Catalytic asymmetric conjugate addition of various α-mercaptoketones to α,β-unsaturated N-acylated oxazolidin-2-ones with bifunctional organocatalyst

Abstract

A bifunctional squaramide catalysed enantioselective conjugate Michael addition reaction of various α-mercaptoketones to α,β-unsaturated N-acylated oxazolidinones under mild reaction conditions has been developed. This catalytic reaction afforded the corresponding adducts in good yields with high enantioselectivities (up to 92% ee). This is the first example of organocatalysed sulfa-Michael addition using various α-mercaptoketones as the Michael donors.

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Introduction

Optically active, chiral sulfur-containing compounds have been found to have important functional roles in many compounds¹ in the areas of chemistry and biology, for example, serving as antibiotics,² ligands for metal-based catalysts,³ as catalysts themselves,⁴ and as chiral auxiliaries.⁵ In particular, enantiomerically pure β-sulfurated carboxylic acid derivatives as substructures, exist in pharmaceuticals and various biologically active compounds.⁶ However, due to the sensitive nature of thiols and sulfides toward oxidations, efficient and well-documented ways to access these compounds are still rare. The asymmetric conjugate additions with sulfur–nucleophile, or sulfa-Michael additions, constitute a direct and versatile method toward optically active chiral sulfur compounds. Accordingly, considerable efforts have been devoted to the development of catalytic enantioselective sulfa-Michael reactions.^7a The first example was appeared in 1999 reported by Kanemasa et al.; the highly enantioselective reactions of several thiols to (E)-3-crotonoyloxazolidin-2-one under the catalysis of Ni/DBFOX.^7b Then, three groups used different chiral Yb,⁸ Hf,⁹ and Sc (ref. 10) complexes to perform this kind of reaction by performing this work independently. After their pioneering work, the asymmetric conjugate addition of thiols to acyclic α,β-unsaturated carbonyl systems has been widely studied and become a very important approach for the formation of carbon–sulflur (C–S) bond in recent years.¹¹ Most of the research focus on the organocatalytic variant of the process. However, despite of considerable endeavour in this field, the scope of the thiols is reasonably narrow. Specifically, the asymmetric additions of benzyl mercaptans and other alkyl thiols to a range of Michael acceptors promoted by bifunctional tertiary amine-based catalysts are now relatively less investigated. Although different types of catalysts have been utilized in sulfa-Michael additions, such as cinchona alkaloids,¹² chiral proline derivatives,⁸ salens,⁹N-oxides,^13,11h a chiral amino ether–lithium thiolate complex,¹⁴ and lanthanoid tris(binaphthoxide),¹⁵ the catalysts incorporating cinchona alkaloids as a series of chiral organocatalysts has been widely used in the reactions for asymmetric synthesis of sulfur-containing compounds and obtain good results.¹⁶ There are also many related reports about the use of organocatalysis in the synthesis of medicinal and bioactive products in recent years.¹⁷

As a rational extension of our project on sulfa-Michael additions for the synthesis of important chiral bioactive building blocks or heterocyclic compounds,^16e–g we report herein the use of bifunctional cinchona alkaloids-derived squaramide¹⁸ organocatalysts to realize an efficient enantioselective sulfa-Michael addition of various α-mercaptoketones to α,β-unsaturated N-acylated oxazolidin-2-ones. The enantiomerically β-sulfurated carboxylic acid derivatives were obtained in high yields with high enantioselectivities. To the best of our knowledge, α-mercaptoketones, which known as a flavor enhancers,¹⁹ have rarely been used as Michael donors.²⁰ The β-sulfurated carboxylic acid derivatives obtained in this study bearing additional keto group will be synthetically useful for further transformation.

Results and discussion

At the outset of our investigation, a series of organocatalysts were evaluated in the model reaction of N-cinnamoyloxazolidin-2-one 1a and α-mercaptoketone 2a in dichloromethane (1.0 mL) at room temperature. The squaramide catalysts I–VIII (Fig. 1) incorporating cinchona alkaloid and (1S,2S)-(+)-1,2-diaminocyclohexane were screened.

Fig. 1 The organocatalysts tested in this study.

As shown in Table 1, whatever in terms of yield or enantioselectivity, the chiral squaramide catalysts I and II could only afford the desired addition product 3aa with up to 57% ee and up to 67% yield (Table 1, entries 1 and 2). A substantial increase of enantioselectivity and yield was observed by employing cinchonidine-based squaramide III as the H-bond donor (Table 1, entry 3). The reaction could afford the better results by changing the cinchonidine-derived squaramide III to its quinine and hydroquinine analogue IV–VIII (Table 1, entry 4–8). From the above evaluation, squaramide catalyst VI was identified as the best catalyst, which afforded the product 3aa in 82% yield with 83% ee.

