Allium Chemistry: Synthesis of 1-[Alk(en)ylsulfinyl]propyl Alk(en)yl Disulfides (Cepaenes), Antithrombotic Flavorants from Homogenates of Onion (Allium cepa)

Article abstract of DOI:10.1021/jf9705126

A series of 1-[alk(en)ylsulfinyl]propyl alk(en)yl disulfides (α-sulfinyl disulfides) of structure RS(O)-CHEtSSR′, R, R′ = Me, (E,Z)-MeCH=CH, n-Pr, and CH₂=CHCH₂, termed cepaenes, have been synthesized by a variety of routes including oxidation of 1-[alk(en)ylthio]propyl alk(en)yl disulfides, RSCHEtSSR′, termed deoxycepaenes. The cepaenes are identical to compounds isolated from homogenates of onion (Allium cepa) and to compounds identified in these homogenates by liquid chromatography/mass spectrometry, while the deoxycepaenes are identical to compounds found in Allium distilled oils and in other materials. The antithrombotic activities for several cepaenes are reported.

Full text of DOI:10.1021/jf9705126

4414
J. Agric. Food Chem. 1997, 45, 4414−4422
Alliu m Ch em istr y: Syn th esis of 1-[Alk (en )ylsu lfin yl]p r op yl Alk (en )yl
Disu lfid es (Cep a en es), An tith r om botic F la vor a n ts fr om
Hom ogen a tes of On ion (Alliu m cepa )
Eric Block,* Harsh Gulati, David Putman, Deyou Sha, Niannian You, and Shu-Hai Zhao
Department of Chemistry, State University of New York at Albany, Albany, New York 12222
A series of 1-[alk(en)ylsulfinyl]propyl alk(en)yl disulfides (R-sulfinyl disulfides) of structure RS(O)-
CHEtSSR′, R, R′ ) Me, (E,Z)-MeCHdCH, n-Pr, and CH2dCHCH2, termed cepaenes, have been
synthesized by a variety of routes including oxidation of 1-[alk(en)ylthio]propyl alk(en)yl disulfides,
RSCHEtSSR′, termed deoxycepaenes. The cepaenes are identical to compounds isolated from
homogenates of onion (Allium cepa) and to compounds identified in these homogenates by liquid
chromatography/mass spectrometry, while the deoxycepaenes are identical to compounds found in
Allium distilled oils and in other materials. The antithrombotic activities for several cepaenes are
reported.
Keyw or d s: Allium chemistry; onion (Allium cepa); a-sulfinyl disulfides; cepaenes; antithrombotic
compounds
INTRODUCTION
Sch em e 1
Folk wisdom has it that raw onion (Allium cepa)
relieves pain and inflammation, that cough syrups made
from chopped onion alleviate symptoms of asthma and
other respiratory ailments, and that regular ingestion
of onion benefits the cardiovascular system (Block, 1985,
1992). Research on the composition of onion extracts,
stimulated by these long-standing beliefs, has led to the
discovery of a remarkable variety of organosulfur com-
pounds, some of which possess antiasthmatic, anti-
inflammatory, antiallergic, and antithrombotic activity,
most likely associated with inhibition of cyclooxygenase
(CO) and lipoxygenase (LO) enzymes (Bayer et al., 1988,
1989; Kawakishi and Morimitsu, 1988, 1994; Morimitsu
and Kawakishi, 1990, 1991; Block and Bayer, 1990).
When an onion is cut, alliinase enzymes act on S-alk-
(en)yl cysteine S-oxides 1a -d (Scheme 1) giving sulfenic
acids 2a -d , which rearrange to onion lachrymatory
factor 3 (LF; C2H5CHdS+sO-; from 2b, CH3CHdCH-
SOH) or couple affording thiosulfinates 4, zwiebelanes
5, or bissulfine 6, by processes described elsewhere
(Block et al., 1996a-c). Notable among the natural
products formed on cutting onion are “cepaenes”, a class
of structurally related R-sulfinyl disulfides, more pre-
cisely 1-[alk(en)ylsulfinyl]propyl alk(en)yl disulfides,
RS(O)CHEtSSR′ (7), which are potent inhibitors of
platelet aggregation and CO and LO enzymes (Kawak-
ishi and Morimitsu, 1988, 1994; Morimitsu and Kawak-
ishi, 1990, 1991; Morimitsu et al., 1992; Bayer et al.,
1988, 1989a; Dorsch et al., 1990; Wagner et al., 1990).
Cepaenes bear an interesting resemblance to ajoene,
CH2dCHCH2S(O)CH2CHdCHSSCH2CHdCH2, and ho-
mologs RS(O)CH2CHdCHSSR′ (8), alk(en)yl 3-[alk(en)-
ylsulfinyl]prop-1-enyl disulfide antithrombotic sub-
stances from extracts of garlic (Allium sativum) and wild
garlic (ramson; Allium ursinum) (Block et al., 1986;
Sendl and Wagner, 1991). Until recently (Block and
Zhao, 1992), cepaenes have only been available for study
in minute quantities through extraction of onion fol-
lowed by repetitive chromatography.
The accompanying paper (Calvey et al., 1997) de-
scribes the use of reversed-phase liquid chromatography
atmospheric pressure chemical ionization mass spec-
trometry (LC/APCI-MS) to identify 3-8 in CO2 super-
critical fluid extracts of crushed onion, garlic, and ramp
(Allium tricoccum). Since these LC/MS studies indicate
that compounds derived from all four precursor com-
pounds 1a -d are present in each plant extract, 16
individual cepaenes and their geometric isomers and
diastereomers are possible (Scheme 2). Definitive LC/
MS identification of individual components of complex
mixtures, such as those from Allium extracts, requires
retention time and fragmentation patterns of authentic
standards. Therefore, to assist in the identification of
cepaenes as well as make available samples for deter-
mination of antithrombotic activity, we sought ste-
reospecific syntheses of representative cepaenes. We
report our results herein.
* Author to whom correspondence should be ad-
dressed [telephone (518) 442-4459; fax (518) 442-3462;
e-mail EB801@csc.albany.edu].
S0021-8561(97)00512-8 CCC: $14.00
© 1997 American Chemical Society

Cepaenes from Onion
J. Agric. Food Chem., Vol. 45, No. 11, 1997 4415
Sch em e 2
EXPERIMENTAL PROCEDURES
aqueous layer was extracted with ether (3 × 20 mL), and the
combined organic layers were dried and concentrated in vacuo
to give 9a , a yellow oil (0.98 g, 61% yield): 1H NMR δ 3.67
(dd, J ) 8.0, 5.0 Hz, 1 H), 2.43 (s, 3 H), 2.15 (s, 3 H), 2.03 (m,
1 H), 1.83 (m, 1 H), 1.06 (t, J ) 7.2 Hz, 3 H); 13C NMR δ 61.14,
28.12, 24.29, 14.61, 11.79; EI-MS m/ z (% abundance) 168 (M+,
0.2), 89 (100), 79 (21), 74 (8), 73 (17), 64 (8), 61 (45).
General experimental conditions for syntheses are given
elsewhere (Block et al., 1996a).
Caution: Several of the following procedures involve highly
odoriferous low molecular weight thiols and related com-
pounds. All operations should be conducted in
a well-
ventilated hood. Glassware should be rinsed with bleach or
alkaline KMnO4 immediately after completion of work.
1-Ch lor op r op a n esu lfen yl Ch lor id e (14). Dipropyl dis-
ulfide (5 g, 33 mmol) in CH2Cl2 (50 mL) was cooled to 0 °C
under argon. With stirring, SO2Cl2 (15.7 g, 116 mmol) in CH2-
Cl2 (20 mL) was added slowly. The mixture was stirred at 0
°C (2 h), warmed to room temperature (3 h), and concentrated
in vacuo to afford the known (Tjan et al., 1972) but incom-
pletely characterized 14 as a yellow, pungent oil (9.6 g, 100%
yield): 1H NMR δ 5.24 (t, J ) 6.9 Hz, 1 H), 2.15 (m, 2 H), 1.13
(t, J ) 7.4 Hz, 3 H); 13C NMR δ 71.84, 30.78, 11.27.
1-Ch lor op r op yl Meth yl Disu lfid e (15a ). Methanethiol
[0.73 g, 15 mmol; measured volumetrically (density 0.9 g/mL)]
and then Et3N (2.1 g, 21 mmol) were added at 0 °C to a solution
of 14 (2.0 g, 14 mmol) in tetrahydrofuran (THF) (40 mL), and
the mixture was stirred for 30 min at 0 °C and for 1 h at room
temperature. The product was washed with 10% aqueous HCl
solution (3 × 20 mL), the aqueous layer was extracted with
ether (3 × 20 mL), and the combined organic layers were dried
and concentrated in vacuo to give 15a , a yellow oil with
pungent odor (1.86 g, 86%): 1H NMR δ 4.97 (t, J ) 7.2 Hz, 1
H), 2.54 (s, 1 H), 2.08 (m, 2 H), 1.07 (t, J ) 7.8 Hz, 3 H); 13C
NMR δ 74.31, 32.03, 24.16, 11.39.
