NMR 1.82 (300 (s, 3H), MHz, 1.70–1.53 CDCl3) (m, δ 4.24 2H), (q, 1.41–1.21 J = 7.1 Hz, (m, 2H), 9H), 3.30 0.94–0.83 (td, J =(m, 7.4, 3H) 2.1 Hz, ppm. 2H),C 1.86 NMR (s, 13 3H), 1.82 (s, 3H), 1.70–1.53 (m, 2H), 1.41–1.21 (m, 9H), 0.94–0.83 (m, 3H) ppm. 13 C NMR 3H),(75 MHz, 1.82 (s, CDCl 3H),3) 1.70–1.53δ 170.68, 163.34,(m, 2H), 130.91 1.41–1.21 (q, J =(m, 309.1 9H), Hz), 0.94–0.83 65.06, 62.65,(m, 3H) 51.61, ppm. 31.76, C NMR 30.14, (75 MHz, CDCl3) δ 170.68, 163.34, 130.91 (q,19 J = 309.1 Hz), 65.06, 62.65, 51.61, 31.76, 30.14, (7529.84, MHz, 27.16, CDCl 23.28,3) δ 22.75, 170.68, 14.18, 163.34, 13.98 130.91 ppm. (q,F J NMR= 309.1(282 Hz), MHz, 65.06, CDCl 62.65,) δ51.61,−37.77 31.76, ppm. 30.14,MS 19 3 29.84, 27.16, 23.28, 22.75, 14.18, 13.98 ppm.19 F NMR (282 MHz, CDCl3) δ −37.77 ppm. MS 29.84,(ESI+) 27.16,C12H 1923.28,NOF 22.75,3S: 282.113910 14.18, 13.98 (Calc. ppm. Mass F 282.113946).NMR (282 MHz, CDCl3) δ −37.77 ppm. MS (ESI+) C12H19NOF3S: 282.113910 (Calc. Mass 282.113946). (ESI+) C12H19NOF3S: 282.113910 (Calc. Mass 282.113946). 3.4. General Non Enantioselective Procedure for α-SCF3 SUBSTITUTED β-Ketoesters 3.4. General Non Enantioselective Procedure for α-SCF3 SUBSTITUTED β-Ketoesters 3.4. GeneralThe achiral Non Enantioselective enamine (0.14 mmol, Procedure 1 eq) for was α-SCF3 dissolved SUBSTITUTED in 1.4 mL of β-Ketoesters dry CH2Cl 2 (0.1 M) The achiral enamine (0.14 mmol, 1 eq) was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and theThe trifluorometyltiolationachiral enamine (0.14 mmol, agent 1 (0.16 eq) was mmol, dissolved 1.2 eq) in was 1.4 added.mL of dry The CH reaction2Cl2 (0.1 was M) andstirredand thethe at trifluorometyltiolationtrifluorometyltiolation dark at r.t. for 18 h under agentagent static (0.16(0.16 nitrogen mmol,mmol, atmosphere. 1.21.2 eq)eq) waswas After added.added. this The time,The reactionreaction the reaction waswas stirredmixturestirred atat was darkdark quenched atat r.t.r.t. forfor with 1818 hh 2underunder mL × staticstatic2 of nitrogen Hnitrogen2O and atmosphere.atmosphere. extracted with AfterAfter 2 mL thisthis× time,time,2 of the CHthe reac-2reac-Cl2: 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 (Figure4). Symmetry 2021, 13, x FOR PEER REVIEW 13 of 16 Symmetry 2021, 13, x FOR PEER REVIEW 13 of 16

