Organocatalyzed Enantioselective Conjugated Addition of Sodium

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Organocatalyzed Enantioselective Conjugated Addition of Sodium Bisulfite to #-Tri#uoromethyl-#,#-Unsaturated Ketones Wen-Fei Hu, Jian-Qiang Zhao, Yong-Zheng Chen, Xiao-Mei Zhang, Xiao-Ying Xu, and Wei-Cheng Yuan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00171 • Publication Date (Web): 19 Apr 2018 Downloaded from http://pubs.acs.org on April 19, 2018

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The Journal of Organic Chemistry

Organocatalyzed Enantioselective Conjugated Addition of Sodium Bisulfite to β-Trifluoromethyl-α,β-Unsaturated Ketones Wen-Fei Hu,†,↕ Jian-Qiang Zhao,‡ Yong-Zheng Chen,§ Xiao-Mei Zhang,† Xiao-Ying Xu*,† and Wei-Cheng Yuan*,† †

National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry,

Chinese Academy of Sciences, Chengdu, 610041, China ‡Institute

§School

for Advanced Study, Chengdu University, Chengdu 610106, China

of Pharmacy, Zunyi Medical University, Zunyi, 563000, China

↕University

of Chinese Academy of Sciences, Beijing, 100049, China

Graphic Abstract

Abstract

An efficient organocatalyzed enantioselective conjugated addition of sodium bisulfite to β-trifluoromethyl-α,β-unsaturated ketones using a cinchona alkaloid-derived squaramide catalyst is presented. A series of optically active sulfonic acids, bearing a tertiary stereocenter connecting a CF3 group and a SO3H group, were obtained in excellent yields with high enantioselectivities (up to 99% yield and 97% ee) under mild conditions. This method will provide an efficient, economic, and green route to access chiral sulfonic acid compounds.

Sulfonic acids are among the most important classes of organic acids and are extensively

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involved in drugs1 and physiological processes.2 Moreover, chiral sulfonic acids, particularly those bearing a chiral α-carbon centre, have been widely used in the areas of biochemistry3 and in the pharmaceutical industry serving as resolving agents4 (Figure 1). Much effort has been devoted to the development of efficient strategies for the synthesis of various chiral sulfonic acids. In this research area, the most common approach to obtain chiral sulfonic acids is resolution of the corresponding racemates with chiral amines, but the highest theoretical yield is just 50%.5 Additionally, some chiral sulfonic acid derivatives also could be prepared with the help of chiral auxiliary6 or obtained via multistep synthesis from chiral starting materials.7 However, the most straightforward and efficient approach to access enantiopure sulfonic acids should be the catalytic asymmetric synthesis strategy. To the best of our knowledge, there are very few examples were reported in the catalytic asymmetric research field so far. Peters reported an enantio- and diastereoselective formation of chiral β-sultones in 2007.8a After that, different asymmetric catalytic methods to access chiral sulfonic acids were also successively reported by the same group.8b-c In 2011, Adamo described an organocatalytic asymmetric addition of sodium bisulfite to chalcones for the preparation of chiral sulfonic acids.9 Afterwards, Zhao et al. successively uncovered the enantioselective allylations of Na2SO3 with chiral iridium or palladium complex as the catalyst.10 Recently, Dong and Zhang presented their pioneering Rh-catalyzed asymmetric hydrogenation of sodium α-arylethenylsulfonates to access chiral α-arylethenylsulfonic acids.11 Although these progresses have been made, we noticed that there is only one report about the organocatalyzed enantioselective conjugated addition with sodium bisulfite as nucleophile for the generation of chiral sulfonic acids.9 In this context, it is highly desirable that exploring new conjugated addition reactions for the construction of chiral sulfonic acids by taking advantage of


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the nucleophilicity of cheap and readily available NaHSO3.

Figure 1. Selected drugs or biologically active compounds with a chiral sulfonic acid moiety.

Asymmetric organocatalysis has been proved to be an effective and versatile strategy for a variety of organic transformations.12 In particular, cinchona alkaloid-derived bifunctional catalysts have been widely used in a diverse range of asymmetric conjugated addition reactions.13 Meanwhile, it is well known that incorporating trifluoromethyl group (CF3) into an organic molecular structure can greatly modify its physicochemical features and biological properties. CF3-containing compounds have played an important role in both pharmaceutical and agricultural chemistry.14 On the other hand, the use of β-trifluoromethyl-α,β-unsaturated ketones as highly reactive Michael acceptors to generate chiral CF3-containing compounds has been gaining more and more attention.15 However a catalytic procedure for the enantioselective conjugated addition of sodium bisulfite to β-trifluoromethyl-α,β-unsaturated ketones has not been reported yet, and new approaches to effectuate this reaction are therefore of significant interest. Herein, we describe our studies on the addition reaction of sodium bisulfite to β-trifluoromethyl-α,β-unsaturated ketones catalyzed by a cinchona alkaloid-derived squaramide bifunctional catalyst, affording optically active sulfonic acids, bearing a tertiary stereocenter connecting a CF3 group and a SO3H group, in excellent yields with high enantioselectivities (up to 99% yield and 97% ee).