Method 2. A solution of 15a (1.0 g, 6.4 mmol) in CH3CN (5
mL) was added dropwise to a well-stirred solution of AgOTs
in CH3CN (60 mL) under argon at -30 °C. After 30 min, a
light yellow precipitate of AgCl appeared. Stirring was
continued at this temperature for a total of 6 h, followed by
stirring at -5 °C for 4 h. Methanethiol (0.31 g, 6.4 mmol) in
CH3CN (3 mL) was added. The mixture was stirred for 30
min, whereupon a black precipitate appeared. The reaction
mixture was diluted with ether (50 mL), filtered, and washed
with brine (3 × 30 mL), the aqueous layer was extracted with
ether (3 × 20 mL), and the combined organic layers were dried
and concentrated in vacuo to give 9a (0.70 g, 65% yield).
Met h yl 1-(Met h ylsu lfin yl)p r op yl Disu lfid e (7a ).
A
solution of 9a (2.23 g, 13.3 mmol) in CH2Cl2 (60 mL) was cooled
to -78 °C and treated with solid m-CPBA (2.70 g, 15.7 mmol)
and catalytic anhydrous Na2CO3. The mixture was stirred for
1 h at -78 °C and for 6 h at 0 °C. The mixture was washed
with cold saturated Na2CO3 (3 × 40 mL), the aqueous layer
was extracted with CH2Cl2 (3 × 40 mL), and the combined
organic layers were dried (K2CO3) and concentrated in vacuo.
The crude product was purified by chromatography (CH2Cl2/
acetone, 9:1) affording 7a , a yellow liquid with a mild onion-
like odor (0.91 g, yield 37%), which by NMR was a 2:1 mixture
of diastereomers. Isomers could be separated by reversed-
phase HPLC (21 mm RP column, 10 mL/min, 3:7 CH3CN/H2O).
Major isomer: 1H NMR δ 3.45 (dd, J ) 11, 3.3 Hz, 1 H), 2.67
(s, 3 H), 2.40 (s, 3 H), 2.31 (m, 1 H), 1.84 (m, 1 H), 1.10 (t, J )
7.8 Hz, 3 H); 13C NMR δ 75.13, 36.76, 24.86, 19.86, 11.04;
HRMS (CI/CH4) m/ z calcd for C5H13S3O (MH+) 185.0129,
Meth yl 1-(Meth ylth io)p r op yl Disu lfid e (9a ). Method 1.
Sodium (0.40 g, 17 mmol) was carefully added to anhydrous
MeOH (30 mL) in a 100 mL flask. Methanethiol (0.69 g, 14
mmol) was added all at once. A solution of 15a (1.50 g, 9.58
mmol) in THF (5 mL) was added dropwise, and the solution
was stirred for 16 h at room temperature. The solution was
washed with 10% aqueous HCl solution (3 × 20 mL), the

4416 J. Agric. Food Chem., Vol. 45, No. 11, 1997
Block et al.
found 185.0134. Minor isomer: 1H NMR δ 3.60 (dd, J ) 11,
3.3 Hz, 1 H), 2.49 (s, 3 H), 2.44 (s, 3 H), 2.25 (m, 1 H), 1.60 (m,
1 H), 1.15 (t, J ) 7.3 Hz, 3 H); 13C NMR δ 73.79, 32.59, 24.60,
) 14.7, 7.4, 3.6 Hz, 1 H), 1.79 (d, J ) 6.0 Hz, 3 H), 1.60 (ddq,
J ) 14.5, 10.5, 6.7 Hz, 1 H), 1.17 (dd, J ) 7.5, 7.0 Hz, 3 H);
13C NMR δ 133.63, 124.65, 72.93, 32.58, 18.59, 18.37, 12.14;
IR (νmax) 2965 (m), 1455 (m), 1044 (s; SdO) cm-1. Isomer 2:
1H NMR δ 6.03 (d, J ) 15 Hz, 1 H), 5.82 (dq, J ) 14.5, 5.9 Hz,
1 H), 3.49 (dd, J ) 11.7, 3.6 Hz, 1 H), 2.72 (s, 3 H), 2.32 (dqd,
J ) 14.6, 7.3, 3.5 Hz, 1 H), 1.85 (dqd, J ) 14.7, 10.7, 7.2 Hz,
1 H), 1.77 (d, J ) 5.4 Hz, 3 H), 1.12 (dd, J ) 7.6, 7.1 Hz, 3 H);
13C NMR δ 133.84, 125.17, 74.89, 37.39, 20.48, 18.36, 11.29;
HRMS (CI/CH4) m/ z calcd for C7H15S3O (MH+) 211.0285,
found 211.0293.
1-(Meth ylth io)p r op yl Disu lfid e (Z)-1-P r op en yl [(Z)-9c].
As in the synthesis of (E)-9c, (Z)-15c (0.30 g, 1.65 mmol) was
reacted with AgOTs (0.92 g, 3.30 mmol) and then MeSH (0.16
g, 3.30 mmol), affording (Z)-9c as a light brown oil (0.197 g,
62%): 1H NMR δ 6.16 (d, J ) 10.5 Hz, 1 H), 5.74 (m, 1 H),
3.70 (dd, J ) 8.1, 4.9 Hz, 1 H), 2.22 (s, 3 H), 2.10 (m, 2 H),
1.77 (d, J ) 7.8 Hz, 3 H), 1.09 (t, J ) 7.2 Hz, 3 H); 13C NMR
δ 129.94, 127.13, 61.39, 28.10, 18.60, 14.59, 11.52.
18.45, 11.79; IR (νmax) 1046 (vs) cm-1
.
1-Ch lor op r op yl P r op yl Disu lfid e (15b). The method for
synthesis of 15a was followed, using PrSH (1.47 g, 20 mmol),
Et3N (3 g, 30 mmol), and 14 (2.88 g, 20 mmol) in THF (50
mL), giving 15b, a yellow, pungent smelling oil (3.02 g, 82%):
1H NMR δ 4.96 (t, J ) 7.2 Hz, 1 H), 2.72 (m, 2 H), 2.13 (m, 2
H), 1.72 (m, 2 H), 1.12 (t, J ) 7.8 Hz, 3 H), 1.01 (t, J ) 7.8 Hz,
3 H); 13C NMR δ 74.34, 41.59, 32.05, 22.57, 13.09, 11.36.
1-(Meth ylth io)p r op yl P r op yl Disu lfid e (9b). Method 2
for the synthesis of 9a was followed, using a solution of 15b
(0.50 g, 2.70 mmol) in CH3CN (5 mL), AgOTs (0.75 g, 2.7 mmol)
in CH3CN (30 mL), and then MeSH (0.13 g, 2.70 mmol) in CH3-
CN (3 mL), giving 9b, a light brown oil (0.39 g, yield, 74%):
1H NMR δ 3.65 (t, J ) 6.8 Hz, 1 H), 2.74 (t, J ) 8.1 Hz, 2 H),
2.51 (m, 2 H), 2.11 (s, 3 H), 1.81 (m, 2 H), 1.08 (t, J ) 7.8 Hz,
3 H), 1.01 (t, J ) 7.8 Hz, 3 H); 13C NMR δ 56.35, 41.70, 33.87,
28.29, 22.61, 13.09, 12.25; EI-MS m/ z 196 (M+, 0.14%), 122
(12), 117 (3), 89 (71), 74 (16), 73 (14), 59 (9), 58 (8), 45 (64), 43
(32), 41 (100), 39 (32).
1-(Meth ylsu lfin yl)p r op yl P r op yl Disu lfid e (7b). Oxida-
tion of 9b (0.30 g, 1.5 mmol) with m-CPBA (0.34 g, 2.0 mmol)
as described for 7a gave, after chromatography, 7b (0.098 g,
31%), a pale yellow oil with a mild onion-like odor: 1H NMR
δ 3.50 (dd, J ) 11.1 Hz, 3.3 Hz, 1 H), 3.08 (m, 1 H), 2.70 (m,
2 H), 2.45 (s, 3 H), 1.90 (ddq, J ) 14.8, 11.0, 7.3 Hz, 2 H), 1.71
(tq, J ) 7.5, 7.1 Hz, 1 H), 1.14 (dd, J ) 7.2, 6.8 Hz, 3 H), 1.10
(t, J ) 7.8 Hz, 3 H); 13C NMR δ 72.91, 52.51, 42.50, 20.03,
16.56, 13.39, 11.14; IR (νmax) 2965 (m), 1455 (m), 1046 (s) cm-1
(SdO); HRMS (CI/CH4) m/ z calcd for C7H17S3O (MH+) 213.0442,
found 213.0454.
1-(Meth ylsu lfin yl)p r op yl (Z)-1-P r op en yl Disu lfid e [(Z)-
7c]. Oxidation of (Z)-9c (0.154 g, 0.80 mmol) with m-CPBA
(0.174 g, 1.01 mmol) as described for 7a gave by chromatog-
raphy two isomers of (Z)-7c (1:1 by NMR; 0.068 g, 41%).