Table 1 Screening of different chiral catalysts

Entry^a	Catalyst	Yield^b (%)	ee^c (%)
a Reaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), dichloromethane (1.0 mL), 5 mol% catalyst, room temperature, 36–48 h. b Isolated yields after column chromatography purification. c Determined by HPLC on Daicel Chiralpak AD-H column (n-hexane–2-propanol 80 : 20, 1.0 mL min^−1).
1	I	47	7
2	II	67	57
3	III	74	76
4	IV	80	77
5	V	74	81
6	VI	82	83
7	VII	76	77
8	VIII	76	77

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To improve the enantioselectivity of this organocatalytic reaction, we further evaluated effect of various solvents, reaction temperature and catalyst loading using organocatalyst VI as the optimal catalyst. The results are summarized in Table 2. Solvent screening revealed that nonpolar solvents were more suitable for this organocatalysed sulfa-Michael addition (Table 2, entries 1–7), and toluene was the solvent of choice leading to 82% yield and 90% ee (Table 2, entry 4). The reaction was performed at −10 °C lead to a significant drop in enantioselectivity and the loss of chemical yield (Table 2, entry 9), but increasing the reaction temperature to 50 °C did not improve the enantioselectivity as compared with room temperature (Table 2, entry 8 vs. entry 4). Further evaluations revealed that increasing the catalyst loading to 10 mol% could improve the yield (Table 2, entry 10). However, the yield was not significantly improved and the enantioselectivity has a downward trend when increasing the catalyst loading to 15 mol% (Table 2, entry 11). From the above optimization of reaction conditions, the best result was obtained when the reaction was performed at room temperature and the catalyst loading was maintained at 10 mol% (86% yield, 92% ee).

Table 2 Optimization of reaction conditions for the asymmetric Michael addition^a

Entry	Solvent	Loading	Yield^b (%)	ee^c (%)
a Reaction conditions: unless noted otherwise, reactions were carried out with 1a (0.2 mmol) and 2a (0.3 mmol) in 1.0 mL of solvent for 36–48 h at room temperature. b Isolated yields after column chromatography purification. c Determined by HPLC on Daicel Chiralpak AD-H column (n-hexane–2-propanol 80 : 20, 1.0 mL min^−1). d The reaction was performed at 50 °C for 24 h. e The reaction was performed at −10 °C for 7 d.
1	CH2Cl2	5	82	83
2	CHCl3	5	78	80
3	ClCH2CH2Cl	5	79	82
4	PhMe	5	82	90
5	Xylene	5	77	90
6	THF	5	67	88
7	Ether	5	57	55
8^d	PhMe	5	54	82
9^e	PhMe	5	47	66
10	PhMe	10	86	92
11	PhMe	15	88	90

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After optimization of the reaction conditions, the asymmetric conjugate addition was extended to other α,β-unsaturated N-acylated oxazolidin-2-ones and various α-mercaptoketones under the optimized same conditions. As summarized in Table 3, in most cases, the desired products were obtained with good to high enantioselectivities. However, the position of the substituent on the aromatic ring of Michael acceptor has an evident effect on enantioselectivity (Table 3, entry 2). When the β-substituted position of 1 was replaced by alkyl group, the yield of the target product decreased significantly (Table 3, entry 9). Heterocyclic-substituted substrates are also well adapted to the reaction (Table 3, entry 8). The electronic nature of the substituent on the aromatic ring of Michael acceptors or donors has little effect on the product enantioselectivity (Table 3, entries 3–6 and 10–14).

Table 3 Asymmetric conjugate addition of 2 to 1 with catalyst VI^a

Entry	R^1	R^2	Product	Time/h	Yield^b (%)	ee^c (%)
a Reaction conditions: unless noted otherwise, reactions were carried out with 1 (0.2 mmol) and 2 (0.3 mmol) in 1.0 mL of toluene with 10 mol% catalyst VI at room temperature. b Isolated yields by column chromatography. c Determined by HPLC on Daicel Chiralpak IB, AS-H or AD-H column.
1	C6H5 (1a)	C6H5 (2a)	3aa	48	86	92
2	2-ClC6H4 (1b)	C6H5 (2a)	3ba	72	62	71
3	4-BrC6H4 (1c)	C6H5 (2a)	3ca	48	81	90
4	4-MeC6H4 (1d)	C6H5 (2a)	3da	72	90	90
5	4-MeOC6H4 (1e)	C6H5 (2a)	3ea	72	91	90
6	4-NO2C6H4 (1f)	C6H5 (2a)	3fa	48	83	88
7	1-Naphthyl (1g)	C6H5 (2a)	3ga	72	76	84
8	2-Furyl (1h)	C6H5 (2a)	3ha	72	85	88
9	Me (1i)	C6H5 (2a)	3ia	48	26	78
10	C6H5 (1a)	4-ClC6H4 (2b)	3ab	48	82	90
11	C6H5 (1a)	4-BrC6H4 (2c)	3ac	48	84	90
12	C6H5 (1a)	4-MeC6H4 (2d)	3ad	48	93	90
13	C6H5 (1a)	4-MeOC6H4 (2e)	3ae	48	95	90
14	C6H5 (1a)	3-MeOC6H4 (2f)	3af	48	85	90

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We also try to use the alkyl-substituted α-mercaptoketone (Scheme 1). We carry out the reaction at 50 °C for 48 h because no significant reaction product was observed by TLC at room temperature. The Michael addition product 3ag and Michael/aldol cascade product 4ag were obtained with total 77% yield (these two products can not be separated by column chromatography).

Scheme 1 Further investigation of the alkyl-substituted α-mercaptoketone.

The configuration of the sulfa-Michael addition product 3aa was determined to be (R) (Fig. 2) by X-ray diffraction analysis,²¹ and the configurations of other products were assigned by analogy.

Fig. 2 The X-ray crystal structure of product 3aa.

To demonstrate the synthetic potential of this methodology, a gram-scale synthesis of 3aa was performed (Scheme 2). The reaction proceeded smoothly affording the corresponding product in slightly decreased yield and stereoselectivity.

Scheme 2 The gram-scale preparation of 3aa.

