Preparation and odour properties of (S)-3-mercapto-1-heptyl acetate

Article abstract of DOI:10.3184/174751914X13989627250405

Synthesis of (S )-3-mercapto-1-heptyl acetate was achieved in four steps. Sharpless asymmetric epoxidation of (E )-2-heptenol yielded (2R,3R )-2,3-epoxy-1-heptanol, which was treated with thiourea in the presence of Ti(OPri)4 to give (2S,3S )-2,3-epithio- 1-heptanol, reduction of which followed by acetylation afforded (S )-3-mercapto-1-heptyl acetate in 91% ee. The optically active product possessed a tropical fruit aroma reminiscent of mango and passion fruit, with berry, ester-like, sweet, and pepper-like aspects.

Full text of DOI:10.3184/174751914X13989627250405

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 343–346
RESEARCH PAPER 343
Preparation and odour properties of (S)-3-mercapto-1-heptyl acetate
Sen Liang, Baoguo Sun, Shaoxiang Yang, Yongguo Liu, Hongyu Tian*, Yuping Liu and
Haitao Chen
School of Food Chemistry, Beijing Key Laboratory of Flavour Chemistry, Beijing Technology and Business University, Beijing 100048, P.R. China
Synthesis of (S)-3-mercapto-1-heptyl acetate was achieved in four steps. Sharpless asymmetric epoxidation of (E)-2-heptenol
yielded (2R,3R)-2,3-epoxy-1-heptanol, which was treated with thiourea in the presence of Ti(OPri)4 to give (2S,3S)-2,3-epithio-
1-heptanol, reduction of which followed by acetylation afforded (S)-3-mercapto-1-heptyl acetate in 91% ee. The optically active
product possessed a tropical fruit aroma reminiscent of mango and passion fruit, with berry, ester-like, sweet, and pepper-like
aspects.
Keywords: (E)-2-heptenol, Sharpless asymmetric epoxidation, (2R,3R)-2,3-epoxy-1-heptanol, (2S,3S)-2,3-epithio-1-heptanol,
chiral flavour
Sulfur-containing compounds are an important family of aroma
chemicals due to their low odour thresholds and high impact
nature. More and more sulfur-containing aroma chemicals have
been identified as volatile components of various foods and
plants 1–5 as a result of ongoing interest in discovering new types of
flavours. In particular, polyfunctional thiols and their derivatives
having pronounced odour qualities have been the subject of many
publications.6–11 A lot of compounds containing 1,3-oxygen–
sulfur functionality, such as 3-mercapto-1-hexanol and its
derivatives,12 and 4-mercapto-2-heptanol and its derivatives,13
have been found to possess tropical, fruity or vegetable odour
notes. As a result, the 1,3-oxygen–sulfur functionality has been
described as the “olfactophore” for these notes.
3-Mercaptoheptyl acetate containing the 1,3-oxygen–
sulfur olfactophore has been detected in the volatiles of Ruta
chalepensis L. plant material14 and approved as a flavour
ingredient by the Flavour and Extract Manufacturers’
Association (FEMA) in 2007 to appear in the GRAS (Generally
Recognised as Safe) list 23 with FEMA No. 4289.15 It has
been reported to be a valuable flavour ingredient, which is
distinguished by its highly appreciated and performing bottom
notes of tea, citrus-grapefruit and fruity-pear-peach type.16
Flavouring ingredients capable of imparting well-balanced
bottom notes are especially desirable for the flavourists due
to their relative rareness. Thus the organoleptic advantages
of 3-mercaptoheptyl acetate make it an asset to flavourists. It
can be used as the racemate, but the (S)-antipode is the more
appreciated one. For comparison of the two, both enantiomers
have been a target for synthesis.16
Escher et al.16 prepared racemic 3-mercaptoheptyl acetate and
its enantiomers from the racemic or enantiomerically enriched
heptane-1,3-diol, respectively, through a four-step route,
including selective acetylation of the primary hydroxy group,
nucleophilic substitution of the secondary hydroxy group via its
sulfonate, reductive removal of acetate and thioacetyl groups
of the intermediate, and selective acetylation of the hydroxy
group of 3-mercapto-1-heptanol (Scheme 1). Enantiomerically
enriched heptane-1,3-diols were obtained by the reduction
of methyl (R)- or (S)-3-hydroxyheptanoate with LiAlH4,
respectively. Methyl (R)-3-hydroxyheptanoate was prepared in
>98% ee according to the method reported by Utaka et al.17
and methyl (S)-3-hydroxyhepatanoate was prepared according
to the method reported by Oppolzer and Strakemann.18
Allyl alcohols have become very versatile substrates since
Sharpless first reported their asymmetric epoxidation in 1980.19
In view of the aforementioned desirable organoleptic properties
of (S)-3-mercaptoheptyl acetate, we decided to prepare this
enantiomer by a simpler four-step approach starting from
2-hepten-1-ol, which is easily accessible by the Knoevenagel
condensation of n-pentanal with malonic acid (Scheme 2). The
odour features of the synthesised product were evaluated by gas
chromatography-olfactometry (GC-O) analysis.