Symmetry 2021, 13, x FOR PEER REVIEW 13 of 16

tion mixture was quenched with 2 mL × 2 of H2O and extracted with 2 mL × 2 of CH2Cl2: tion 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. tion mixture was quenched with 2 mL × 2 of H2O and2 extracted4 with 2 mL × 2 of CH2Cl2: Thethe combinedcrude was organicdissolved layers in 5.4 were mL ofdried acetonitrile over Na (0.025SO and M), aconcentrated solution of CAN under (4.2 vacuum. mmol, the combined organic layers were dried over Na2SO4 and concentrated under vacuum. 3The eq) crude in 1.5 was mL dissolvedof H2O was in 5.4added mL atof 0acetonitrile °C, and the (0.025 stirring M), was a solution continued of CAN at 0 (4.2°C for mmol, 4 h. 3The eq) crude in 1.5 was mL dissolved of H2O was in 5.4 added mL of at acetonitrile 0 °C, and (0.025the stirring M), a solution was continued of CAN at(4.2 0 mmol,°C for 4 h. Then, after this time, the reaction mixture was quenched with 5 mL of H2O and extracted Then,3 eq) in after 1.5 mLthis of time, H2O the was reaction added atmixture 0 °C, and was the quenched stirring was with continued 5 mL of H at2 O0 °Cand for extracted 4 h. with 5 mL of CH2Cl2: the combined organic layers were dried over Na2SO4 and concen- Then, after this time, the reaction mixture was quenched with 5 mL of H2O and extracted tratedwith 5 undermL of vacuum.CH2Cl2: the The combined crude was organic purified layers by werefiltration dried on over silica Na gel2SO 4flash and concen-column Symmetry 2021, 13, 92 with 5 mL of CH2Cl2: the combined organic layers were dried over Na2SO4 and concen-13 of 16 (Figuretrated under 4). vacuum. The crude was purified by filtration on silica gel flash column (Figuretrated under 4). vacuum. The crude was purified by filtration on silica gel flash column (Figure 4). R' O O 1) CH2Cl2, rt, R' NH O O O 1) CH2Cl2, rt, O O O SO 1) CHdark,18hCl rt, O O R' NH O S dark,18h2 2, O O NH O S N SCF3 dark,18h R OR N SCF R1 OR3 1 3 N SCF 3 2) CAN, ACN R OR R1 OR3 3 R 1 R ORSCF3 3 R1 R OR3 2) CAN, ACN 1 2 SCF3 2 O 2) CAN,0 °C, ACN 4h SCFR2 3 R2 0 °C, 4h R2 3 R2 OO 0 °C, 4h Figure 4. Synthesis of β ketoesters. Figure 4. Synthesis of β ketoesters. FigureFigure 4.4. Synthesis of of ββ ketoesters.ketoesters. 3.5. General Enantioselective Procedure for Chiral α-SCF3 Substituted β-Ketoesters 3.5.3.5. GeneralGenerall EnantioselectiveEnantioselective Procedure ProcedureProcedure for forfor Chiral ChiralChiral α-SCF3 αα-SCF3-SCF3 SubstitutedSubstituted Substituted β-Ketoestersβ β-Ketoesters-Ketoesters The chiral enamine (0.14 mmol, 1 eq), was dissolved in 1.4 mL of dry CH2Cl2 (0.1 M) and NTheThe-trifluoromethylthio chiralchiral enamine enamineenamine (0.14 (0.14 saccharin mmol, mmol, 1 11eq),(0.16 eq),eq), was mmol, waswas dissolved dissolveddissolved 1.2 eq) in was 1.4 in 1.4 mLadded. mLmL of dryofof The drydry CH reaction CH2CHCl2 2Cl(0.1Cl2 2mixture (0.1(0.1M) M)M) andwasand NNstirred-trifluoromethylthio-trifluoromethylthio at dark at r.t. saccharinfor saccharinsaccharin 18 h under (0.16 (0.16(0.16 mmol, static mmol,mmol, 1.2nitrogen 1.21.2 eq) eq)eq) was was wasatmosphere. added. added.added. The TheThe reactionAfter reactionreaction this mixture time, mixturemixture the waswas stirredstirred at at dark dark at at r.t. r.t. r.t. for for for 18 18 18h hunder hunder under static static static nitrogen nitrogen nitrogen atmosphere. atmosphere. atmosphere. After After this After thistime, this time, the time, the reaction mixture was quenched with 2 mL × 2 of H2O and extracted with 2 mL × 2 of thereactionreaction reaction mixturemixture mixture waswas wasquenched quenched quenched with with with2 2mL mL 2 × mL 2× of2× ofH2 2 ofHO 2 HandO2 andO extracted and extracted extracted with with 2 with mL 2 mL 2× mL2 of× ×2 of2 CH2Cl2: the combined organic layers were dried over Na2SO4 and concentrated under ofCH CH2Cl2Cl: the: the combined combined organic organic layers layers were were dried dried over over Na Na2SO24SO and4 and concentrated concentrated under under vacuum.CH Cl2 : the 2The combined crude was organic purified layers by filtration were dried on silica over gel Na flash2SO 4column and concentrated (Figure 5). under vacuum.vacuum. TheThe crudecrude was waswas purified purifiedpurified by byby filtration filtrationfiltration on onon silica silicasilica gel gelgel flash flashflash column columncolumn (Figure (Figure (Figure 5). 5 ).5).