We initiated our investigation with the reaction of (E)-4,4,4-trifluoro-1-phenylbut-2-en-1-one



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(1a) and NaHSO3 (0.48 M aqueous solution) in a mixture solvent of MeOH/toluene (v:v = 1:1) at 0 oC. As shown in Table 1, with 20 mol % quinine A as catalyst, the reaction gave the desired β-sulfonylation product 2a in 66% yield with only 9% ee (entry 1). And then, employing the cinchona alkaloid-derived thiourea bifunctional catalyst B in the reaction, 2a was obtained in 78% yield with 79% ee (entry 2). When catalyst C was used, the reaction gave 2a in 82% yield with 92% ee (entry 3). To our delight, another cinchona alkaloid-squaramide catalyst D could give 2a in quantitative yield with high to 95% ee (entry 4). Further screening of the solvents revealed that the mixture solvent of MeOH/toluene (v:v = 1:1) was better than other mixed solvents (entries 5-8) and single solvents (entries 9-10). Afterwards, adjusting the ratio of MeOH/toluene from 1:1 to 2:1, the ee value could be slightly improved to 96% ee (entry 11). Lowering the temperature to -10 oC resulted in a decreased yield and ee value (entry 12). Importantly, the best results were also obtained when the catalyst loading was decreased to 15 mol % (entry 13). However, further decreasing the catalyst loading to 10 mol %, product 2a was obtained with 92% ee (entry 14). Table 1. Optimization of the Reaction Conditionsa

entry 1 2 3

Cat. A B C

solvent MeOH/toluene (1:1) MeOH/toluene (1:1) MeOH/toluene (1:1)

yield (%)b 66 78 82


ee (%)c 9 79 92

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4 5 6 7 8 9 10 11 12 13 14

D D D D D D D D D D D

MeOH/toluene (1:1) MeOH/DCM (1:1) MeOH/MeCN (1:1) MeOH/THF (1:1) i PrOH/toluene (1:1) MeOH toluene MeOH/toluene (2:1) MeOH/toluene (2:1) MeOH/toluene (2:1) MeOH/toluene (2:1)

99 78 99 93 61 92 trace 99 87 99 97

95 92 84 87 86 90 nd 96 91d 96e 92f

a

Unless noted, the reactions were carried out with 1a (0.1 mmol), NaHSO3 (0.12 mmol, 0.48 M),

and 20 mol % catalyst in 1.0 mL of solvent at 0 °C for 24 h. bFree sulfonic acids were obtained by passing the crude reaction mixture through freshly activated acidic ion-exchange resin. c

Enantiomeric excess was determined by chiral HPLC analysis after the sulfonic acid was methyl

esterified by reacting with CH3C(OMe)3. dRun at -10 oC. e15 mol % catalyst was used. f10 mol % catalyst was used. nd = not determined.

With the optimized reaction conditions in hand, the substrate scope of the enantioselective conjugated addition of sodium bisulfite to (E)-β-trifluoromethyl-α,β-unsaturated ketones was examined (Scheme 1). The β-trifluoromethyl-α,β-unsaturated ketones 1b-d, bearing an electron-donating group at different positions on the phenyl ring, were readily transformed into the corresponding β-sulfonylation products 2b-d under the standard conditions in excellent yields with 89-95% ee. Substrates 1e-n containing diverse electron-withdrawing group at different positions on the phenyl ring could afford their respective adduct 2e-n in 96-99% yields with 75-93% ee values. Moreover, the product 2o bearing two chlorine substituent groups could be readily obtained in 99% yield with 87% ee. Introducing sterically hindered 2-naphthyl substituent group into the α,β-unsaturated ketone had no effect on the course of the reaction, yielding 2p in 97% yield with 92% ee. Notably, heteroaryl substituted substrates were also well tolerated, such as furan substituted product 2q and thienyl substituted product 2r was obtained in quantitative yield



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with 97% ee and 93% ee, respectively. To our delight, changing the trifluoromethyl group of 1a to methyl or phenyl group also had no significant impact on the reactivity and enantioselectivity of the reaction, affording the expected products 2s and 2t in quantitative yields with 90% and 96% ee, respectively. However, replacing the trifluoromethyl group with an ester group such as in substrate 1u, the reaction provided 2u in 99% yield but as a racemate. We also found that changing the R1 group from aryl substituent to alkyl substituent such as substrate 1v, the desired 2v was obtained in

92%

yield

but

with

only

52%

ee.

Unfortunately,

the

reaction

with

β-trifluoromethyl-β,β-disubstituted-α,β-unsaturated ketone 1w as substrate proceeded slowly under the standard conditions, giving 2w with only a trace amount. It was probably due to the highly steric hindrance at the β-position.

Scheme 1. Substrate Scope of Enantioselective Conjugated Addition of NaHSO3 to β-Trifluoromethyl-α,β-unsaturated Ketonesa

a

Reaction conditions: the reactions were carried out with 1 (0.2 mmol), NaHSO3 (0.24 mmol, 0.48


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M), and 15 mol % D in 2.0 mL of MeOH/toluene (2:1) at 0 °C for 24 h. bFree sulfonic acids were obtained by passing the crude reaction mixture through freshly activated acidic ion-exchange resin. c

Enantiomeric excess was determined by chiral HPLC analysis after the free sulfonic acids were

methyl esterified by reacting with CH3C(OMe)3.