OH
SAc
SH
*
OH
*
OAc
*
OAc
Scheme 1
H
O
O
HOOC
COOH
OH
SOCl2
O
OH
OCH3
CH3OH
1
2
AlH3
thiourea
*
*
*
epoxidation
*
OH
OH
O
S
3
4
5
SH
SH
Ac2O
Red-Al
*
*
OAc
OH
6
7
Scheme 2
* Correspondent. E-mail: tianhy@btbu.edu.cn
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344 JOURNAL OF CHEMICAL RESEARCH 2014
with an ee of 52 and 78% respectively.20 Since we avoided acid
conditions in our work and observed no racemisation in the
reduction of thiiranes, and neither of the last two steps could be
responsible, it seems to us very possible that the racemisation
occurred owing to the acidic conditions used in their preparation
of the thiiranes from the epoxides.
The odour from a smelling strip was described for (±)-7 as
sulfurous, sweet, fruity. The odour properties of (3S)-7 were
evaluated by chiral GC-O. (3S)-7 possessed a tropical fruit
aroma reminiscent of mango and passion fruit, with berry,
ester-like, sweet, and pepper-like aspects.
In summary, the preparation of (±)-3-mercapto-1-heptyl
acetate and the (S)-enantiomer could be performed in acceptable
chemical and/or high optical yields starting from (E)-2-heptenol
via epoxidation, substitution with thiourea, reduction and
acetylation. The conversion of epoxide to the corresponding
thiirane in the presence Ti(OPri)4 avoided the occurrence of
racemisation and the formation of certain by-products. The (S)-
enantiomer offers a unique powerful odour and exhibits good
potential as a flavouring ingredient.
Results and discussion
(E)-2-Heptenoic acid 1 produced by Knoevenagel condensation
of n-pentanal with malonic acid was converted to (E)-2-hepten-
1-ol 3 via esterification followed by reduction. The direct
reduction of (E)-2-heptenoic acid 1 by LiAlH4 gave a mixture of
(E)-2-hepten-1-ol 3 and heptan-1-ol with poor chemoselectivity,
whereas methyl (E)-2-heptenoate 2 was reduced by AlH3 to
produce 3 exclusively without the formation of the unwanted
saturated alcohol.
In order to obtain reference samples for the determination
of ee, the racemate of 3-mercaptoheptyl acetate was prepared
first. (E)-2-Hepten-1-ol 3 was epoxidised by MCPBA to afford
(±)-2,3-epoxy-1-heptanol 4, treatment of which with thiourea
in the presence of Ti (OPri)4 and then by saturated aqueous
NaHCO3 led to (±)-2,3-epithio-1-heptanol 5 in ~81% yield.
Pickenhagen and Brönner–Schindler had shown that treatment
of optically active 2,3-epoxy-1-hexanols with thiourea under
acidic conditions afforded the corresponding 2,3-epithio-1-
hexanols containing 10% by-product of 1,2-epithio-3-hexanol
and the desired product was separated from the by-product
by preparative GC.20 In the present work, (±)-1,2-epithio-3-
heptanol in (±)-5 was not detected by 1H NMR analysis, which
is consistent with results in the literature.21 (±)-3-Mercapto-1-
heptanol 6 was produced by the reduction of (±)-5 with Red-Al
in THF in about 60% yield. Treatment of (±)-6 with acetic
anhydride in pyridine at –20 °C afforded (±)-3-mercapto-1-
heptyl acetate 7 in about 53% yield.