According to the above experimental results and previously similar reports, the substrates involved in the transition state are activated by squaramide VI as proposed in Fig. 3. The N-cinnamoyloxazolidin-2-one is assumed to be activated and oriented by the hydrogen bonds of the squaramide, while the tertiary amine of the catalyst would provide suitable basicity to enhance the nucleophilicity of the α-mercaptoketone. Initially, the anion of α-mercaptoketone attack the N-cinnamoyloxazolidin-2-one from the Re-face via transition state A forming the corresponding Michael adduct anion, subsequent the generated enolate abstract the proton from the quinuclidine nitrogen leads to the formation of the major enantiomer 3aa with (R)-configuration.

Fig. 3 Proposed transition states for sulfa-Michael addition.

Conclusions

In summary, we have developed a new protocol for the organocatalytic asymmetric sulfa-Michael addition of various α-mercaptoketones as the donor to the easily available α,β-unsaturated N-acylated oxazolidinones, and the corresponding products were obtained in good yields with high enantioselectivities (up to 92% ee). The methodology presented herein provides a facile access to β-sulfurated carboxylic acid derivatives bearing additional keto group, which can be transformed into other functional compounds. Mild conditions and a broad scope of substrates make this approach very competitive in the synthesis of enantiomerically pure β-sulfurated carboxylic acid derivatives.

Experimental section

General methods

Commercially available compounds were used without further purification. Solvents were dried according to standard procedures. Column chromatography was performed with silica gel (200–300 mesh). Melting points were determined on an XT-4 melting-point apparatus and are uncorrected. ¹H NMR spectra were measured with a Varian Mercury-plus 400 MHz or Bruker Avance 400 MHz spectrometer. Chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as the internal standard. ¹³C NMR spectra were measured at 100 MHz; chemical shifts were reported in ppm relative to TMS with the solvent resonance as internal standard. Infrared spectra were obtained with a Perkin Elmer Spectrum One spectrometer. High resolution mass spectra (Electron spray ionization) were measured with a Bruker APEX IV Fourier-transform mass spectrometer. Optical rotations were measured with a WZZ-3 polarimeter. Enantiomeric excesses were determined by chiral HPLC analysis using an Agilent 1200 LC instrument with a Daicel Chiralpak IB, AD-H or AS-H column.

Materials

Chiral squaramide catalysts I–V,²²VII (ref. 23) and VIII,²⁴ were prepared according to the reported procedures.

Synthesis of organocatalyst VI

In 25 mL round-bottomed flask, p-nitroaniline (0.69 g, 5.0 mmol) was added to dimethyl squarate (0.71 g, 5.0 mmol) which was dissolved in 10 mL of methanol. The mixture was stirred at room temperature for 48 h, the large precipitate was filtered to afford the mono-squaramide as a red solid (1.00 g, 81% yield). To a solution of 9-amino(9-deoxy)epiquinine²² (325 mg, 1.0 mmol) in CH₂Cl₂ (10 mL) was added mono-squaramide (248 mg, 1 mmol). After stirring for 48 h at room temperature, the squaramide catalyst VI was obtained by filtration as a yellow solid (421 mg, 78% yield); mp 213–215 °C, [α]²⁰_D = −68.9 (c = 0.50 g/100 mL, CHCl₃). ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 9.2 Hz, 2H), 7.97 (d, J = 9.2 Hz, 1H), 7.73 (br s, 1H), 7.67 (d, J = 4.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.42 (dd, J₁ = 9.2 Hz, J₂ = 2.4 Hz, 1H), 6.03–5.91 (m, 2H), 5.03–4.95 (m, 2H), 3.94 (s, 3H), 3.49 (br s, 2H), 3.30 (br s, 2H), 3.21 (br s, 1H), 2.74–2.65 (m, 2H), 2.25 (br s, 1H), 1.56 (s, 1H), 1.50 (br s, 3H), 0.66 (br s, 1H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 185.1, 179.6, 168.9, 162.5, 157.8, 147.7, 144.9, 144.2, 142.7, 142.0, 141.5, 131.5, 127.4, 127.3, 125.4, 121.8, 117.7, 114.3, 101.3, 58.9, 55.6, 55.5, 48.5, 27.2, 27.1, 25.9 ppm; IR (KBr): ν 3074, 3002, 2942, 2865, 1793, 1693, 1623, 1600, 1589, 1550, 1511, 1473, 1435, 1418, 1334, 1312, 1273, 1242, 1230, 1188, 1112, 1027, 979, 916, 850, 763, 750, 734, 711, 690, 631 cm⁻¹; HRMS (ESI): m/z calcd for C₃₀H₃₀N₅O₅ [M + H]⁺ 540.22415, found 540.22471.

General procedure for enantioselective sulfa-Michael addition. To a dried small bottle was added α,β-unsaturated N-acylated oxazolidin-2-one 1 (0.2 mmol) and catalyst VI (10.8 mg, 0.02 mmol, 10 mol%), followed by addition of the toluene (1.0 mL). The mixture was stirred at room temperature for 15 min, then the donor of α-mercaptoketone 2 (0.3 mmol) was added in one portion. After stirring at room temperature for 48–72 h, the reaction mixture was concentrated and directly purified by silica gel column chromatography to afford the desired product 3.