We assign the absolute configuration of chiral 2a by comparing electronic circular dichroism (ECD) spectrum which was recorded in MeOH with the theoretically calculated results.17 As showed in Figure 2, the experimental ECD spectrum of chiral 2a matches quite well to the calculated one of (R)-2a. Therefore, the chiral center of 2a is probably in R-configuration (See Supporting Information). Meanwhile, the absolute configurations of products 2s and 2t could be determined to as R-configuration by comparing with the rotation of known compounds.9

Experiments with other bisulfite and sulfite reagents were also conducted. Reaction of potassium bisulfite with 1a proceeded well affording the product 2a in 99% ee with 84% ee (Scheme 2 (2)). Comparing with the reaction of sodium bisulfite with 1a (Scheme 2 (1)), these two reactions showed the similar reactivity but provided significantly different enantioselectivity. It suggested that the metal cation of the bisulfite probably has a considerable impact on the asymmetric induction of the catalyst. Nevertheless, we also found that the reaction of sodium sulfite with 1a was able to give product 2a in 98% yield, but as a racemate (Scheme 2 (3)). This reaction revealed that the bisulfite anion (HSO3ˉ) is crucial to the enantioselectivity of the enantioselective conjugated addition.

Scheme 2. Comparative Experiments of NaHSO3, KHSO3, and Na2SO3 Conjugated Addition to β-Trifluoromethyl-α,β-unsaturated Ketones 1a



To understand the possible stereocontrol of this reaction, we attempted to examine the reactions of sodium bisulfite to (E)-1a and (Z)-1a with the same reaction conditions, respectively. As shown in Scheme 3, the reaction of (E)-1a and sodium bisulfite afforded (R)-2a in 99% yield with 95% ee with R-configuration, but the reaction to (Z)-1a gave (S)-2a in only 55% yield and 72% ee with S-configuration. These two comparative experiments suggested that the addition of sodium bisulfite to the β-position of the (E)-1a should preferentially attack to the Re-face, but to the β-position of the (Z)-1a should preferentially attack to the Si-face. Additionally, the (E)-1a displays higher reactivity than (Z)-1a in the enantioselective conjugated addition.

Scheme 3. Enantioselective Conjugated Addition of NaHSO3 to (E)-1a and (Z)-1a

Based on our experimental results and the relevant reports,9,15-16 a plausible transition state was presented to account for the stereochemistry of this reaction (Figure 2). The dual hydrogen-bonding interaction between the squaramide N-H and the carbonyl oxygen atom of the (E)-β-trifluoromethyl-α,β-unsaturated ketone 1a facilitates the electrophilicity of the β-position of the ketone. Simultaneously, the bisulfite is activated by the tertiary amine of catalyst to enhance


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the nucleophilicity of the sulfur anion. Under the stereocontrol of chiral skeleton of the bifunctional catalyst, the addition of bisulfite to the β-position from the Re-face of (E)-β-trifluoromethyl-α,β-unsaturated ketone ((E)-1a) thus leads to the formation of the R-configuration product.

Figure 2. Proposed transition state for the enantioselective conjugated addition reaction.

In conclusion, we have developed an efficient organocatalyzed enantioselective conjugated addition of sodium bisulfite to β-trifluoromethyl-α,β-unsaturated ketones using a cinchona alkaloid-derived squaramide bifunctional catalyst. With the developed protocol, a series of optically active sulfonic acids, bearing a tertiary stereocenter connecting a CF3 group and a SO3H group, were obtained in excellent yields with high enantioselectivities under mild reaction conditions. This method will provide an efficient, economic, and green route to access chiral sulfonic acid compounds.

Experimental Section General Methods Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by TLC.1H NMR and 13C NMR spectra were recorded in CDCl3, DMSO-d6 and D2O. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the residual non-deuterated solvent resonance employed as the



internal standard (CHCl3 at 7.26 ppm, DMSO at 2.50 ppm, H2O at 4.79 ppm). 13C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the residual non-deuterated solvent resonance as the internal standard (CHCl3 at 77.20 ppm, DMSO at 39.51 ppm). Melting points were recorded on a melting point apparatus with capillary method. General Experimental Procedures for Asymmetric Synthesis of Compounds 2. In an ordinary vial equipped with a magnetic stirring bar, the compounds 1 (0.20 mmol) and catalyst D (15 mol %) were dissolved in 2.0 mL of MeOH/toluene (2:1), stirred for 10 minutes at 0 °C, then a freshly made aqueous sodium bisulfite (0.48 M, 0.5 mL, 1.2 equiv.) was added. The reaction was vigorously stirred at 0 °C for 24 h. After completion of the reaction, the mixture was filtered off over a celite pad and then the solvent evaporated under reduced pressure. The crude products were then dissolved in a mixture of H2O/THF = 1:1 (3.0 mL), passed through a plug of freshly activated acidic ion exchange resin (Amberlyst@ 15 ion-exchange resin, 5.0 g) and then washed with deionized water for three consecutive times (3 x 3.0 mL).The the aqueous solution was dried first under reduced pressure and finally in high vacuum. Finally, the crude product was chromatographed on silica gel eluting with DCM/MeOH = 20:1~10:1 to afford the desired sulfonic acids 2. Standard Procedure for the methyl esterification of Sulfonic Acids. Sulfonic acids 2 (0.1 mmol) were dissolved in 1mL of DCM and then 0.5 mL of CH3C(OCH3)3 was added. The reaction was stirred for 2 hours then the solvent was removed under reduced pressure and in high vacuum. The methyl esterified sulfonic acids were purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 5:1).