Asymmetric epoxidation of 3 under the Sharpless conditions
using D-(–)-diethyl tartrate afforded (2R,3R)-4 (94% ee) which
was treated with thiourea in the presence of Ti(OPri)4 to give
(2S,3S)-5(92%ee), athiiraneofinvertedabsoluteconfiguration.
The ee values of both of the epoxides and thiiranes were
determined by the resolution of their trifluoroacetate derivatives
on a G-TA column of 50 m. The thiirane was obtained from the
epoxide with an ee value very close to that of the precursor.
The substitution reaction proceeded with high stereoselectivity
just as Gao and Sharpless have shown.21 (2S,3S)-5 (92% ee)
was reduced with Red-Al to afford (3S)-6 (92% ee), treatment
of which with acetic anhydride in pyridine at –20 °C led to
(3S)-7 (91% ee). The ee values of optically active 6 and 7 were
determined by direct resolution on a G-TA column of 50 m. The
results indicated that the reduction of thiirane and acetylation
of 3-mercapto-1-heptanol proceeded nearly without any loss of
enantiomeric excess. We noticed that the specific rotation value
Experimental
D-(–) and L-(–)-Diethyl tartrate, Ti (OPri)4, t-BuOOH, and
sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) were
purchased from Sigma-Aldrich Chemical Co (St. Louis, MO/US).
m-Chloroperoxybenzoic acid (MCPBA, 70%), and LiAlH4 were
purchased from Beijing Bailingwei Science and Technology Company
(Beijing, P.R. China). The others were purchased from Beijing Huaxue
Shiji Company (Beijing, P.R. China). NMR spectra were obtained on
a Bruker AV 300 MHz spectrometer (1H NMR at 300 Hz, 13C NMR
at 75 Hz) in CDCl3 using TMS as internal standard. Chemical shifts
(δ) are given in ppm and coupling constants (J) in Hz. The high
resolution mass spectrum was performed on a Bruker Apex IV FTMS.
Optical rotations were measured on an Autopol IV digital automatic
polarimeter (Rudolph, Hackettstown, NJ, USA).
Chiral GC analysis
An Agilent 6890 GC with a flame ionisation detector (FID) was
used for GC analyses (Agilent Technologies, Santa Clara, CA,
USA). The column used was a G-TA chiral capillary column
(50 m×0.25 mm×0.25 µm) from the ASTEC company (Chattanooga,
TN, USA). The conditions were as follows: injector temperature
250 °C, detector temperature 250 °C, N2 as carrier gas, constant flow
mode 0.8 mL min–1, split ratio 50/1. The concentration of samples was
about 0.5 wt% in dry ether, the injection volume was about 1 µL. The
oven temperature was programmed at different rates for different
samples. For 2,3-epoxy-1-heptanols 4, it was from 50 °C to 100 °C at
a rate of 10 °C min–1, and held at 100°C for 1 min; raised to 175 °C at
2 °C min–1, and held at 175°C for 10 min. For 5–7, it was raised from
50 °C to 100 °C at a rate of 2 °C min–1, and held at 100°C for 1 min;
raised to 150 °C at 1 °C min–1, and held at 150°C for 8 min; raised to
175 °C at 10 °C min–1 and held at 175°C for 3 min.
of the intermediate (S)-3-mercapto-1-heptanol (
2.65, CHCl3)) was not consistent with that in the literature16
=+4.4o (c 5.0, CHCl3)]. In order to ensure the reliability
= –1.3o (c
[
of the results, a set of parallel experiments were carried out
starting from (E)-2-hepten-1-ol 3 using L-(+)-diethyl tartrate
as a chiral ligand in Sharpless AE. The specific rotation value
of the intermediate (R)-3-mercapto-1-heptanol obtained from
Chiral GC‑O analysis and evaluation
L-(+)-diethyl tartrate was
= +1.3o (c 2.85, CHCl3), which is
Chiral GC-O analysis was carried out using an Agilent 6890N
gas chromatograph installed with a chiral capillary column G-TA
(50ꢀmꢀ×ꢀ0.25ꢀmmꢀ×ꢀ0.25ꢀμm),ꢀaꢀFIDꢀandꢀaꢀsniffingꢀportꢀ(Snifferꢀ9000,ꢀ
Brechbühler Scientific Analytical Solutions INC, Switzerland). The
conditions were the same as those in GC analysis. The column effluent
was divided (ratio 1:1) between the FID detector and the sniffing
port through a “Y” shape glass splitter. The effluent from the sniffing
port was captured with a stream of humidified air of 16 mL min–1
and transferred to the glass detection cone by one length of capillary
column at the temperature of 220 °C. Sniffings were carried out by a
panel composed of three judges.
