Enantioselective Syntheses and Sensory Properties of 2-Methyl

School of Food Chemistry, Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University, Beijing 100048, China. J. Agric. Foo...
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Enantioselective Syntheses and Sensory Properties of 2‑Methyltetrahydrofuran-3-thiol Acetates Yifeng Dai, Junqiang Shao, Shaoxiang Yang, Baoguo Sun, Yongguo Liu, Ting Ning, and Hongyu Tian* School of Food Chemistry, Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University, Beijing 100048, China ABSTRACT: The enantioselective synthesis of four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate was achieved. The two enantiomers of the important intermediate cis-2-methyl-3-hydroxy-tetrahydrofuran were obtained by Sharpless asymmetric dihydroxylation (AD), whereas the two enantiomers of trans-2-methyl-3-hydroxy-tetrahydrofuran were derived from the corresponding optically active cis-isomers by Mitsunobu reaction. Each stereoisomer of 2-methyl-3-hydroxy-tetrahydrofuran went through mesylation and nucleophilic substitution to afford the corresponding product with specific configuration. (2R,3S)and (2R,3R)-2-methyl-tetrahydrofuran-3-thiol acetate were obtained in 80% ee, whereas the (2S,3R)- and (2S,3S)-isomers were in 62% ee. The odor properties of the synthesized four stereoisomers were evaluated by gas chromatography−olfactometry (GC−O), which revealed perceptible differences among stereoisomers both in odor features and in intensities. KEYWORDS: 2-methyl-tetrahydrofuran-3-thiol acetate, Sharpless AD, Mitsunobu reaction, enantioselective synthesis, sensory properties, GC−O

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INTRODUCTION The olfactory properties of over 1400 enantiomers have been reported1 since Rienäcker and Ohloff published the first data regarding the enantioselective perception of β-citronellol in 1961.2 It is now well recognized that stereoisomers of many chiral chemical compounds are perceived differently as odorants by the human nose.3 In addition to the differences in sensory properties, the stereoisomers of chiral odorants, such as Galaxolide and Tonalide, also have been found to be metabolized in living beings at different rates.4 Therefore, it is significant to identify the desired odor-active isomers and further fulfill their commercial application from the prospective of improving odor qualities and reducing potential toxicological risks. Many research interests have been focused on the enantioselective preparation and organoleptic properties of chiral aroma compounds in recent years.5−11 Sulfur-containing compounds are an important category of flavor compounds due to their low odor thresholds and their unique odor features.12,13 They are identified widely in volatile components of many foods and make significant contribution to food flavor,14−18 especially to meat aroma.19−23 2-Methytetrahydrofuran-3-thiol is a representative sulfur-containing compound having meat aroma, which exists in four stereoisomers due to the two chiral centers in the molecule. It is wellknown that (±)-trans-isomer possesses stronger meaty and roasted notes while (±)-cis-isomer is weaker and has more sulfury and musty notes. Goeke prepared the four stereoisomers by resolution and found their remarkable differences in odor features and intensities.24 In comparison, the information about its acetylated form, 2-methyl-tetrahydrofuran-3-thiol acetate, is far more retarded, which was not been approved as a flavor compound in the United States by the Flavor Expert Panel (FEXPAN) before 2011 and appeared on the FEMA (Flavor and Extract Manufactures’ Association) GRAS (generally recognized as safe) list 25 under no. 4686.25 In © 2015 American Chemical Society

our previous work, (±)-trans- and (±)-cis-isomers of 2-methyltetrahydrofuran-3-thiol acetate were prepared, and the odor properties were evaluated.26 The results indicated that the diastereoisomers presented some organoleptic differences. However, as far as we know, the sensory properties of the four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate 1 (Figure 1) are still unknown. Therefore, the aim of this work

Figure 1. Four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate.

was to synthesize the four stereoisomers enantioselectively and investigate their sensory properties. In Goeke’s work, the racemic diastereoisomers of 2-methyl-tetrahydrofuran-3-thiol were prepared by an iodocyclization approach starting from (3Z)- and (3E)-pent-3-en-1-ols, respectively. Also, (±)-cis-thiol was resolved via the camphanic acid thioesters to give the two enantiomers separately, whereas the two enantiomers of transthiol were produced via enzymatic resolution of cis-2-methyl-3hydroxytetrafuran using the lipase pseudomonas f luorescence. Our present work tried a different way to prepare the four stereoisomers of 1 via chemical asymmetric catalytic approach (Figure 2). Received: Revised: Accepted: Published: 464

August 11, 2014 January 5, 2015 January 5, 2015 January 5, 2015 DOI: 10.1021/jf503866x J. Agric. Food Chem. 2015, 63, 464−468

Article

Journal of Agricultural and Food Chemistry

Figure 2. Synthetic routes leading to the optically active 2-methyl-tetrahydrofuran-3-thiol acetates.