R' R'' R '' '' R OROR'' R OR OOO O O O NH O O S O OO O NH O S CHCH2Cl22Cl2 O O NH + SN SCF CH2Cl2 * * + N SCF3 3 R * ''OR'' + N SCF3 24 h, RT R OR '' 24 h, RT R' RSCF' SCFOR NH OO 24 h, RT ' 3 3 NH OO R SCF3 O O R OROR'''' R OR'' R'' R' R FigureFigure 5. EnantioselectiveEnantioselective Synthesis Synthesis of of β βketoesters. ketoesters. FigureFigure 5.5. EnantioselectiveEnantioselective SynthesisSynthesis ofof ββ ketoesters.ketoesters. 3.5.1.3.5.1. Ethyl 2-Methyl-3-oxo-2-((triflu2-Methyl-3-oxo-2-((trifluoromethyl)thio)butanoateoromethyl)thio)butanoate 4 4 3.5.1.3.5.1. EthylEthyl 2-Methyl-3-oxo-2-((triﬂuoromethyl)thio)butanoate2-Methyl-3-oxo-2-((trifluoromethyl)thio)butanoate4 4

PreparedPrepared according to to the the general general procedure. procedure. The The crude crude mixture mixture was was purified puriﬁed by by 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 columnPrepared chromatography according on to silicathe general gel (Hexane-CH procedure.2Cl 2The7:3) crude to afford mixture the desired was purified product asby column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product aas colorless a colorless oil oil in in 68% 68% yield. yield. 2 2 ascolumn a colorless chromatography oil in 68% yield. on silica gel (Hexane-CH Cl 7:3) to afford the desired product 1as1H-NMR a colorless (300 oilMHz, in 68% CDCl yield.3): δ 4.31 δ (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.90 (s, 3H), 1.33 (t, J = 1H-NMR (300 MHz, CDCl3): 4.31 (q, J = 7.1 Hz, 2H), 2.35 (s, 3H), 1.90 (s, 3H), 1.33 (t, 7.1H-NMR Hz, 3H) (300 ppm. MHz, 13C CDClNMR13 3 ):(75 δ 4.31MHz, (q, CDCl J = 7.13): Hz,δ 198.17, 2H), 2.35167.99, (s, 3H),129.58 1.90 (q, (s,J = 3H), 308.6 1.33 Hz), (t, J = J1H-NMR= 7.1 Hz, (300 3H) MHz, ppm. CDClC NMR3): δ 4.31(75 (q, MHz, J = 7.1 CDCl Hz,3 2H),): δ 198.17,2.35 (s, 167.99,3H), 1.90 129.58 (s, 3H), (q, 1.33J = 308.6(t, J = 7.165.76, Hz, 63.41, 3H) ppm.24.89, 1321.52,C NMR 13.75 (75 ppm. MHz, 19 FCDCl NMR3): (282δ 198.17, MHz, 167.99, CDCl3) 129.58 δ −36.75 (q, Jppm. = 308.6 MS Hz), 13 19 δ − Hz),7.1 Hz, 65.76, 3H) 63.41, ppm. 24.89, C NMR 21.52, (75 13.75 MHz, ppm. 19CDClF NMR3): δ 198.17,(282 MHz, 167.99, CDCl3) 129.58 (q,36.75 J = 308.6 ppm. Hz),MS Symmetry 2021, 13, x FOR PEER REVIEW65.76,(ESI+) 63.41,C8H11O 24.89,3F3SNa: 21.52, 267.0283 13.75 (Calc. ppm. Mass F 267.0279). NMR (282 MHz, CDCl3) δ −36.75 ppm.14 ofMS 16 (ESI+)65.76, C63.41,8H11 O24.89,3F3SNa: 21.52, 267.0283 13.75 (Calc.ppm. Mass19F NMR 267.0279). (282 MHz, CDCl3) δ −36.75 ppm. MS (ESI+) C8H11O3F3SNa: 267.0283 (Calc. Mass 267.0279). (ESI+) C8H11O3F3SNa: 267.0283 (Calc. Mass 267.0279). 3.5.2.3.5.2. MethylMethyl 2-Methyl-3-oxo-3-phenyl-2-((tr 2-Methyl-3-oxo-3-phenyl-2-((triﬂuoromethyl)thio)propanoateifluoromethyl)thio)propanoate 5 5 3.5.2. Methyl 2-Methyl-3-oxo-3-phenyl-2-((trifluoromethyl)thio)propanoate 5 3.5.2. Methyl 2-Methyl-3-oxo-3-phenyl-2-((trifluoromethyl)thio)propanoate 5

3.5.3. Ethyl 2-Benzyl-3-oxo-2-((trifluoromethyl)thio)butanoate 6

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 41% yield.