oppositeandequaltothatof(S)-3-mercapto-1-heptanolobtained
from D-(–)-diethyl tartrate. (R)-3-Mercapto-1-heptanol was
acylated with acetic anhydride to give (R)-3-mercaptoheptyl
acetate, which gave a very close specific rotation value to that
of (R)-enantiomer in the literature.16
Compared with the method of Escher et al.,16 our synthetic
route is more straightforward, although with a slightly lower
ee value. In the synthetic route of Pickenhagen and Brönner–
Schindler,20 (2R,3R)- or (2S,3S)-2,3-epithio-1-hexanol was
prepared from the Sharpless AE products of (E)-2-hexenol by
treatment with thiourea in the presence of H2SO4. The obtained
thiiranes were reduced by Red-Al followed by treatment with
NaOH/MeI to lead to (R)- and (S)-3-methylthio-1-hexanols
(E)‑2‑Heptenoic acid 1: A mixture of malonic acid (18 g, 0.2 mol),
n-pentanal (8.6 g, 0.1 mol) and piperidine (0.5 mL, 5 mmol) in pyridine
(50 mL) was stirred at room temperature for 20 h. The mixture was
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JOURNAL OF CHEMICAL RESEARCH 2014 345
heated to 45 °C and stirred for 4 h. Then the solution was poured into
the mixture of crushed ice and concentrated HCl (50 mL). The layers
were separated and the aqueous phase was extracted with CH2Cl2
(3×80 mL). The combined organic layers were washed with brine,
dried over anhydrous MgSO4 and then concentrated under reduced
pressure. The crude product was distilled under reduced pressure to
afford (E)-2-heptenoic acid 1 (11 g, 86%) as a pale yellow liquid, b.p.
(2.84 g, 0.01 mol) were added sequentially via syringe with stirring.
The reaction mixture was stirred at –20 °C as t-BuOOH (36.4 mL,
5.5 mol L–1 in decane) was added through the addition funnel over
~10 min. The resulting mixture was stirred at –20 °C for 1 h. (E)-2-
Heptenol (11.4 g, 0.1 mol) was added dropwise over a period of 20 min,
taking care to maintain the reaction temperature between –20 and
–15 °C. The mixture was stirred for an additional 8 h at –20 to –15 °C
and then warmed to ~0 °C. The reaction mixture was slowly poured
into a beaker containing a precooled (0 °C) solution 200 mL (200 mL)
of FeSO4.7H2O (33 g, 0.12 mol) and citric acid monohydrate (12.6 g,
0.06 mol). The two-phase mixture was stirred for 40 min at 0 °C and
then transferred to a separatory funnel. The phases were separated
and the aqueous phase was extracted with CH2Cl2 (2×80 mL).
The combined organic layers were treated with a precooled (0 °C)
solution of 30% NaOH (w/v) in saturated brine (180 mL). The two-
phase mixture was stirred vigorously for 1 h at 0 °C. The phases were
separated and the aqueous layer was extracted with CH2Cl2 (2×ꢀ80 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered and concentrated. The residue was distilled under reduced
pressure to afford (2R,3R)-2,3-epoxy-1-heptanol as a colourless
oil (10.8 g, 83%, 93% ee, tR 20.80 min for its trifluoroacetate), b.p.