Isomer 1: 1H NMR δ 6.15 (dq, J ) 9.5, 1.5 Hz, 1 H), 5.80 (dq,
J ) 9.1, 6.5 Hz, 1 H), 3.63 (dd, J ) 10.7, 3.8 Hz, 1 H), 2.56 (s,
3 H), 2.32 (dqd, J ) 14.4, 7.2, 3.7 Hz, 1 H), 1.79 (dd, J ) 6.3,
1.4 Hz, 3 H), 1.58 (ddq, J ) 14.7, 10.0, 6.7 Hz, 1 H), 1.21 (t, J
) 7.5 Hz, 3 H); 13C NMR δ 129.75, 128.05, 73.30, 32.59, 18.42,
14.51, 11.53; IR (νmax) 2965 (m), 1455 (m), 1044 (s; SdO) cm-1
.
Isomer 2: 1H NMR δ 6.09 (dq, J ) 9.1, 1.6 Hz, 1 H), 5.82 (dq,
J ) 9.1, 7.2 Hz, 1 H), 3.49 (dd, J ) 10.4, 4.0 Hz, 1 H), 2.75 (s,
3 H), 2.34 (dqd, J ) 15.2, 6.9, 3.5 Hz, 1 H), 1.90 (ddq, J )
14.7, 10.0, 7.0 Hz, 1 H), 1.80 (dd, J ) 6.5, 1.6 Hz, 3 H), 1.12
(dd, J ) 7.2, 7.0 Hz, 3 H); 13C NMR δ 129.81, 128.51, 74.77,
37.28, 20.12, 14.23, 11.12.
1-Ch lor op r op yl (E)-1-P r op en yl Disu lfid e [(E)-15c]. (E)-
1-Propenyl propyl sulfide (1.5 g, 13 mmol) was slowly added
to a stirred blue solution of lithium (0.16 g, 23 mmol) in liquid
NH3 (15 mL) at -78 °C under argon. Stirring was continued
for 45 min, and then NH3 was pumped away (0.2 mmHg and
-50 °C) from the resulting white suspension during 5 h. Ether
(30 mL) was added at -55 °C followed by 14 (2.0 g, 14 mmol).
The mixture was stirred at -55 °C for 20 h and quenched with
water (30 mL). The aqueous layer was extracted with ether
(2 × 20 mL), and the combined organic layers were washed
with NH4Cl solution (2 × 30 mL) and brine (3 × 30 mL), dried,
and concentrated in vacuo to give 15c as a yellow oil (1.73 g,
73%): 1H NMR δ 6.17 (d, J ) 15 Hz, 1 H), 5.99 (m, 1 H), 4.92
(dd, J ) 6, 9 Hz, 1 H), 2.1 (m, 2 H), 1.78 (d, J ) 6.6 Hz, 3 H),
1.08 (t, J ) 7.2 Hz, 3 H); 13C NMR δ 131.70, 125.15, 72.80,
31.83, 18.19, 11.23; EI-MS m/ z 184 (M+, 37Cl, 35%) 182 (M+,
35Cl, 85%), 147 (6%), 106 (100%); HRMS (EI) m/ z calcd for
C6H11S2Cl (M+) 181.9991, found 181.9991; IR (νmax) 2972 (s),
Bis(1-ch lor op r op yl) Disu lfid e (17). A solution of KI
(2.89g, 17 mmol) in water (50 mL) was added to a stirred
solution of 14 (2.53 g, 17 mmol) in CH2Cl2 (50 mL) at room
temperature. The resultant dark red-purple solution was
stirred for 15 min and washed with aqueous Na2S2O3 to remove
liberated iodine. The organic layer was separated, washed
with water (3 × 20 mL), dried, and concentrated in vacuo. The
known (Tjan et al., 1972) but incompletely characterized 17
(1.76 g, 47%) was obtained as a pungent smelling dark red
oil: 1H NMR δ 5.15 (dd, J ) 7.0, 1.8 Hz, 1 H), 5.11 (dd, J )
7.2, 1.8 Hz, 1 H), 2.12 (m, 4 H), 1.13 (t, J ) 7.2 Hz, 3 H), 1.09
(t, J ) 7.2 Hz, 3 H); 13C NMR δ 73.72, 72.90, 31.96, 31.93,
11.23, 11.17.
(E)-4-Eth yl-3,5-d ith ia oct-6-en e-2-on e [(E)-16a ]. A solu-
tion of (E)-1-bromopropene (1.0 g, 8.2 mmol; Hayashi et al.,
1986) in THF (28 mL), ether (7 mL), and pentane (7 mL) was
cooled to -110 °C, and tert-butyllithium (t-BuLi) (1.7 M in
hexanes, 9.6 mL, 16.4 mmol) was added dropwise, resulting
in a pale yellow color. The reaction was stirred for 1 h at -110
°C and was then warmed to -95 °C. Compound 17 (2.15 g,
9.9 mmol) was added dropwise, and the solution was stirred
for an additional 1 h. The solution was warmed to -78 °C,
and sodium thiolacetate (4 equiv) in 200 mL of THF (also at
-78 °C) was added quickly by cannula or large-capacity
syringe, stirred for 1 h at -78 °C, and then slowly warmed to
-30 °C, at which temperature it was allowed to stir for 1 h.
The solution was then warmed quickly to 0 °C and poured into
ether (500 mL), washed with saturated aqueous NH4Cl (200
mL), dried, and concentrated in vacuo. Chromatography (CH2-
Cl2/hexanes 3:7) gave (E)-16a as a brown-yellow, pungent oil
(1.2 g; 76%): 1H NMR δ 5.97 (dd, J ) 15, 1.5 Hz, 1H), 5.86
(dq, J ) 15, 5.5 Hz, 1H), 4.58 (t, J ) 6.9 Hz, 1 H), 2.34 (s, 3
H), 1.9 (m, 2 H), 1.75 (dd, J ) 6.4, 1.9 Hz, 3 H), 1.04 (t, J )
7.4 Hz, 3 H); 13C NMR δ 195.13 (C), 131.82 (CH), 120.63 (CH),
51.84 (CH), 30.42 (CH3), 29.33 (CH2), 18.61 (CH3), 11.73 (CH3);
EIMS m/ z 190 (M+, 6%), 117 (13%), 75 (15%), 74 (18%), 73
(8%), 59 (6%), 47 (9%), 40 (100%); IR (νmax) 2970 (m), 1700 (vs),
2935 (m), 1653 (m), 1459 (s), 1379 (m), 806 (m), 650 (s) cm-1
.
1-Ch lor op r op yl (Z)-1-P r op en yl Disu lfid e [(Z)-15c]. The
synthesis of (E)-15c was followed. From (Z)-1-propenyl propyl
sulfide (1.5 g, 13 mmol) (Z)-15c was obtained as a yellow oil
(1.76 g, 74%): 1H NMR δ 6.20 (d, J ) 9 Hz, 1 H), 5.76 (m, 1
H), 4.93 (dd, J ) 5.7, 7.2 Hz, 1 H), 2.2 (m, 2 H), 1.79 (d, J )
5.6 Hz, 3 H), 1.09 (t, J ) 7.2 Hz, 3 H); 13C NMR δ 128.68,
128.19, 73.07, 31.72, 14.25, 11.19; EI-MS m/ z 184 (M+, 37Cl,
27%) 182 (M+, 35Cl, 68%), 106 (100%); HRMS (EI) m/ z calcd
for C6H11S2Cl (M+) 181.9991, found 181.9991; IR (νmax) 2969
(s), 2934 (s), 1613 (w), 1454 (s), 1379 (s), 699 (s), 670 (s) cm-1
.
1-(Meth ylth io)p r op yl (E)-1-P r op en yl Disu lfid e [(E)-9c].
Method 2 for the synthesis of 9a was followed, using (E)-15c
(0.30 g, 1.65 mmol), AgOTs (0.92 g, 3.30 mmol), and MeSH
(0.16 g, 3.30 mmol). Workup afforded (E)-9c as a light brown
oil (0.174 g, 54%): 1H NMR δ 6.07 (d, J ) 15 Hz, 1 H), 5.96
(m, 1 H), 3.70 (dd, J ) 8.1, 4.7 Hz, 1 H), 2.22 (s, 3 H), 2.10 (m,
2 H), 1.78 (d, J ) 7.8 Hz, 3 H), 1.07 (t, J ) 7.2 Hz, 3 H); 13C
NMR δ 129.81, 126.27, 60.79, 27.96, 18.24, 14.36, 11.64.
1-(Meth ylsu lfin yl)p r op yl (E)-1-P r op en yl Disu lfid e [(E)-
7c]. Oxidation of (E)-9c (0.163 g, 0.84 mmol) with m-CPBA
(0.174 g, 1.01 mmol) as described for 7a gave by chromatog-
raphy two isomers (1:1 by NMR; 0.076 g, 43%). Isomer 1: 1H
NMR δ 6.04 (d, J ) 15 Hz, 1 H), 5.80 (dq, J ) 15.2, 4.7 Hz, 1
H), 3.63 (dd, J ) 11.1, 3.3 Hz, 1 H), 2.52 (s, 3 H), 2.29 (dqd, J
1440 (m), 1130 (m) cm-1
.