(R)-3-(3-((2-Oxo-2-phenylethyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3aa). Compound 3aa was obtained according to the general procedure as a white solid (63.5 mg, 86% yield), mp 98–100 °C. HPLC (Daicel Chiralpak AD-H column, n-hexane–2-propanol 80 : 20, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 50.4 min (major enantiomer), t_R = 55.3 min (minor enantiomer), 92% ee. [α]²⁵_D + 120.0 (c 0.33, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.84 (d, J = 7.2 Hz, 2H, ArH), 7.54 (t, J = 7.4 Hz, 1H, ArH), 7.42 (t, J = 7.8 Hz, 4H, ArH), 7.31 (t, J = 7.4 Hz, 2H, ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH), 4.52 (t, J = 7.4 Hz, 1H, CH), 4.37–4.27 (m, 2H, CH₂), 3.94–3.83 (m, 2H, CH₂), 3.78 (d, J = 14.8 Hz, 1H, CH₂), 3.61 (dd, J₁ = 17.2 Hz, J₂ = 7.6 Hz, 1H, CH₂), 3.56 (d, J = 14.8 Hz, 1H, CH₂), 3.52 (dd, J₁ = 17.4 Hz, J₂ = 7.0 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.5, 169.8, 153.4, 140.5, 135.4, 133.2, 128.5, 128.1, 127.6, 62.1, 44.6, 42.4, 41.1, 36.9 ppm. IR (KBr): ν 3060, 3028, 2987, 2960, 2923, 2854, 1777, 1698, 1597, 1580, 1492, 1478, 1449, 1389, 1362, 1345, 1278, 1224, 1202, 1113, 1078, 1039, 1008, 958, 758, 732, 701, 692, 672, 622, 566 cm⁻¹. HRMS (ESI): m/z calcd for C₂₀H₂₀NO₄S [M + H]⁺ 370.11076, found: 370.11038.

(R)-3-(3-(2-Chlorophenyl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3ba). Compound 3ba was obtained according to the general procedure as a yellow oil (50.1 mg, 62% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 26.1 min (minor enantiomer), t_R = 32.2 min (major enantiomer), 71% ee. [α]²⁵_D + 48.4 (c 0.23, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d, J = 7.2 Hz, 2H, ArH), 7.57–7.52 (m, 2H, ArH), 7.42 (t, J = 8.0 Hz, 2H, ArH), 7.34 (dd, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H, ArH), 7.24 (dd, J₁ = 7.6 Hz, J₂ = 1.2 Hz, 1H, ArH), 7.19–7.15 (m, 1H, ArH), 5.07 (t, J = 7.2 Hz, 1H, CH), 4.40–4.36 (m, 2H, CH₂), 3.97–3.92 (m, 2H, CH₂), 3.90 (ABq, J = 15.2 Hz, 2H, CH₂), 3.74 (dd, J₁ = 17.4 Hz, J₂ = 7.2 Hz, 1H, CH₂), 3.50 (dd, J₁ = 17.2 Hz, J₂ = 7.2 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.5, 169.7, 153.4, 138.2, 135.5, 133.6, 133.3, 129.7, 129.0, 128.7, 128.54, 128.49, 127.3, 62.2, 42.4, 41.2, 40.9, 38.3 ppm. IR (KBr): ν 3062, 2991, 2960, 2922, 2850, 1778, 1699, 1597, 1580, 1476, 1448, 1389, 1319, 1277, 1224, 1201, 1112, 1036, 1011, 957, 758, 689, 671, 647, 563 cm⁻¹. HRMS (ESI): m/z calcd for C₂₀H₁₉ClNO₄S [M + H]⁺ 404.07178, found: 404.07234.

(R)-3-(3-(4-Bromophenyl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3ca). Compound 3ca was obtained according to the general procedure as a white solid (72.6 mg, 81% yield), mp 39–40 °C. HPLC (Daicel Chiralpak IB column. n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 24.8 min (minor enantiomer), t_R = 31.1 min (major enantiomer), 90% ee. [α]²⁵_D + 162.1 (c 0.53, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, J = 7.6 Hz, 2H, ArH), 7.55 (t, J = 7.2 Hz, 1H, ArH), 7.45–7.41 (m, 4H, ArH), 7.29 (d, J = 8.4 Hz, 2H, ArH), 4.47 (dd, J₁ = 8.0 Hz, J₂ = 6.8 Hz, 1H, CH), 4.39–4.29 (m, 2H, CH₂), 3.94–3.83 (m, 2H, CH₂), 3.80 (d, J = 14.8 Hz, 1H, CH₂), 3.57 (dd, J₁ = 17.2 Hz, J₂ = 8.0 Hz, 1H, CH₂), 3.52 (d, J = 14.8 Hz, 1H, CH₂), 3.47 (dd, J₁ = 16.8 Hz, J₂ = 6.4 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.3, 169.5, 153.3, 139.6, 135.2, 133.3, 131.5, 129.8, 128.52, 128.45, 121.3, 62.1, 43.8, 42.3, 41.0, 36.7 ppm. IR (KBr): ν 3060, 2987, 2960, 2924, 1778, 1699, 1597, 1580, 1488, 1448, 1388, 1320, 1277, 1223, 1202, 1183, 1115, 1073, 1039, 1010, 958, 815, 758, 736, 709, 690, 677, 648, 638, 617, 564, 532 cm⁻¹. HRMS (ESI): m/z calcd for C₂₀H₁₉BrNO₄S [M + H]⁺ 448.02127, found: 448.02153.