1
80–82 °C (1.32 kPa); HꢀNMR:ꢀδꢀ0.90ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.26–1.52
(4 H, m), 2.26 (2 H, qd, J=6.9, 1.5 Hz), 5.81 (1 H, td, J=15.6, 1.5 Hz),
7.08 (1 H, td, J=15.6, 6.9 Hz), 12.06 (1H, br); 13CꢀNMR:ꢀδꢀ13.8,ꢀ22.2,ꢀ
29.9, 32.0, 120.6, 152.5, 172.3; GC/MS (EI): m/z (%) 41 (73), 55 (39), 68
(60), 73 (100), 86 (31), 99 (54), 110 (18, [M-18]+). The NMR data were
consistent with those described in the literature.22
Methyl (E)‑2‑heptenoate 2: To a solution of (E)-2-heptenoic acid
1 (32 g, 0.25 mol) in methanol (120 mL) was added SOCl2 (35.7 g,
0.3 mol) dropwise. The mixture was then heated to reflux for 4 h. Most
of the methanol and excess SOCl2 were removed by rotary evaporation.
The residue was diluted with water and adjusted pH to 8 by 10% NaOH.
The mixture was extracted with CH2Cl2 (3×80 mL) and the combined
organic layers were washed with brine and dried over anhydrous
MgSO4. The solution was concentrated by rotary evaporation and the
residue was distilled under reduced pressure to afford methyl (E)-2-
heptenoate 2 (32 g, 90%) as a colourless oil, b.p. 30–32 °C(1.32 kPa);
1HꢀNMR:ꢀδꢀ0.89ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.23–1.50 (4 H, m), 2.19 (2 H, qd,
J=6.9, 1.5 Hz), 3.71 (3 H, s), 5.81 (1 H, td, J=15.6, 1.5 Hz), 6.96 (1
H, td, J=15.6, 6.9 Hz); 13CꢀNMR:ꢀδꢀ13.6,ꢀ22.0,ꢀ30.0,ꢀ31.8,ꢀ51.2,ꢀ120.7,ꢀ
149.6, 167.0; GC/MS (EI): m/z (%) 41 (57), 55 (93), 69 (37), 87 (100), 111
(63), 113 (83), 142 (14, M+). The NMR data were consistent with those
described in the literature.23
(E)‑2‑Heptenol 3: A solution of LiAlH4 (3.75 g, 0.1 mol) in dry ether
(100 mL) was cooled to 0 °C, and a solution of AlCl3 (20 g, 0.15 mol) in
dry ether (80 mL) was added dropwise. Then, the solution was stirred
at 0 °C for 1 h and methyl (E)-2-heptenoate 2 (14.2 g, 0.1 mol) was
added slowly. The mixture was stirred at 0 °C for 5 h. It was quenched
by dropwise addition of water followed by 10% sodium bicarbonate.
After filtration, the phases were separated, and the aqueous phase was
extracted with ether. The combined organic phases were washed with
brine and then dried over anhydrous MgSO4. After evaporation of the
solvent by rotary evaporation, the residue was distilled under reduced
pressure to give (E)-2-heptenol 3 (9.7 g, 85%) as a colourless oil, b.p.
52–54 °C (1.32 kPa); 1HꢀNMR:ꢀδꢀ0.88ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.22–1.43 (4
H, m), 1.92 (1 H, br), 2.03 (2 H, q, J=6.9 Hz), 4.07 (2 H, d, J=4.8 Hz),
5.65 (2 H, m); 13CꢀNMR:ꢀδꢀ13.8,ꢀ22.1,ꢀ31.2,ꢀ31.8,ꢀ63.3,ꢀ128.8,ꢀ133.0;ꢀ
GC/MS (EI) m/z (%) 41 (41), 55 (32), 57 (100), 68 (17), 81 (28), 96 (16,
[M-18]+). The 1H NMR data were consistent with those described in the
literature.24
55–57 °C (1.32 kPa);
1, MeOH)]. The spectroscopic properties of the optically active product
were the same as for (±)-4.
= +31.7o (c 2.52, MeOH) [lit.27,
= +32o (c
(±)‑2,3‑Epithio‑1‑heptanol (±)-5: The procedure used was that
reported by Gao and Sharpless.21 To a suspension of (±)-2,3-epoxy-
1-heptanol 4 (6.5 g, 0.05 mol) and thiourea (4.6 g, 0.06 mol) in dry
THF (100 mL) was added Ti(OPri)4 (18.2 mL, 0.06 mol) at room
temperature under nitrogen. After addition, thiourea gradually
dissolved and a clear solution formed. The mixture was stirred for 2 h.
The solution was then diluted with ether (80 mL) and quenched with
saturated aqueous NaHCO3 solution. The resulting mixture was stirred
vigorously for ~1 h as a white precipitate separated from solution.