(R)-1,1,1-trifluoro-4-oxo-4-phenylbutane-2-sulfonic acid (2a). White solid; 55.8 mg, 99%


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yield; 96% ee; [α]D20 = +1.8 (c 1.00, EtOH); m.p. = 137.3-138.5 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.47min (major), 7.99min (minor); 1H NMR (300 MHz, D2O) δ 7.86 (d, J = 7.6 Hz, 2H), 7.65-7.51 (m, 1H), 7.50-7.33 (m, 2H), 4.48-4.42 (m, 1H), 3.72 (dd, J = 18.2, 6.3 Hz, 1H), 3.41 (dd, J = 18.3, 4.4 Hz, 1H); 13C NMR (75 MHz, D2O) δ 198.2, 135.3, 134.2, 128.8, 128.2, 123.9 (q, J = 277.3 Hz), 57.4 (q, J = 27.5), 34.8; HRMS (ESI-TOF) calcd. for C10H7F3O4S [M-H]-: 281.0101; found: 281.0101.

(R)-methyl 1,1,1-trifluoro-4-oxo-4-phenylbutane-2-sulfonate . Off white solid; 18.4 mg, 62% yield; 96% ee; [α]D20 = +2.0 (c 2.15, CHCl3); m.p. = 52.8-53.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.47 min (major), 7.99 min (minor); 1H NMR (300 MHz, CDCl3) δ 8.09-7.85 (m, 2H), 7.72-7.57 (m, 1H), 7.58-7.42 (m, 2H),, 5.28-4.78 (m, 1H), 4.00 (s, 3H), 3.87 (dd, J = 18.7, 6.1 Hz, 1H), 3.50 (dd, J = 18.7, 4.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 192.4, 135.0, 134.3, 128.9, 128.3, 122.8(q, J = 278.6 Hz), 57.8, 57.1 (q, J = 30.1 Hz), 34.1 (d, J = 1.1 Hz); HRMS (ESI-TOF) calcd. for C11H11F3O4NaS [M+Na]+: 319.0216; found:319.0222 (R)-1,1,1-trifluoro-4-oxo-4-(p-tolyl)butane-2-sulfonic acid (2b). Off white solid; 57.4 mg, 97% yield; 93% ee; [α]D20 = +3.0 (c 2.13, EtOH); m.p. = 141.3-142.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.18 min (major), 8.22 min (minor); 1H NMR (300 MHz, D2O) δ 7.90 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 4.67-4.41 (m, 1H), 3.82 (dd, J = 18.4, 6.4 Hz, 1H), 3.50 (dd, J = 18.1, 5.0 Hz, 1H), 2.40 (s, 3H); 13C NMR (75 MHz, D2O) δ 197.9, 145.9, 132.8, 129.4, 128.4, 123.9 (q, J = 277.5 Hz), 57.5 (q, J = 27.5),



34.6, 20.7; HRMS (ESI-TOF) calcd. for C11H9F3O4S [M-H]-: 295.0257; found: 295.0268. (R)-1,1,1-trifluoro-4-(3-methoxyphenyl)-4-oxobutane-2-sulfonic acid (2c). Pale brown solid; 61.3 mg, 97% yield; 89% ee; [α]D20 = +4.9 (c 0.68, EtOH); m.p. = 154.8-155.4 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 8.86 min (major), 9.56 min (minor); 1H NMR (300 MHz, D2O) δ 7.44 (d, J = 7.8 Hz, 1H), 7.36-7.23 (m, 2H), 7.14-6.97 (m, 1H), 4.53-4.38 (m, 1H), 3.80-3.58 (m, 4H), 3.36 (dd, J = 18.4, 5.1 Hz, 1H); 13C NMR (75 MHz, D2O) δ 197.5, 158.8, 136.6,130.0, 123.9 (q, J = 277.4 Hz), 121.1, 120.1, 112.5, 57.3 (q, J = 27.5), 55.2, 34.9; HRMS (ESI-TOF) calcd. for C11H9F3O5S [M-H]-: 311.0207; found: 311.0197. (R)-1,1,1-trifluoro-4-(4-methoxyphenyl)-4-oxobutane-2-sulfonic acid (2d). Off white solid; 62.1 mg, 99% yield; 95% ee; [α]D20 = +6.2 (c 1.49, EtOH); m.p. = 172.3-173.2 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 9.60 min (major), 11.00 min (minor); 1H NMR (300 MHz, D2O) δ 7.84 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.52-4.39 (m, 1H), 3.77 (s, 3H), 3.68 (dd, J = 18.1, 5.5 Hz, 1H), 3.35 (dd, J = 17.9, 4.0 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.4, 163.7, 130.8, 128.4, 123.9 (q, J = 277.3 Hz), 113.9, 57.4 (q, J = 27.5 Hz), 55.4, 34.3; HRMS (ESI-TOF) calcd. for C11H9F3O5S [M-H]-: 311.0207; found: 311.0217. (R)-1,1,1-trifluoro-4-(2-fluorophenyl)-4-oxobutane-2-sulfonic acid (2e). Off white solid; 57.3 mg, 96% yield; 90% ee; [α]D20 = +4.5 (c 1.97, EtOH); m.p. = 142.1-143.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with