(R)-3-(3-((2-Oxo-2-phenylethyl)thio)-3-(p-tolyl)propanoyl)oxazolidin-2-one (3da). Compound 3da was obtained according to the general procedure as a yellow oil (69.1 mg, 90% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 80 : 20, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 30.4 min (minor enantiomer), t_R = 34.6 min (major enantiomer), 90% ee. [α]²⁵_D + 115.3 (c 0.47, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.54 (t, J = 7.6 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 2H, ArH), 7.29 (d, J = 8.0 Hz, 2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 4.49 (t, J = 7.6 Hz, 1H, CH), 4.38–4.30 (m, 2H, CH₂), 3.95–3.82 (m, 2H, CH₂), 3.78 (d, J = 14.8 Hz, 1H, CH₂), 3.59 (dd, J₁ = 17.0 Hz, J₂ = 7.8 Hz, 1H, CH₂), 3.56 (d, J = 14.8 Hz, 1H, CH₂), 3.51 (dd, J₁ = 16.8 Hz, J₂ = 6.8 Hz, 1H, CH₂), 2.31 (s, 3H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.5, 169.9, 153.4, 137.4, 137.3, 135.5, 133.2, 129.2, 128.52, 128.49, 127.9, 62.1, 44.4, 42.4, 41.2, 36.9, 21.1 ppm. IR (KBr): ν 3055, 3025, 2987, 2960, 2923, 2858, 1778, 1699, 1680, 1617, 1606, 1598, 1580, 1513, 1478, 1448, 1389, 1363, 1325, 1277, 1224, 1202, 1183, 1111, 1073, 1039, 1009, 958, 813, 758, 736, 690, 673, 645, 637, 564, 536 cm⁻¹. HRMS (ESI): m/z calcd for C₂₁H₂₂NO₄S [M + H]⁺ 384.12641, found: 384.12696.

(R)-3-(3-(4-Methoxyphenyl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3ea). Compound 3ea was obtained according to the general procedure as a yellow oil (72.7 mg, 91% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 80 : 20, flow rate 1.0 mL min⁻¹; detection at 254 nm): t_R = 46.9 min (minor enantiomer), t_R = 55.6 min (major enantiomer), 90% ee. [α]²⁵_D + 97.6 (c 0.54, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, J = 7.2 Hz, 2H, ArH), 7.54 (t, J = 7.6 Hz, 1H, ArH), 7.42 (t, J = 7.6 Hz, 2H, ArH), 7.33 (d, J = 8.4 Hz, 2H, ArH), 6.83 (d, J = 8.8 Hz, 2H, ArH), 4.49 (t, J = 7.2 Hz, 1H, CH), 4.38–4.27 (m, 2H, CH₂), 3.95–3.83 (m, 2H, CH₂), 3.78 (d, J = 14.4 Hz, 1H, CH₂), 3.77 (s, 3H, OCH₃), 3.59 (dd, J₁ = 16.6 Hz, J₂ = 7.8 Hz, 1H, CH₂), 3.54 (d, J = 14.4 Hz, 1H, CH₂), 3.49 (dd, J₁ = 17.2 Hz, J₂ = 6.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.6, 169.9, 158.9, 153.3, 135.5, 133.2, 132.3, 129.2, 128.5, 113.8, 62.1, 55.2, 44.1, 42.4, 41.2, 36.9 ppm. IR (KBr): ν 3063, 2998, 2960, 2926, 2838, 1777, 1698, 1678, 1608, 1599, 1580, 1512, 1477, 1464, 1448, 1423, 1389, 1363, 1325, 1305, 1278, 1249, 1224, 1198, 1176, 1109, 1073, 1037, 1014, 958, 831, 757, 690, 672, 631, 553 cm⁻¹. HRMS (ESI): m/z calcd for C₂₁H₂₅N₂O₅S [M + NH₄]⁺ 417.14787, found: 417.14886.

(R)-3-(3-(4-Nitrophenyl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3fa). Compound 3fa was obtained according to the general procedure as a white solid (68.8 mg, 83% yield), mp 39–40 °C. HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 59.7 min (minor enantiomer), t_R = 65.2 (major enantiomer), 88% ee. [α]²⁵_D + 211.3 (c 0.50, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 8.15 (d, J = 8.8 Hz, 2H, ArH), 7.86 (dd, J₁ = 7.8 Hz, J₂ = 1.4 Hz, 2H, ArH), 7.60 (d, J = 8.4 Hz, 2H, ArH), 7.56 (d, J = 7.2 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz, 2H, ArH), 4.60 (dd, J₁ = 8.2 Hz, J₂ = 6.6 Hz, 1H, CH), 4.43–4.33 (m, 2H, CH₂), 3.97–3.86 (m, 2H, CH₂), 3.85 (d, J = 14.8 Hz, 1H, CH₂), 3.62 (dd, J₁ = 17.2 Hz, J₂ = 8.4 Hz, 1H, CH₂), 3.54 (dd, J₁ = 17.4 Hz, J₂ = 6.6 Hz, 1H, CH₂), 3.50 (d, J = 14.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.0, 169.2, 153.4, 148.3, 147.1, 135.0, 133.5, 129.1, 128.6, 128.5, 123.7, 62.2, 43.7, 42.3, 41.0, 36.6 ppm. IR (KBr): ν 3104, 3061, 2989, 2960, 2924, 2854, 1776, 1701, 1678, 1597, 1580, 1522, 1490, 1478, 1448, 1390, 1347, 1322, 1277, 1224, 1200, 1111, 1039, 1013, 957, 857, 842, 833, 757, 736, 697, 644, 620, 565 cm⁻¹. HRMS (ESI): m/z calcd for C₂₀H₁₉N₂O₆S [M + H]⁺ 415.09583, found: 415.09601.