The mixture was filtered through a pad of Celite, and the residue was
washed thoroughly with ether and CH2Cl2. The combined organic
phases were then washed with water and brine and then dried over
anhydrous MgSO4. After solvent removal, the residue was purified
by flash chromatography on silica gel (petroleum/EtOAc, 15:1) to
1
afford (±)-2,3-epithio-1-heptanol 5 (5.9 g, 81%) as a colourless oil, H
NMR:ꢀδꢀ0.91ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.23–1.61 (5 H, m), 1.71 (1 H, br), 1.83
(1 H, m), 2.83 (1 H, m), 2.98 (1 H, q, J=4.8 Hz), 3.67 (1 H, dd, J=12.0,
4.8 Hz), 3.89 (1 H, dd, J=12.0, 4.2 Hz); 13CꢀNMR:ꢀδꢀ13.9,ꢀ22.2,ꢀ31.2,ꢀ
35.2, 40.8, 44.6, 63.7; GC/MS (EI): m/z (%) 41 (59), 45 (36), 55 (38), 57
(41), 69 (33), 73 (100), 81 (59), 85 (32), 95 (67), 112 (38), 115 (41), 146
(57, M+); HRESIMS, m/z 169.06542 [M+Na+] (Calcd. for C7H14NaOS,
169.06576).
(±)‑2,3‑Epoxy‑1‑heptanol (±)-4: A solution of m-CPBA (29.6 g,
70%, 0.12 mol) in CH2Cl2 (120 mL) was added to a solution of (E)-
2-heptenol 3 (11.4 g, 0.1 mol) in CH2Cl2 (60 mL). The solution was
stirred for 10 h at –25 °C. The mixture was quenched with 10% NaOH
solution and extracted by CH2Cl2. The combined extracts were washed
with saturated Na2SO3 and brine, dried over anhydrous MgSO4, and
concentrated. The residue was distilled under reduced pressure to
afford (±)-2,3-epoxy-1-heptanol 4 (11 g, 85%) as a colourless oil, b.p.
55–57 °C (1.32 kPa); 1HꢀNMR:ꢀδꢀ0.90ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.20–1.49 (4 H,
m), 1.56 (2 H, m), 1.92 (1 H, br), 2.95 (2 H, m), 3.63 (1 H, d, J=12.3 Hz),
3.92 (1 H, d, J=12.3 Hz); 13Cꢀ NMR:ꢀ δꢀ 13.9,ꢀ 22.4,ꢀ 28.0,ꢀ 31.2,ꢀ 56.0,ꢀ
58.5, 61.7. The NMR data were consistent with those described in the
literature.25
(2R,3R)‑2,3‑Epoxy‑1‑heptanol (2R,3R)-4: The procedure used was
similar to that used in our previous work.26 Crushed 4Å molecular
sieves were heated in a vacuum oven at 200 °C and 1 mmHg for at
least 3 h. Dichloromethane was distilled over CaH2. An oven-dried
250 mL three-necked round-bottomed flask equipped with a magnetic
stirbar, pressure equalising addition funnel, thermometer, nitrogen
inlet, and bubbler was charged with 4Å powered activated molecular
sieves (4.0 g) and dry CH2Cl2 (200 mL). The flask was cooled to
–20 °C. D-(–)-Diethyl tartrate (2.48 g, 0.012 mol) and Ti (OPri)4
(2S,3S)‑2,3‑Epithio‑1‑heptanol (2S,3S)-5: Obtained by following the
same experimental procedure as described above for (±)-5. (2S,3S)-5
was obtained with 92% ee from (2R,3R)-4 (94% ee, tR 45.66 min for
its trifluoroacetate).
= –119.5o (c 2.75, CHCl3). The spectroscopic
properties of the optically active product were the same as for (±)-5.