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NMR (75 MHz, CDCl3): δ 17.5 (Me (C-5), 31.9 (C-2), 36.8 (Me (mesyl)), 69.4 (C-1), 124.5 (C-4), 128.7 (C-3). (2R,3R)- or (2S,3S)-cis-2-Methyl-3-hydroxy-tetrahydrofuran 5. The procedure for the Sharpless AD was adapted from the literature.29 To a well-stirred mixture of AD-mix-β or AD-mix-a (11.05 g) in tbutyl alcohol−water (50 mL/50 mL) at room temperature was added 4 (1.312 g, 8 mmol). The reaction mixture was stirred at 5−10 °C overnight in the dark. Next, solid sodium sulfite (4 g) was added, and the mixture was stirred for an additional hour. Methylene chloride (30 mL) was added to the reaction mixture, and after separation of the layers, the aqueous phase (upper layer) was further extracted with CH2Cl2. The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give an oil, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 3/1) to afford (2R,3R)- or (2S,3S)-5 as a light yellow oil. Data of (2R,3R)-5 (from AD-mix-β). 88% yield; purity, 95% by GC; 1 80% ee; [α]20 D = −30.6° (c 4.80, CHCl3). H NMR (300 MHz, CDCl3): δ 1.27 (3H, d, J = 6.3 Hz, Me), 1.93 (1H, m, H-4a), 2.22 (1H, m, H-4b), 3.73 (2H, m, H-3, H-5a), 4.03 (1H, dd, J = 15.9, 8.1 Hz, H-5b), 4.17 (1H, m, H-2). 13C NMR (75 MHz, CDCl3): δ 13.7 (Me), 35.4 (C-4), 65.5 (C-5), 72.8 (C-3), 78.6 (C-2). Data of (2S,3S)-5 (from AD-mix-α). 85% yield; purity, 96% by GC; 1 13 62% ee; [α]20 D = +23.7° (c 4.50, CHCl3). The H NMR and C NMR spectra of (2S,3S)-5 were the same as those of the antipode. (2R,3R)- or (2S,3S)-cis-2-Methyl-3-mesyloxy-tetrahydrofuran 6. (2R,3R)- or (2S,3S)-6 was prepared according to our previously published procedures.26 (2R,3R)- or (2S,3S)-5 reacted with MsCl to give (2R,3R)- or (2S,3S)-6. Data of (2R,3R)-6. 89% yield; purity, 98% by GC; 80% ee; [α]20 D = −19.7° (c 5.23, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.33 (3H, d, J = 6.6 Hz, Me-2), 2.34 (2H, m, H-4), 3.05 (3H, s, Me (mesyl)), 3.80 (1H, td, J = 8.4, 5.4 Hz, H-5a), 4.08 (1H, q, J = 8.1 Hz, H-5b), 3.95 (1H, qd, J = 6.3, 3.6 Hz, H-2), 5.13 (1H, ddd, J = 5.4, 3.6, 2.1 Hz, H3). 13C NMR (75 MHz, CDCl3): δ 14.4 (Me-2), 34.0 (C-4), 38.5 (Me (mesyl)), 65.8 (C-5), 77.2 (C-2), 81.9 (C-3). Data of (2S,3S)-6. 90% yield; purity, 96% by GC; 62% ee; [α]20 D = +15.5° (c 5.06, CHCl3). The 1H NMR and 13C NMR spectra of (2S,3S)-6 were in line with those of the antipode. (2R,3S)- or (2S,3R)-trans-2-Methyl-tetrahydrofuran-3-thiol Acetate 1. (2R,3S)- or (2S,3R)-1 was prepared according to our previously published procedures.26 (2R,3R)- or (2S,3S)-6 reacted with AcSH to give (2R,3S)- or (2S,3R)-1.