(R)-3-(3-(Naphthalen-1-yl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3ga). Compound 3ga was obtained according to the general procedure as a white solid (63.7 mg, 76% yield), mp 45–46 °C. HPLC (Daicel Chiralpak AD-H column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 32.8 min (minor enantiomer), t_R = 36.7 min (major enantiomer), 84% ee. [α]²⁵_D + 36.6 (c 0.39, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 8.23 (d, J = 7.6 Hz, 1H, ArH), 7.83 (d, J = 8.4 Hz, 1H, ArH), 7.76 (t, J = 8.4 Hz, 3H, ArH), 7.66 (d, J = 6.8 Hz, 1H, ArH), 7.53–7.34 (m, 6H, ArH), 5.42 (s, 1H, CH), 4.36–4.25 (m, 2H, CH₂), 3.93–3.80 (m, 3H, CH₂), 3.79 (d, J = 14.8 Hz, 1H, CH₂), 3.72 (dd, J₁ = 17.2 Hz, J₂ = 6.8 Hz, 1H, CH₂), 3.70 (d, J = 14.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.7, 170.2, 153.5, 135.8, 135.4, 133.2, 130.9, 128.8, 128.5, 128.43, 128.39, 126.4, 125.8, 125.2, 62.1, 42.4, 41.1, 37.5 ppm. IR (KBr): ν 3058, 2987, 2956, 2924, 2858, 1777, 1698, 1680, 1613, 1597, 1580, 1511, 1477, 1448, 1389, 1368, 1306, 1276, 1223, 1201, 1114, 1075, 1040, 1015, 1000, 958, 800, 779, 757, 736, 690, 646, 564 cm⁻¹. HRMS (ESI): m/z calcd for C₂₄H₂₅N₂O₄S [M + NH₄]⁺ 437.15295, found: 437.15380.

(R)-3-(3-(Furan-2-yl)-3-((2-oxo-2-phenylethyl)thio)propanoyl)oxazolidin-2-one (3ha). Compound 3ha was obtained according to the general procedure as a yellow oil (61.1 mg, 85% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 31.3 min (minor enantiomer), 36.8 min (major enantiomer), 88% ee. [α]²⁵_D + 125.8 (c 0.38, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.89 (d, J = 7.2 Hz, 2H, ArH), 7.56 (t, J = 7.2 Hz, 1H, ArH), 7.45 (t, J = 8.0 Hz, 2H, ArH), 7.34 (s, 1H, ArH), 6.30–6.27 (m, 2H, ArH), 4.63 (t, J = 7.2 Hz, 1H, CH), 4.41–4.36 (m, 2H, CH₂), 3.99–3.92 (m, 2H, CH₂), 3.91 (d, J = 15.2 Hz, 1H, CH₂), 3.75 (d, J = 15.2 Hz, 1H, CH₂), 3.61 (d, J = 7.6 Hz, 2H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.4, 169.6, 153.4, 152.5, 142.2, 135.4, 133.3, 128.53, 128.46, 110.2, 107.7, 62.2, 42.4, 38.8, 37.6, 37.1 ppm. IR (KBr): ν 3116, 3059, 2960, 2925, 2873, 2854, 1778, 1698, 1682, 1618, 1597, 1580, 1502, 1478, 1448, 1390, 1341, 1277, 1224, 1202, 1148, 1114, 1075, 1039, 1014, 958, 884, 806, 751, 690, 647, 599, 563 cm⁻¹. HRMS (ESI): m/z calcd for C₁₈H₂₁N₂O₅S [M + NH₄]⁺ 377.11657, found: 377.11698; C₁₈H₁₇NNaO₅S [M + Na]⁺ 382.07196, found: 382.07161.

(S)-3-(3-((2-Oxo-2-phenylethyl)thio)butanoyl)oxazolidin-2-one (3ia). Compound 3ia was obtained according to the general procedure as a yellow oil (15.9 mg, 26% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 18.1 min (minor enantiomer), t_R = 21.7 min (major enantiomer), 78% ee. [α]²⁵_D + 47.8 (c 0.26, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J = 7.2 Hz, 2H, ArH), 7.58 (t, J = 7.2 Hz, 1H, ArH), 7.47 (t, J = 7.6 Hz, 2H, ArH), 4.40 (t, J = 8.0 Hz, 2H, CH₂), 3.98 (t, J = 8.4 Hz, 2H, CH₂), 3.95 (ABq, J = 14.4 Hz, 2H, CH₂), 3.45–3.31 (m, 2H, CH + CH₂), 3.08 (dd, J₁ = 16.4 Hz, J₂ = 6.4 Hz, 1H, CH₂), 1.38 (d, J = 6.8 Hz, 3H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.9, 170.7, 153.4, 135.4, 133.3, 128.7, 128.6, 62.1, 42.43, 42.38, 36.9 36.5, 21.4 ppm. IR (KBr): ν 3059, 2962, 2923, 2873, 2850, 1778, 1697, 1597, 1580, 1478, 1388, 1367, 1318, 1277, 1224, 1199, 1132, 1123, 1105, 1075, 1040, 1005, 963, 758, 706, 690, 655, 622, 564 cm⁻¹. HRMS (ESI): m/z calcd for C₁₅H₁₈NO₄S [M + H]⁺ 308.09511, found: 308.09490; C₁₅H₁₇NNaO₄S [M + Na]⁺ 330.07705, found: 330.07689.