(±)‑3‑Mercapto‑1‑heptanol (±)-6: To a solution of (±)-2,3-epithio-1-
heptanol 5 (3.7 g, 0.025 mol) in dry THF (30 mL) was added a 65 wt%
solution of Red-Al in toluene (15.6 mL, 0.05 mmol) dropwise under
nitrogen at 0 °C. After stirring at room temperature for 6 h, the solution
was diluted with ether and quenched with 5% HCl solution. After
further stirring at room temperature for 30 min, the white precipitate
formed was removed by filtration. The filtrate was extracted with
CH2Cl2 (3×ꢀ40 mL), The combined organic extracts were dried
over anhydrous Na2SO4, filtered and concentrated. Purification by
column chromatography on silica gel (petroleum/EtOAc, 15: 1) gave
1
(±)-3-mercapto-1-heptanol 6 (2.2 g, 60%); Hꢀ NMR:ꢀ δꢀ 0.91ꢀ (3ꢀ H,ꢀ t,
J=7.2 Hz), 1.20–1.45 (4 H, m), 1.40 (1 H, d, J=7.5 Hz), 1.51 (1 H, m),
1.59–1.74 (3 H, m), 1.97 (1 H, m), 2.94 (1 H, m), 3.83 (2 H, m); 13C NMR:
δꢀ14.0,ꢀ22.4,ꢀ29.2,ꢀ38.1,ꢀ39.3,ꢀ41.3,ꢀ60.8;ꢀGC/MSꢀ(EI):ꢀm/z (%) 41 (57),
55 (100), 57 (56), 61 (45), 69 (44), 81 (70), 96 (29), 114 (69), 148 (28, M+).
NMR data were consistent with those described in the literature.16
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346 JOURNAL OF CHEMICAL RESEARCH 2014
(3S)‑3‑Mercapto‑1‑heptanol (3S)-6: Obtained by following the
same experimental procedure as described above for (±)-6. (3S)-6
was obtained with 92% ee (tR 63.31 min) from (2S,3S)-5 (92% ee).
References
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R.G. Buttery, R. Teranishi, L.C. Ling and J.G. Turnbaugh, J. Agric. Food
Chem., 1990, 38, 336.
= –1.3o (c 2.65, CHCl3) [lit.16,
=+4.4o (c 5.0, CHCl3)]. The
2
3
4
5
6
M.H. Boelens and L.J. van Gemert, Perfum. Flavour., 1993, 18, 29.
H. Simian, F. Robert and I. Blank, J. Agric. Food Chem., 2004, 52, 306.
R. Naef, A. Velluz and A. Jaquier, J. Agric. Food Chem., 2008, 56, 517.
C. Starkenmann and Y. Niclass, J. Agric. Food Chem., 2011, 59, 3358.
S. Widder, C. Sabater Lüntzel, T. Dittner and W. Pickenhagen, J. Agric.
Food Chem., 2000, 48, 418.
NMR data of the optically active products were the same as for (±)-6.
(±)‑3‑Mercapto‑1‑heptyl acetate (±)-7: A mixture of (±)-3-mercapto-
1-heptanol 6 (1.5 g, 10 mmol) and acetic anhydride (1.2 g, 11 mmol) in
pyridine (25 mL) was stirred for 8 h at –20 °C. Then the solution was
poured into diluted HCl and extracted with CH2Cl2 (3×ꢀ30 mL), The
combined organic extracts were dried with anhydrous MgSO4, filtered
and concentrated. Purification by column chromatography on silica gel
(petroleum/EtOAc, 15: 1) gave (±)-3-mercapto-1-heptyl acetate 7 (1.0 g,
53%); 1HꢀNMR:ꢀδꢀ0.91ꢀ(3ꢀH,ꢀt, J=7.2 Hz), 1.20–1.40 (3 H, m), 1.39 (1 H,
d, J=7.2 Hz), 1.44–1.60 (2 H, m), 1.60–1.80 (2 H, m), 1.95–2.08 (1 H, m),
2.05 (3 H, s), 2.85 (1 H, m), 4.24 (2 H, m); 13CꢀNMR:ꢀδꢀ13.9,ꢀ20.9,ꢀ22.3,ꢀ
29.0, 37.5, 37.6, 38.7, 62.2, 170.9; GC/MS (EI): m/z (%) 43 (71), 55 (49),
69 (15), 73 (23), 88 (100), 97 (20), 101 (26), 130 (25, [M-60]+). The NMR
data were consistent with those described in the literature.16
7
8
9
C. Vermeulen and S. Collin, J. Agric. Food Chem., 2002, 50, 5654.
C. Vermeulen and S. Collin, J. Agric. Food Chem., 2003, 51, 3618.
S. Bailly, V. Jerkovic, J. Marchand-Brynaert and S. Collin, J. Agric. Food
Chem., 2006, 54, 7227.