MATERIALS AND METHODS

Chemicals. Triphenylphosphine (Ph3P), diisopropyl azodicarboxylate (DIAD), and LiAlH4 were purchased from Beijing Bailingwei Science and Technology Co. (Beijing, China), AD-mix-α and AD-mixβ were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO), and the others were purchased from Beijing Huaxue Shiji Co. (Beijing, China). Syntheses. (3E)-Pent-3-enoic Acid 2. The procedure for the preparation of 2 was adapted from the literature.27 To a 1 L round bottomed flask equipped with a condenser and a bubbler connected to the exit of the condenser was added a solution of malonic acid (1 mol, 104 g), piperidinium acetate (from 0.85 g of piperidine and 0.6 g of acetic acid, 0.01 mol), and propionaldehyde (0.5 mol, 36.3 mL) in DMSO (400 mL). The reaction mixture was stirred at 40 °C for 2 h. Next, the solution was heated in an oil bath at 100 °C. A rapid evolution of carbon dioxide was observed. Heating was maintained until the evolution of carbon dioxide ceased. The solution was cooled to room temperature, poured into cold water (1 L), and extracted with diethyl ether. The combined extracts were washed with water, brine, dried over anhydrous MgSO4, and evaporated under reduced pressure. The residue was distilled under vacuum (0.4 kPa, 60−65 °C) to give (3E)-pent-3-enoic acid 2 as a colorless oil (30 g, 60% yield). The product was used without further purification for the next step. 1H NMR (300 MHz, CDCl3): δ 1.68 (3H, d, J = 6.0 Hz, H-5), 3.05 (2H, d, J = 5.7 Hz, H-2), 5.54 (2H, m, H-3, H-4), 10−12 (1H, br, −COOH). 13C NMR (75 MHz, CDCl3): δ 17.9 (C-5), 37.8 (C-2), 121.9 (C-4), 130.0 (C-3), 179.0 (C-1). The spectral data of the obtained product were consistent with those as described by Thibonnet.28 (3E)-Pent-3-en-1-ol 3 and (3E)-Pent-3-en-1-yl Mesylate 4. These two compounds were prepared according to our previously published procedures.26 3 was obtained by reduction of 2 with LiAlH4 (88% yield), and then reacted with MsCl to give 4 (92% yield). Data of 3, 1H NMR (300 MHz, CDCl3): δ 1.65 (3H, d, J = 6.3 Hz, H-5), 2.22 (2H, m, H-2), 3.59 (2H, t, J = 6.3 Hz, H-1), 5.38 (1H, m, H-4), 5.57 (1H, m, H-3). 13C NMR (75 MHz, CDCl3): δ 18.0 (C-5), 35.9 (C-2), 62.0 (C-1), 127.2 (C-4), 128.1 (C-3). Data of 4, 1H NMR (300 MHz, CDCl3): δ 1.64 (3H, d, J = 6.3 Hz, H-5), 2.39 (2H, q, J = 6.9 Hz, H-2), 2.96 (3H, s, Me (mesyl)), 4.17 (2H, t, J = 6.9 Hz, H-1), 5.36 (1H, m, H-4), 5.57 (1H, m, H-3). 13C 465

DOI: 10.1021/jf503866x J. Agric. Food Chem. 2015, 63, 464−468

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Journal of Agricultural and Food Chemistry

