Enantioselective syntheses and sensory properties of 2-methyl-tetrahydrofuran-3-thiol acetates

Article abstract of DOI:10.1021/jf503866x

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 di fferences among stereoisomers both in odor features and in intensities.

Full text of DOI:10.1021/jf503866x

Article
pubs.acs.org/JAFC
Enantioselective Syntheses and Sensory Properties of 2‑Methyl-
tetrahydrofuran-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
our previous work, ( )-trans- and ( )-cis-isomers of 2-methyl-
tetrahydrofuran-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
INTRODUCTION
■
The olfactory properties of over 1400 enantiomers have been
reported1 since Rienacker 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
Figure 1. Four stereoisomers of 2-methyl-tetrahydrofuran-3-thiol
acetate.
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-Methy-
tetrahydrofuran-3-thiol is a representative sulfur-containing
compound having meat aroma, which exists in four stereo-
isomers due to the two chiral centers in the molecule. It is well-
known 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 stereo-
isomers 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
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 trans-
thiol were produced via enzymatic resolution of cis-2-methyl-3-
hydroxytetrafuran using the lipase pseudomonas fluorescence.
Our present work tried a different way to prepare the four
stereoisomers of 1 via chemical asymmetric catalytic approach
(Figure 2).
Received: August 11, 2014
Revised: January 5, 2015
Accepted: January 5, 2015
Published: January 5, 2015
© 2015 American Chemical Society
464
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Journal of Agricultural and Food Chemistry
Article
Figure 2. Synthetic routes leading to the optically active 2-methyl-tetrahydrofuran-3-thiol acetates.
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).
MATERIALS AND METHODS
■
Chemicals. Triphenylphosphine (Ph3P), diisopropyl azodicarbox-
ylate (DIAD), and LiAlH4 were purchased from Beijing Bailingwei
Science and Technology Co. (Beijing, China), AD-mix-α and AD-mix-
β were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO),
and the others were purchased from Beijing Huaxue Shiji Co. (Beijing,
China).
(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 t-
butyl 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;
80% ee; [α]2D0 = −30.6° (c 4.80, CHCl3). 1H 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).
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
Data of (2S,3S)-5 (from AD-mix-α). 85% yield; purity, 96% by GC;
62% ee; [α]2D0 = +23.7° (c 4.50, CHCl3). The 1H NMR and 13C 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.
1
product was used without further purification for the next step. H
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
Data of (2R,3R)-6. 89% yield; purity, 98% by GC; 80% ee; [α]D20
=
−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, H-
3). 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).
(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 (2S,3S)-6. 90% yield; purity, 96% by GC; 62% ee; [α]D20
=
+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 Ac-
etate 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.
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
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Journal of Agricultural and Food Chemistry
Article
Data of (2R,3S)-1. 81% yield; purity, 97% by GC; 80% ee (tR
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]2D0 = −8.09° (c 4.37, CHCl3). The NMR data were consistent
with those of (2R,3R)-1.
21.540 min); [α]2D0 = +27.6° (c 4.63, CHCl3). H NMR (300 MHz,
1
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, H-
3). 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).
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.
Data of (2S,3R)-1. 83% yield; purity, 98% by GC; 62% ee (tR
20.694 min); [α]2D0 = −20.5° (c 4.49, CHCl3). The H NMR and 13C
1
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-tetrahy-
drofuran 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]2D0 = +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]2D0 = −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.
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-i-
PrOH (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,
(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 chromatog-
raphy (petroleum ether/ethyl acetate, 6/1) to give (2R,3S)- or
(2S,3R)-5 as a light yellow oil.
and a sniffing port (Sniffer 9000; Brechbuhler 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.
Data of (2R,3S)-5. 90% yield; purity, 97% by GC; 80% ee; [α]D20
=
+35.5° (c 2.74, MeOH) [lit.30 [α]2D3 +11.7° (c 2.5, MeOH, 27% ee)].
1H 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).
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.
Data of (2S,3R)-5. 87% yield; purity, 96% by GC; 62% ee; [α]D20
=
−26.8° (c 4.28, MeOH) [lit.30 [α]D23 = −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]D20
=
+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]D20
=
Optical Rotations. Optical rotations were measured on an Autopol
IV digital automatic polarimeter (Rudolph, Hackettstown, NJ).
−14.5° (c 5.50, CHCl3). The NMR data were consistent with those of
(2R,3R)-6.
RESULTS AND DISCUSSION
(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.
■
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
Data of (2R,3R)-1. 85% yield; purity, 97% by GC; 80% ee (tR
1
21.939 min); [α]2D0 = +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,
466
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Article
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.
Table 1. Odor Descriptions and Odor Thresholds of the
Four Stereoisomers of 1
odor thresholds in
a
stereoisomers
odor description
air (ng/L)
(2R,3S)-1
meaty, sesame paste, fried onion and
garlic, sweet, sulfurous
18.6
The chiral centers of the four stereoisomers of 2-methyl-
tetrahydrofuran-3-thiol acetate 1 were originated from Sharp-
less AD of (3E)-pent-3-en-1-yl mesylate 4. 2-Methyl-3-hydroxy-
tetrahydrofuran 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-3-
hydroxy-tetrahydrofuran synthesized by oxidation of (3E)-pent-
3-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-p-
nitrobenzoyloxy-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.
(2S,3R)-1
(2R,3R)-1
roasted meat, burnt, fried onion
7.3
3.8
raw garlic and onion-like, savory, musty,
sulfurous
(2S,3S)-1
raw garlic and onion-like, sulfurous
5.7
a
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-tetrahy-
drofuran-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.
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 cis-
1 also exited. For the enantiomers of trans-1, (2S,3R)-1 smelled
like roasted meat with an undernote of burnt and fried onion;
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

Journal of Agricultural and Food Chemistry
Article
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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.
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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J. L. Identification and origin of odorous sulfur compounds in cooked
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