1H-NMR (300 MHz, CDCl3): δ 7.40–7.23 (m, 3H), 7.19 (dd, J = 7.0, 2.5 Hz, 2H), 4.19 (qq, J = 10.7, 7.2 Hz, 2H), 3.55 (dd, J = 55.1, 14.9 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 197.57, 166.66, 134.27, 130.42, 129.36 (q, J = 309.3 Hz), 128.30, 127.56, 71.13, 63.41, 38.91, 29.69, 25.88, 13.68 ppm. 19F NMR (282 MHz, CDCl3) δ −36.39 ppm. MS (ESI+) C14H15F3O3SH: 321.0770 (Calc. Mass: 321.0772). The enantiomeric excess was determined by HPLC on chiral stationary phase with Daicel Chiralpack OJ-H 10 μm column, eluent Hexane/iPrOH 99-1, flow rate 0.8 mL/min, pressure: 31 bar λ = 210 nm, τminor: 8.177 min, τmajor: 8.790 min.

3.5.4. 3-Benzoyl-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-one 7

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.

1H-NMR (300 MHz, CDCl3): δ 8.31 (d, J = 8.2 Hz, 2H), 7.75–7.53 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H), 4.55 (td, J = 8.8, 1.8 Hz, 1H), 4.41 (ddd, J = 10.1, 8.9, 5.8 Hz, 1H), 3.62 (dd, J = 13.1, 5.9 Hz, 1H), 2.95–2.78 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3): δ 188.58, 170.03, 134.09, 133.29, 130.73, 129.12 (q, J = 309.6 Hz), 128.37, 68.22, 62.08, 36.88 ppm. 19F NMR (282 MHz, CDCl3) δ −37.28 ppm. MS (ESI+) C12H9O3F3SNa: 313.0124 (Calc. Mass 313.0122). The enantiomeric excess was determined by HPLC on chiral stationary phase with Phenomenex Lux 3 μm Amylose-1 column, eluent Hexane/iPrOH 98-2, flow rate 0.8 mL/min, pressure: 63 bar λ = 260 nm, τminor 1: 10.195 min, τmajor 2: 10.847 min.

3.5.5. Ethyl 2-Oxo-1-((trifluoromethyl)thio)cyclopentanecarboxylate 8

Symmetry 2021, 13, x FOR PEER REVIEW 14 of 16

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 colorlessPrepared oil according in 68% yield. to the general procedure. The crude mixture was purified by column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product as1H-NMR a colorless (300 oil MHz, in 68% CDCl yield.3): δ 7.92 (d, J = 7.5 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 3.73 (s, 3H), 2.11 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 190.76, 170.00, 1 133.78,H-NMR 133.23, (300 MHz, 129.70 CDCl (q, J3 ):= δ308.8 7.92 Hz),(d, J =129.07, 7.5 Hz, 128.79, 2H), 7.58 63.83, (t, J 53.91,= 7.4 Hz, 24.33 1H), ppm. 7.45 19 (t,F JNMR = 7.7 Hz, 2H), 3.73 (s, 3H), 2.11 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 190.76, 170.00, (282 MHz, CDCl3) δ −36.70 ppm. MS (EI+) C12H11F3O3SH 293.0463 (Calc. Mass 293.0459). Symmetry 2021, 13, 92 133.78, 133.23, 129.70 (q, J = 308.8 Hz), 129.07, 128.79, 63.83, 53.91, 24.33 ppm. 19F14 NMR of 16 (2823.5.3. MHz, Ethyl CDCl2-Benzyl-3-oxo-2-((trifluor3) δ −36.70 ppm. MSomethyl)thio)butanoate (EI+) C12H11F3O3SH 293.0463 6 (Calc. Mass 293.0459).

3.5.3. Ethyl 2-Benzyl-3-oxo-2-((trifluoromethyl)thio)butanoate 6 3.5.3. Ethyl 2-Benzyl-3-oxo-2-((triﬂuoromethyl)thio)butanoate 6