10 J. Gros, S. Nizet and S. Collin, J. Agric. Food Chem., 2011, 59, 8853.
11 J. Gros, F. Peeters and S. Collin, J. Agric. Food Chem., 2012, 60, 7805.
12 M. van de Waal, Y. Niclass, R.L. Snowden, G. Bernardinelli and S. Escher,
Helv. Chim. Acta, 2001, 84, 1246.
13 S. Nörenberg, B. Reichardt, V. Andelfinger, W. Eisenreich and K.-H.
Engel, J. Agric. Food Chem., 2013, 61, 2062.
14 S. Escher, Y. Niclass, M. van de Waal and C. Starkenmann, Chem.
Biodiver., 2006, 3, 943.
(3S)‑3‑Mercapto‑1‑heptyl acetate (3S)-7: Obtained by following the
same experimental procedure as described above for (±)-7. (3S)-7 was
15 W.J. Waddell, S.M. Cohen, V.J. Feron, J.I. Goodman, L.J. Marnett, P.S.
Portoghese, I.M.C.M. Reitjiens, R.L. Smith, T.B. Adams, C. Lucas Gavin,
M.M. McGowen and M.C. Williams, Food Technol., 2007, 61, 22.
16 S.D. Escher, Y. Niclass and L. Saudan, WO 2006/120625.
17 M. Utaka, H. Watabu, H. Higashi, T. Sakai, S. Tsuboi and S. Torii, J. Org.
Chem., 1990, 55, 3917.
18 W. Oppolzer and C. Starkemann, Tetrahedron Lett., 1992, 33, 2439.
19 T. Katsuki and K.B. Sharpless, J. Am. Chem. Soc., 1980, 102, 5974.
20 W. Pickenhagen and H. Brönner-Schindler, Helv. Chim. Acta, 1984, 67,
947.
obtained with 91% ee (tR 65.61 min) from (3S)-6 (92% ee).
(c 2.10, CHCl3) [lit.16, = +7.3o (c 5.0, CHCl3)]. The NMR data of the
= +7.0o
optically active products were the same as for (±)-7.
(3R)‑3‑Mercapto‑1‑heptanol (3R)-6 and its acetate (3R)-7: Prepared
by the similar approach as (3S)-6 and (3S)-7 except using L-(+)-
diethyl tartrate as a chiral ligand in Sharpless AE. (3R)-6, 91% ee (tR
63.97 min),
= –7.0o (c 2.05, CHCl3) [lit.16,
= +1.3o (c 2.85, CHCl3); (3R)-7, 90% ee (tR 65.15 min),
= –7.5o (c 5.0, CHCl3)].
21 Y. Gao and K.B. Sharpless, J. Org. Chem., 1988, 53, 4114.
22 S. Karlsson and H.-E. Hogberg, Org. Lett., 1999, 1, 1667.
23 A. El-Batta, C. Jiang, W. Zhao, R. Anness, A.L. Cooksy and M. Bergdahl,
J. Org. Chem., 2007, 72, 5244.
24 V. Shekhar, D.K. Reddy and Y. Venkateswarlu, Helv. Chim. Acta, 2012, 95,
1593.
Financial support from the National Natural Science Foundation
of China (no. 31271932), the National Key Technology R&D
Program (2011BAD23B01) and the Importation and Development
of High-Calibre Talents Project of Beijing Municipal Institutions
(CIT&TCD20140306) is gratefully acknowledged.
25 C.L. Pereira, Y.-H. Chen and F.E. McDonald, J. Am. Chem. Soc., 2009,
131, 6066.
26 H. Tian, B. Sun, L. Tang and H. Ye, Flavour Frag. J., 2011, 26, 65.
27 C. Apfel, D.W. Banner, D. Bur, M. Dietz, T. Hirata, C. Hubschwerlen,
H. Locher, M.G.P. Page, W. Pirson, G. Rossé and J.-L. Specklin, J. Med.
Chem., 2000, 43, 2324.
Received 16 March 2014; accepted 1 April 2014
Paper 1402530 doi: 10.3184/174751914X13989627250405
Published online: 10 June 2014
JCR1402530_FINAL.indd 346
10/06/2014 09:27:24

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