m, H-3). 13C NMR (75 MHz, CDCl3): δ 16.8 (Me-2), 30.6 (Me (Ac)), 33.5 (C-4), 46.3 (C-3), 65.9 (C-5), 76.5 (C-2), 195.4 (CO). Data of (2S,3S)-1. 84% yield; purity, 98% by GC; 62% ee (tR 22.265 min); [α]20 D = −8.09° (c 4.37, CHCl3). The NMR data were consistent with those of (2R,3R)-1. Analytical Methods. Enantioselective Analysis. An Agilent 6890 GC with a flame ionization detector (FID) was used for GC analyses (Agilent Technologies, Santa Clara, CA). The columns used included a B-PM chiral capillary column (50 m × 0.25 mm × 0.25 μm), and a G-TA (50 m × 0.25 mm × 0.125 μm) from the ASTEC Co. (Chattanooga, TN). The analytical conditions for 1 and 5 (G-TA, 50 m) were as follows: injector temperature 250 °C, detector temperature 250 °C, N2 as carrier gas, constant flow mode 0.8 mL/min, split ratio 50/1. The oven temperature was programmed from 50 to 170 °C at a rate of 5 °C/min, and held at 170 °C for 10 min. A different oven temperature program used for cis-6 (B-PM, 50 m) was as follows: raised from 50 to 140 °C at a rate of 20 °C/min, and held at 140 °C for 2 min; raised to 155 °C at 0.2 °C/min, and was held at 155 °C for 5 min, then raised to 200 °C at 20 °C/min, and was held at 200 °C for 2 min. For trans-6 (B-PM, 50 m), the conditions were as follows: raised from 50 to 120 °C at a rate of 5 °C/min, and held at 120 °C for 10 min; raised to 200 °C at 8 °C/min, and was held at 200 °C for 2 min. The concentration of samples was about 0.5 wt % in ethanol, and the injection volume was about 0.6 μL. Chiral HPLC Analysis. HPLC analyses were conducted by an Agilent 1200 HPLC apparatus (column, Chiralcel OD-H or OB-H column (0.46 cm, ϕ × 15 cm) (Daicel, Japan); solvent, n-hexane-iPrOH (9/1); flow rate, 0.5 mL/min; UV detection, 254 nm). Chiral GC−O Analysis and Evaluation. Chiral GC−O analysis was carried out using an Agilent 6890N gas chromatograph installed with a chiral capillary column G-TA (50 m × 0.25 mm × 0.25 μm), a FID, and a sniffing port (Sniffer 9000; Brechbühler Scientific Analytical Solutions, Schlieren, Switzerland). The analytical conditions were the same as those in the determination of ee values by GC analysis. The column effluent was divided (ratio 1:1) between the FID detector and the sniffing port through one Y-shaped glass splitter. The effluent to the sniffing port was enclosed with a stream of humidified air of 16 mL/min and transferred to the glass detection cone by one length of capillary column at the temperature of 250 °C. Sensory Panel. The panel consisted of 5 healthy, nonsmoking judges, 2 males and 3 females, aged 23−29. All panelists belong to the Beijing Key Laboratory of Flavor Chemistry, Beijing Technology and Business University. The judges were selected for their experience in assessing volatile flavor compounds of foods. A verbal description of the odor was obtained from the panelist when the peak appeared at the GC at the same time. General Conditions for Odor Thresholds. Odor thresholds were determined according to the procedure described by Ullrich and Grosch.31 The defined amounts of samples and the internal standard trans-2-decenal, the odor threshold of which in air is 2.7 ng/L,32 were dissolved in EtOH and diluted stepwise by a factor of 1:1 (v/v). The aliquots were analyzed by GC−O until no odor was detectable. NMR Spectroscopy. 1H NMR and 13C NMR spectra were recorded at 300 and 75 MHz, respectively, with an Avance 300 spectrometer. The experiments were done in full automation using standard parameter sets of the TOPSPIN 2.0 software package (Bruker). The compounds were dissolved in deuterated chloroform. The spectra were recorded at 25 °C. Optical Rotations. Optical rotations were measured on an Autopol IV digital automatic polarimeter (Rudolph, Hackettstown, NJ).