Prepared according to the general procedure. The crude mixture was purified by columnPrepared chromatography according toon the silica general gel (Hexane-CH procedure.2Cl The2 7:3) crude to afford mixture the was desired purified product by as a colorlessPrepared oil according in 41% yield. 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 column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product a1 colorless oil in 41% yield. asH-NMR a colorless (300 oil MHz, in 41% CDCl yield.3): δ 7.40–7.23 (m, 3H), 7.19 (dd, J = 7.0, 2.5 Hz, 2H), 4.19 (qq, J = 1 10.7,H-NMR 7.2 Hz,(300 2H), MHz, 3.55 CDCl (dd,3 J): =δ 55.1,7.40–7.23 14.9 Hz, (m, 2H), 3H), 2.36 7.19 (s, (dd, 3H),J =1.22 7.0, (t, 2.5 J = Hz, 7.2 2H),Hz, 3H) 4.19 ppm. (qq, 1H-NMR (300 MHz, CDCl3): δ 7.40–7.23 (m, 3H), 7.19 (dd, J = 7.0, 2.5 Hz, 2H), 4.19 (qq, J = J13=C 10.7 NMR, 7.2 (75 Hz, MHz, 2H), CDCl 3.553 (dd,): δ 197.57,J = 55.1, 166.66, 14.9 Hz,134.27, 2H), 130.42, 2.36 (s, 129.36 3H), (q, 1.22 J = (t, 309.3J = 7.2Hz), Hz, 128.30, 3H) 10.7, 7.213 Hz, 2H), 3.55 (dd, J = 55.1, 14.9 Hz, 2H), 2.3619 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H) ppm. ppm.127.56, C71.13, NMR 63.41,(75 MHz, 38.91, CDCl 29.69,3): 25.88,δ 197.57, 13.68 166.66, ppm. 134.27,F NMR 130.42, (282129.36 MHz, (q,CDCl3)J = 309.3 δ −36.39 Hz), 13C NMR (75 MHz, CDCl3): δ 197.57, 166.66, 134.27, 130.42, 129.36 (q, J = 309.3 Hz), 128.30, 128.30,ppm. MS 127.56, (ESI+) 71.13, C14H 63.41,15F3O3 38.91,SH: 321.0770 29.69, 25.88, (Calc. 13.68 Mass: ppm. 321.0772).19F NMR (282 MHz, CDCl3) δ 127.56, 71.13, 63.41, 38.91, 29.69, 25.88, 13.68 ppm. 19F NMR (282 MHz, CDCl3) δ −36.39 −36.39 ppm. MS (ESI+) C14H15F3O3SH: 321.0770 (Calc. Mass: 321.0772). ppm.The MS enantiomeric(ESI+) C14H15 Fexcess3O3SH: was 321.0770 determined (Calc. Mass:by HPLC 321.0772). on chiral stationary phase with DaicelThe Chiralpack enantiomeric OJ-H excess 10 μm was column, determined eluent byHexane/ HPLCiPrOH on chiral 99-1, stationary flow rate phase0.8 mL/min, with DaicelThe Chiralpack enantiomeric OJ-H excess 10 µm was column, determined eluent Hexane/ by HPLCiPrOH on chiral 99-1, flowstationary rate 0.8 phase mL/min, with pressure: 31 bar λ = 210 nm, τminor: 8.177 min, τmajor: 8.790 min. pressure:Daicel Chiralpack 31 bar λ = OJ-H 210 nm,10 μτmminor column,: 8.177 eluent min, τ Hexane/major: 8.790iPrOH min. 99-1, flow rate 0.8 mL/min, pressure:3.5.4. 3-Benzoyl-3-((trifluoromethyl)t 31 bar λ = 210 nm, τminor: 8.177hio)dihydrofuran-2(3H)-one min, τmajor: 8.790 min. 7 3.5.4. 3-Benzoyl-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-one 7 3.5.4. 3-Benzoyl-3-((trifluoromethyl)thio)dihydrofuran-2(3H)-one 7