(Z)-4-Eth yl-3,5-d ith ia oct-6-en e-2-on e [(Z)-16a ]. Substi-
tution of (Z)-1-bromopropene (Fuller and Walker, 1991) for the
E-isomer in the procedure for (E)-16a gave, after chromatog-

Cepaenes from Onion
J. Agric. Food Chem., Vol. 45, No. 11, 1997 4417
raphy, (Z)-16a (0.85 g; 54%): 1H NMR δ 6.00 (dd, J ) 9.5, 1.7
Hz, 1H), 5.75 (dq, J ) 9.5, 7 Hz, 1 H), 4.58 (t, J ) 7 Hz, 1 H),
2.34 (s, 3 H), 1.9 (m, 2 H), 1.75 (dd, J ) 7, 1.7 Hz, 3 H), 1.04
(t, J ) 7 Hz, 3 H); 13C NMR δ 195.13 (C), 131.82 (CH), 120.61
(CH), 51.83 (CH), 30.40 (CH3), 29.33 (CH2), 14.46 (CH3), 11.71
(CH3); EIMS m/ z 190 (M+, 6%), 117 (13%), 75 (15%), 74 (18%),
73 (8%), 59 (6%), 47 (9%), 40 (100%); IR (νmax) 2970 (m), 1700
(0.50 g, 2.70 mmol), AgOTs (0.75 g, 2.7 mmol), and then PrSH
(0.21 g, 2.7 mmol), giving 9f, a pungent smelling yellow liquid
1
(0.47 g, 78%): H NMR δ 3.66 (t, J ) 7.0 Hz, 1 H), 2.65 (m, 4
H), 1.75 (m, 6 H), 1.06 (t, J ) 7.2 Hz, 3 H), 1.01 (t, J ) 7.8 Hz,
3 H), 0.98 (t, J ) 7.8 Hz, 3 H); 13C NMR δ 53.74, 41.13, 32.20,
29.29, 22.82, 22.47, 13.64, 13.09, 12.18; EI-MS m/ z (%
abundance) 192 (0.22), 150 (15), 117 (40), 75 (32), 74 (20), 73
(16), 47 (23), 45 (44), 43 (100), 41 (90).
(vs), 1440 (m), 1130 (m) cm-1
(E,Z)-4-Eth yl-3,5-d ith ia oct-6-en e-2-on e [(E,Z)-16a ].
.
A
P r op yl 1-(P r op ylsu lfin yl)p r op yl Disu lfid e (7f). Method
1. Oxidation of 9f (0.30 g, 1.30 mmol) with m-CPBA (0.28 g,
1.60 mmol) as described for 7a gave, after chromatography,
two isomers (1:2 by NMR) of 7f as a pale yellow oil with an
onion-like odor (0.106 g, 34%). Minor isomer: 1H NMR δ 3.49
(dd, J ) 10.9 Hz, 3.1 Hz, 1 H), 3.12 (dt, J ) 13.2, 8.0 Hz, 1 H),
2.74 (t, J ) 7.2 Hz, 2 H), 2.71 (dt, J ) 12.6, 7.2 Hz, 1 H), 2.37
(dqd, J ) 14.7, 7.4, 3.3 Hz, 1 H), 1.95 (ddq, J ) 14.6, 10.8, 7.0
Hz, 1 H), 1.91 (tq, J ) 7.6, 7.0 Hz, 2 H), 1.72 (tq, J ) 7.4, 7.0
Hz, 2 H), 1.14 (t, J ) 7.8 Hz, 3 H), 1.11 (t, J ) 7.8 Hz, 3 H),
1.01 (dd, J ) 7.6, 7.0 Hz, 3 H); 13C NMR δ 72.78, 52.56, 42.50,
22.20, 20.01, 16.49, 13.33, 12.97, 11.08. Major isomer: 1H
NMR δ 3.64 (dd, J ) 10.9 Hz, 3.2 Hz, 1 H), 2.89 (dt, J ) 11.6,
7.1 Hz, 2 H), 2.77 (t, J ) 7.2 Hz, 2 H), 2.64 (dt J ) 12.6, 7.3
Hz, 1 H), 2.30 (dqd, J ) 14.8, 7.4, 3.6 Hz, 1 H), 1.86 (tq, J )
7.2, 7.0 Hz, 2 H), 1.74 (tq, J ) 7.2, 7.0 Hz, 2 H), 1.62 (ddq, J
) 14.7, 11.5, 7.1 Hz, 1 H), 1.24 (t, J ) 7.8 Hz, 3 H), 1.13 (t, J
) 7.8 Hz, 3 H), 1.04 (t, J ) 7.8 Hz, 3 H); 13C NMR δ 73.89,
100 mL three-neck flask was charged with a solution of bis-
(1-propenyl)sulfide (19; Trofimov et al., 1986) (2.0 g, 7.5mmol)
in ether/hexanes (1:3, 12 mL). A slow stream of HCl gas was
introduced through a glass pipet into the reaction mixture,
and the progress of the reaction giving 1-chloropropyl (E,Z)-
1-propenyl sulfide [(E,Z)-18] was monitored by GC. Sodium
thiolacetate (4 equiv) at -78 °C was added dropwise to the
(E,Z)-18 solution. The mixture was then warmed to room
temperature, stirred for 17 h, and taken into ether, and the
organic layer was washed with saturated aqueous NH4Cl,
dried, and concentrated in vacuo, yielding a brown-red oil that
was purified by chromatography (CH2Cl2/hexanes 3:7) giving
(E,Z)-16b (2.72 g, 80%).
Meth yl (E)-1-(1-P r op en ylth io)p r op yl Disu lfid e [(E)-
9d ]. A 50 mL three-neck flask was charged with K2CO3 (0.58
g, 4.2 mmol) and MeOH (25 mL). The mixture was stirred at
room temperature for 30 min and cooled to -55 °C. A solution
of (E)-16a (0.20 g, 1 mmol) in MeOH (5 mL) was added
dropwise. When thiolacetate hydrolysis was complete (TLC),
MeSO2SMe (0.63 g, 5 mmol) was added dropwise. The solution
was then warmed to room temperature, hexanes were added,
and the product was washed with water (5 × 50 mL). The
organic layer was separated, dried, and concentrated in vacuo.
Chromatography (hexanes) gave (E)-9d , (0.083 g, 43%) as a
pale yellow oil: 1H NMR δ 6.05 (dq, J ) 14.5, 2.5 Hz, 1 H),
5.85 (dq, J ) 15, 6.5 Hz, 1H), 3.86 (dd, J ) 8, 5 Hz, 1 H), 2.48
(s, 3 H), 2.0 (m, 2 H), 1.78 (dd, J ) 5.5, 1.5 Hz, 3 H), 1.09 (t,
J ) 7.4 Hz, 3 H); 13C NMR δ 131.11 (CH), 123.20 (CH), 52.31
(CH), 28.37 (CH2), 25.19 (CH3), 18.62 (CH3), 12.24 (CH3); EIMS
m/ z 194 (M+, 0.3%), 120 (13%), 116 (4%), 115 (56%), 87 (5%),
79 (17%), 74 (17%), 73 (42%), 59 (24%), 46 (14%), 45 (100%).
Meth yl (E)-1-(1-P r op en ylsu lfin yl)p r op yl Disu lfid e [(E)-
7d ]. Oxidation of (E)-9d (0.083 g, 0.43 mmol) with m-CPBA
(0.089 g, 0.52 mmol) as described for 7a gave, after chroma-
tography, (E)-7d (0.048 g, 53%), a pale yellow oil that was a
2:1 mixture of diastereomers: 1H NMR (of mixture; unadjusted
integration) δ 6.45 (m, 6 H), 3.68 (dd, J ) 3.5, 10.6 Hz, 1 H),
3.50 (dd, J ) 3.3, 10.6 Hz, 2 H), 2.51 (s, 3 H), 2.46 (s, 6 H),
2.22 (m, 3 H), 1.95 (dd, J ) 6.2, 1.9 Hz, 9 H), 1.87 (m, 3 H),
1.15 (m, 9 H); 13C NMR (major isomer) δ 138.32 (CH), 131.65
48.77, 41.35, 22.22, 19.48, 17.07, 13.55, 13.04, 12.11; IR (νmax
)
1046 (s) cm-1 (SdO); HRMS (CI/CH4) m/ z calcd for C9H21S3O
(MH+) 241.0755, found 241.0760.
Method 2. A solution of PrS(O)SPr (0.10 g, 0.60 mmol) in
benzene (10 mL)/water (6 mL) was kept at 60 °C for 36 h. The
aqueous layer was extracted with ether (3 × 5 mL), and the
combined organic layers were dried and concentrated in vacuo.
After purification by column chromatography (CH2Cl2/acetone,
9:1), 7f was obtained as a yellow oil consisting of two isomers
(1:1 by NMR; 0.013 g, 9.6%); 1H and 13C NMR and IR spectra
were identical to product prepared according to method 1.
(E)-1-P r op en yl 1-(P r op ylth io)p r op yl Disu lfid e [(E)-9g].
Method 2 for the synthesis of 9a was followed, using (E)-15c
(0.30 g, 1.65 mmol), AgOTs (0.46 g, 1.65 mmol), and PrSH (0.16
g, 1.65 mmol). Workup afforded (E)-9g, a pungent smelling
yellow oil (0.32 g, 87%): 1H NMR δ 6.08 (d, J ) 15 Hz, 1 H),
5.95 (m, 1 H), 3.77 (dd, J ) 8.0, 4.8 Hz, 1 H), 2.68 (m, 2 H),
2.13 (m, 1 H), 1.81 (d, J ) 6.8 Hz, 3 H), 1.67 (m, 3 H), 1.09 (t,
J ) 7.6 Hz, 3 H), 1.02 (t, J ) 7.2 Hz, 3 H); 13C NMR δ 129.65,
126.08, 59.04, 34.11, 28.39, 23.03, 18.28, 13.66, 11.50.