Data of (2R,3S)-1. 81% yield; purity, 97% by GC; 80% ee (tR 1 21.540 min); [α]20 D = +27.6° (c 4.63, CHCl3). H NMR (300 MHz, CDCl3): δ 1.28 (3H, d, J = 6.0 Hz, Me-2), 1.85 (1H, m, H-4a), 2.49 (1H, m, H-4b), 2.34 (3H, s, Me (Ac)), 3.52 (1H, td, J = 8.7, 7.2 Hz, H-5), 3.96 (1H, td, J = 8.7, 5.7 Hz, H-5), 3.71−3.88 (2H, m, H-2, H3). 13C NMR (75 MHz, CDCl3): δ 19.2 (Me-2), 30.6 (Me (Ac)), 33.2 (C-4), 46.6 (C-3), 66.7 (C-5), 79.9 (C-2), 195.3 (CO). Data of (2S,3R)-1. 83% yield; purity, 98% by GC; 62% ee (tR 1 13 20.694 min); [α]20 D = −20.5° (c 4.49, CHCl3). The H NMR and C NMR spectra of (2S,3R)-1 were in line with those of the antipode. (2R,3S)- or (2S,3R)-trans-2-Methyl-3-p-nitrobenzoyloxy-tetrahydrofuran 7. (2R,3S)- or (2S,3R)-7 was prepared according to our previously published procedures.26 (2R,3R)- or (2S,3S)-5 was treated with Ph3P, DIAD, and p-nitrobenzoic acid to give (2R,3S)- or (2S,3R)7. Data of (2R,3S)-7. 69% yield; mp 46−49 °C; [α]20 D = +21.3° (c 4.80, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.31 (3H, d, J = 6.3 Hz, Me-2), 2.10 (1H, m, H-4a), 2.35 (1H, m, H-4b), 3.83 (1H, m, H-5a), 4.06 (1H, m, H-5b), 4.14 (1H, m, H-2), 5.14 (1H, m, H-3), 8.18 (2H, d, J = 9 Hz, H-aryl), 8.27 (2H, d, J = 9 Hz, H-aryl). 13C NMR (75 MHz, CDCl3): δ 18.9 (Me-2), 32.0 (C-4), 66.6 (C-5), 79.9 (C-2), 81.1 (C-3), 123.0 (C-3′ and C-5′ (aryl)), 130.2 (C-2′ and C-6′ (aryl)), 134.9 (C-1′ (aryl)), 150.0 (C-4′ (aryl)), 164.2 (CO). Data of (2S,3R)-7. 68% yield; mp 47−51 °C; [α]20 D = −15.8° (c 4.80, CHCl3). The 1H NMR and 13C NMR spectra of (2S,3R)-7 were in line with those of the antipode. (2R,3S)- or (2S,3R)-trans-2-Methyl-3-hydroxy-tetrahydrofuran 5. To a solution of NaOH (6.4 g, 160 mmol) in methanol/ tetrahydrofuran (124 mL, 30:1) was added (2R,3S)- or (2S,3R)-7 (12 g, 48 mmol) at room temperature. The mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and the mixture was extracted four times with diethyl ether. The combined organic phases were washed once with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate, 6/1) to give (2R,3S)- or (2S,3R)-5 as a light yellow oil. Data of (2R,3S)-5. 90% yield; purity, 97% by GC; 80% ee; [α]20 D = +35.5° (c 2.74, MeOH) [lit.30 [α]23 D +11.7° (c 2.5, MeOH, 27% ee)]. 1 H NMR (300 MHz, CDCl3): δ 1.76 (3H, d, J = 6.3 Hz, Me-2), 1.84 (1H, m, H-4a), 2.16 (1H, m, H-4b), 2.23 (1H, br, −OH), 3.82 (1H, m, H-3), 3.87−4.01 (3H, m, H-2, H-5). 13C NMR (75 MHz, CDCl3): δ 18.8 (Me-2), 34.3 (C-4), 66.0 (C-5), 76.7 (C-3), 81.7 (C-2). Data of (2S,3R)-5. 87% yield; purity, 96% by GC; 62% ee; [α]20 D = −26.8° (c 4.28, MeOH) [lit.30 [α]23 D = −29.9° (c 2.5, MeOH, 70% ee)]. The NMR data were consistent with those of (2R,3S)-5. (2R,3S)- or (2S,3R)-trans-2-Methyl-3-mesyloxytetrahydrofuran 6. (2R,3S)- or (2S,3R)-5 was converted to the corresponding mesylate (2R,3S)- or (2S,3R)-6 by the same procedure for (2R,3R)- or (2S,3S)6. Data of (2R,3R)-6. 91% yield; purity, 97% by GC; 80% ee; [α]20 D = +20.0° (c 6.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.26 (3H, d, J = 6.6 Hz, Me-2), 2.18 (1H, m, H-4a), 2.24 (1H, m, H-4b), 3.04 (3H, s, Me (mesyl)), 3.89 (1H, td, J = 9.3, 6.6 Hz, H-5a), 4.01 (1H, td, J = 8.4, 3.3 Hz, H-5b), 4.12 (1H, m, H-2), 4.82 (1H, m, H-3). 13C NMR (75 MHz, CDCl3): δ 18.5 (Me-2), 32.5 (C-4), 38.4 (Me (mesyl)), 66.3 (C-5), 79.7 (C-2), 85.1 (C-3). Data of (2S,3S)-6. 92% yield; purity, 98% by GC; 62% ee; [α]20 D = −14.5° (c 5.50, CHCl3). The NMR data were consistent with those of (2R,3R)-6. (2R,3R)- or (2S,3S)-cis-2-Methyl-tetrahydrofuran-3-thiol Acetate 1. (2R,3S)- or (2S,3R)-6 was converted to the corresponding acetate (2R,3R)- or (2S,3S)-1 by the same procedure for (2R,3S)- or (2S,3R)1. Data of (2R,3R)-1. 85% yield; purity, 97% by GC; 80% ee (tR 1 21.939 min); [α]20 D = +10.7° (c 4.95, CHCl3). H NMR (300 MHz, CDCl3): δ 1.19 (3H, d, J = 6.3 Hz, Me-2), 1.93 (1H, m, H-4a), 2.48 (1H, m, H-4b), 2.34 (3H, s, Me (Ac)), 3.75 (1H, td, J = 8.4, 6.3 Hz, H-5), 3.90 (1H, td, J = 8.4, 6.3 Hz, H-5), 4.13 (1H, m, H-2), 4.05 (1H,