Prepared according to the general procedure. The crude mixture was purified by Prepared according to the general procedure. The crude mixture was purified by columncolumn chromatographychromatography onon silicasilica gelgel (Hexane-AcOEt(Hexane-AcOEt 9:1->9:1-> 8:2)8:2) toto affordafford thethe desireddesired productproductPrepared asas aa colorlesscolorless according oil oil in into 45% 45%the yield. generalyield. procedure. The crude mixture was purified by column chromatography on silica gel (Hexane-AcOEt 9:1-> 8:2) to afford the desired 1H-NMR (300 MHz, CDCl ): δ 8.31 (d, J = 8.2 Hz, 2H), 7.75–7.53 (m, 1H), 7.47 (t, J = 7.7 Hz, product1H-NMR as (300 a colorless MHz, CDCl oil in33): 45% δ 8.31 yield. (d, J = 8.2 Hz, 2H), 7.75–7.53 (m, 1H), 7.47 (t, J = 7.7 Hz, 2H),2H), 4.554.55 (td,(td, JJ = 8.8, 1.8 1.8 Hz, Hz, 1H), 1H), 4.41 4.41 (ddd, (ddd, J J== 10.1, 10.1, 8.9, 8.9, 5.8 5.8 Hz, Hz, 1H), 1H), 3.62 3.62 (dd, (dd, J =J 13.1,= 13.1, 5.9 1 13 5.9H-NMR Hz, 1H), (300 2.95–2.78 MHz, CDCl (m, 1H)3): δ ppm.8.31 (d,13 CJ = NMR 8.2 Hz,(75 2H), MHz, 7.75–7.53 CDCl3 ):(m,δ 188.58,1H), 7.47 170.03, (t, J = 134.09,7.7 Hz, Hz, 1H), 2.95–2.78 (m, 1H) ppm. C NMR (75 MHz, CDCl3): δ 188.58, 170.03, 134.09, 133.29, 130.73, 129.12 (q, J = 309.6 Hz), 128.37, 68.22, 62.08, 36.88 ppm. 19F NMR (282 MHz, 2H),133.29, 4.55 130.73, (td, J 129.12= 8.8, 1.8 (q, Hz, J = 309.6 1H), 4.41Hz), (ddd,128.37, J =68.22, 10.1, 62.08,8.9, 5.8 36.88 Hz, ppm.1H), 3.62 19F NMR (dd, J (282= 13.1, MHz, 5.9 CDCl3)Hz, 1H),δ −2.95–2.7837.28 ppm. (m,MS 1H) (ESI+) ppm. C1312CH NMR9O3F3 SNa:(75 MHz, 313.0124 CDCl (Calc.3): δ Mass188.58, 313.0122). 170.03, 134.09, CDCl3) δ −37.28 ppm. MS (ESI+) C12H9O3F3SNa: 313.0124 (Calc. Mass 313.0122). 133.29,The 130.73, enantiomeric 129.12 (q, excess J = 309.6 was determinedHz), 128.37, by 68.22, HPLC 62.08, on chiral 36.88 stationaryppm. 19F NMR phase (282 with MHz, Phe- nomenexCDCl3)The δ Luxenantiomeric−37.28 3 µ ppm.m Amylose-1 MS excess (ESI+) was column, C determined12H9 eluentO3F3SNa: Hexane/ by 313.0124 HPLCiPrOH on(Calc. chiral 98-2, Mass flowstationary 313.0122). rate 0.8 phase mL/min, with Symmetry 2021, 13, x FOR PEER REVIEWpressure:Phenomenex 63 bar Luxλ = 3 260 μm nm, Amylose-1τ 1: 10.195column, min, eluentτ Hexane/2: 10.847iPrOH min. 98-2, flow rate15 of 0.816 The enantiomeric excessminor was determined by majorHPLC on chiral stationary phase with mL/min, pressure: 63 bar λ = 260 nm, τminor 1: 10.195 min, τmajor 2: 10.847 min. 3.5.5.PhenomenexEthyl 2-Oxo-1-((trifluoromethyl)thio)cyclopentanecarboxylate Lux 3 μm Amylose-1 column, eluent Hexane/8iPrOH 98-2, flow rate 0.8 mL/min,3.5.5. Ethyl pressure: 2-Oxo-1-((trifluoromethyl)th 63 bar λ = 260 nm, τio)cyclopentanecarboxylateminor 1: 10.195 min, τmajor 2: 8 10.847 min.

3.5.5. Ethyl 2-Oxo-1-((trifluoromethyl)thio)cyclopentanecarboxylate 8

PreparedPrepared accordingaccording toto thethe generalgeneral procedure.procedure. The crudecrude mixturemixture waswas puriﬁedpurified byby column chromatography on silica gel (Pentane-CH Cl 6:4) to afford the desired product column chromatography on silica gel (Pentane-CH22Cl22 6:4) to afford the desired product asas aa pale-yellowpale-yellow oiloil inin 39%39% yield.yield. AllAll analyticalanalytical datadata areare inin agreementagreement withwith thethe [[24].24]. 1 1H-NMR (300 MHz, CDCl3): 4.44–4.14 (m, 2H), 3.07–2.86 (m, 1H), 2.56–2.46 (m, 2H), 2.44– H-NMR (300 MHz, CDCl3): 4.44–4.14 (m, 2H), 3.07–2.86 (m, 131H), 2.56–2.46 (m, 2H), 2.44– 2.32 (m, 1H), 2.28–2.06 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H) ppm. C NMR (75 MHz, CDCl3): 2.32 (m, 1H), 2.28–2.06 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ δ 206.56, 166.93, 129.56 (q, J = 309.2 Hz), 63.67, 63.27, 36.01, 35.75, 19.73, 13.83 ppm. 19F 206.56, 166.93, 129.56 (q, J = 309.2 Hz), 63.67, 63.27, 36.01, 35.75, 19.73, 13.83 ppm. 19F NMR NMR (282 MHz, CDCl3) δ −36.78 ppm. MS (ESI+) C9H11O3F3SNa: 279.0277 (Calc. Mass (282 MHz, CDCl3) δ −36.78 ppm. MS (ESI+) C9H11O3F3SNa: 279.0277 (Calc. Mass 279.0279). 279.0279). The enantiomeric excess was determined by HPLC on chiral stationary phase with DaicelThe Chiralpack enantiomeric OD-H excess 10µm was column, determined eluent Hexane/ by HPLCiPrOH on chiral 98-2, ﬂowstationary rate 0.8 phase mL/min, with pressure:Daicel Chiralpack 32 bar λ = OD-H 210 nm, 10μτmminor column,: 7.431 eluent min, τ Hexane/major: 8.781iPrOH min. 98-2, flow rate 0.8 mL/min, pressure: 32 bar λ = 210 nm, τminor: 7.431 min, τmajor: 8.781 min.