(E)-1-P r op en yl 1-(P r op ylsu lfin yl)p r op yl Disu lfid e [(E)-
7g]. Oxidation of (E)-9g (0.30 g, 1.4 mmol) with m-CPBA (0.28
g, 1.6 mmol) as described for 7a gave by chromatography two
isomers of (E)-7g, a light yellow oil (1:2 by NMR; 0.12 g, 39%).
Minor isomer: 1H NMR δ 6.08 (d, J ) 14.5 Hz, 1 H), 5.80 (m,
1 H), 3.52 (dd, J ) 11, 3.9 Hz, 1 H), 3.11 (m, 1 H), 2.70 (m, 1
H), 2.36 (m, 1 H), 1.91 (m, 3 H), 1.80 (d, J ) 4.6 Hz, 3 H), 1.16
(t, J ) 7.8 Hz, 3 H), 1.10 (t, J ) 7.6 Hz, 3 H); 13C NMR δ
133.93, 125.48, 72.49, 52.69, 20.40, 18.34, 16.65, 13.51, 11.19.
Major isomer: 1H NMR δ 6.10 (d, J ) 14 Hz, 1 H), 5.80 (m, 1
H), 3.68 (dd, J ) 11, 3.7 Hz, 1 H), 2.75 (m, 2 H), 2.33 (m, 1 H),
1.95 (m, 3 H), 1.80 (d, J ) 4.6 Hz, 3 H), 1.20 (t, J ) 7.8 Hz, 3
H), 1.12 (t, J ) 7.8 Hz, 3 H); 13C NMR δ 131.81, 125.19, 74.86,
48.92, 19.63, 18.02, 17.65, 13.54, 12.09; IR (νmax) 1049 (s; SdO)
cm-1; HRMS (CI/CH4) m/ z calcd for C9H19S3O (MH+) 239.0598,
found 239.0603.
(E)-1-(1-P r op en ylth io)p r op yl P r op yl Disu lfid e [(E)-9h ].
This compound was prepared according to the procedure given
for (E)-9d using (E)-16a (0.15g, 0.79 mmol), K2CO3 (0.44 g,
3.2 mmol), and PrSO2SPr (0.72 g, 3.9 mmol), giving (E)-9h
(0.072 g, 41%) as a pale yellow oil: 1H NMR δ 6.05 (dq, J )
14.5, 2.5 Hz, 1 H), 5.85 (dq, J ) 15, 6.5 Hz, 1 H), 3.86 (dd, J
) 8, 5 Hz, 1 H), 2.75 (t, J ) 7 Hz, 2 H), 2.11 (m, 1 H), 1.85 (m,
1 H),1.78 (dd, J ) 5.5, 1.5 Hz, 3 H), 1.71 (m, 2 H), 1.07 (t, J )
7.4 Hz, 3 H), 1.00 (t, J ) 7.4 Hz, 3 H); 13C NMR δ 131.15 (CH),
122.72 (CH), 60.25 (CH), 41.71 (CH2), 27.84 (CH2), 22.67 (CH2),
18.61 (CH3), 13.13 (CH3), 11.63 (CH3); EIMS m/ z 224 (M + 2,
0.05%), 222 (M+, 0.3%), 115 (100%), 105 (6%), 81 (45%), 74
(12%), 73 (61%), 45 (97%).
(CH), 75.61 (CH), 24.81 (CH3), 20.33 (CH2), 18.04 (CH3), 11.25
+
(CH3); CIMS (NH3) m/ z 421 (2M + H+, 4%), 228 (M + NH4
,
29%), 213 (M + 2, 10%), 211 (MH+, 62%), 195 (100%), 137
(15%); HRMS (CI/CH4) m/ z calcd for C7H15S3O (MH+) 211.0285,
found 211.0286; IR (νmax) 1440 (m), 1035 (vs) cm-1
.
Meth yl 1-(2-P r open ylth io)pr opyl Disu lfide (9e). Method
2 for the synthesis of 9a was followed, using 15a (0.30 g, 1.92
mmol), AgOTs (0.53 g, 1.92 mmol), and 2-propenethiol (0.14
g, 1.92 mmol), giving 9e, a yellow oil (0.28 g, 76%): 1H NMR
δ 5.78 (m, 1 H), 5.20 (d, J ) 12.0 Hz, 2 H), 3.58 (t, J ) 7.0 Hz,
1 H), 3.26 (d, J ) 7.2 Hz, 2 H), 2.50 (s, 3 H), 2.18 (m, 1 H),
1.80 (m, 1 H), 1.02 (t, J ) 7.8 Hz, 3H); 13C NMR δ 134.36,
117.21, 74.27, 33.44, 31.96, 19.17, 11.41.
Meth yl 1-(2-P r op en ylsu lfin yl)p r op yl Disu lfid e (7e).
Oxidation of 9e (0.20 g, 1.03 mmol) with m-CPBA (0.19 g, 1.10
mmol) as described for 7a gave, after chromatography, 7e, a
yellow liquid with an onion-like odor (0.072 g, 33%): 1H NMR
δ 5.97 (m, 1 H), 5.45 (d, J ) 12.3 Hz, 2 H), 3.60 (dd, J ) 11.3,
3.7 Hz, 1 H), 3.32 (d, J ) 7.8 Hz, 2 H), 2.50 (s, 3 H), 2.35 (m,
1 H), 1.96 (m, 1 H), 1.15 (t, J ) 7.8 Hz, 3 H); 13C NMR δ 133.26,
118.48, 69.93, 52.84, 33.96, 19.45, 11.03; IR (νmax) 1044 (s) cm-1
(SdO); HRMS (CI/CH4) m/ z calcd for C7H15S3O (MH+) 211.0285,
found 211.0297. Analysis by LC/MS indicates that the chro-
matographed product contains some 2-propenyl 1-(2-prop-
enylsulfinyl)propyl disulfide.
P r op yl 1-(P r op ylth io)p r op yl Disu lfid e (9f). Method 2
for the synthesis of 9a was followed, using a solution of 15b

4418 J. Agric. Food Chem., Vol. 45, No. 11, 1997
Block et al.
(E)-1-(1-P r op en ylsu lfin yl)p r op yl P r op yl Disu lfid e [(E)-
7h ]. Oxidation of (E)-9h (0.07 g, 0.32 mmol) with m-CPBA
(0.067 g, 0.39 mmol) as described for 7a gave (E)-7h (0.041 g,
53%), a pale yellow oil that was a 2:1 mixture of diastereo-
mers: 1H NMR (of mixture; unadjusted integration) δ 6.5 (m,
6 H), 3.67 (dd, J ) 3.3, 10.7 Hz, 1 H), 3.48 (dd, J ) 3.3, 10.7
Hz, 2 H), 2.73 (m, 6 H), 2.27 (m, 3 H), 1.96 (d, J ) 5.6 Hz, 9
H), 1.88 (m, 3 H), 1.70 (apparent sextet, J ) 7 Hz, 6 H), 1.14
(t, J ) 7.4 Hz, 9 H), 0.99 (t, 7.4 Hz, 9 H); 13C NMR (major
isomer) δ 138.44 (CH), 131.81 (CH), 75.63 (CH), 42.47 (CH2),
22.31 (CH2), 20.31 (CH2), 18.05 (CH3), 13.04 (CH3), 11.28 (CH3);
CIMS (NH3) m/ z 477 (2M + H+, 13%), 256 (M + NH4+, 31%),
241 (MH+, 25%), 240 (20%), 239 (MH+, 100%), 166 (20%), 165
(20%), 149 (91%); HRMS (CI/CH4) m/ z calcd for C9H19S3O
(MH+) 239.0598, found 239.0592; IR (νmax) 1440 (m), 1035 (vs)
2 Hz, 3 H), 1.85 (m, 1 H), 1.75 (d, J ) 5.5 Hz, 3 H), 1.1 (t, J )
7.2 Hz, 3 H); 13C NMR δ 138.3, 133.03, 131.71, 125.38, 74.75,
20.35, 18.16, 17.95, 11.10; MS (EI) m/ z 147 (84), 115 (68), 105
(100), 73 (55); HRMS (CI/CH4) m/ z calcd for C9H17S3O (MH+)
237.0442, found 237.0437; IR (νmax) 2965 (m), 1440 (m), 1047
(s; SdO) cm-1
.
(E)-1-P r op en yl (Z)-1-(1-P r op en ylth io)p r op yl Disu lfid e
[(E,Z)-9i]. Method 2 for the synthesis of (E,E)-9i was followed.