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CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 5.68 min (major), 6.19 min (minor); 1H NMR (300 MHz, D2O) δ 7.82-7.63 (m, 1H), 7.54 (dd, J = 13.5, 7.6 Hz, 1H), 7.25-7.07 (m, 2H), 4.49-4.42 (m, 1H), 3.66 (dd, J = 18.1, 6.5 Hz, 1H), 3.42 (dd, J = 18.6, 4.2 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.2 (d, J = 3.0 Hz), 161.3 (d, J = 253.2 Hz), 135.9 (d, J = 9.5 Hz), 130.2 (d, J = 1.5 Hz), 123.9 (q, J = 277.3 Hz), 124.6 (d, J = 3.3 Hz), 124.1 (d, J = 11.4 Hz), 116.7 (d, J = 22.95 Hz), 57.2 (q, J = 27.8 Hz), 38.7 (d, J = 7.0 Hz); HRMS (ESI-TOF) calcd. for C10H6F4O4S [M-H]-: 299.0007; found: 299.0014. (R)-1,1,1-trifluoro-4-(3-fluorophenyl)-4-oxobutane-2-sulfonic acid (2f). Off white solid; 60.3 mg, 99% yield; 84% ee; [α]D20 = +0.7 (c 0.97, EtOH); m.p. = 187.1-188.3 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.54 min (major), 8.60 min (minor); 1H NMR (300 MHz, D2O) δ 7.87 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 9.8 Hz, 1H), 7.70-7.54 (m, 1H), 7.53-7.39 (m, 1H), 4.65-4.56 (m, 1H), 3.88 (dd, J = 18.5, 6.9 Hz, 1H), 3.59 (dd, J = 18.4, 4.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 197.1 (d, J = 2.2 Hz), 162.5 (d, J = 243.83 Hz), 137.5 (d, J = 6.6 Hz), 130.8 (d, J = 8.0 Hz), 123.9 (q, J = 277.1 Hz), 124.4 (d, J = 2.8 Hz), 121.1 (d, J = 21.5 Hz), 114.8 (d, J = 22.8 Hz), 57.5 (q, J = 27.7 Hz) 35.1; HRMS (ESI-TOF) calcd. for C10H6F4O4S [M-H]-: 299.0007; found: 299.0008. (R)-1,1,1-trifluoro-4-(4-fluorophenyl)-4-oxobutane-2-sulfonic acid (2g). Pale brown oil; 59.5 mg, 99% yield; 89% ee; [α]D20 = +0.8 (c 1.27, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.77 min (major), 8.02 min (minor); 1H

NMR (300 MHz, D2O) δ 8.06-7.93 (m, 2H), 7.28-7.11 (m, 2H), 4.55-4.45 (m, 1H), 3.78 (dd, J



= 18.3, 6.9 Hz, 1H), 3.46 (dd, J = 18.3, 4.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.7, 166.0 (d, J = 252.15 Hz) , 131.9 (d, J = 2.7 Hz), 131.2 (d, J = 9.9 Hz), 123.9 (q, J = 277.2 Hz), 115.8 (d, J = 22.2,), 57.5 (q, J = 27.6 Hz), 34.7; HRMS (ESI-TOF) calcd. for C10H6F4O4S [M-H]-: 299.0007; found: 299.0011. (R)-4-(3-chlorophenyl)-1,1,1-trifluoro -4-oxobutane-2-sulfonic acid (2h). Pale brown oil; 60.9 mg, 96% yield; 88% ee; [α]D20 = +3.7 (c 2.09, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol l = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.45 min (major), 9.16 min (minor); 1H NMR (300 MHz, D2O) δ 7.90-7.81 (m, 2H), 7.63-7.52 (m, 1H), 7.49-7.38 (m, 1H), 4.58-4.46 (m, 1H), 3.77 (dd, J = 18.4, 6.6 Hz, 1H), 3.48 (dd, J = 18.4, 4.9 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.8, 136.9, 134.3, 133.8, 130.3, 127.9, 126.6, 123.9 (q, J = 277.4 Hz), 57.3 (q, J = 27.5 Hz), 34.9; HRMS (ESI-TOF) calcd. for C10H6ClF3O4S [M-H]-: 314.9711; found: 314.9724. (R)-4-(4-chlorophenyl)-1,1,1-trifluoro-4-oxobutane-2-sulfonic acid (2i). Off white solid; 62.5 mg, 99% yield; 86% ee; [α]D20 = -2.8 (c 1.35, EtOH); m.p. = 230.1-231.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.53 min (major), 8.44 min (minor); 1H NMR (300 MHz, D2O) δ 7.83 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.52-4.40 (m, 1H), 3.73 (dd, J = 18.4, 6.7 Hz, 1H), 3.42 (dd, J = 18.3, 4.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 194.7, 137.7, 131.6, 127.5, 125.7, 121.7 (q, J = 277.2 Hz), 55.1 (q, J = 27.6 Hz), 32.5; HRMS (ESI-TOF) calcd. for C10H6ClF3O4S [M-H]-: 314.9711; found: 314.9712.