(R)-3-(3-((2-(4-Chlorophenyl)-2-oxoethyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3ab). Compound 3ab was obtained according to the general procedure as a white solid (66.2 mg, 82% yield), mp 33–34 °C. HPLC (Daicel Chiralpak AS-H column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 50.0 min (major enantiomer), t_R = 65.9 min (minor enantiomer), 90% ee. [α]²⁵_D + 133.1 (c 1.00 g/100 mL, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 8.8 Hz, 2H, ArH), 7.40–7.37 (m, 4H, ArH), 7.30 (t, J = 7.2 Hz, 2H, ArH), 7.26–7.23 (m, 1H, ArH), 4.49 (t, J = 7.6 Hz, 1H, CH), 4.39–4.28 (m, 2H, CH₂), 3.95–3.82 (m, 2H, CH₂), 3.74 (d, J = 14.4 Hz, 1H, CH₂), 3.60 (dd, J₁ = 17.2 Hz, J₂ = 8.0 Hz, 1H, CH₂), 3.522 (dd, J₁ = 17.2 Hz, J₂ = 7.2 Hz, 1H, CH₂), 3.520 (d, J = 14.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 193.3, 169.7, 153.3, 140.3, 139.6, 133.7, 129.9, 128.8, 128.5, 128.0, 127.6, 62.1, 44.6, 42.3, 41.0, 36.8 ppm. IR (KBr): ν 3061, 3029, 2991, 2960, 2923, 1778, 1698, 1621, 1588, 1571, 1489, 1479, 1453, 1389, 1363, 1344, 1274, 1224, 1202, 1178, 1113, 1091, 1039, 1010, 958, 846, 819, 761, 736, 701, 670, 627, 525 cm⁻¹. HRMS (ESI): m/z calcd. for C₂₀H₁₉ClNO₄S [M + H]⁺ 404.07178, found: 404.07221.

(R)-3-(3-((2-(4-Bromophenyl)-2-oxoethyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3ac). Compound 3ac was obtained according to the general procedure as a white solid (75.3 mg, 84% yield), mp 35–36 °C. HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 28.4 min (minor enantiomer), t_R = 31.0 (major enantiomer), 90% ee. [α]²⁵_D + 116.1 (c 0.56, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.69 (d, J = 8.4 Hz, 2H, ArH), 7.55 (d, J = 8.4 Hz, 2H, ArH), 7.39 (d, J = 7.2 Hz, 2H, ArH), 7.32–7.22 (m, 3H, ArH), 4.49 (t, J = 7.6 Hz, 1H, CH), 4.39–4.28 (m, 2H, CH₂), 3.95–3.82 (m, 2H, CH₂), 3.73 (d, J = 14.8 Hz, 1H, CH₂), 3.59 (dd, J₁ = 17.2 Hz, J₂ = 8.0 Hz, 1H, CH₂), 3.53 (t, J = 8.6 Hz, 1H, CH₂), 3.51 (d, J = 14.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 193.4, 169.7, 153.3, 140.3, 134.0, 131.8, 130.0, 128.5, 128.4, 127.6, 62.1, 44.6, 42.3, 41.0, 36.8 ppm. IR (KBr): ν 3085, 3060, 3030, 2960, 2924, 2873, 2854, 1778, 1698, 1622, 1585, 1568, 1480, 1453, 1389, 1363, 1279, 1224, 1202, 1178, 1113, 1071, 1039, 1007, 958, 843, 814, 759, 737, 701, 671, 626, 577, 538, 501 cm⁻¹. HRMS (ESI): m/z calcd for C₂₀H₁₉BrNO₄S [M + H]⁺ 448.02127, found: 448.02195; C₂₀H₂₂BrN₂O₄S [M + NH₄]⁺ 465.04782, found: 465.04906.

(R)-3-(3-((2-Oxo-2-(p-tolyl)ethyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3ad). Compound 3ad was obtained according to the general procedure as a yellow oil (71.2 mg, 93% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 22.9 min (minor enantiomer), t_R = 25.3 (major enantiomer), 90% ee. [α]²⁵_D + 152.8 (c 0.62, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, J = 8.0 Hz, 2H, ArH), 7.41 (d, J = 7.2 Hz, 2H, ArH), 7.30 (t, J = 7.2 Hz, 2H, ArH), 7.25–7.20 (m, 3H, ArH), 4.52 (t, J = 7.6 Hz, 1H, CH), 4.38–4.27 (m, 2H, CH₂), 3.95–3.81 (m, 2H, CH₂), 3.75 (d, J = 14.8 Hz, 1H, CH₂), 3.62 (dd, J₁ = 17.0 Hz, J₂ = 7.8 Hz, 1H, CH₂), 3.54 (d, J = 14.8 Hz, 1H, CH₂), 3.52 (dd, J₁ = 17.0 Hz, J₂ = 7.0 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.1, 169.8, 153.3, 144.1, 140.5, 132.9, 129.2, 128.6, 128.5, 128.1, 127.5, 62.1, 44.6, 42.4, 41.1, 36.9, 21.6 ppm. IR (KBr): ν 3060, 3031, 2987, 2960, 2923, 1777, 1699, 1670, 1606, 1585, 1573, 1492, 1478, 1453, 1388, 1342, 1313, 1279, 1223, 1200, 1181, 1134, 1113, 1078, 1039, 1008, 958, 914, 896, 838, 808, 760, 736, 701, 672, 629, 593, 553 cm⁻¹. HRMS (ESI): m/z calcd for C₂₁H₂₂NO₄S [M + H]⁺ 384.12641, found: 384.12675.