From the reaction as above involving (E)-1-propenyl propyl
sulfide (1.5 g, 13 mmol), lithium (0.16 g, 26 mmol) in liquid
NH3 (15 mL), 14 (2.0 g, 11 mmol), and ether (20 mL), followed
by chromatography (hexane/EtOAc, 9/1), (E,Z)-9i was obtained
as a yellow oil (1.08 g, 45%) containing ca. 20% (E,E)-9i: 1H
NMR δ 6.10 (m, 2 H), 5.92 (m, 1 H), 5.72 (m, 1 H), 3.86 (dd, J
) 4.7, 8.4 Hz, 1 H), 2.1 (m, 2 H), 1.74 (m, 6 H), 1.06 (t, J ) 7.2
Hz, 3 H); 13C NMR δ 129.98, 127.08, 126.47, 122.60, 60.02,
27.72, 18.16, 14.79, 11.49; GC/MS (EI) m/z 220 (M+, 44), 205
(100%), 115 (38).
cm-1
.
(E)-1-P r op en yl (E)-1-(P r op en ylt h io)p r op yl Disu lfid e
[(E,E)-9i]. Method 1. Lithium (0.56 g, 80 mmol) was added
to liquid NH3 (50 mL) in a three-neck round-bottom flask at
-78 °C. After 15 min, a solution of (E)-1-propenyl propyl
sulfide (4.64 g, 40 mmol) in THF (30 mL) was added. The NH3
was removed at -60 °C (0.5 mmHg) using a liquid nitrogen
trap until the reaction mixture was almost dry. More THF
(80 mL) was added, and the reaction mixture was pumped at
-60 °C for another 15 min. Methanesulfonyl chloride (3.66
g, 0.8 equiv, 32 mmol) in THF (5 mL) was added at -65 °C;
the resultant white mixture was stirred at -5 °C for 2 h. Cold
water (50 mL) was added, and after 30 min, the mixture was
extracted with pentane, dried, and concentrated. GC/MS
analysis (decane internal standard) showed (E,E)-9i (27%),
(E,E)-5,8-diethyl-4,6,7,9-tetrathiadodeca-2,10-diene (18% yield),
(E,E)-bis(1-propenyl) disulfide, and 2,4,6-triethyl-1,3,5-trithiane.
Chromatography (silica gel, hexanes) gave (E,E)-9i (730 mg;
25%) and (E,E)-5,8-diethyl-4,6,7,9-tetrathiadodeca-2,10-diene
(250 mg; 9%). (E,E)-9i: 1H NMR δ 6.15-5.85 (m, 4 H), 3.83
(dd, J ) 8.2, 5 Hz, 1 H), 2.1 (m, 1 H), 1.78 (m, 4 H), 1.05 (t, J
) 7.3); 13C NMR (APT) δ 131.12 (CH), 129.82 (CH), 126.19
(CH), 120.79 (CH), 59.61 (CH), 27.68 (CH2), 18.65 (CH3), 18.12
(CH3), 11.41 (CH3); IR (neat, νmax) 2964 (s), 1615 (w), 1442 (s),
936 (s) cm-1; GC/MS (EI) m/z (rel intensity) 220 (M+, 0.2), 146
(4), 115 (66), 45 (100); HRMS (EI) m/ z calcd for C9H16S3
220.0414, found 220.0434. Minor component: 1H NMR δ
5.75-6.15 (m, 4 H), 3.95-4.03 (m, 2 H), 2.04-2.17 (m, 2 H),
1.70-1.88 (m, 8 H), 1.02-1.11 (m, 6 H); 13C NMR δ 131.01,
130.78, 121.03, 120.68, 60.62, 60.02, 28.04, 27.72, 18.66, 18.62,
11.60, 11.56; GC/MS (EI) m/ z (rel intensity) 294 (M+, 0.5), 146
(7), 115 (70), 45 (100).
(E)-1-P r op en yl (Z)-1-(1-P r op en ylsu lfin yl)p r op yl Di-
su lfid e [(E,Z)-7i]. Oxidation of (E,Z)-9i (0.20 g, 0.91 mmol)
with m-CPBA (0.186 g, 1.08 mmol) as described for 7a gave,
after chromatography (9:1 CH2Cl2/acetone), (E,Z)-7i, a pale
yellow oil that was a 1:1 mixture of diastereomers (0.084 g,
39%). Isomer 1: 1H NMR δ 6.43 (m, 1 H), 6.20 (m, 1 H), 6.09
(m, 1 H), 5.79 (m, 1 H), 3.57 (dd, J ) 4.6, 3.4 Hz, 1 H), 2.33
(m, 1 H), 2.03 (m, 3 H), 1.95 (m, 3 H), 1.76 (d, J ) 2.1 Hz, 3
H), 1.16 (t, J ) 7.5 Hz, 3 H); 13C NMR δ 140.26, 140.13, 134.25,
129.27, 74.39, 20.35, 18.25, 16.02, 11.21. Isomer 2: 1H NMR
δ 6.39 (m, 1 H), 6.17 (m, 1 H), 6.04 (m, 2 H), 3.54 (dd, J ) 5.0,
3.5 Hz, 1 H), 2.28 (m, 1 H), 2.01 (m, 3 H), 1.90 (m, 1 H), 1.78
(d, J ) 2.9 Hz, 3 H), 1.12 (t, J ) 7.3 Hz, 3 H); 13C NMR δ
140.68, 133.38, 128,28, 125.43, 74.33, 20.28, 18.59, 14.46,
11.84; EI-MS m/ z 236 (M+, 100%), 220 (28%), 147 (31%);
HRMS (CI/CH4) m/ z calcd for C9H17S3O (MH+) 237.0442,
found 237.0439; IR (neat, νmax) 1445 (m), 1048 (s) cm-1
.
RESULTS AND DISCUSSION
Isola t ion a n d Occu r r en ce of Cep a en es a n d
“Deoxycep a en es”. In 1988 the isolation of methyl
1-(methylsulfinyl)propyl disulfide [MeS(O)CHEtSSMe,
7a ] from fresh onion extracts was reported. This
compound displayed an IC50 of 67.6 µmol against an in
vitro platelet suspension (Kawakishi and Morimitsu,
1988). It was suggested, without elaboration, that 7a
“is probably formed by the interaction of thiopropanal
S-oxide and methanesulfenic acid produced in crushed
onion”. Simultaneously, a paper appeared on the isola-
tion of a series of related compounds of the type
MeCHdCHS(O)CHEtSSR, termed “cepaenes”, showing
interesting biological activity [e.g. for (E)-MeCHdCHS-
(O)CHEtSSPr [(E)- 7h ]: IC50 ) 2.5 µM and 0.8 µM on
sheep seminal microsome CO and porcine leucocyte
5-LO, respectively] (Bayer et al., 1988). More recently,
it has been shown that mixing onion homogenates with
S-alk(en)yl-L-cysteine sulfoxides or with other Allium
species affords various cepaenes (Morimitsu et al.,
1992). Oxygen-free analogs of cepaenes, alk(en)yl 1-[alk-
(en)ylthio]propyl disulfides [RSCHEtSSR′, 9; termed
“deoxycepaenes” by Block and Zhao (1992)], occur rather
widely in natural product volatiles. Thus, methyl
1-(methylthio)propyl disulfide (MeSCHEtSSMe; 9a ) oc-
curs in the headspace of meat; syntheses of 9a and
homologs were reported (Dubs and Stu¨ssi, 1978). The
compound MeSCHEtSSCHdCHMe (9c) is found in
Asafoetida essential oil (Naimie et al., 1972; Noleau et
al., 1991) and Ferula species (Dai and Qiu, 1992), while
MeCHdCHSCHEtSSCHdCHMe (9i) and related com-
pounds occur in distilled oils of onion (Farkas et al.,
1992), shallot (Allium ascalonicum), Welsh onion (Al-
lium fistulosum) (Kuo et al., 1990; Kuo and Ho, 1992a,b),
and Chinese chive (Allium tuberosum) (Meng et al.,
Method 2. An ether (15 mL) solution of (E)-MeCHdCHSPr
(3.0 g, 26 mmol) was added slowly to a stirred blue solution of
Li (0.32 g, 46 mmol) in NH3 (20 mL) at -78 °C under argon.
The white suspension was stirred for 1 h. Excess NH3 was
removed at -50 °C/0.2 mmHg during 5 h. Ether (30 mL) was
added at -50 °C followed by 14 (1.88 g, 13 mmol) in ether (20
mL). The mixture was stirred at -5 °C for 20 h and then
quenched with water (30 mL). The aqueous layer was
extracted with ether (2 × 20 mL), and the combined organic
layers were washed with aqueous NH4Cl (2 × 30 mL) and
brine (3 × 30 mL), dried, and concentrated in vacuo to give
1
(E,E)-9i, a yellow oil (1.28 g, 45%). The H/13C NMR spectra
and EI-MS match those of (E,E)-9i prepared according to
method 1.