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(R)-4-(4-bromophenyl)-1,1,1-trifluoro-4-oxobutane-2-sulfonic acid (2j). Pale brown solid; 70.7 mg, 98% yield; 93% ee; [α]D20 = +4.8 (c 1.25, EtOH); m.p. = 242.1-243.7 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 8.67 min (major), 9.44 min (minor); 1H NMR (300 MHz, D2O) δ7.90-7.85 (m, 2H), 7.73-7.67 (m, 2H), 4.63-4.54 (m, 1H), 3.85 (dd, J = 18.3, 6.9 Hz, 1H), 3.54 (dd, J = 18.4, 4.9 Hz, 1H); 13C NMR (75 MHz, D2O) δ 197.3, 134.3, 132.0, 129.9, 128.8, 124.0 (q, J = 277.4 Hz), 57.4 (q, J = 27.6 Hz), 34.9 (d, J = 18.4 Hz); HRMS (ESI-TOF) calcd. for C10H6BrF3O4S [M-H]-: 358.9206; found: 358.9210. (R)-1,1,1-trifluoro-4-(4-nitrophenyl)-4-oxobutane-2-sulfonic acid (2k). Pale brown oil; 64.7 mg, 99% yield; 93% ee; [α]D20 = +1.8 (c 1.77, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 16.87 min (major), 22.46 min (minor); 1H NMR (300 MHz, D2O) δ 8.37-8.34 (m, 2H), 8.20-8.17 (m, 2H), 4.62-4.56 (m, 1H), 3.93 (dd, J = 18.4, 7.1 Hz, 1H), 3.63 (dd, J = 18.5, 4.5 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.9, 150.4, 140.4, 129.4, 123.9, 123.8 (q, J = 277.2 Hz), 57.4 (q, J = 28.0 Hz), 35.5; HRMS (ESI-TOF) calcd. for C10H6F3NO6S [M-H]-: 325.9952; found: 325.9951. (R)-1,1,1-trifluoro-4-(3-nitrophenyl)-4-oxobutane-2-sulfonic acid (2l). Yellowish solid; 63.4 mg, 97% yield; 91% ee; [α]D20 = +2.0 (c 1.79, EtOH); m.p. = 211.4-212.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 13.53 min (major), 17.40 min (minor); 1H NMR (300 MHz, D2O) δ 9.00-8.73 (m, 1H), 8.61-8.43



Page 16 of 23

(m, 1H), 8.45-8.21 (m, 1H), 7.99-7.63 (m, 1H), 4.70-4.55 (m, 1H), 3.95 (dd, J = 18.5, 7.1 Hz, 1H), 3.65 (dd, J = 18.5, 4.6 Hz, 1H);

13

C NMR (75 MHz, D2O) δ 196.0, 148.0, 136.7, 134.4, 130.3,

128.2, 124.0 (q, J = 277.8 Hz), 123.1, 57.4 (q, J = 27.8 Hz), 35.2 (d, J = 1.5 Hz).; HRMS (ESI-TOF) calcd. for C10H6F3NO6S [M-H]-: 325.9952; found: 325.9960. (R)-4-(4-cyanophenyl)-1,1,1-trifluoro-4-oxobutane-2-sulfonic acid (2m). Off white solid; 59.8 mg, 97% yield; 75% ee; [α]D20 = +2.4 (c 0.86, EtOH); m.p. = 167.5-168.9 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 12.88 min (major), 17.49 min (minor); 1H NMR (300 MHz, D2O) δ 8.07 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 4.64-4.50 (m, 1H), 3.87 (dd, J = 18.5, 6.9 Hz, 1H), 3.57 (dd, J = 18.5, 4.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.9, 138.8, 132.9, 128.6, 123.9 (q, J = 277.3 Hz), 118.5, 115.8, 57.3 (q, J = 27.7 Hz), 35.2;. HRMS (ESI-TOF) calcd. for C11H6F3NO4S [M-H]-: 306.0053; found: 306.0049. (R)-1,1,1-trifluoro-4-oxo-4-(4-(trifluoromethyl)phenyl)butane-2-sulfonic

acid

(2n).