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RESULTS AND DISCUSSION Preparation and Configuration Assignment of the Four Stereoisomers of 2-Methyl-tetrahydrofuran-3-thiol Acetate. The substrate for Sharpless AD, (3E)-pent-3-en-1-yl mesylate 4, was easily prepared by the Knoevenagel condensation of propanal and malonic acid, followed by reduction with LiAlH4 and mesylation. The procedure for Knoevenagel condensation was modified according to the 466

DOI: 10.1021/jf503866x J. Agric. Food Chem. 2015, 63, 464−468

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Journal of Agricultural and Food Chemistry literature using DMSO as solvent instead of xylene,27 which led to the remarkable improvements of both chemical selectivity and yield as compared to the results we published earlier.26 (3E)-Pent-3-enoic acid 2 was obtained in about 60% yield with only 2% byproduct (2E)-pent-2-enoic acid. The chiral centers of the four stereoisomers of 2-methyltetrahydrofuran-3-thiol acetate 1 were originated from Sharpless AD of (3E)-pent-3-en-1-yl mesylate 4. 2-Methyl-3-hydroxytetrahydrofuran 5 was produced by Sharpless AD of 4 followed by an intramolecular SN2 nucleophilic substitution in situ. The relative configuration of 5 was determined to be cis by comparing the 1H NMR data with those of 2-methyl-3hydroxy-tetrahydrofuran synthesized by oxidation of (3E)-pent3-en-1-yl mesylate with H2O2/HCOOH or KMnO4.26 Also, the absolute configuration of 5 was tentatively assigned according to an empirical model developed by Sharpless et al.33 (2R,3R)cis-5 was obtained using AD-mix-β as an oxidant, whereas (2S,3S)-cis-5 was obtained from AD-mix-α. The specific rotation value of optically active (2R,3S)- or (2S,3R)-trans-5 derived from the above obtained (2R,3R)- or (2S,3S)-cis-5 by Mitsunobu reaction was consistent with the literature data,30 which confirmed the aforementioned tentative assignment of absolute configuration. The chiral GC analysis of cis-5 was carried out on G-TA (50 m × 0.25 mm × 0.125 μm) using trifluoroacetyl γ-cyclodextrin as chiral stationary phase, which enabled the separation of the two enantiomers of cis-5. (2R,3R)-5 from AD-mix-β was obtained in 80% ee, whereas (2S,3S)-5 was found in a relatively lower ee of 62%. (2R,3R)- or (2S,3S)-5 was converted to the target compound (2R,3S)- or (2S,3R)-1, respectively, through SN2 substitution of the corresponding mesylate by AcSH. The ee values of the intermediate mesylates were determined on B-PM (50 m × 0.25 mm × 0.125 μm), and the target compounds were analyzed by the same way as 5. The obtained results of optical purity were consistent with those of 5. To obtain the two enantiomers of cis-1, (2R,3R)- or (2S,3S)5 produced by the Sharpless AD was subjected to Mitsunobu reaction, which gave (2R,3S)- or (2S,3R)-trans-2-methyl-3-pnitrobenzoyloxy-tetrahydrofuran 7. The determination of the ee values of the obtained benzoates failed by HPLC analyses on different columns, such as Chiralcel column OD-H and OB-H. The benzoates were then hydrolyzed to produce the two enantiomers of trans-5, respectively, which went through mesylation and nucleophilic substitution to afford the two enantiomers of cis-1, that is, (2R,3R)- and (2S,3S)-1. The ee values of (2R,3R)- and (2S,3S)-1 were in accord with the starting material (2R,3R)- and (2S,3S)-5, which indicated no racemization occurred in Mitsunobu reaction, mesylation, and nucleophilic substitution. Determination of Odor Properties. The enantiomers of cis- or trans-1 were separated completely by a chiral GC column G-TA (50 m × 0.25 mm × 0.25 μm), on which the peak resolution Rs for two enantiomers of cis- or trans-1 was 1.5 and 4.0, respectively. The odor properties of the four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate 1 were evaluated by the panel via chiral GC−O (Table 1). Among the four stereoisomers, both enantiomers of trans-1 were found to possess meaty aroma as a top note, whereas the two enantiomers of cis-1 were described to present mainly a top note of pungent smell of raw garlic and onion. In addition, the odor discrepancy between the two enantiomers of trans-1 or cis1 also exited. For the enantiomers of trans-1, (2S,3R)-1 smelled like roasted meat with an undernote of burnt and fried onion;