(E)-1-P r op en yl (E)-1-(P r op en ylsu lfin yl)p r op yl Disu l-
fid e [(E,E)-7i]. Oxidation of (E,E)-9i (0.22 g, 1 mmol) with
m-CPBA (0.184 g, 1.06 mmol) as described for 7a gave (E,E)-
7i, a liquid (0.155 g, 64%) consisting of two diastereomers (1:2
by NMR). Pure isomers were obtained by flash chromatog-
raphy (silica gel, AcOEt/hexanes, 3:7): (minor isomer, less
polar) 1H NMR δ 6.48 (dq, J ) 15, 7 Hz, 1 H), 6.3 (dq, J ) 15,
2 Hz, 1 H), 6.1 (d, J ) 15 Hz, 1 H), 6.02 (dq, J ) 15, 6 Hz, 1
H), 3.66 (dd, J ) 10.5, 3.5 Hz, 1 H), 2.18 (m, 1 H), 1.93 (dd, J
) 7, 2 Hz, 3 H), 1.78 (d, J ) 6 Hz, 3 H), 1.41 (m, 1 H), 1.13 (t,
J ) 7.2 Hz, 3 H); 13C NMR δ 138.6, 133.2, 128.32, 125.05,
74.05, 18.74, 18.52, 18.18, 11.73; (major isomer, more polar)
1H NMR δ 6.51 (dq, J ) 15, 6 Hz, 1 H), 6.4 (dq, J ) 15, 2 Hz,
1 H), 6.05 (d, J ) 15 Hz, 1 H), 5.98 (dq, J ) 15, 5.5 Hz, 1 H),
3.48 (dd, J ) 11, 3.5 Hz, 1 H), 2.22 (m, 1 H), 1.92 (dd, J ) 6,

Cepaenes from Onion
J. Agric. Food Chem., Vol. 45, No. 11, 1997 4419
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
Sch em e 7
1996), as well as in volatiles from roasted onion (Toki-
tomo, 1995).
Mech a n ism of F or m a tion of Cep a en es. In an
earlier study we reported the conversion of alkyl al-
kanethiosulfinates to R-sulfinyl disulfides, RCH2S(O)-
SCH2R′ (10) f RCH2S(O)CHR′SSCH2R′ (11) (Scheme
3), predicting that compounds such as 11 would possess
unusual physiological properties (Block and O’Connor,
1973). There are several difficulties with the application
of this mechanism to cepaene formation in onions: (1)
In our earlier work, thiosulfinates possessing CH3S
groups afforded R-sulfinyl disulfides more efficiently
than those with other RS groups, leading to the expec-
tation that R-sulfinyl disulfides of type 11, R′ ) H
(Scheme 3), should be formed from mixtures of thiosul-
finates containing 10, R or R′ ) H. In fact, only
cepaenes 7 with an ethyl group on the carbon between
the sulfurs have been found naturally. (2) In our earlier
work, the formation of R-sulfinyl disulfides from thio-
sulfinates was a slow process, requiring prolonged
heating. As noted in the accompanying paper (Calvey
et al., 1997), cepaene formation/extraction in supercriti-
cal CO2 treatment of onion homogenates is rapid.
Because of these problems with the mechanism of
Scheme 3, an alternative mechanism is proposed to
explain cepaene formation (Scheme 4). We suggest that
sulfenic acids 2 add to LF 3, giving internally hydrogen-
bonded R-sulfinylsulfenic acids 12 (it is known that
intramolecular hydrogen bonding greatly stabilizes
sulfenic acids). The reaction between 2 and 3 is
analogous to other reported carbophilic addition reac-
tions of sulfines (Yagami et al., 1980; Block and Aslam,
1985). Intermediate 13 may mediate conversion of 12
to cepaenes 7.
HEtSSPr (9f), at the sulfide sulfur. Three syntheses of
1-[alk(en)ylthio]propyl alk(en)yl disulfides (deoxyce-
paenes; 9) have been reported. The first (Dubs and
Stu¨ssi, 1978) involves treatment of 1-chloropropane-
sulfenyl chloride, EtCHClSCl (14), with excess meth-
anethiolate. Although not mentioned by the authors,
1-chloropropyl methyl disulfide (15a ; EtCHClSSMe) is
a likely intermediate in the latter synthesis. The second
synthesis involves hydrolysis of 3-ethyl-2,4-dithiahexan-
5-one, MeSCHEtSAc (16a ), in the presence of a thio-
sulfenylating agent such as a disulfide (Scheme 5; Dubs
and Stu¨ssi, 1978). The nonstereospecific reaction of
(E,Z)-1-propenethiol with 1-(methylthio)-1-propanesulfe-
nyl thiocyanate, MeSCHEtSSCN, is the basis for the
third synthesis (Meijer and Vermeer, 1974).
Results. Two-step syntheses of (E,E)- or (Z,Z)-1-
propenyl 1-(1-propenylsulfinyl)propyl disulfide [(E,E)-
or (Z,Z)-7i] were developed on the basis of the seren-
dipitous finding that low-temperature treatment of
lithium (E)- or (Z)-1-propenethiolate with MeSO2Cl
affords (E,E)- or (Z,Z)-1-propenyl 1-(1-propenylthio)-
propyl disulfide [(E,E)- or (Z,Z)-9i], respectively, in 23-
27% yields (Scheme 6). The mechanism of this reaction
is discussed elsewhere (Block and Zhao, 1992). Oxida-
tion of (E,E)- or (Z,Z)-9i with m-CPBA gives the respec-
tive isomers of 7i in 64% isolated yield. This approach
could not be used to prepare (E,Z)-7i, so a lengthier
approach was employed, involving sequential treatment
of EtCHClSSCHdCHMe-(Z) [(Z)-15c] with silver tosyl-
ate in acetonitrile at low temperatures followed by (E)-
MeCHdCHSLi giving (E,Z)-9i (Scheme 7). If (E)-15c
was substituted for the Z-isomer in the above procedure,
(E,E)-9i was obtained. Stereoisomeric compounds 15c
were prepared by reaction of EtCHClSCl (14) with 1
Syn th esis of Cep a en es. Background. Refluxing
thiosulfinates 10 in benzene/water affords R-sulfinyl
disulfides 11 in one step (Scheme 3) (Block and O’Connor,
1973, 1974). Application of this procedure to PrS(O)-
SPr (10, R ) R′ ) Et) (Block et al., 1986) affords PrS-
(O)CHEtSSPr [11, R ) R′ ) Et () 7f)] in 10% yield as
a 1:1 mixture of diastereomers. A more general ap-
proach to cepaenes such as 7f involves selective oxida-
tion of the corresponding deoxycepaene, e.g. PrSC-

4420 J. Agric. Food Chem., Vol. 45, No. 11, 1997
Block et al.
Ta ble 1. Syn th etic Cep a en es a n d Deoxycep a en es
NMR of CHEt group
synth methodp isomer
formula
n
cepaene/deoxycepaene (compd no.)
MeSCHEtSSMe (9a )
nat occ
(yield)q
ratio
1H (J , Hz)
13C
C5H12S3On
0
a-c
A (61%)r
B (65%)
G (37%)
3.67 (dd, 8, 5)
61.14
1
MeS(O)CHEtSSMe (7a )
k, l
2:1
3.60 (dd, 11, 3.3)
3.45 (dd, 11, 3.3)
3.65 (t, 6.8)
73.98
75.34
56.35
72.91
C7H16S3On
C7H14S3On
0
1
0
1
MeSCHEtSSPr (9b)
MeS(O)CHEtSSPr (7b)
MeSCHEtSSCHdCHMe-(E) [(E)-9c]
MeS(O)CHEtSSCHdCHMe-(E) [(E)-7c]
d, e
l
b, f-h
l
B (74%)r
G (31%)
B (54%)r,s
G (43%)
1:1
1:1
3.50 (dd, 11, 3.3)
3.70 (dd, 81.1, 4.7) 60.79
3.63 (dd, 11.1, 3.3) 72.93
3.49 (dd, 11.7, 3.6) 74.89
3.70 (dd, 8.1, 4.9)
3.63 (dd, 10.7, 3.8) 73.30
3.49 (dd, 10.4, 4.0) 74.77
3.86 (dd, 8, 5)
3.50 (dd, 10.6, 3.3) 75.61
3.68 (dd, 10.6, 3.5)
3.90 (dd, 8.7, 5.4)
3.57 (dd, 10.7, 3.4) 75.14
3.60 (dd, 10.5, 3.1)
3.58 (t, 7.0)
3.60 (dd, 11.3, 3.7) 69.93
3.66 (t, 7.0) 53.74
3.64 (dd, 10.9, 3.2) 73.89
3.49 (dd, 10.9, 3.1) 72.78
3.77 (dd, 8.0, 4.8)
3.68 (dd, 11, 3.7)
3.52 (dd, 11, 3.9)
3.77 (dd, 7.8, 4.5)
3.64 (dd, 10.7, 4.1) 73.00
3.50 (dd, 11, 3.7)
3.86 (dd, 8, 5)
3.67 (dd, 10.7, 3.3) 75.63
3.48 (dd, 10.7, 3.3)
3.86 (dd, 8, 5)
0
1
MeSCHEtSSCHdCHMe-(Z) [(Z)-9c]
MeS(O)CHEtSSCHdCHMe-(Z) [(Z)-7c]
j
l
B (62%)r,s
G (41%)
61.39
1:1
2:1
2:1
0
1
(E)-MeCHdCHSCHEtSSMe [(E)-9d ]
(E)-MeCHdCHS(O)CHEtSSMe [(E)-7d ]
c-e
m
C (43%)
G (53%)
52.31
0
1
(Z)-MeCHdCHSCHEtSSMe [(Z)-9d ]
(Z)-MeCHdCHS(O)CHEtSSMe [(Z)-7d ]
C (32%)
G (53%)
52.30
0
1
0
1
CH2dCHCH2SCHEtSSMe (9e)
CH2dCHCH2S(O)CHEtSSMe (7e)
PrSCHEtSSPr (9f)
B (76%)r
G (33%)
B (78%)r
G (34%)
74.27
C9H20S3On
C9H18S3On
PrS(O)CHEtSSPr (7f)
2:1
2:1
1:1
2:1
3:1
0
1
(E)-PrSCHEtSSCHdCHMe [(E)-9g]
(E)-PrS(O)CHEtSSCHdCHMe [(E)-7g]
d
m
B (87%)r
G (39%)
59.04
74.86
72.49
59.36
0
1
(Z)-PrSCHEtSSCHdCHMe [(Z)-9g]
(Z)-PrS(O)CHEtSSCHdCHMe [(Z)-7g]
B (87%)r
G (31%)
m
72.23
60.25
0
1
(E)-MeCHdCHSCHEtSSPr [(E)-9h ]
(E)-MeCHdCHS(O)CHEtSSPr [(E)-7h ]
d, j
n
C (41%)
G (53%)
0
1
(Z)-MeCHdCHSCHEtSSPr [(Z)-9h ]
(Z)-MeCHdCHS(O)CHEtSSPr [(Z)-7h ]
C (44%)
G (49%)
60.25
3.53 (dd, 10.7, 3.3) 75.28
3.66 (dd, 10.7, 3.3)
C9H16S3On
0
1
(E,E)-MeCHdCHSCHEtSSCHdCHMe [(E,E)-9i]
e, i, j
D (25%)
E (45%)
A (50%)
3.83 (dd, 8.2, 5)
59.61
(E,E)-MeCHdCHS(O)CHEtSSCHdCHMe [(E,E)-7i] n, o
2:1
1:1
3.48 (dd, 11, 3.5)
3.66 (dd, 10.5, 3.5) 74.05
3.86 (dd, 8.4, 4.7)
3.57 (dd, 4.6, 3.4)
3.54 (dd, 5.0, 3.5)
74.75
0
1
(E,Z)-MeCHdCHSCHEtSSCHdCHMe [(E,Z)-9i]
(E,Z)-MeCHdCHS(O)CHEtSSCHdCHMe [(E,Z)-7i]
e, i, j
n
F (45%)
G (49%)
60.02
74.39
74.33
a
b
d
Dubs and Stu¨ssi (1978). Meng et al. (1996). c Kuo et al. (1990). Kuo and Ho (1992a). e Farkas et al. (1992). f Noleau et al. (1991).