Pale

brown solid; 69.5 mg, 99% yield; 88% ee; [α]D20 = +1.0 (c 0.87, EtOH); m.p. = 161.3-162.1 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 6.05 min (major), 6.89 min (minor); 1H NMR (300 MHz, D2O) δ 7.84 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 4.58-4.19 (m, 1H), 3.69 (dd, J = 18.6, 6.0 Hz, 1H), 3.37 (dd, J = 18.4, 4.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.6, 138.1, 134.0 (q, J = 32.5 Hz), 128.4, 125.5 (q, J = 3.4 Hz), 123.9 (q, J = 277.1 Hz), 123.3 (q, J = 270.5 Hz), 57.2 (q, J = 27.7 Hz), 35.0; HRMS (ESI-TOF) calcd. for C10H6F3NO6S [M-H]-: 348.9975; found: 325.9981.


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(R)-4-(3,4-dichlorophenyl)-1,1,1-trifluoro-4-oxobutane-2-sulfonic acid (2o). Pale brown oil; 69.7 mg, 99% yield; 87% ee; [α]D20 = +0.8 (c 0.83, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak IA column after esterification with CH3C(OCH3)3: hexane: ethanol = 95:5; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 13.48 min (major), 16.82 min (minor); 1H NMR (300 MHz, D2O) δ 7.86 (s, 1H), 7.80-7.48 (m, 1H), 7.52-7.24 (m, 1H), 4.55-4.29 (m, 1H), 3.70 (d, J = 18.6 Hz, 1H), 3.43 (d, J = 18.6 Hz, 1H); 13C NMR (75 MHz, D2O) δ 195.3, 137.8, 135.0, 132.6, 130.7, 129.8, 127.6, 124.0 (q, J = 277.28 Hz), 57.2 (q, J = 27.5 Hz), 35.0; HRMS (ESI-TOF) calcd. for C10H5Cl2F3O4S [M-H]-: 348.9321; found: 325.9330. (R)-1,1,1-trifluoro-4-(naphthalen-2-yl)-4-oxobutane-2-sulfonic acid (2p). Yellowish solid; 64.7 mg, 97% yield; 92% ee; [α]D20 = -27.6 (c 1.28, EtOH); m.p. = 212.1.3-213.4 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.88 min (major), 9.53 min (minor); 1H NMR (300 MHz, D2O) δ 7.76 (s, 1H), 7.38-7.20 (m, 3H), 7.19-6.97 (m, 3H), 4.68-4.01 (m, 1H), 3.61 (dd, J = 18.3, 5.3 Hz, 1H), 3.24 (dd, J = 18.5, 5.6 Hz, 1H); 13C NMR (75 MHz, D2O) δ 196.7, 135.0, 131.8, 131.4, 130.1, 129.3, 128.6, 127.9, 127.1, 126.5, 124.1 (q, J = 277.5 Hz), 122.6, 57.2 (q, J = 27.4 Hz), 34.7; HRMS (ESI-TOF) calcd. for C14H9F3O4S [M-H]-: 331.0257; found: 331.0260. (R)-1,1,1-trifluoro-4-(furan-2-yl)-4-oxobutane-2-sulfonic acid (2q). Light orange oil; 53.8 mg, 99% yield; 97% ee; [α]D20 = +6.1 (c 2.24, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 5.41 min (major), 5.78 min (minor); 1H

NMR (300 MHz, D2O) δ 7.88 (s, 1H), 7.59 (d, J = 3.7 Hz, 1H), 6.83-6.63 (m, 1H), 4.68-4.28



(m, 1H), 3.72 (dd, J = 17.7, 7.4 Hz, 1H), 3.42 (dd, J = 17.7, 4.9 Hz, 1H); 13C NMR (75 MHz, D2O) δ 185.9, 150.9, 149.2, 123.9 (q, J = 277.4 Hz), 121.4, 113.0, 57.3 (q, J = 27.7 Hz), 34.2 (d, J = 1.5 Hz); HRMS (ESI-TOF) calcd. for C8H5F3O5S [M-H]-: 270.9894; found: 270.9902. (R)-1,1,1-trifluoro-4-oxo-4-(thiophen-2-yl)butane-2-sulfonic acid (2r). Pasty oil; 57.1 mg, 99% yield; 93% ee; [α]D20 = +4.9 (c 0.88, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 7.39 min (major), 9.90 min (minor); 1H NMR (300 MHz, D2O) δ 8.14-8.00 (m, 1H), 8.00-7.93 (m, 1H), 7.38-7.23 (m, 1H), 4.60-4.49 (m, 1H), 3.83 (dd, J = 17.7, 7.2 Hz, 1H), 3.53 (dd, J = 17.8, 4.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 190.8, 141.8, 136.5, 135.0, 129.0, 123.9 (q, J = 277.4 Hz), 57.6 (q, J = 27.6 Hz), 35.1; HRMS (ESI-TOF) calcd. for C8H5F3O4S2 [M-H]-: 286.9665; found: 286.9671. (S)-4-oxo-4-phenylbutane-2-sulfonic acid (2s). Off white solid; 45.2 mg, 99% yield; 90% ee; [α]D20 = +35.4 (c 2.10, MeOH); m.p. = 123.7.-124.6 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR= 12.92 min (major), 9.90 min (minor); 1H

NMR (300 MHz, D2O) δ 7.87 (d, J = 7.8 Hz, 2H), 7.66-7.54 (m, 1H), 7.50-7.38 (m, 2H), 3.57