3.5.6. Ethyl 2-Oxo-1-((trifluoromethyl)thio)cyclohexanecarboxylate 9

1H-NMR (300 MHz, CDCl3): δ 4.45–4.19 (m, 2H), 3.09 (d, J = 13.8 Hz, 1H), 2.72–2.59 (m, 1H), 2.45 (td, J = 13.8, 5.9 Hz, 1H), 2.19–1.98 (m, 2H), 1.97–1.66 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 201.12, 167.09, 130.05 (q, J = 308.7 Hz), 67.48, 62.96, 40.28, 38.39, 27.13, 22.89, 13.73 ppm. 19F NMR (282 MHz, CDCl3) δ −36.21 ppm The enantiomeric excess was determined by HPLC on chiral stationary phase with Phenomenex Lux 3 μm Cellulose-1 column, eluent Hexane/iPrOH 98-2, flow rate 0.8 mL/min, pressure: 63 bar λ = 210 nm, τminor 1: 10. 287 min τmajor 2: 10. 749 min.

4. Conclusions Organic chemists are always looking for new methodologies to stereoselectively in- troduce fluorinated residues in organic molecules. Here we have reported our studies, which aimed to synthesize enantioenriched α-SCF3-β−ketoesters featuring a quaternary stereocenter. The use of a chiral auxiliary was crucial to synthesize enantiopure enamines which were reacted with N-trifluoromethylthio saccharin to afford enantiomerically enriched α-SCF3-tetrasubstitued β-keto esters and β-imino esters, depending on the work up at the end of the reaction. 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.

Supplementary Materials: The following are available online at www.mdpi.com/xxx/s1, Synthesis of starting materials, general procedures for the synthesis of chiral imino esters and ketoesters; products characterization; NMR, GC, HPLC traces.

Author Contributions: M.F.B., C.F. and E.M. performed the synthetic works. A.P. and L.R. analyzed the results. M.B. designed the experiments of the project and supervised the whole studies reported in the manuscript. All authors have read and agreed to the published version of the manuscript.

Symmetry 2021, 13, x FOR PEER REVIEW 15 of 16

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].

1H-NMR (300 MHz, CDCl3): 4.44–4.14 (m, 2H), 3.07–2.86 (m, 1H), 2.56–2.46 (m, 2H), 2.44– 2.32 (m, 1H), 2.28–2.06 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 206.56, 166.93, 129.56 (q, J = 309.2 Hz), 63.67, 63.27, 36.01, 35.75, 19.73, 13.83 ppm. 19F NMR (282 MHz, CDCl3) δ −36.78 ppm. MS (ESI+) C9H11O3F3SNa: 279.0277 (Calc. Mass 279.0279). The enantiomeric excess was determined by HPLC on chiral stationary phase with Symmetry 2021, 13, 92 Daicel Chiralpack OD-H 10μm column, eluent Hexane/iPrOH 98-2, flow rate 0.8 mL/min,15 of 16 pressure: 32 bar λ = 210 nm, τminor: 7.431 min, τmajor: 8.781 min.

3.5.6. Ethyl 2-Oxo-1-((trifluoromethyl)thio)cyclohexanecarboxylate 9 3.5.6. Ethyl 2-Oxo-1-((triﬂuoromethyl)thio)cyclohexanecarboxylate 9