(R)-3-(3-((2-(4-Methoxyphenyl)-2-oxoethyl)thio)-3-phenylpropanoyl) oxazolidin-2-one (3ae). Compound 3ae was obtained according to the general procedure as a yellow oil (75.9 mg, 95% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 34.3 min (minor enantiomer), t_R = 37.7 min (major enantiomer), 90% ee. [α]²⁵_D + 171.5 (c 0.67, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.82 (d, J = 9.2 Hz, 2H, ArH), 7.41 (d, J = 7.2 Hz, 2H, ArH), 7.30 (t, J = 7.2 Hz, 2H, ArH), 7.25–7.21 (m, 1H, ArH), 6.89 (d, J = 9.2 Hz, 2H, ArH), 4.52 (t, J = 7.2 Hz, 1H, CH), 4.38–4.27 (m, 2H, CH₂), 3.95–3.81 (m, 2H, CH₂), 3.85 (s, 3H, OCH₃), 3.73 (d, J = 14.8 Hz, 1H, CH₂), 3.61 (dd, J₁ = 17.2 Hz, J₂ = 8.0 Hz, 1H, CH₂), 3.524 (d, J = 14.8 Hz, 1H, CH₂), 3.520 (dd, J₁ = 17.0 Hz, J₂ = 7.0 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 193.1, 169.8, 163.5, 153.3, 140.6, 130.8, 128.5, 128.4, 128.0, 127.5, 113.7, 62.1, 55.4, 44.6, 42.3, 41.1, 36.7 ppm. IR (KBr): ν 3060, 3029, 3006, 2966, 2924, 2841, 1777, 1699, 1668, 1599, 1575, 1511, 1492, 1478, 1454, 1422, 1388, 1311, 1282, 1261, 1224, 1206, 1173, 1138, 1113, 1079, 1036, 1013, 958, 914, 845, 833, 808, 760, 736, 701, 672, 627, 602, 561, 552, 510 cm⁻¹. HRMS (ESI): m/z calcd for C₂₁H₂₂NO₅S [M + H]⁺ 400.12132, found: 400.12138.

(R)-3-(3-((2-(3-Methoxyphenyl)-2-oxoethyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3af). Compound 3af was obtained according to the general procedure as a yellow oil (67.9 mg, 85% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): t_R = 25.9 min (minor enantiomer), t_R = 27.9 min (major enantiomer), 90% ee. [α]²⁰_D + 157.8 (c 1.67, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ 7.42–7.38 (m, 4H, ArH), 7.33–7.29 (m, 3H, ArH), 7.26–7.22 (m, 1H, ArH), 7.10–7.07 (m, 1H, ArH), 4.52 (t, J = 7.2 Hz, 1H, CH), 4.38–4.27 (m, 2H, CH₂), 3.95–3.81 (m, 2H, CH₂), 3.83 (s, 3H, OCH₃), 3.77 (d, J = 14.8 Hz, 1H, CH₂), 3.61 (dd, J₁ = 17.0 Hz, J₂ = 7.8 Hz, 1H, CH₂), 3.54 (d, J = 14.8 Hz, 1H, CH₂), 3.52 (dd, J₁ = 17.2 Hz, J₂ = 6.8 Hz, 1H, CH₂) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 194.3, 169.8, 159.7, 153.3, 140.5, 136.8, 129.5, 128.5, 128.1, 127.6, 121.1, 119.8, 112.7, 62.1, 55.4, 44.6, 42.3, 41.1, 37.0 ppm. IR (KBr): ν 3056, 3028, 2987, 2964, 2918, 2835, 1778, 1698, 1597, 1583, 1487, 1464, 1453, 1430, 1388, 1337, 1287, 1267, 1224, 1112, 1079, 1039, 1008, 958, 893, 865, 757, 736, 702, 685 cm⁻¹. HRMS (ESI): m/z calcd for C₂₁H₂₂NO₅S [M + H]⁺ 400.12132, found: 400.12167.

(R)-3-(3-((2-oxopropyl)thio)-3-phenylpropanoyl)oxazolidin-2-one (3ag) and 3-((3S)-4-hydroxy-4-methyl-2-phenyltetrahydrothiophene-3-carbonyl)oxazolidin-2-one (4ag). Compound 3ag and 4ag was obtained according to the general procedure as a colorless oil (47.3 mg, 77% yield). HPLC (Daicel Chiralpak IB column, n-hexane–2-propanol 70 : 30, flow rate 1.0 mL min⁻¹, detection at 254 nm): 3ag: t_R = 8.7 min (minor enantiomer), t_R = 9.3 min (major enantiomer), 85% ee; 4ag: t_R = 19.3 min (minor enantiomer), t_R = 23.1 min (major enantiomer), 72% ee. HRMS (ESI): m/z calcd for C₁₅H₁₈NO₄S [M + H]⁺ 308.09511, found: 308.09490; calcd for C₁₅H₁₇NNaO₄S [M + Na]⁺ 330.07705, found: 330.07684.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (Grant no. 21272024).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of new compounds, and HPLC chromatograms. CCDC 982304. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra02400a

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