(dd, J = 16.9, 4.1 Hz, 1H), 3.51-3.39 (m, 1H), 3.05 (dd, J = 16.6, 8.3 Hz, 1H), 1.26 (d, J = 6.7 Hz, 3H);

13C

NMR (75 MHz, D2O) δ 201.6, 136.0, 134.0, 128.8, 128.2, 51.9, 40.5, 14.9; HRMS

(ESI-TOF) calcd. for C10H10O4S [M-H]-: 227.0384; found: 227.0386. (R)-3-oxo-1,3-diphenylpropane-1-sulfonic acid (2t). White solid; 56.7 mg, 98% yield; 96% ee; [α]D20 = +48.6 (c 1.70, EtOH); m.p. = 176.8-177.9 °C; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane:


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ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 220 nm; tR = 13.15 min (major), 16.03 min (minor); 1H NMR (300 MHz, DMSO) δ 7.91 (d, J = 7.3 Hz, 2H), 7.66-7.55 (m, 1H), 7.54-7.43 (m, 2H), 7.36 (d, J = 7.1 Hz, 2H), 7.27-7.09 (m, 3H), 4.27 (dd, J = 9.5, 3.7 Hz, 1H), 3.84 (dd, J = 17.3, 3.8 Hz, 1H), 3.65 (dd, J = 17.2, 9.6 Hz, 1H); 13C NMR (75 MHz, DMSO) δ 197.8, 138.7, 136.8, 133.2, 129.3, 128.8, 127.9, 127.5, 126.4, 61.3, 41.1; HRMS (ESI-TOF) calcd. for C15H12O4S [M-H]-: 289.0540; found: 289.0544. (R)-1-ethoxy-1,4-dioxo-4-phenylbutane-2-sulfonic acid (2u). Pasty oil; 57.0 mg, 99% yield; 0% ee; The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 254 nm; tR = 8.47 min (major), 9.45 min (minor); 1H NMR (300 MHz, D2O) δ 7.96 (d, J = 8.2 Hz, 2H), 7.76-7.62 (m, 1H), 7.60-7.47 (m, 2H), 4.43-4.12 (m, 3H), 3.91 (dd, J = 18.4, 10.8 Hz, 1H), 3.77 (dd, J = 18.5, 3.9 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, D2O) δ 200.3, 169.5 135.2, 134.4, 128.8, 128.1, 63.0, 61.7, 37.9, 13.1; HRMS (ESI-TOF) calcd. for C15H12O4S [M-H]-: 285.0438; found: 285.0447. (R)-1,1,1-trifluoro-4-oxo-5-phenylpentane-2-sulfonic acid (2v). Yellowish oil; 55.6 mg, 94% yield; 52% ee; [α]D20 = +6.9 (c 2.12, EtOH); The enantiomeric excess was determined by HPLC on Chiralpak AD-H column after esterification with CH3C(OCH3)3: hexane: ethanol = 70:30; flow rate = 1.0 mL/min; UV detection at 220 nm; tR = 5.15 min (major), 5.56 min (minor); 1H NMR (300 MHz, D2O) δ 7.45-7.30 (m, 3H), 7.29-7.16 (m, 2H), 4.51-4.20 (m, 1H), 3.97 (s, 2H), 3.33 (dd, J = 18.2, 7.1 Hz, 1H), 3.12 (dd, J = 18.3, 4.8 Hz, 1H);

13C

NMR (75 MHz, D2O) δ 207.7,

133.6, 129.8, 128.9, 127.4, 123. 9 (q, J = 277.3 Hz), 57.3 (q, J = 27.7 Hz), 49.1, 38.1 (d, J = 1.4 Hz); HRMS (ESI-TOF) calcd. for C11H9F3O4S [M-H]-: 295.0257; found: 295.0268.



ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website http://pubs.acs.org. Copies of 1H, 13C NMR and HPLC spectra data for all compounds. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT We are grateful for financial support from the National NSFC (No. 21372217, 21572223, 21572224), Sichuan Youth Science and Technology Foundation (2015JQ0041 and 2016JQ0024). REFERENCES (1) (a) Pechtold, F. Arzneim.-Forsch. 1964, 14, 1056. (b) Morimoto, S.; Nomura, H.; Ishiguro, T.; Fugono, T.; Maeda, K. J. Med. Chem. 1972, 15, 1105. (c) Morimoto, S.; Nomura, H.; Fugono, T.; Azuma, T. Minami, J. J. Med. Chem. 1972, 15, 1108. (d) Tsuchiya, K.; Kondo, M. Antimicrob. Agents Chemother. 1978, 13, 536. (e) Qiu, X.; Miles, A.; Jiang, X.; Sun, X.; Yang, N. J. Evidence-Based Complementary Altern. Med., 2012, 715790. (2) (a) Huxtable, R. J. Physiol. Rev., 1992, 72, 101. (b) Yoshikawa, M.; Yamaguchi, S.; Kunimi, K.; Matsuda, H.; Okuno, Y.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull., 1994, 42, 1226. (3) (a) Li, H. Y.; Matsunaga, S.; Fusetani, N. J. Med. Chem. 1995, 38, 338. (b) Yang, S. Q.;


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