Table 1. Odor Descriptions and Odor Thresholds of the Four Stereoisomers of 1 odor thresholds in aira (ng/L)

stereoisomers

odor description

(2R,3S)-1

meaty, sesame paste, fried onion and garlic, sweet, sulfurous roasted meat, burnt, fried onion raw garlic and onion-like, savory, musty, sulfurous raw garlic and onion-like, sulfurous

(2S,3R)-1 (2R,3R)-1 (2S,3S)-1 a

18.6 7.3 3.8 5.7

Mean values of duplicates, differing not more than ±10%.

in comparison, (2R,3S)-1 smelled meaty with an undernote of sesame paste, fried onion and garlic, sweet, and sulfurous. Also, the former smelled more pleasant. For the enantiomers of cis-1, (2R,3R)-1 presented additional savory and musty notes as compared to (2S,3S)-1. Determination of Odor Thresholds. The odor thresholds of the four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate 1 were determined following the procedure described by Ullrich and Grosch.31 Ethanol was used as solvent instead of diethyl ether because it was difficult to guarantee the accuracy of the sample concentration due to the high volatility of ether solution. For each stereoisomer, the sensory evaluations were performed in duplicate, and two stock solutions with similar concentration were prepared for each stereoisomer. The samples were evaluated by one judge, and the lowest concentration was double-checked by three consecutive GC− O runs. The odor thresholds of the two enantiomers of trans-1, that is, (2R,3S)- and (2S,3R)-1, were determined to be 18.6 and 7.3 ng/L air, respectively. In comparison, the odor thresholds of cis-1, that is, (2R,3R)- and (2S,3S)-1, were slightly lower, which were 3.8 and 5.7 ng/L air, respectively. The (2R,3R)-isomer was observed to have the lowest threshold, whereas the (2R,3S)-isomer had the highest threshold. Both isomers with relatively lower thresholds of cis- and trans-1 were found to be (3R)-configuration. As compared to the odor thresholds of four stereoisomers of the corresponding thiol reported by Goeke,24 the acetates had much higher thresholds. We tried to use the same procedure to determine the odor thresholds of the thiols prepared by hydrolysis of the corresponding stereoisomers of acetates. However, the separation of stereoisomers of thiols failed on chiral GC columns we have in our lab. In conclusion, the four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol acetate were prepared by application of Sharpless AD in conjunction with the Mitsunobu reaction. The GC−O data revealed that the four stereoisomers presented perceptible differences in odor properties. It looked as though the corresponding thiols had much lower odor thresholds. However, further work is needed, such as the preparation of enantiomerically pure stereoisomers, to determine the odor thresholds of these pure samples in water or air accurately.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: 86-10-68984545. Fax: 86-10-68985219. E-mail: tianhy@ btbu.edu.cn. Funding

This work was supported by the National Natural Science Foundation of China (no. 31271932), the National Key Technology R&D Program (2011BAD23B01), and the 467

DOI: 10.1021/jf503866x J. Agric. Food Chem. 2015, 63, 464−468

Article

Journal of Agricultural and Food Chemistry

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Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions (CIT&TCD20140306). Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED DIAD, diisopropyl azodicarboxylate; MsCl, methanesulfonyl chloride; AcSH, thiolacetic acid; AD, asymmetricdihyoxylation; HPLC, high-performance liquid chromatography; Ph3P, triphenylphosphine; PNBA, p-nitrobenzoic acid; DMSO, dimethyl sulfoxide; GC−O, gas chromatography−olfactometry; FEMA, Flavor and Extract Manufacturers’ Association; FEXPAN, Flavor Expert Panel; GRAS, generally recognized as safe; FID, flame ionization detector

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DOI: 10.1021/jf503866x J. Agric. Food Chem. 2015, 63, 464−468