g
h
i
j
k
l
Dai and Qiu (1992). Naimie et al. (1972). Tokitomo (1995). Kuo and Ho (1992b). Kawakishi and Morimitsu (1988). Morimitsu
and Kawakishi (1990). Morimitsu et al. (1992). Bayer et al. (1989). o Bayer et al. (1988). Methods of preparations: A, MeSNa plus
m
n
p
EtCHClSSR; B, RSH + EtCHClSSR′ + AgOTs; C, (E)- or (Z)-MeCHdCHSCHEtSAc/K2CO3 + RSO2SR; D, MeCHdCHSLi + MsCl; E,
q
2MeCHdCHSLi + EtCHClSCl; F, EtCHClSSR + MeCHdCHSLi; G, oxidation with m-CPBA. Unless otherwise indicated, yields are
r
s
after chromatographic purification. Crude yields; products used directly for subsequent step. Earlier nonstereospecific synthesis: Meijer
t
and Vermeer (1974). Chemical Abstracts Service names (provided by the author): methyl 1-(methylthio)propyl disulfide (9a ); methyl
1-(methylsulfinyl)propyl disulfide (7a ); 1-(methylthio)propyl propyl disulfide (9b); 1-(methylsulfinyl)propyl disulfide (7b); 1-(methylthi-
o)propyl (E,Z)-1-propenyl disulfide [(E,Z)-9c]; 1-(methylsulfinyl)propyl (E,Z)-1-propenyl disulfide [E,Z)-7c]; methyl (E,Z)-1-(1-propenylthi-
o)propyl disulfide [(E,Z)-9d ]; methyl (E,Z)-1-(1-propenylsulfinyl)propyl disulfide [(E,Z)-7d ]; methyl 1-(2-propenylthio)propyl disulfide (9e);
methyl 1-(2-propenylsulfinyl)propyl disulfide (7e); propyl 1-(propylthio)propyl disulfide (9f); propyl 1-(propylsulfinyl)propyl disulfide (7f);
(E,Z)-1-propenyl 1-(propylthio)propyl disulfide [(E,Z)-9g]; (E,Z)-1-propenyl 1-(propylsulfinyl)propyl disulfide [(E,Z)-7g]; (E,Z)-1-propenyl
(E)-1-(propenylthio)propyl disulfide [(E,E)- or (E,Z)-9h ]; (E,Z)-1-(1-propenylsulfinyl)propyl propyl disulfide [(E,Z)-7h ]; (E,E)- or (E,Z)-1-
propenyl (E)-1-(propenylthio)propyl disulfide [(E,E)- or (E,Z)-9i]; (E,E)- or (E,Z)-1-propenyl (E)-1-(propenylsulfinyl)propyl disulfide [(E,Z)-
7i].
equiv of lithium (E)- or (Z)-1-propenethiolate (Block et
al., 1996b). Silver tosylate presumably converts R-chlo-
rodisulfides into R-tosylatodisulfides (not isolated), which
undergo nucleophilic displacement more rapidly at
carbon than at disulfide sulfur. The technique of
chloride activation by silver tosylate proved particularly
useful with saturated thiols, which are even more
nucleophilic in the anionic form than the delocalized
1-propenethiolate, especially toward the activated S-S
bond in a 1-propenyl disulfide. Reaction at low tem-
perature of R-tosylatodisulfides with the less nucleo-
philic thiol, rather than more nucleophilic thiolate,
affords deoxycepaenes, in most cases with minimal
contamination by the dimeric disulfides formed as side
products in the Dubs and Stu¨ssi (1978) procedure.
Several deoxycepaenes were prepared by base-in-
duced cleavage of 1-[alk(en)ylthio]propyl thioacetates
(RSCHEtSAc, 16) in the presence of thiosulfonates
(RSO2SR′) as sulfenylating agents (Scheme 8). Thus,
(E)- and (Z)-1-(propenylthio)propyl thioacetate [(E,Z)-
MeCHdCHSCHEtSAc [(E,Z)-16a ] were prepared by
treatment of bis(1-chloropropyl) disulfide (17; from
reaction of 14 with KI (Tjan et al., 1972)] with (E)- and
(Z)-1-propenyllithium at low temperature to give 1-chlo-
ropropyl (E)- and (Z)-1-propenyl sulfide [(E,Z)-18]; this
step was followed by displacement of the R-chloro group
with thioacetate. Compound (E,Z)-18 can also be
prepared nonstereospecifically by addition of 1 equiv of
HCl to bis(1-propenyl) sulfide (19) (Trofimov et al.,
1986). The various deoxycepaenes prepared are sum-

Cepaenes from Onion
J. Agric. Food Chem., Vol. 45, No. 11, 1997 4421
Sch em e 8
diastereomers), (Z,Z)-7i (19). For collagen, average
response of two different blood donors is given. The
experimental procedure is given elsewhere (Block et al.,
1986). These values, revealing a higher degree of
antithrombotic activity than found by us for ajoene from
garlic [8, R ) R′ ) allyl; µM ID50 213/166 (ADP) and
243/196 (collagen); (E)-/(Z)-ajoene) (Block et al, 1986)],
are in good agreement with published data (Morimitsu
and Kawakishi, 1990; Kawakishi and Morimitsu, 1994).
ACKNOWLEDGMENT
We thank Dr. J . Catalfamo for platelet data and Dr.
Elizabeth Calvey for helpful discussions and LC/MS
analysis.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures for (Z)-9d , (E,Z)-9d , (Z)-7d , (E,Z)-7d , (Z)-9h , (E,Z)-9h ,
(Z)-7h , (E,Z)-7h , (Z)-9g, and (Z)-7g (3 pages). Ordering
information is given on any current masthead page.
marized in Table 1 along with their conversion to the
corresponding cepaenes. All cepaenes and deoxyce-
paenes were fully characterized by spectroscopic meth-
ods. Deoxycepaenes readily disproportionate to sym-
metrical disulfides (Dubs and Stu¨ssi, 1978). Thus, crude
compounds were immediately oxidized to the cepaenes,
less prone to disproportionate, and easier to purify by
chromatography, due to their polarity.
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isomer mix for each of the cepaenes and deoxycepaenes
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taste threshold of 10 ppb, while deoxycepaene 9i has a
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4422 J. Agric. Food Chem., Vol. 45, No. 11, 1997
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Received for review J une 16, 1997. Revised manuscript
received August 18, 1997. Accepted August 19, 1997.X This
work was supported by grants from NSF, NIH-NCI, NRI
Competitive Grants Program/USDA (Awards 92-37500-8068
and 96-35500-3351), and McCormick & Co.
J F9705126
X Abstract published in Advance ACS Abstracts, Oc-
tober 1, 1997.