Prepared according to the general procedure. The crude mixture was purified by 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 column chromatography on silica gel (Hexane-CH2Cl2 7:3) to afford the desired product a colorless oil in 77% yield. All analytical data are in agreement with the [24]. as a colorless oil in 77% yield. All analytical data are in agreement with the [24]. 1 H-NMR (300 MHz, CDCl3): δ 4.45–4.19 (m, 2H), 3.09 (d, J = 13.8 Hz, 1H), 2.72–2.59 (m, 1H-NMR (300 MHz, CDCl3): δ 4.45–4.19 (m, 2H), 3.09 (d, J = 13.8 Hz, 1H), 2.72–2.59 (m, 1H), 2.45 (td, J = 13.8, 5.9 Hz, 1H), 2.19–1.98 (m, 2H), 1.97–1.66 (m, 3H), 1.32 (t, J = 7.1 Hz, 1H), 2.45 (td, J = 13.8, 5.9 Hz, 1H), 2.19–1.98 (m, 2H), 1.97–1.66 (m, 3H), 1.32 (t, J = 7.1 Hz, 13 δ 3H) ppm. 13C NMR (75 MHz, CDCl3): 201.12, 167.09, 130.05 (q, J = 308.7 Hz), 67.48, 62.96, 3H) ppm. C NMR (75 MHz, CDCl19 3): δ 201.12, 167.09, 130.05 (q, J = 308.7 Hz), 67.48, 40.28, 38.39, 27.13, 22.89, 13.73 ppm. F NMR (282 MHz, CDCl3) δ −36.21 ppm 62.96, 40.28, 38.39, 27.13, 22.89, 13.73 ppm. 19F NMR (282 MHz, CDCl3) δ −36.21 ppm The enantiomeric excess was determined by HPLC on chiral stationary phase with Phe- nomenexThe Luxenantiomeric 3 µm Cellulose-1 excess was column, determined eluent Hexane/ by HPLCiPrOH on chiral 98-2, flowstationary rate 0.8 phase mL/min, with pressure:Phenomenex 63 bar Luxλ = 3 210 μm nm, Cellulose-1τminor 1: 10. column, 287 min eluentτmajor Hexane/2: 10. 749iPrOH min. 98-2, flow rate 0.8 mL/min, pressure: 63 bar λ = 210 nm, τminor 1: 10. 287 min τmajor 2: 10. 749 min. 4. Conclusions 4. ConclusionsOrganic chemists are always looking for new methodologies to stereoselectively introduceOrganic fluorinated chemists residues are always in organiclooking molecules.for new methodologies Here we have to stereoselectively reported our stud- in- ies,troduce which fluorinated aimed to synthesizeresidues in enantioenrichedorganic molecules.α-SCF Here3-β we−ketoesters have reported featuring our studies, a qua- ternarywhich aimed stereocenter. to synthesize The use enantioenriched of a chiral auxiliary α-SCF was3-β− crucialketoesters to synthesize featuring enantiopurea quaternary enaminesstereocenter. which The were use reactedof a chiral with auxiliaryN-trifluoromethylthio was crucial to synthesize saccharin enantiopure to afford enantiomer- enamines icallywhich enriched were reactedα-SCF with3-tetrasubstitued N-trifluoromethylthioβ-keto esters saccharin and β to-imino afford esters, enantiomerically depending onen- theriched work α-SCF up at3-tetrasubstitued the end of the reaction.β-keto esters By using and β a-imino readily esters, available, depending inexpensive on the chiral work diamine,up at the such end as oftrans- the 1,2-diaminocyclohexane,reaction. By using a readily the fluorinatedavailable, inexpensive products could chiral be obtaineddiamine, insuch modest-to-good as trans-1,2-diaminocyclohexane, yields, and, after the removalthe fluorinated of the chiral products auxiliary, couldα -substituted-be obtained αin trifluoromethylthio-modest-to-good yields,β−ketoesters and, after were the isolatedremoval with of the up tochiral 91% auxiliary, enantioselectivity. α-substituted- α trifluoromethylthio-β−ketoesters were isolated with up to 91% enantioselectivity. Supplementary Materials: The following are available online at https://www.mdpi.com/2073-899 4/13/1/92/s1Supplementary, Synthesis Materials: of startingThe following materials, are available general procedures online at www.mdpi.com/xxx/s1, for the synthesis of chiral Synthesis imino estersof starting and ketoesters; materials, productsgeneral procedures characterization; for the NMR,synthesis GC, of HPLC chiral traces. imino esters and ketoesters; Authorproducts Contributions: characterization;M.F.B., NMR, C.F. GC, and HPLC E.M. performed traces. the synthetic works. A.P. and L.R. analyzed the results. M.B. designed the experiments of the project and supervised the whole studies reported inAuthor the manuscript. Contributions: All authors M.F.B., have C.F. readand E.M. and performed agreed to the the publishedsynthetic works. version A.P. of theand manuscript. L.R. analyzed the results. M.B. designed the experiments of the project and supervised the whole studies reported Funding:in the manuscript.This research All authors was funded have byread MUR, and Grantagreed the to projectthe pub PRINlished 2017 version “SURSUMCAT” of the manuscript. and by ITN-EID project Marie Sklodowska-Curie Actions Innovative Training Network—TECHNOTRAIN H2020-MSCA-ITN-2018 Grant Agreement 812944—www.technotrain-ITN.eu. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Acknowledgments: M.F.B. acknowledges UNIMI for a PhD fellowship. Conflicts of Interest: The authors declare no conflict of interest.

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